DOI: 10.1002/pbc.
30714
ABSTRACTS
Abstracts from the 39th Annual Meeting of the Histiocyte
Society
Held Virtually and In Person in Athens, Greece from October 22-24, 2023
OUTCOMES WITH BRAF AND MEK INHIBITORS AMONG
ADULT PATIENTS WITH LANGERHANS CELL HISTIOCYTOSIS
(LCH): A MULTI-INSTITUTIONAL STUDY FROM THE ADULT LCH
WORKING GROUP FOR THE HISTIOCYTE SOCIETY
Aldo Acosta-Medina1 , Xinxin Cao2 , Dana Bosert3 , Matthew Collin4 ,
Polyzois Makras5 , Omar Abdel-Wahab3 , Jithma P. Abeykoon1 ,
Rodothea Amerikanou4 , Corrie R. Bach1 , N. Nora Bennani1 , Ben-
jamin H. Durham3 , Jasmine Francis3 , Christopher Hook1 , Min Lang2 ,
Mario Lacouture3 , Kseniya Petrova-Drus3 , Karen L. Rech1 ,Veronica
Rotemberg3 , Gordon Ruan1 , Mithun V. Shah1 , Mariko Yabe3 ,
R. Young6 , Saurabh Zanwar1 , Ronald S. Go1 , Eli Diamond3 , Gaurav
Goyal7
1 Mayo Clinic, Rochester, MN USA; 2 Department of Hematology, Peking
Union Medical College Hospital, Chinese Academy of Medical Sciences &
Peking Union Medical College, Beijing, China; 3 Memorial Sloan Kettering
Cancer Center, New York City, NY USA; 4 University College London Hospi-
tals NHS Foundation, London, UK 5Department of Medical Research, LCH
Adult Clinic, 5 Hellenic Air Force and VA General Hospital, Athens, Greece;
6 Mayo Clinic, Jacksonville, FL USA; 7 University of Alabama at Birmingham,
Birmingham, AL USA
Purpose: In this study, we aimed to evaluate outcomes of patients
with LCH receiving BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)
through a large, multicenter collaboration.
Methods: Adults with LCH from five institutions were included. Objec-
tive response rate (ORR), progression-free (PFS), and overall survival
(OS) were calculated from targeted therapy (TT) initiation.
Results: 64 patients were included; median age at TT initiation 41.5y
(IQR 29-54). Most common systems involved at diagnosis were bone
(61%), pituitary (50%), and lung (36%). Risk organ involvement was
observed in 13 (20%) and 9 (14%) additional patients had intra-axial
CNS involvement. Median lines of prior therapy received were 2 (range:
1-5), and 20 (29%) patients received TT in first line. BRAF muta-
tional status was available in 60 cases and 40 (67%) underwent broad
NGS. Mutations identified included: BRAFV600E (34/60, 57%), non-
V600E BRAF mutations (12/40 30%) and MAP2K/KRAS mutations
(5/40, 13%). Overall, 34 patients received BRAFi (vemurafenib n=20;
dabrafenib n=14) and 31 MEKi (cobimetinib n=12; trametinib n=19).
Five patients received a second TT: 4/5 MEKi after prior BRAFi and
1/5 viceversa. Adverse events (AEs) were reported in 52%, 17% grade
3-4. Most common AEs included rash (n=20), fatigue (n=11), and myal-
Pediatr Blood Cancer. 2023;70(Suppl. 7):e30714. wileyonlinelibrary.com/journal/pbc
https://doi.org/10.1002/pbc.30714
Pediatric
Blood &
Cancer The American Society of
Pediatric Hematology/Oncology
gia/arthralgia (n=10). Median follow-up after TT initiation was 27
months (95%CI 20 - 34 months). Response assessment was not avail-
able in 7 patients. ORR was 74% (71.4% BRAFi vs. 75% MEKi; p=0.76).
At last follow-up, 52 patients were alive and 43 remained on TT. Com-
mon causes of discontinuation included AEs (n=7), progression (n=5),
and drug holiday (n=4). Death was attributable to LCH (8/12), concomi-
tant malignancy (1/12), or unrelated/unknown causes (3/12). 2-year
PFS and OS were 80.2% and 84.5%, respectively.
Conclusions: In this multi-institutional series of adults with LCH,
targeted therapies were highly efficacious in the front-line as well
Jason as relapsed/refractory setting, including patients with high-risk
disease.
DIFFERENTIAL EFFECTS OF JAK1 VS. JAK2 INHIBITION IN
MURINE MODELS OF HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS
Sabrin Albeituni1 , Camille Keenan1 , Ninad Oak1 , Alexa Stroh1 ,
Heather S. Tillman2 , Yingzhe Wang3 , Burgess B. Freeman III3 , Silvia
Aleman Arteaga4 , Katherine C. Verbist5 , Yinmei Zhou6 , Cheng Cheng6 ,
Kim E. Nichols1
1 Department of Oncology, St. Jude Children’s Research Hospital, Mem-
phis, TN USA; 2 Department of Comparative Pathology Core, St. Jude
Children’s Research Hospital, Memphis, TN USA; 3 Department of Preclin-
ical PK Shared Resource, St. Jude Children’s Research Hospital, Memphis,
TN USA; 4 Experimental Therapeutics and Translational Oncology Program,
Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de
Investigaciones Cientí-ficas/Universidad de Salamanca, Salamanca, Spain;
5 Department of Immunology, St. Jude Children’s Research Hospital, Mem-
phis, TN USA; 6 Department of Biostatistics, St. Jude Children’s Research
Hospital, Memphis, TN USA
Purpose: Hemophagocytic lymphohistiocytosis (HLH) comprises a het-
erogeneous group of disorders characterized by the hyperactivation
of immune cells and over production of numerous pro-inflammatory
cytokines, many of which signal through JAK1 and/or JAK2. Indeed,
treatment with the JAK1/2 inhibitor ruxolitinib has shown efficacy
in ameliorating disease in mouse models and patients with HLH.
However, cytopenias remain a concern due to ruxolitinib-mediated
blockade of hematopoietic growth factors such as EPO, TPO, G-CSF
and GM-CSF, which utilize JAK2. In this study, we examined whether
© 2023 Wiley Periodicals LLC. S1 of S64

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selective inhibition of JAK1, while sparing JAK2, might dampen inflam-
mation and minimize hematologic toxicities in mouse models of HLH.
Methods: To this end, we carried out experiments incorporating
clinically-relevant doses of the JAK1 inhibitor itacitinib, the JAK2
inhibitor fedratinib, and the JAK1/2 inhibitor ruxolitinib.
Results: At the doses used, each JAK inhibitor was well-tolerated
and comparably suppressed IFNg mediated STAT1 phosphorylation in
vivo. In a model of CpG-induced secondary HLH, itacitinib reduced
the numbers of activated neutrophils and serum levels of several
pro-inflammatory cytokines, while its efficacy was less prominent in
a model of primary HLH in which perforin-deficient (Prf1–/–) mice
are infected with lymphocytic choriomeningitis virus. Interestingly,
fedratinib exerted beneficial effects in both models, significantly ame-
liorating cytopenias, and reducing splenomegaly, hypercytokinemia,
and accumulation of cytokine-producing CD8 T cells. RNA sequencing
revealed that itacitinib exerted only modest effects on gene expres-
sion of CD8 T cells and monocytes in primary HLH, while fedratinib
downregulated the expression of genes involved pathways related to
cell proliferation, metabolism, and oxidative phosphorylation.
Conclusion: Selective inhibition of JAK1 or JAK2 signaling is well-
tolerated in mouse models of HLH. Surprisingly, JAK2 inhibition
resulted in partial disease improvement in secondary HLH and showed
broad anti-inflammatory effects in primary HLH, often rivaling or supe-
rior to those observed following treatment with the JAK1/2 inhibitor
ruxolitinib.
EMAPALUMAB EFFECTIVELY BRIDGES TO HEMATOPOIETIC
STEM CELL TRANSPLANTATION IN PATIENTS WITH PRIMARY
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH): THE
REAL-HLH STUDY
Carl Allen1 , Shanmuganathan Chandrakasan2a , Michael B. Jordan3,4 ,
Jennifer W. Leiding5,6 , Abiola Oladapo7 , Priti Pednekar8 , Kelly J.
Walkovich9 , John Yee7b , on behalf of the REAL-HLH Study Group
1 Division of Pediatric Hematology and Oncology, Baylor College of
Medicine, Houston, TX USA; 2 Division of Bone and Marrow Transplant
Research, Aflac Cancer and Blood Disorders Center, Children’s Healthcare
of Atlanta, Emory University, Atlanta, GA USA; 3 Division of Bone Mar-
row Transplantation and Immune Deficiency, Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH USA; 4 Department of Pediatrics, University
of Cincinnati College of Medicine, Cincinnati, OH USA; 5 Division of Allergy
and Immunology, Department of Pediatrics, Johns Hopkins University, Bal-
timore, MD USA; 6 bluebird bio, Cambridge, MA USA; 7 Sobi Inc, Waltham,
MA USA; 8 Employed at PRECISIONheor, Bethesda, MD USA, at the time the
work was done; 9 Division of Pediatric Hematology Oncology, Department of
Pediatrics, University of Michigan Medical School, Ann Arbor, MI USA
aAuthors are listed in alphabetical order.
bEmployed at Sobi, Inc. at the time the work was done.
Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-
threatening, hyperinflammatory syndrome caused by overproduction
of proinflammatory cytokines, such as interferon gamma (IFNγ). Real-
world evidence is limited on emapalumab (an anti-IFNγ monoclonal
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ABSTRACTS
antibody approved by the FDA in November 2018) use in patients with
primary HLH (pHLH).
Methods: A retrospective medical chart review conducted across
33 US hospitals identified patients treated with ≥1 dose of ema-
palumab between November 20, 2018, and October 31, 2021. Data
were extracted from time of emapalumab initiation to end of data
availability, death, or study end (December 31, 2021).
Results: Of 105 study patients, 46 (43.8%) met the pHLH classification
criteria. Median (range) age at HLH diagnosis was 1 (0.3-21) year. Ema-
palumab was primarily initiated to treat refractory (41.3%), recurrent
(30.4%), or progressive (15.2%) disease. Median (range) emapalumab
starting dose, maximum administered single dose, and cumulative
treatment doses were 1.1 (0.8-9.8), 6.1 (1.0-12.8), and 65.6 (1.0-512.2)
mg/kg, respectively. Median (range) treatment duration was 71 (1-523)
days. Emapalumab treatment resulted in normalization of key labora-
tory parameters, including chemokine ligand 9 (CXCL9, 24/33; 72.7%),
ferritin (20/45; 44.4%), fibrinogen (37/38; 97.4%), platelets (39/46;
84.8%), soluble CD25 (20/37; 54.1%), alanine transaminase (31/45;
68.9%), and absolute neutrophil count (40/45; 88.9%). Median time to
first normalization of these laboratory parameters ranged from 7 to
28.5 days. Of 42 (91.3%) transplant-eligible patients, 73.8% (31/42)
proceeded to transplant. Pre-transplant and post-transplant survival
rates were 90.5% (38/42) and 74.2% (23/31), respectively. Twelve-
month survival probability from emapalumab initiation for the entire
cohort was 73.1%. There were no discontinuations due to adverse
events.
Conclusion: Results from the REAL-HLH study, which describes treat-
ment patterns and outcomes in patients with pHLH treated with ema-
palumab in real-world settings, are consistent with the emapalumab
pivotal phase 2/3 pHLH trial (NCT01818492).
BLOOD NEUROFILAMENT LIGHT CHAIN MEASUREMENTS IN
ADULTS WITH CNS HISTIOCYTIC NEOPLASMS
Samantha Bank s1 , Paul Decker2 , Eoin P. Flanagan 1,3,4 , Anastasia
Zekeridou1,3,4 , Ronald S. Go5 , Jithma P. Abeykoon5 , Gaurav Goyal6 ,
Jason R. Young7 , Matthew J. Koster8 , Robert Vassallo9 , Jay H. Ryu5,9 ,
Caroline J. Davidge-Pitts10 , Aishwarya Ravindran11 , Julio C. Sartori
Valino tti12 , N Nora Bennani5 , Mithun V. Shah5 , Karen L. Rech13 , Cor-
rie R. Bach7 , Jeanette E. Eckel-Passow2 , W Oliver Tobin1,4 , on behalf
of the Mayo Clinic-University of Alabama at Birmingham Histiocyto-
sis Working Group and Center for Multiple Sclerosis and Autoimmune
Neurology at Mayo Clinic.
1 Mayo Clinic College of Medicine, Department of Neurology, Rochester,
MN USA; 2 Mayo Clinic College of Medicine, Quantitative Health Sciences,
Rochester, MN USA; 3 Mayo Clinic College of Medicine, Laboratory Medicine
and Pathology, Rochester, MN USA; 4 Mayo Clinic Center for Multiple Sclero-
sis and Autoimmune Neurology, Rochester, MN USA; 5 Mayo Clinic College of
Medicine, Hematology, Rochester, MN USA; 6 University of Alabama at Birm-
ingham, Division of Hematology-Oncology, Birmingham, AL USA; 7 Mayo
Clinic College of Medicine, Radiology, Rochester, MN USA; 8 Mayo Clinic Col-
lege of Medicine, Rheumatology, Rochester, MN USA; 9 Mayo Clinic College

ABSTRACTS
of Medicine, Pulmonary and Critical Care Medicine, Rochester, MN USA;
10 Mayo Clinic College of Medicine, Endocrinology, Diabetes, and Nutrition,
Rochester, MN USA; 11 University of Alabama at Birmingham, Division of
Laboratory Medicine-Hematopathology, Department of Pathology, Birming-
ham, AL USA; 12 Mayo Clinic College of Medicine, Dermatology, Rochester,
MN USA; 13 Mayo Clinic College of Medicine, Hematopathology, Rochester,
MN USA
Background: Central nervous system (CNS) involvement in histi-
ocytic neoplasms is associated with high morbidity and mortality.
Neurofilament light chain (NfL), a neuronal cytoplasmic protein, is
an indirect measure of axonal damage, measurable in blood and
CSF, and may be useful in screening for neurologic involvement,
staging disease, and monitoring treatment response in histiocytic dis-
orders. Our objective was to evaluate the association between NfL
level in adult patients with histiocytic disorders and the presence of
CNS involvement.
Methods: Data came from 27 patients with a histiocytic disorder and
39 healthy controls who were seen at Mayo Clinic Rochester and had
available stored plasma sample for NfL testing.
Results: Of the 27 patients with histiocytic disorders, 4 had Langerhans
cell histiocytosis (LCH), 21 had Erdheim- Chester Disease (ECD), and 2
had mixed histiocytosis (ECD+RDD, ECD+LCH). Median age at onset
was 47 years (range 19-82), 12/27 were female. BRAF V600E mutation
was present in 13/23. Patients with histiocytic disorder had signifi-
cantly higher (48.1 vs 17.1 pg/mL, p<.0001) NfL than healthy controls.
Of patients with histiocytic disorders, patients with CNS involvement
had higher NfL compared with the patient’s without CNS disease (63.7
vs 21.1 pg/mL, p=0.002). Those with parenchymal CNS involvement
had higher NfL than those without (58.4 vs 28.8 pg/mL, p=0.04). Post
gadolinium enhancing lesions on brain or spine MRI were associated
with higher NfL levels (69.5 vs 28.8 pg/mL, p=0.003).
Conclusion: Elevated blood NfL is associated with CNS involvement in
histiocytic neoplasms, and is associated with active parenchymal dis-
ease. Further studies are needed to evaluate whether NfL can be used
to screen for CNS involvement and monitor treatment response in
patients with histiocytic disorders.
BRAFV600E MUTATIONAL LOAD INTO DIFFERENT BONE
MARROW COMPARTMENTS IN CHILDREN WITH MULTISYSTEM
LANGERHANS CELL HISTIOCYTOSIS
Linda Beneforti1 , Aurora Chinnici1 , Maria Luisa Coniglio1 , Irene
Trambusti1 , Francesco Pegoraro1 , Fabiola dell’Acqua2 , Carmen de
Fusco3 , Maria Elena Cantarini4 , Annalisa Tondo1 , Elena Sieni1
1 Pediatric Hematology-Oncology Department, IRCCS Meyer Children’s Uni-
versity Hospital, Florence, Italy; 2 Department of Pediatrics, Fondazione
MBBM, University of Milano-Bicocca, Monza, Italy; 3 Department of Haema-
tology, AORN “Santobono-Pausilipon”, Naples, Italy; 4 Pediatric Oncology
and Hematology Unit “Lalla Serí gnoli”, IRCCS, Bologna University Hospital,
Bologna, Italy
Purpose: to evaluate BRAFV600E load in different bone marrow (BM)
compartments in children affected by multisystem Langerhans Cell
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Histiocytosis (MS-LCH) as possible biomarker of disease severity and
therapy response.
Methods: Mononuclear cells were isolated by gradient stratification
and subjected to CD34 immunomagnetic separation. PMN cells were
collected from the red pellet after erytrocytes lysis. BRAFV600E load
was evaluated into plasmatic circulating cell-free (ccf) and cellular DNA
by droplet digital PCR (ddPCR). Results were expressed as percent-
age of fractional abundance (MUT/WT+MUT*100). Seven BM samples
were collected: 5 at treatment intensification and 2 after second-line
therapy. 5 MS-LCH children, median age 3 months (range, 2 months -
10 years), were included: 2/5 with bone marrow/liver/spleen involve-
ment (risk-organ positive, RO+), 3/5 without RO involvement (RO-).
All received first-line therapy according to LCH-IV stratum I protocol.
Vemurafenib was administered as second-line therapy in 4/5 refrac-
tory patients as single agent (n=2) or in combination with chemother-
apy (aracytin+cladribine,n=1; vinblastine+prednisone,n=1).
Results: BRAFV600E mutation was detected in all BM compartments
in 5/5 patients and its values did not significantly differ in plasmatic
ccfDNA compared to cell subsets in individual patients. At the time
of therapy intensification, RO+ patients showed higher BRAFV600E
load in the BM compared to RO- patients (mean, all compartments:
RO+ 3.73%, RO- 0.28%; p<0.001). Interestingly, among cell subsets,
the CD34+ compartment showed the most striking difference in
BRAFV600E load between RO+ and RO- patients. Moreover, in the
2 RO+ analyzed after treatment intensification, a 4-fold decrease of
BRAFV600E was observed in both ccfDNA and CD34+ cells.
Conclusion: BRAFV600E was present in the BM of both RO+ and
RO- MS-LCH patients supporting the “haematopoietic origin” of MS-
LCH. Whether BRAFV600E load in BM compartments could be used
for patient stratification and monitoring should be confirmed in larger
cohorts.
CO-OCCURRENCE OF LANGERHANS CELL HISTIOCYTOSIS AND
HODGKIN LYMPHOMA IN A PATIENT HARBOURING THE
GERMLINE ANKRD26 c.-118 C>G VARIANT
Jon Bjørn1 , Andreas Glenthøj1,2 , Eva Birgitte Leinøe1 , Ulrik Malthe
Overgaard1 , Karsten Nysom3 , Jan-Inge Henter4,5 , Daniel El Fassi1,2
1 Department of Hematology, Rigshospitalet Copenhagen University Hospi-
tal, Copenhagen, Demark; 2 Department of Clinical Medicine, University of
Copenhagen, Denmark; 3 Department of Pediatrics, Rigshospitalet Copen-
hagen University Hospital, Copenhagen, Denmark; 4 Childhood Cancer
Research Unit, Department of Women’s and Children’s Health, Karolin-
ska Institutet, Stockholm, Sweden; 5 Astrid Lindgren Children’s Hospital,
Karolinska University Hospital, Stockholm, Sweden
Purpose: We report the first case of Langerhans cell histiocytosis (LCH)
in a patient with congenital thrombocytopenia due to an ankyrin repeat
domain 26 (ANKRD26) germline variant.
Methods: Case report.
Results: At age 46, a male patient with a known history of throm-
bocytopenia caused by a pathogenic germline variant in ANKRD26
(c.-118C>G) presented with a single 6x5x3 cm osteolytic BRAF

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V600E-mutated LCH lesion in the femoral head. The lesion was treated
with surgical excision. A locoregional relapse one year later was
treated with intralesional methylprednisolone followed by systemic
vinblastine and prednisolone to which the patient did not respond.
Subsequent methotrexate and mercaptopurine, for six months induced
complete remission. Six years after the initial diagnosis, a second
bone-only reactivation occurred in the right scapulae and was treated
successfully with methotrexate + mercaptopurine supplemented with
zoledronic acid infusions. A follow-up PET-CT revealed an enlarged
lymph node which at excision proved to be BRAF-wildtype classi-
cal Hodgkin lymphoma (stage IA) for which he received combination
chemotherapy and local radiotherapy. Surprisingly, no bleeding or
dose-limiting toxicities were encountered on any of the therapies,
despite a baseline platelet count around 40 x 10ˆ9/L. Variants in the
5’untranslated region of ANKRD26 are associated with a markedly
increased risk of acute myeloid leukemia and related myeloid neo-
plasms. There are no reports of increased risk of lymphoid neoplasms.
LCH or other histiocytoses have not been reported in patients with
germline ANKRD26-variants.
Conclusion: While germline ANKRD26-variants are a strong risk
factor for myeloid neoplasms, we report the first case of LCH in
an ANKRD26-mutated patient. Furthermore, the patient developed
Hodgkin lymphoma during LCH-treatment. Unlike the LCH, the lym-
phoma was BRAF-wildtype. Surprisingly, despite constitutive throm-
bocytopenia, treatment could be given without dose-reductions. How-
ever, due to the inherent tendency to genetic instability in ANKRD26-
mutated patients, targeted therapy should be considered in future
patients.
DEVELOPING A LATIN AMERICAN STUDY GROUP OF
HISTIOCYTOSIS (GRUPO LATINOAMERICANO DE ESTUDIOS DE
HISTIOCITOSIS - GELA-H) DURING AND AFTER
COVID-19-PANDEMIA
Jorge Braier1 , Guido Felizzi1 , Diego Rosso2 , Guillermo Chantada3,4 ,
Fernando Gotz5
1 Hospital de Pediatria Garrahan, Buenos Aires, Argentina; 2 Hospital de
Clinicas San Martin, Buenos Aires, Argentina; 3 Hospital Sant Joan de Deu,
Barcelona, Spain; 4 Fundacion Scremini, Montevideo, Uruguay; 5 OR Aso-
ciacion, Barcelona, Spain and Grupo de Estudios Latino Americano de
Histiocitosis (GELA-H).
Purpose: To connect Latin American study groups on Langerhans cell
histiocytosis (LCH), to debate subjects related with all the histiocytic
diseases, to collaborate in the discussion of complex clinical patients,
and to start clinical research studies.
Methods: From October 2021 to May 2023, participants from sixteen
countries met online by zoom every two months. We used the tool Cus-
tomer Relationship Management System (CiviCRM,USA) to notify and
register participants from all countries, including Spain. We shared pro-
tocols using the Resonance system (Resonance Inc., USA). We recorded
and edited meetings for publication at the youtube channel of OR
association.
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ABSTRACTS
Results: The mean of participants per meeting was 41 (Range:20-68).
The following subjects presented and discussed were: presentation of
guidelines for therapy and follow-up for Langerhans cell Histiocyto-
sis (LCH): two proposals of LCH chemotherapy guidelines related to
vinblastine-indomethacin or cytarabine-indomethacin. Oral and poster
presentations of Latin American studies from 2020 to 2022 at Histio-
cyte Society meetings (New score based in blood levels of CD1a/207
cells, rare histiocytic disorders: international registry, Erdheim Chester
disease with CNS involvement and neurodegenerative involvement
in LCH) were also presented and debated. The majority of subjects
were presented together with experts related with the LCH organ
involvement (Neurology, Neumonology, Hepatology, Dermatology and
other related specialties). Multiple complex patients of LCH, and other
histiocytic disorders of different countries of Latin America were
also discussed. Additional unscheduled meetings due to the sever-
ity of cases were made. Other colleagues of Histiocyte Society also
participated in our meetings.
Conclusions: The developed network, with participation of parental
and medical groups, helped build a more efficient and participative
Latin American Histiocytosis Study Group. We optimized the clinical
debate of complex patients and promoted educational activities on
LCH. Our group enhances the possibility of future research on these
rare orphan diseases in countries with limited resources.
THE CLINICAL COMPLEXITY OF LANGERHANS CELL
HISTIOCYTOSIS IN ADULT PATIENTS: EXPERIENCE OF THE
INSTITUTE OF HEMATOLOGY OF BOLOGNA
Alessandro Broccoli1,2 , Gianmarco Bagnato1 , Lisa Argnani1 , Mar-
tina Cantelli1 , Beatrice Casadei2 , Cinzia Pellegrini2 , Sabrina Zoli1 ,
Emanuele Sutto1 , Paolo Elia Coppola1 , Marianna Gentilini1 , Alice
Morigi1 , Matteo Carella1 , Gabriele Gugliotta2 , Laura Nanni1 , Vittorio
Stefoni1,2 , Pier Luigi Zinzani1,2
1 Department of Medical and Surgical sciences (DIMEC), University of
Bologna, Bologna, Italy; 2 IRCCS Azienda Ospedaliero-Universitaria di
Bologna, Istituto di Ematologia “Serí gnoli”, Bologna, Italy
Purpose: Langerhans cell histiocytosis in adult patients has protean
manifestations, including single-system unifocal (SSU) or multifocal
(SSM) presentation or multisystemic (MS) involvement. Clinical care of
adult patients is mainly based on case series and reports.
Methods: This is our single-center experience with LCH. Data on 30
patients diagnosed between 1997-2022 were reviewed. Responses
to treatment were classified according to acknowledged criteria.
Progression-free survival (PFS) was calculated on all treated patients.
Overall survival (OS) was determined on the whole cohort.
Results: Eighteen male and 12 female patients were diagnosed at a
median age of 46 years. Sixteen patients had single-system disease,
with SSU involvement in 12 cases and SSM involvement in 4. The
skeleton was the mostly involved system; SSU extra-skeletal disease
was detected in 25% of cases. Fourteen patients had MS disease:
axial skeleton, lungs, hypophysis, skull, skin and appendicular skeleton
were predominantly involved. Ten patients with single-system disease

ABSTRACTS
received chemotherapy because of symptoms (mostly bone pain) or
due to multifocal dissemination. Two patients underwent radiotherapy
(RT), 2 had their disease excised and 1 received steroids. One patient
was observed. A complete response (CR) was obtained in 60% of cases,
a partial response (PR) in 27%. Four patients relapsed after frontline
therapy and were rescued with RT or autologous transplant. Among
patients with MS disease, chemotherapy (MACOP/VNCOP-B, cladrib-
ine, vinblastine) was applied in 6 cases; 2 patients received RT and 1
steroids. One patient underwent surgery and 4 were observed because
of asymptomatic disease. A CR was obtained in 70% of patients and a
PR in 10%. Five patients relapsed and 3 required retreatment. Median
PFS among all treated patients was 177 months. OS was 91% at 20
years.
Conclusion: Appropriate treatment based on disease extension, site
involvement and clinical manifestations yields high remission rates and
long term PFS and OS.
PEDIATRIC HISTIOCYTIC NEOPLASMS WITH BRAF
REARRANGEMENTS AND LOSS OF CDKN2A: A POSSIBLE
DISTINCT ENTITY WITH UNCERTAIN MALIGNANT POTENTIAL?
Carlos M. Casiano1 , Laura Agresta2 , Rita Alaggio3 , Lara
Antonello Cardoni3 , Gabriela Gheorghe4 , Selene C. Koo4 , Ashish
Kumar1 , Robert Lorsbach1 , Robin Norris1 , Somak Roy1 , Pierre Russo5 ,
Bryan Sisk6 , Lea Surrey5 , Sara Szabo1 , Nitin Wadhwani7 , Joanna
Weinstein7 , Jennifer Picarsic1
1 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA;
2 Michigan State University, East Lansing, MI USA; 3 Ospedale Pediatrico
Bambino Gesù, Rome, Italy; 4 St. Jude Children’s Research Hospital, Mem-
phis, TN USA; 5 Children’s Hospital of Philadelphia, Philadelphia, PA USA;
6 Washington University School of Medicine, St. Louis, MO USA;
Children’s Hospital, Chicago, IL USA
Background: Gene alterations in the mitogen-activated protein kinase-
extracellular signal-regulated kinase (MAPK-ERK) pathway, particu-
larly BRAF mutations, are well-recognized in histiocytic neoplasms.
However, rearrangements of the BRAF gene are infrequently reported
in non-Langerhans cell histiocytosis. Little is known about their associ-
ation with loss of cell cycle control at the CDKN2a/p16 locus.
Methods: Cases included those with a predominantly non-LCH
immunophenotype and loss of p16 immunostaining that harbored
BRAF rearrangements, collected per institutional and/or IRB proto-
col/regulation.
Results: Seven pediatric cases with BRAF rearrangement and loss
of cell cycle control (CDKN2a/p16) included 3 females and 4 males
with age at first diagnosis: 6 months to 12 years. Four had multifo-
cal disease (skin, soft tissue, bone, inguinal region, lungs, and brain).
All cases had epithelioid morphology with low-grade to high-grade
atypia. All 7 cases were positive for at least two macrophage mark-
ers (CD163, CD68, and/or CD14) and showed strong expression of
both p-ERK and, when performed, cyclin D1 (n=6). The mutant spe-
cific BRAF VE1 stain was negative in all cases. The Ki-67 proliferative
index was variable (10-70%) and did not show concordance with the
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S5 of S64
degree of atypia. All cases had CDKN2a loss with confirmed loss of p16
staining in lesional cells, including one that also harbored a germline
homozygous deletion of CDKN2a. The BRAF fusion partners included:
BICD2, PICALM, PLEK, SLC44A1, MTAP, MS4A6A, and NRF1. Clin-
ical behavior ranged from indolent to aggressive with systemic
disease.
Conclusions: Little is known about the clinical, morphologic, and
integrated genomic findings in non-LCH neoplasms with BRAF rear-
rangements. It is possible that the additional loss of cell cycle control
at the CDKN2a/p16 locus may further contribute to the morphology
and/or clinical behavior in these cases. Further investigation is needed
to explore if this group may represent a distinct entity of histiocytic
neoplasms in pediatric patients.
CSF LIGHT NEUROFILAMENT LEVELS FOR EARLY DETECTION
OF NEURODEGENERATION IN PATIENTS WITH LANGERHANS
CELL HISTIOCYTOSIS
Aurora Chinnici1 , Linda Beneforti1 , Maria Luisa Coniglio1 , Irene
Trambusti1 , Francesco Pegoraro1 , Stefania Gaspari2 , Carmen de
Fusco3 , Antonino Trizzino4 , Annalisa Tondo1 , Elena Sieni1
Berklite1 , 1 Pediatric Hematology-Oncology Department, IRCCS Meyer Children’s Uni-
versity Hospital, Florence, Italy; 2 Department of Hematology/Oncology,
Cell and Gene Therapy, Scientific Institute for Research, IRCCS Bam-
bino Gesù Children’s Hospital, Rome, Italy; 3 Department of Haematol-
ogy, AORN “Santobono-Pausilipon”, Naples, Italy; 4 Department of Pedi-
atric Hemato-Oncology, ARNAS Ospedali Civico, G. Di Cristina, Palermo,
Italy
Purpose: To analyse Neurofilament Light (NFL) levels in patients with
Langerhans cell histiocytosis (LCH) for early identification of ND-LCH.
7 Lurie Methods: A total of 24 cerebrospinal fluid (CSF) samples from 24
LCH patients referred from 4 italian centres were analysed for
CSF-NFL by ELISA. Out of the 24 patients, 11 had ND-LCH (9/11
symptomatic), 9 had risk factors (diabetes insipidus and/or cranio-
facial lesions) without ND-LCH, and 4 had no ND-LCH neither risk
factors.
Results: CSF-NFL levels were significantly higher in patients with
ND-LCH (median: 663 pg/mL; range 233 - 3031 pg/mL; p<0.05;
unpaired t-test) than in patients with risk factors alone (median: 126
pg/ml; range 57 - 431 pg/ml) and LCH patients without risk factors
(median: 93 pg/ml; range 40 - 131). ND-LCH patients with overt clinical
manifestations had the highest CSF-NFL values compared to asymp-
tomatic ND-LCH patients. Three pauci-symptomatic patients (abnor-
mal neurological examination and/or evoked potentials) had values
below 380 pg/ml, the threshold proposed by previous literature. One
patient with only risk factors had CSF-NFL values slightly above the
threshold.
Conclusion: Preliminary data from our group confirm CSF-NFL as a
promising biomarker for ND-LCH, suggesting to lower the positivity
threshold to 200 pg/ml in order to identify ND-LCH in the pre-clinical
phase. Larger studies and serial determinations of CSF-NFL are needed
to confirm our findings.

S6 of S64
PRESENTATION OF ALK-POSITIVE NON-LANGERHANS CELL
HISTIOCYTOSES REPORTED THE GERMAN COLLECTION AND
CONSULTATION SERVICE
Carl Friedrich Classen
University Children’s Hospital, Rostock, Ernst-Heydemann-Str. 8 , D - 18057
Rostock, Germany
Purpose: Recently, ALK-positive histiocytosis (ALK+H) has been
defined as a separate subgroup, on a molecular basis, within the
rare or Non-Langerhans cell histiocytoses (non-LCH). In many cases,
conventional histologic appearance of ALK+H resembles juvenile xan-
thogranuloma (JXG), however, other variants have been described as
well. ALK+H are especially common in early childhood - but adults are
described as well, and they often show intracerebral involvement with
neurological sequelae. Both single-system as well as multisystemic
diseases are described.
Methods: In 2012, the German registry and consultation study for non-
LCH - part of the International Rare Histiocytic Disease Registry - was
initiated. While meanwhile, 17 patients have been formally registered,
in about 100 cases, consultation was applied.
Results: Meanwhile, 5 patients with ALK+H have been reported. Since
molecular analysis has only been done in a small proportion of patients,
other ALK+H cases might also be contained, in particular in JXG cases.
The cases include a 4y old boy with large temporal tumor achiev-
ing remission by LCH-like chemotherapy, a 30y old man with spinal
tumor, with ongoing stable disease by inhibitor therapy; an 8y old girl
with retroauricular tumor in continuous first remission after complete
resection, a 10 y old boy with large abdominal tumor, and an 18 mon.old
boy with large maxillar tumor; both planned to be put on inhibitor
therapy.
Conclusion: ALK-positive histiocytoses represent a heterogeneous
disease spectrum, and diagnosis depends on molecular analysis, which
should be performed in all cases of pediatric non-Langerhanscell histi-
ocytosis. Appropriate consultation depends on international prospec-
tive data collection, which should be further propagated.
CASE REPORT: HISTIOCYTIC ALK-POSITIVE CENTRAL
NERVOUS SYSTEM TUMOR IN A PEDIATRIC PATIENT
Marcela Cordova1 , Maricruz Ormeño2 , Katherine Kopp3 , Alejandro
Lastra4 , Lili-Naz Hazrati5
1 Hospital Regional de Talca, Talca, Chile; 2 Hospital Dr. Luis Calvo Mackenna,
Santiago, Chile; 3 Hospital Dr. Luis Calvo Mackenna, Santiago, Chile;
4 Hospital Dr. Sotero del Rio, Santiago, Chile; 5 Hospital for Sick Children,
Toronto, Ontario, Canada
Purpose: to present a clinical case of ALK-positive histiocytosis.
Method: Case report of pediatric case with posterior fossa tumor,
anatomopathological and immunohistochemical study of positive ALK
histiocytosis
Results: Female of 2 years 3 months, previously healthy, who consults
for episode of febrile seizure, brain CT reported normal, then begins
with gait alteration and convergent strabismus of the left eye. Magnetic
Resonance Imaging (MRI) of the brain and spine reports: Tumor-like
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ABSTRACTS
bilateral cerebellar-vermian lesion signs of supra and infratentorial
leptomeningeal dissemination without signs of intraspinal dissemina-
tion. Surgical resection only 60% of the tumor, initial biopsy suggestive
embryonal tumor, mitoses 1/10 HPF. Immunohistochemistry: positive
for vimentin, negative for GFAP, synaptophysin, EMA, ML actin and
p53, Ki67 of 5%, INI1 conserved. With this diagnosis begins Head
Start chemotherapy (vincristine, cisplatin, cyclophosphamide, etopo-
side, methotrexate in high doses) with 2 cycles. Brain MRI after the
first cycle, slight smaller size of left cerebellar tumor, with signs of
intracranial dissemination. MRI after second cycle reports postopera-
tive changes in posterior fossa by partial resection of known intraaxial
infiltrative expansive process, with tumor remanent, intracranial and
spinal dissemination with progressive changes with respect to previous
MRI. Review of pathology is requested for molecular study reporting
Alk positive Histiocytosis KIF5B-ALK fusion identified (trusight). New
staging with negative dissemination study. Since there is no response
with the chemotherapy performed, it was decided to start treatment
with an ALK inhibitor available in our country started 3 weeks ago. Cur-
rently patient is in good general condition, in motor rehabilitation and
awaiting further evaluation with imaging.
Conclusion: Clinical case is presented for the rare of this pathology,
having few studies in relation to the treatment of ALK positive histi-
ocytosis, however good results have been reported with the use of ALK
inhibitors.
TRAMETINIB FOR SINGLE-SITE CNS-RISK ORBITAL
LANGERHANS CELL HISTIOCYTOSIS AFTER SUBTOTAL
RESECTION IN AN ADOLESCENT
Paul R. D’Alessandro, Jennifer L. Picarsic, Ashish R. Kumar
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
Purpose: Adolescents/young adults (AYAs) represent a distinct popu-
lation. Compared to children, AYAs report greater toxicities and more
frequent dose modifications/treatment interruptions on chemother-
apy. We describe an adolescent with orbital Langerhans cell histiocyto-
sis (LCH, CNS-risk, single site) who was treated with subtotal resection
and trametinib.
Methods: A seventeen-year-old male presented with headaches;
diplopia; and left-sided unilateral proptosis with painful extra-ocular
movements. Past medical history included essential hypertension; seb-
orrheic dermatitis in infancy; and childhood eczema (all unrelated.)
Computerized tomography (CT) and magnetic resonance imaging
(MRI) revealed an enhancing soft tissue mass (2.1 x 2.4 x 2.3 cm) that
extended from the left posterolateral orbit into the anterior middle
cranial fossa with bony destruction, lateral rectus involvement, and
dural thickening. Aside from mild mass effect on the left anterior mid-
dle cerebral vein, neurovascular structures were intact. Pathology from
initial biopsy via lateral orbitotomy was inconclusive. Blood HistioTrak
(droplet digital polymerase chain reaction) testing for BRAFV600E
was negative. Repeat lateral orbitotomy with stereotactic guidance
was performed. Pathology was consistent with LCH (histiocytes
positive for CD1a, CD163, Langerin, BRAFV600E.) Post-operative
imaging revealed residual enhancing soft tissue within the resection

ABSTRACTS
cavity (1.5 x 1.8 cm.) His symptoms resolved aside from residual uni-
lateral scotoma. Positron-emission tomography (PET) CT was negative
for other sites of disease. There were no cytopenias. He was offered
treatment with vinblastine/prednisone or trametinib, and chose tram-
etinib.
Results: Trametinib (1 milligram orally daily) was initiated. He experi-
enced acneiform rash necessitating interruptions; modifications; and
adjunct treatments. After six weeks of continuous trametinib, his vision
returned to baseline and PET-CT was negative for residual disease. At
nine months, he remains on trametinib (0.5 milligram orally every other
day) disease-free with regular surveillance imaging and ophthalmology
and cardiology review.
Conclusions: Trametinib is a potential treatment option for adoles-
cents with LCH. Treatment duration and late effects remain undeter-
mined.
ETOPOSIDE BASED TREATMENT STRATEGY FOR IN THE
MANAGEMENT OF LANGERHANS CELL HISTIOCYTOSIS.
EXPERIENCE FROM A TERTIARY CARE CENTER IN INDIA
Chetan Dhamne, Tanuja Shet, Sridhar Epari, Sneha Shah, Vasundhara
Patil, Shyam Srinivasan, Ruchika Gavanang, Nirmalya Roy Moulik,
Gaurav Narula, Shirpad Banavali
Tata Memorial Centre, Mumbai, India; Homi Bhabha National Institute,
Mumbai, India
Background: Inadequate response (Active Disease Sta-
ble/Indeterminate or progressive disease) at 6-week timepoint
portends a poor prognosis. Intensive chemotherapy upfront runs high
risk of mortality in the LMIC setting. Etoposide is an effective medi-
cation in Langerhans cell histiocytosis (LCH). It has gone out of favor
because of its leukemogenic potential. We report 5 year follow up of
addition of oral Etoposide to a backbone of therapy with Vinblastine
and steroids for these poor responders.
Methods: Retrospective review of children <15 years of age treated
at a tertiary care center in India. On a Vinblastine + steroids back-
bone oral metronomic Etoposide was added for high risk(HR) LCH and
low risk(LR) LCH with inadequate response to 6 weeks of therapy as
assessed by PET scan.
Results: Between Jan 2016 to Dec 2021, 80 children with LCH were
treated at our hospital. 18 were single system(SS) bone disease, 7 had
multifocal bone disease, 3 had SS Lymph nodal involvement, 13 had
multisystem(MS) risk organ(RO) negative disease and 10 had MS RO
positive disease. At a median follow up of about 5 years EFS and OS
was 94.4% for SS bone disease, 85% for SS multifocal bone disease 33%
for SS LN disease, 69.2% for MS RO negative disease and 40% for MS
RO positive disease. Ten of twelve children with inadequate response
to week 6 chemotherapy received Etoposide and achieved AD bet-
ter response at 12-week timepoint and eventually achieved complete
remission. Nine of 16 children who received Etoposide and are alive
without evidence of second malignancy.
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S7 of S64
Conclusion: Oral Etoposide was found to be safe and effective in chil-
dren when given on a chemotherapy backbone of Vinblastine and
Steroids. Outcomes of children with risk organ involvement is still a
challenge.
INTRA-ARTERIAL MELPHALAN FOR HISTIOCYTIC NEOPLASMS
INVOLVING NEUROLOGIC, OCULAR, AND HEAD AND NECK
STRUCTURES
Eli L. Diamond1 , Alexander D. Ramos2 , Jared Knopman2 , Andrew
L.A. Garton2 , Julia Reilly1 , Julia Canestaro1 , Vaios Hatzoglou1 , David
Abramson1 , Y. Pierre Gobin2 , Jasmine H. Francis1
1 Memorial Sloan Kettering Cancer Center, New York, NY USA; 2 New York
Presbyterian Hospital, New York, NY USA
Purpose: Histiocytic neoplasms are clonal hematopoietic disorders
of myeloid lineage. Involvement of neurologic structures by histi-
ocytic infiltration or disease-associated neurodegeneration (ND)
represents a severe disease phenotype associated with morbid-
ity and mortality. Despite recent advances with BRAF and MEK
inhibitors, patients with neurohistiocytic involvement continue
to demonstrate suboptimal outcomes. Intra-arterial chemother-
apy (IAC) may represent an effective therapy for this disease
manifestation.
Methods: Patients with biopsy-proven histiocytic neoplasms involv-
ing neurologic, ocular, or head and neck structures were treated
with intra-arterial melphalan delivered via selective catheterization of
tumor arterial vasculature. Patients treated had refractory/persistent
tumorous disease or progressive functional decline despite BRAF/MEK
inhibition, or had limited disease appropriate for local therapy. Patients
were evaluated for radiologic (PET or CT/MRI) response and func-
tional neurologic response with quantified ataxia and dysarthria scales,
or change in visual acuity (VA), as appropriate. Procedure-related
adverse events as well as clinical and laboratory toxicities were
captured.
Results: 74 IAC treatments were administered to 17 patients, 12
with tumorous disease (6 Rosai-Dorfman disease; 3 xanthogranu-
loma; 3 Langerhans cell histiocytosis[LCH]; 1 Erdheim-Chester dis-
ease [ECD]), 5 with ND-LCH/ECD, and ten with disease-related
impairment of VA. Patients received a range of 2-12 IAC doses.
9/12 (75%) patients with tumorous disease had complete or par-
tial radiologic response. 4/5 patients with ND had measurable
improvement in dysarthria and 2/5 had measurable improvement in
ataxia. 4/10 patients had improved VA. Of all patients with clinical
or radiologic response, three have experienced disease recurrence
since IAC in long-term follow-up. No procedural adverse events
were observed, 1 patient had neutropenia and 1 patient melphalan
hypersensitivity.
Conclusions: IA melphalan is a safe and robustly effective treatment
option for tumorous and ND histiocytic neoplasms of neurologic,
ocular, and head and neck structures.
 15455017, 2023, S7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pbc.30714 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [22/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
S8 of S64 ABSTRACTS

CHILDREN WITH REFRACTORY HISTIOCYTOSIS TREATED BY France; 20 CHU Ibn SINA - Souissi • Bd Rochd, Rabat, Marocco; 21 The Divi-
MAPKI HAVE A HIGH RISK OF NEURO DEGENERATION: AN sion of Pediatric Hemato-Oncology The Edmond and Lily Safra Children’s
INTERNATIONAL STUDY Hospital The Sheba Med Center, Tel-Hahsomer, Israel; 22 Hematological

Malignancies Service Schneider Children’s Medical Center 14 Kaplan St.,

Jean Donadieu1 , Dmitry Evseev2 , Elena Sieni3 , Olga Slater4 , Caroline Petah-Tikva, Israel; 23 Pediatric oncology Rambam medical center, Haifa,
Hutter5 , Cor van den Bos6 , Itziar Astigarraga7 , Thomas Lehrnbecher8 , Israel; 24 Pediatric oncology Tel-Aviv Sourasky Medical Center. Tel Aviv,
Martina Ahlmann9 , Mohamed Barkaoui1 , Suzanne Holzhauer10 , Israel; 25 Department of Oncology and Surgical Oncology for Children
Karin Beutel11 , Susana Garcia-Obregon12 , Nabil Kabbara13,14 , Paul and Youth Institute of Mother and Child, Warsaw, Poland; 26 Department

Milne15 , Zofia Helias16 , Alexandra Kolenova17 , Cecile Renard18 , of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire
Julian Thalhammer18 , Alexandra Salmon19 , Laila Hessissen20 , Michal de Grenoble, France; 27 Department of Pediatric Hematology and Oncol-
Golan21 , Sarah Elitzur22 , Myriam Ben Arush23 , Dana Ashkenazi ogy, Centre Hospitalo-Universitaire de Bordeaux, France; 28 Department

Lustig23 , Rina Dvir24 , Anna Raciborska25 , Anne Pagnier26 , Nathalie of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire
Aladjidi27 , Coralie Malebranche28 , Marlene Pasquett29 , Safiatou d’Angers, France; 29 Department of Pediatric Hematology and Oncology,
Diallo30 , Viktoria Efremova31 , Laurence Blanc32 , Monica Cheng Centre Hospitalo-Universitaire de Toulouse, France; 30 Hemato-Oncologie,

Munthe-Kaas33 , Jan Inge Henter34 , Tatiana Von Bahr Greenwood34 , Immunologie et Transplantation Hôpital Universitaire des Enfants Reine
Guido Felizzia35 , Jorge Braier35 , Anne Lambilliote36 , Houda Boudiaf37 , Fabiola (ULB) Avenue J.J. Crocq, 15 1020 Bruxelles, Belgium; 31 University
Karel Svojgr38 , Krenova.Zdenka39 , Fanette Bernard40 , Cecile Hospital, Minsk, Belarus; 32 Department of Pediatric Hematology and Oncol-
Adam41 , Eva Karaoli42 , Christine Dahl43 ; Vassilios Papadakis44 , ogy, Centre Hospitalo-Universitaire de Poitiers, France; 33 Department of
Trung Nguyen45 , Islam Amine Larabi46 , Michael Maschan2 , Gleb Pediatric Oncology and Hematology Oslo University Hospital OUS, Nor-
Bronin47 , Evgueni Burcev47 , Ahmed Idbaih48 , Jean-Claude Alvarez46 , way; 34 Childhood Cancer Research Unit, Department of Women’s and
Olga Novosad49 , Matthew Collin14 , Jean-François Emile16 , Sébastien Children’s Health, Karolinska Institute, and Karolinska University Hospi-
Héritier1 , Milen Minkov5 tal, Stockholm, Sweden; 35 Hematology-Oncology unit Paediatric Hospital
1 French Reference Center for Langerhans Cell Histiocytosis, Trousseau Dr. Juan P. Garrahan, Buenos Aires, Argentina; 36 Department of Pedi-
Hospital, Paris, France; 2 Dmitriy Rogachev National Center for pediatric atric Hematology and Oncology, Centre Hospitalo-Universitaire de Lille,
hematology, oncology and immunology, department of Hematopoietic stem France; 37 Hemato oncologie pédiatrique, CHU Mustafa, Alger, Algeria;
cell transplantation, Moscow, Russia; 3 Dipartimento di Oncoematologia 38 University Hospital Motol and2nd Faculty of Medicine Department of
Pediatrica Azienda Ospedaliero-Universitaria A.Meyer Firenze Italy 3 Der- Pediatric Hematology and Oncology, Prague, Czech Republic; 39 Department
matology Unit, CHU de Grenoble, France; 4 Department of pediatric hemato of Paediatric Oncology, University Hospital Brno, Brno, Czech Repub-
oncology, Great Ormond Street Hospital London, UK; 5 St Anna Kinder- lic; 40 Unité d’Onco-Hématologie pédiatrique Hôpitaux Universitaires de
spital, Department of Pediatrics, Medical University of Vienna, Austria; Genève, Généve, Switzerland; 41 Unité d’Onco-Hématologie pédiatrique
6 Department of hemato oncology Princess Máxima Center for pediatric Centre Hospitalier Universitaire Vaudois, Rue du Bugnon21, 1011 Lau-
oncology Heidelberglaan25, 3584 CS Utrecht; Netherlands; 7 Hospital sanne, Switzerland; 42 Pediatric Oncology-Hematology Department Arch-
Universitario de Cruces. IIS Biocruces Bizkaia. Universidad Paí-s Vasco bishop Makarios Hospital III Nicosia Cyprus; 43 Department of Clinical
UPV/EHU, Unidad de Hematología y Oncologí-a Pediátrica, Barakaldo, Medicine - Department of Oncology AarhusDenmark; 44 Department of
Spain; 8 Klinik für Kinder- und Jugendmedizin Universitätsklinikum Frank- Pediatric Hematology- Oncology Agia Sofia Children’s Hospital| Mari-
furt Theodor-Stern-Kai 7 60590 Frankfurt am Main Germany; 9 Klinik anna, Athens Greece; 45 Hemato Oncology University colleague London
für Pädiatrische Hämatologie und Onkologie Universitätsklinikum Mün- UK; 45 Service de Pharmacologie-Toxicologie Faculté de Médecine PIFO
ster (UKM) Albert-Schweitzer-Campus 1, Gebäude A148149 Münster; Université Versailles Saint-Quentin CHU R. Poincaré, AP-HP 104 Bvd R.
10 Charité - University Medicine Berlin, Campus Virchow Klinikum, CC17 , Poincaré 92380 Garches; 47 Morozov Children’s Hospital, Moscow, Russia;
Pediatric Hematology, Oncology and Stem Cell Transplantation, Berlin, Ger- 48 AP-HP, Service de Neurologie2, Hôpital Universitaire La Pitié Salpêtrière,
many; 11 Pädiatrische Hämatologie und Onkologie Zentrum für Kinder- und Paris, France; 49 National Cancer Institute Mikhail Lomonosov Street, Kyiv,
Jugendmedizin: Eine Kooperation der München Klinik und des Klinikum Ukraine
Rechts der Isar der TUM 80804, München, Germany; 12 Biocruces Bizkaia Purpose: To evaluate the risk of neuro degenerative (ND) compli-
Health Research Institute. UPV/EHU, Pediatric Oncology Group, Barakaldo, cations in children with langerhans cell histiocytosis treated for a
Spain; 13 Division Pediatric Hematology Oncology, Centre Hospitalier d u refractory disease.
Nord, affiliated to Saint Joseph University, Beirut, Lebanon; 14 Pediatric Methods: A cohort of 242 patients with various histiocytosis treated
Hematology Oncology, Rafic Hariri University Hospital, Beirut, Lebanon; by off-label MAP kinase inhibitors (MAPKIs) has been created by col-
15 Newcastle University, Translational and Clinical Research Institute, New- lection of data from 23 countries. Among this cohort 160 patients have
castle upon Tyne, UK and NIHR Newcastle Biomedical Research Centre, UK; been treated for refractory LCH, either RO+ (n=116) or RO-(n=44)
16 EA4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France; . BRAF V600E was present in 142 patients. Vemurafenib (n=124),
17 Brastislava Universty, Bratislava, Slovakia; 18 Institut d’Hémato oncologie Dabrafenib (n=40), Encorafenib (n=1), Cobimetinib (n=21), Trametinib
Pédiatrique, Hospice civil de Lyon, Lyon France; 19 Department of Pediatric (n=17), Binimetinib (n=1) were prescribed with various chemother-
Hematology and Oncology, Centre Hospitalo-Universitaire de Strasbourg, apy association. The chosen end point was ND-MRI-free survival. The

ABSTRACTS
period considered was the interval between D1 of MAPKI and the first
ND MRI, or the last MRI when no ND features were observed.
Results: At the end of June 2023, median follow up after commencing
therapy was 2.8 years (range, 0.2-8.6) for a total of 493 person-years. In
RO+ patients, there was a fast clinical response usually within 2 weeks.
2 deaths were observed within few days of treatment (before steady
state), one secondary to MDS. No deaths were observed among RO-
patients and the response on active LCH disease was also favourable
in all patients. ND-MRI has been evaluated in the follow up for 66
patients. Six of these patients have exhibited mild symptoms, com-
patible with a clinical ND, while in the others, MRI was performed
as a routine evaluation. A ND MRI features were observed in 31
patients. The median time for ND detection was 3.8 years after start-
ing MAPK inhibitors. The 5 year-ND-MRI free survival was 47% (95%
CI: 31-61%).
Conclusion: MAPKIs prescribed off-label for refractory LCH, despite a
clear short term benefit, did not prevent secondary ND. Further stud-
ies are needed to establish the risk factors, while the long term clinical
consequences remain to be assessed.
MULTISYSTEM LANGERHANS CELL HISTIOCYTOSIS (LCH) IN A
CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
TREATED WITH HEMATOPOIETIC STEM CELL
TRANSPLANTATION (HSCT) - CASE REPORT
Katarzyna Drabko , Malgorzata Mitura-Lesiuk
Medical University of Lublin, Department Of Pediatric Hematology, Oncol-
ogy And Transplantology, Lublin, Poland
Introduction: Langerhans cell histiocytosis (LCH), which occurred after
diagnosis of acute lymphoblastic leukemia (ALL) is a rare condition
and 18 pediatric cases have been described in literature. In 12 cases
leukemia were T-cell origin and time between diagnosis of ALL and
occurring LCH was from 5 years to 3 months . Optimal management
of these patients has not been established.
Case Report: We would like to present a case of a boy, diagnosed with
T-ALL in September 2021 at the age of 22 months. He was stratified
as high risk leukemia and treated according to international protocol
AIOP-BFM 2017. Patient achieved complete remission of leukemia at
expected time and his treatment has been conducted without major
complications and delays until the March 2nd 2022. Before last dose
of high methotrexate (protocol M) patient presented with painful swal-
lowing in right elbow and fever. The laboratory abnormalities were:
high C-reactive protein, in imagine studies changes in bone struc-
ture of humerus and small focal lesions in lungs. Biopsy of bone and
lungs confirmed LCH. After consultation with national ALL and LCH
coordinators we decided to continue ALL treatment with prolonged
Dexamethasone course according to first line HLH treatment and as
soon as possible proceed to allogeneic HSCT as the therapeutic option
for both condition. Transplantation was performed in September 2022
and peri-transplant course was uneventful. Now patient is alive and
well, in remission of ALL and without signs of LCH.
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S9 of S64
Conclusion: In case of multisystem LCH occurring during therapy of
malignancy the treatment should be discussed with national and inter-
national coordinators and HSCT is feasible option in such a clinical
situation.
MEK INHIBITOR AND IL6-RECEPTOR ANTIBODY THERAPY FOR
HISTIOCYTOSIS AND INFLAMMATORY MANIFESTATIONS IN
PATIENTS WITH H SYNDROME- A MULTINATIONAL
COLLABORATION
Sarah Elitzur1 , Maurine Jouret2 , Dafna Brik1 , Odeya David3 , Eyal
Kristal4 , Arnon Broides4 , Dan Harlev5 , Shai Izraeli1 , Jean Donadieu6 ,
Ruth Shiloh1
1 Department of Pediatric Hematology-Oncology, Schneider Children’s Med-
ical Center, Tel-Aviv University, Tel Aviv, Israel; 2 Pediatric Hematology-
Immunology and Rheumatology Department, Hôpital Necker-Enfants
Malades, AP-HP, Paris Cité University, Paris, France; 3 Faculty of Health Sci-
ences, Ben-Gurion University, Beer Sheva, Israel; 4 Pediatric Immunology
Clinic, Soroka University Medical Center, Beer Sheva, Israel; 5 Department
of Pediatric Hemato-Oncology, Hadassah University Medical Center,
Jerusalem, Israel; 6 Department of Pediatric Hematology and Oncology,
Trousseau Hospital, AP-HP, Sorbonne Université, Paris, France
Purpose: H syndrome is a rare genetic disorder predisposing to his-
tiocytosis, caused by germline biallelic loss-of-function mutations in
SLC29A3. Results from our previous study (under review) suggest a
novel signaling pathway involving the activation of Toll-like receptors
by impaired nucleoside trafficking, leading to persistent activation of
ERK and histiocytosis, in the absence of somatic mutations in MAPK
cascade genes. There is limited data on these patients’ clinical mani-
festations and response to different therapeutic modalities. Treatment
has included a range of immunomodulatory and chemotherapeutic
agents, with limited success. Tocilizumab therapy has recently been
reported in isolated case reports. Data is lacking on MEK inhibitor
therapy in this population.
Methods: Preliminary results from a multinational retrospective
cohort of patients with H syndrome.
Results: Twenty-four patients harboring nine pathogenic germline
SLC29A3 variants were identified in nine centers (median age-13
years [range:1.8-43];14 female). Clinical manifestations included: skin
lesions (n=20), extracutaneous histiocytic infiltrates (n=10), persis-
tently elevated CRP (n=18), hepatosplenomegaly (n=11), anemia
(n=8), hearing loss (n=16), joint deformities (n=8) and diabetes mel-
litus (n=4). Histiocytic infiltrates were reported in multiple sites:
retroperitoneal, pericardial, pleural, periaortic, perirenal and sinonasal.
Histopathology disclosed Rosai Dorfman disease-like morphology
and fibrosis. Assessment for somatic genetic alterations was per-
formed in seven patients, yet these were not identified. PhosphoERK
immunostaining was positive in three. Twelve patients were treated
with tocilizumab with improvement of inflammatory symptoms. Of
those with histiocytic infiltrates, two achieved complete response,
three- partial response and three did not respond. Five patients with

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insufficient response to tocilizumab received MEK inhibitors; three of
these demonstrated a significant response.
Conclusions: MEK inhibitor and anti-IL6R therapy are effective for
the treatment of histiocytosis and inflammatory manifestations in
patients with H syndrome, yet response patterns are variable and
should be studied in a larger cohort. Due to the rarity of this disorder,
international collaboration is important.
PATIENT ADVOCACY AMBASSADOR LEADERSHIP PROGRAM:
A MODEL FOR BRIDGING GAPS FOR RARE DISEASE
Deanna Fournier1 , Melinda Atnip1 , Kristen Nesensohn1 , Kathy
Wisniewski2
1 Histiocytosis Association, Pitman, NJ USA; 2 Histiocyte Society, Pitman,
NJ USA
Purpose: The Histiocytosis Association (HA), a global nonprofit
addressing needs of patients/families impacted by histiocytic dis-
orders. The HA connects patient/medical communities around the
world with the resources needed along every step of the way,
while leading the search for a cure. HA identified gaps both nation-
ally and globally through community surveys, including needs for
psycho-social support, healthcare navigation, and equity. The His-
tio Ambassador program aims to: 1)Empower and engage individuals
to enable education to local medical communities, aiding early diag-
nosis and improving access to therapies for histiocytic disorders;
2)Raise histiocytosis awareness both locally and beyond, through
outreach projects; 3)Create a focus group to identify needs of the
histiocytosis community; 4)Bring patient voice into advocacy and
research, working alongside the medical community to drive pro-
gram development and research priorities; 5)Actively provide support
to other patients and families, increasing connections and offering
HOPE.
Methods: HA identified community leaders and sought volunteers.
Through a structured application and interview process, histio
community leaders receive specialized training and evaluation to
become Histio Ambassadors. They are required to attend regu-
lar meetings, conduct one event per year, and attend educational
webinars.
Results: In less than one year, the HA recruited 25 ambassadors
representing six histiocytic disorders, every patient-family relation-
ship, and span 17-US-states; they completed 77 projects, recruited
93 new volunteers to aid events, assisted in research-study-design,
boosted social-media reach by over 2,000, connected 5 institutions for
newly-diagnosed-patient care-bags.
Conclusion: Creating a Patient Advocacy Leadership Program has
proven successful at expanding the Histiocytosis Association’s capac-
ity to support its mission and consequently, the histio community.
As the program continues to grow and evolve, goals and priori-
ties are driven through survey of the ambassadors and community,
ultimately increasing the HA’s knowledge of the persistence, scope,
and breadth of gaps and challenges that exist for our rare disease
community.
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ABSTRACTS
INDETERMINATE DENDRITIC CELL HISTIOCYTOSIS IS DISTINCT
FROM LANGERHANS CELL HISTIOCYTOSIS AND OFTEN
ASSOCIATED WITH OTHER HEMATOPOIETIC NEOPLASMS
Jean-François Emile1*, Neval Ozkaya2*, Sarah Melloul Benizri1 , Laszlo
J Karai3 , Sylvie Fraitag4 , Stefania Pittaluga2 , Maxime Battistella5 , Svet-
lana Pack2 , François Le Pelletie6 , Liqiang Xi2 , Anne Moreau7 , Ina Lee2 ,
Girish Venkataraman8 , Claire Pluchart9 , Zofia Helias-Rodzewicz1 ,
Jean Donadieu10 , Julien Haroche6 , Mark Raffeld2 , Elaine S. Jaffe2*
* Equally contributed authors.
1 Paris-Saclay University, Versailles SQY University, EA4340-BECCOH,
Assistance Publique-Hôpitaux de Paris (AP-HP), Ambroise-Paré Hospital,
Pathology Department, Boulogne, France; 2 National Institutes of Health,
Bethesda, MD USA; 3 Department of Dermatology, Larkin Community Hos-
pital, Miami, FL USA; 4 Hôpital Necker-Enfants Malades, AP-HP, Paris,
France; 5 Hôpital Saint-Louis, AP-HP, Paris, France; 6 Hôpital de la Pitié-
Salpêtrière, AP-HP, Paris, France; 7 Centre Hospitalier Universitaire de
Nantes, Nantes, France; 8 University of Chicago, Chicago, IL USA ; 9 American
Memorial Hospital, Reims, France; 10 Hôpital Armand-Trousseau, AP-HP,
Paris, France
Purpose: Indeterminate dendritic cell histiocytosis (IDCH) is a rare
histiocytic/dendritic-cell neoplasm histologically characterized by a
proliferation of mononuclear cells that mimic the neoplastic cells of
Langerhans cell histiocytosis (LCH) cytologically and immunopheno-
typically but lack Langerin expression. IDCH has been documented in
sporadic case reports and small case series.
Methods: Patients were retrieved from two institutions in the USA
and France. Inclusion criteria were: (1) biopsy with an atypical his-
tiocytic infiltrate indicative of neoplasia, (2) expression of at least 1
histiocyte marker (3) CD1a expression in the great majority of lesional
cells, and (4) langerin expression in no more than 20% of the infil-
trate. All cases were reviewed collectively by NO, SMB, ESJ and JFE.
Additional immunohistochemical studies as well as targeted DNA/RNA
sequencing were performed when biopsy material was still available.
Results: 42 cases were confirmed as IDCH, including 28 males and 14
females. The most common sites of involvement were skin (n=28) and
lymph node (n=12). In 18 patients (47%), ICH was associated with an
additional hematopoietic malignancy including 13 with myeloid malig-
nancies and 6 with lymphoid malignancies. Also, 7 patients (21%) had
a concurrent or prior histiocytosis diagnosis with non-IDCH histol-
ogy consistent with mixed histiocytosis. Molecular analyses revealed
frequent and mutually exclusive KRAS (n=12) or BRAF (n=11) muta-
tions. Six of the 7 NRAS mutation detected were associated with
another gain-of-function alteration. RNA analysis also revealed fre-
quent fusions: 5 ETV3::NCOA2, 2 BRAF fusion, 1 LMNA::NTRK1, as
well as 2 IGH::BCL2 and 1 KMT2A::MLLT1. Finally, several biopsies also
carried concurrent myeloid neoplasm-associated mutations (MNAMs)
that are rare in histiocytoses as follows: TET2, DNMT3A, ASXL1,
SRSF2, ZRSR2, SF3B1, ETV6, EZH2, STAG2, CEBPA, CBL, U2AF1, and
TP53.
Conclusion: Contrasting with LCH, IDCH has a complex genomic pro-
file with a high frequency of associated hematopoietic malignancy
including other forms of histiocytosis.

ABSTRACTS
NTRK1 RELATED HISTIOCYTOSIS: A SERIES OF 13 CASES
Jean-François Emile1 , Sylvie Fraitag2 , Zofia Helias-Rodzewicz1 ,
Benjamin Bonsang1 , Jean Donadieu3 , Jean-David Bouaziz4 , Julien
Haroche5 , Sébastien Héritier3
1 Paris-Saclay University, Versailles SQY University, EA4340-BECCOH,
Assistance Publique-Hôpitaux de Paris (AP-HP), Ambroise-Paré Hospital,
Pathology Department, Boulogne, France; 2 Necker-Enfants Malades hospi-
tal, AP-HP, Paris, France; 3 Armand-Trousseau hospital, AP-HP, Paris, France;
4 Saint-Louis hospital, AP-HP, Paris, France; 5de la Pitié-Salpêtrière hospital,
AP-HP, Paris, France
Purpose: Histiocytoses are myeloid neoplasms defined by tissue infil-
tration by cells of the macrophage or dendritic cells lineage. Most of
them harbor an oncogenic alteration activating the MAP kinase path-
way, the most frequent being mutations of BRAF or MAK2K1 genes.
Gene fusion responsible for the expression of an oncogenic chimeric
protein have also been described, such as ALK fusion in ALK-positive
histiocytosis and BRAF in some Langerhans cell histiocytosis. The
frequency of each genetic alteration depends on the subtype of histi-
ocytosis. We aimed to defined the characteristics of histiocytosis with
NRTK1 fusion.
Methods: Cases were retrieved from the database and biobank of
Ambroise Paré hospital. Fusion of NRTRK1 were detected by RNA
sequencing on biopsies of patient with centrally validated diagnosis of
histiocytosis.
Results: 13 patients had a confirmed histiocytosis with NTRK1 fusion.
The median age at time of biopsy was 25 years (range birth to 70.2
years), and male/female ratio was 6/7. All samples were skin biop-
sies, mostly involving head & neck (4), and lower (3) or upper (3)
limbs. 11 cases had a unique nodule, while the 2 other patients had
2 or 3 nodules. They were classified as C group histiocytosis, with
juvenile xanthogranuloma (JXG) histology. Five gene fusions were
detected: IRF2BP2::NTRK1 (6), TPM3::NTRK1 (4), KCTD5::NTRK1,
LMNA::NTRK1 or PRDX1::NTRK1.
Conclusion: To our knowledge, only 5 cases of histiocytoses with
NTRK1 fusion (LMNA (3), IRF2BP2 and TFG) have been reported so
far, two of which with few clinicopathological data. We provide herein
an overview of this entity, which is potentially accessible to targeted
therapy.
FAILURE OF
VINCRISTINE-CYTARABINE-PREDNISONE-INDOMETHACIN AS A
SECOND LINE OF TREATMENT IN HIGH RISK AND NON HIGH
RISK LANGERHANS CELLS HISTIOCYTOSIS
Guido Felizzia1 , Natalia Fontana1 , Eric Warriner1 , Daniela Fortunatti1 ,
Belen Popon1 , Marianela Viso1 , Adriana Rose1 , Michelle Schvartz1 ,
Giulia Racca1 , Laura Galluzzo2 , Nicolas Pinto3 , Jorge Braier1
1 Hematology / Oncology,2 Pathology and 3Translational Medicine Depart-
ments. Hospital Nacional de Pediatría “Prof. Dr. J. P. Garrahan”, Buenos Aires,
Argentina
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S11 of S64
Purpose: To report the results of a modified version of the scheme
prednisone and low doses of cytarabine used as 2nd line of treatment
in our institution.
Methods: The treatment consisted of oral prednisone 40mg/m2/day
during 6 week and three weeks courses of Vincristine 1.5mg/m2 +
cytarabine 100mg/m2/day IV x 4 days for 8 courses. At week 6 pred-
nisone was replaced for indomethacin 2mg/kg/day for two years in
case of complete response. Evaluation after 4th and 8th cycle were
performed.
Results: Total of patients:11 (Male:5/Female:6) Median age at diag-
nosis 18 months. Risk organ involvement (RO+) n=7; Low risk organ
involvement (RO-) n=4, BRAFV600E+ 6 out of 8 performed; Seven
RO+ Patients: Median age at treatment 24 months. Involved sites:
liver 6 patients, spleen 2, hematological 1, skin 5, bone 5. Status after
4th cycle: Active Disease Better(ADB) 5, Stable Disease(SD) 2. Three
patients did not complete chemotherapy (reactivation 1, progression
1, no response 1); Four patients completed 8 cycles: No Active Dis-
ease(NAD) 1; ADB 2, AD worse 1. None of the patients completed
all the treatment. (Progressive disease[PD] 4 patients, Reactivation 2,
SD 1). Two-year EFS=0.0; 2y OS=0.83 (0.27-0.97). Median Follow-up
37 months. Four RO- patients: Median age at treatment 32 months.
MS-OR- 2 patients, Unisystemic multifocal involvement 2. Involved
sites: Bone 4 patients, skin 2. Status after 4th cycle: ADB 3 patients;
SD 1. One patient progressed during chemotherapy. Three patients
completed 8 cycles with No Active Disease(NAD). None patients
completed all the treatment (Reactivation 2; PD 1, Lost follow-up
1). Two-year Event Free Survival(EFS)=0.25 (0.008-0.66) 2y Overall
Survival (OS)=1; Median Follow-Up:29 months.
Conclusion: Although a good initial response was seen in the major-
ity of RO+ and RO- patients, none of them completed the treatment.
In our cohort more intensive or target therapy is needed for reacti-
vated/refractory patients.
HYPERINFLAMMATORY PLASMA PROTEIN CLASSIFIER
CORRELATES COVID-19 SEVERITY TO HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSS (HLH)
Ryan Fleischmann1 , Brooks Scull1 , Harshal Abhyankar1 , Jenny
Agrusa2 , Kenneth McClain1,2 , Trung Nguyen3,4 , Mark Hicar3 ,
Tsz-Kwong Man1,2 , Sridevi Devaraj1,2 , Carl Allen1,2
1 Division of Pediatric Hematology-Oncology, Department of Pediatrics,
Baylor College of Medicine, Houston, TX USA; 2 Texas Children’s Cancer
Center, Texas Children’s Hospital, Houston, TX USA; 3 Division of Critical
Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Hous-
ton, TX USA; 4 Michael E. DeBakey Veteran Affairs Medical Center, Center
for Translational Research on Inflammatory Diseases, Houston, TX USA
Purpose: Pathologic inflammation can arise from many intrinsic
and extrinsic factors that impact regulation of immune response.
Approaches to guide optimal diagnosis, risk prediction, supportive
and therapeutic care are limited. Development of a range of clinical
phenotypes observed in children responding to SARS-CoV2 highlight

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the challenges and clinical importance of tools to characterize and
counter pathologic inflammatory responses. We therefore tested the
ability of inflammatory classifiers, based on plasma protein profiles and
immunophenotypes of patients with prototypical inflammatory condi-
tions, to predict clinical presentation and outcomes in children with
SARS-CoV2.
Methods: The Luminex platform measured 150 analytes in 108
patients with pediatric COVID19, 32 of which developed MIS-C, 16
with HLH, 14 with severe sepsis, 25 with Kawasaki disease, 21 with
febrile viral illness, and 20 health controls. The results were tested for
significant proteins with a FDR cut off of 0.1 and 80% confidence. Semi-
supervised learning using protein analyte profiles of inflammatory
disease were used to reclassify COVID19 and clinical outcomes were
compared to separate COVID patients into severe and non-severe
groups. Immunophenotype by cytometry time of flight compared 37
different immune subsets the COVID severity groups
Results: Analyte profile reclassification of COVID19 patients revealed
patients with plasma profiles similar to HLH had more severe form
of COVID19 with higher instances of MIS-C, longer hospital stay,
and higher instance of respiratory failure. Immunophenotyping also
showed the HLH-like COVID had higher proportion of naïve T and B
cells.
Conclusion: This evaluation of plasma proteins demonstrated that
pediatric patients with SARS-Cov2 infection with inflammatory plasma
profile similar to an HLH signature experienced more severe disease.
These results demonstrate the ability of comparison of patients who
present with complex immune dysregulation to prototype inflamma-
tory signatures (e.g. HLH) to predict risk, and potentially identify driver
inflammation pathways.
TRANSCRIPTION FACTOR NRF2 IS ACTIVATED BY
ERYTHROPHAGOCYTOSIS AND IS A MAJOR REGULATOR OF
INFLAMMATION AND REDOX STRESS IN MURINE
HYPERINFLAMMATION
Paul Gallo1 , Em Elliott2 , Grace Ford2 , Jadyn Wheaton2 , Chhanda
Biswas2 , Niansheng Chu2 ,
Edward Behrens2
1 Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia,
PA USA; 2 Division of Rheumatology, Children’s Hospital of Philadelphia,
Philadelphia, PA USA
Purpose: Hyperinflammatory syndromes including macrophage acti-
vation syndrome (MAS) are characterized by multi-lineage cytopenias,
hypercytokinemia, and tissue hemophagocytosis. The mechanisms by
which hemophagocytes regulate the hyperactive immune response
remain unclear. The transcription factor Nrf2 is an important sensor for
inflammatory and redox stress. Downstream of Nrf2 are antioxidant
response elements responsible for restoration of redox homeostasis
within the cell. Here we aim to investigate the mechanisms by which
hemophagocytes regulate hyperinflammation.
Methods: We use a murine model of secondary HLH using TLR9-
agonist CpG. CpG treatment induces a secondary hyperinflamma-
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ABSTRACTS
tory state which recapitulates the clinical findings of HLH. Clinical
and biochemical markers of disease were measured by complete
blood count, liver and spleen pathology, serum free heme, ferritin,
and cytokine profiles. In vivo oxidative stress was measured by
MDA assay and glutathione levels. In vitro bone marrow derived
macrophages and dendritic cells are used to investigate regulation
of CpG-induced cytokine expression by oxidized red blood cells and
heme.
Results: Mice with CpG-induced hyperinflammation have evidence
of systemic oxidative and nitrosative stress - including increased
serum nitric oxide and elevated systemic lipid peroxidation. In this
model, Nrf2 knockout mice develop significantly worse organomegaly,
organ pathology, and hypercytokinemia compared to wildtype con-
trols. Notably, the hypercytokinemia in the Nrf2 KO mice favors
cytokines that are central to HLH physiology: IL-12, IFNg, and IL-10.
Nrf2 KO mice also have an increased serum free heme and an ane-
mia with elevated reticulocytosis - suggesting red cell consumption by
intravascular hemolysis. In vitro we have found that oxidized red blood
cell lysates and heme itself are both able to suppress IL-12 transcrip-
tion and protein production from bone marrow derived dendritic cells
in a Nrf2-dependent manner.
Conclusion: Together our findings suggest erythrophagocytosis has
a protective role in hyperinflammatory states in part due to Nrf2-
mediated suppression of proinflammatory cytokine production.
BRAF MUTATION DETECTION AS A PROGNOSTIC MARKER
AND PREDICTOR OF DISEASE REACTIVATION IN LANGERHANS
CELL HISTIOCYTOSIS
Gabriel Gallo-Oller1*, Lorena Valero-Arrese2*, Lucas Moreno1, 2 , Josep
Roma1
1 Laboratory of Childhood Cancer and Blood Disorders, Vall d’Hebron
Research Institute, Hospital Universitari Vall d’Hebron, Universitat
Autònoma de Barcelona, Barcelona, Spain; 2 Pediatric Oncology and
Hematology Department, Hospital Universitari Vall d’Hebron, Universitat
Autònoma de Barcelona, Barcelona, Spain
*Both authors contributed equally to this work
Purpose: Langerhans cell histiocytosis (LCH) is a rare and potentially
debilitating disease that primarily affects children and young adults,
involving the abnormal accumulation of Langerhans cells, a type of
immune cell. This disorder can cause a range of symptoms and compli-
cations, including bone lesions, skin rashes, organ dysfunction, and in
some cases central nervous system complications. In order to enhance
our understanding of LCH and improve patient outcomes, this study
aimed to assess the significance of detecting BRAF V600E mutation
in plasma as a prognostic marker for predicting disease outcome and
reactivation.
Methods: In this study, we used droplet PCR and the Idylla ctBRAF
Mutation Test to detect BRAF V600E in plasma samples from patients
with confirmed BRAF mutation. Patients were closely monitored and
clinical outcomes and reactivation of the disease were assessed in
relation to BRAF V600E detection.

ABSTRACTS
Results: We found that BRAF V600E detection in plasma correlated
with clinical outcome and the reactivation of the disease. In patients
who did not respond to treatment or experienced disease reactivation,
an elevation in BRAF mutation levels was observed. Specifically, indi-
viduals with a positive BRAF mutation in plasma showed an increased
susceptibility to disease reactivation when compared to those with a
negative BRAF mutation status.
Conclusion: The detection of BRAF V600E in LCH patients using
plasma samples can serve as a valuable predictor of treatment effec-
tiveness and disease reactivation. This approach holds promise for
improving patient management and optimizing therapeutic interven-
tions in LCH. Further studies are needed to validate these findings
and to explore the potential of BRAF V600E detection as a routine
prognostic tool in LCH.
SEARCHING FOR DIFFERENTIAL DIAGNOSTIC BIOMARKERS
BETWEEN SEVERE SEPSIS AND HEMOPHAGOCYTIC
SYNDROME FOR A BETTER CLINICAL MANAGEMENT IN
PEDIATRIC PATIENTS
Susana Garcia-Obregon1,2 , David Martin-Pestana1 , Mikel
Azkargorta3 , Lide Martinez-Insausti1 , Miriam Sanchez-Saez1 , Sil-
via Redondo4 , Manuel Nieto4 , Victoria Boado-Varela5 , Francisco
Javier Pilar-Orive4 , Felix Elortza3 , Itziar Astigarraga1,6,7
1 Pediatric Oncology Group, Biobizkaia Health Research Institute,
Barakaldo, Spain; 2 Physiology Department, Universidad del Paí-s Vasco
UPV/EHU, Leioa, Spain; 3 Proteomics Platform, CIC bioGUNE, Basque
Research and Technology Alliance (BRTA), CIBERehd, Bizkaia Science and
Technology Park, Derio, Spain; 4 Pediatric Intensive Care Department,
Hospital Universitario Cruces, Barakaldo, Spain; 5 Intensive Care Depart-
ment Hospital Universitario Cruces, Barakaldo, Spain; 6 Pediatric Oncology
Department Hospital Universitario Cruces, Barakaldo, Spain; 7 Pediatric
Department, Universidad del Paí-s Vasco UPV/EHU, Leioa, Spain
Purpose: Hemophagocytic Lymphohistiocytosis (HLH) shares many
clinical features with severe sepsis. In order to improve diagnosis
of HLH and its differential diagnosis with sepsis, serum proteomic
analyses of HLH and septic patients were performed.
Methods: In this study, 24 serum samples were included in a label
free nLC MS/MS proteomic analysisProtein identification and quantifi-
cation was performed with PEAKS software. Proteomic results were
subjected to functional analysis to study impaired processes in each
condition. Information obtained from proteomics analysis and biblio-
graphic searches was used to select which proteins should be validated
by ELISA in a larger cohort of patients and healthy donors.
Results: Serum proteomics was performed in eight HLH (median age
atm diagnosis: 2.39; sex distribution: 5males/3females), eight severe
sepsis (median age at diagnosis: 3.8; sex distribution: 5males/3females)
and eight healthy donors (median age at diagnosis: 6.1; sex distribu-
tion: 6males/2females). Proteomic results revealed 537 differentially
expressed proteins (DEP) between HLH and severe sepsis, 471 DEP
between HLH and healthy donors and 37 DEP between severe sep-
sis and healthy donors. Functional analysis of DEP with fold change
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higher than 1.3 showed that, apart from inflammatory processes and
lipid metabolism, the proteostasis network was deeply impaired in HLH
condition. Considering protein fold change, their function and biblio-
graphic research, some proteins were validated in a larger cohort of
patients and healthy donors.
Conclusion: Our results revealed that sCD300a, sCD300b could be
specific serum biomarkers for HLH diagnosis as well as sCD25. SAA-
1 and LRG1 might be biomarkers for differential diagnosis between
sepsis and HLH, and PSMB1 showed promising results for HLH spe-
cific and differential diagnosis, but validation in a larger cohort is
needed. These results could be used in combination with clinical fea-
tures to develop panels of clinical biological markers to improve the
management of patients suffering from HLH and sepsis in childhood.
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
FOR DENDRITIC/HISTIOCYTIC NEOPLASMS
Charles Gaulinź, Fiona Craig2 , Shannon Fortin Ensignź, Ryan
Robetorye2 , Sarah Gibson2 , Katalin Kelemen2 , Nandita Kheraź,
Jose Leisź, Mazie Tsangź, Allison Rosenthalź, Javier Munozź, Jeanne
Palmerź, Talal Hilalź
1 Division of Hematology and Medical Oncology, Department of Medicine,
Mayo Clinic, Phoenix, AZ USA; 2 Division of Hematopathology, Department
of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ USA
Purpose: Dendritic/histiocytic neoplasms are diagnostically challeng-
ing and lack standard therapy. Here, we report our experience
with allogeneic hematopoietic stem cell transplantation (alloHCT) in
patients with aggressive dendritic/histiocytic neoplasms.
Methods: Patients who underwent alloHCT for dendritic/histiocytic
neoplasms at Mayo Clinic Arizona were retrospectively identified.
Cases were pathologically reviewed at diagnosis and retrospectively.
Results: Three patients were included. Patient 1: 33-year-old man
with Langerhans cell histiocytosis and morphologic atypia worrisome
for Langerhans cell sarcoma involving his mediastinal lymph nodes
(LNs). He rapidly developed lung involvement during cytarabine ther-
apy resulting in superior vena cava syndrome requiring radiotherapy.
He received cladribine/cytarabine and achieved a partial response (PR)
followed by alloHCT consolidation resulting in complete response (CR).
At 56 months, he remains in CR without evidence of graft versus
host disease. Patient 2: 51-year-old woman with histiocytic sarcoma
(HS) involving her pancreas, abdominal LNs, and marrow. Her tumor
had 70% programmed death-ligand 1 expression. She received pem-
brolizumab with CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone) and achieved a PR. She experienced disease progression
and second line therapy with pembrolizumab with ICE (ifosfamide,
carboplatin, etoposide) did not yield a response. She had a PR to
clofarabine and underwent alloHCT. She had disease progression 4
months post-alloHCT and received radiotherapy. She died from HS
17 months post-alloHCT while on an investigational agent. Patient 3:
38-year-old man with HS involving gluteal soft tissue and abdominal
LNs. His disease progressed during CHOP and clofarabine chemother-
apy. His tumor harbored a BRAF- DOCK8 fusion. He had a PR to

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cobimetinib and underwent alloHCT resulting in CR on day +60 from
transplant.
Conclusion: AlloHCT may be a therapeutic option for select patients
with dendritic/histiocytic neoplasms. Targeted therapies may serve as a
bridge to transplant. Further research is needed to define the subgroup
of patients who derive the most benefit from this approach.
STUDY ON THE EFFICACY AND SAFETY OF TRAMETINIB IN
THE TREATMENT OF REFRACTORY LANGERHANS CELL
HISTIOCYTOSIS IN CHILDREN
Jian Ge, Zhigang Li, Tianyou Wang, Rui Zhang
Hematology Center, Beijing Children’s Hospital, Capital Medical University
Purpose: To investigate the efficacy and safety of trametinib for the
treatment of MAP2K1 mutation-positive, refractory Langerhans cell
histiocytosis (LCH) in children.
Methods: Fourteen patients from China took trametinib Trametinib
0.025mg/kg/d (maximum dose 2mg/d). The main evaluation criteria
were therapeutic responses according to Disease Activity Score and
adverse events.
Results: 14 LCH patients (8 female, 6 male) with MAP2K1 mutation
were treated by trametinib monotherapy in Beijing children’s hospital.
Median age at diagnosis was 1.8 years and median age at trame-
tinib initiation was 3.1 years. The median treatment duration was 23.1
months. At month 6, disease status was nonactive (n=4), better (n=9),
or stable (n=1), with an overall response rate of 92.9%. The median
Disease Activity Score decreasing from 8 at diagnosis to 1 (P<0.01).
The most commonly reported treatment-related adverse events were
rash, which was observed in 5 patients. Additionally, paronychia was
reported in 2 patients, and epistaxis was observed in 1 patient.
Conclusion: trametinib was safe and effective in children with refrac-
tory MAP2K1-positive LCH. Additional investigation is necessary to
explore and identify optimal strategies for maintaining treatment
effectiveness.
A RARE CASE OF MIXED NON-LANGERHANS CELL
HISTIOCYTOSIS RESPONSIVE TO COBIMETINIB THERAPY
Wilmar Ghuijs1 , Astrid G.S. van Halteren3, Robert M. Verdijk2 , Jan
A.M. van Laar1,3
1 Department of Internal Medicine, Erasmus Medical Center Rotterdam,
Rotterdam, The Netherlands; 2 Department of Pathology, Erasmus Medical
Center Rotterdam, Rotterdam, Tbe Netherlands; 3 Department of Immunol-
ogy, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
Rosai-Dorfman disease (RDD) and Erdheim-Chester disease (ECD) are
rare non-Langerhans cell histiocytoses both characterized by inflam-
matory lesions containing xanthomatous CD68+ macrophages. We
present a case of a 51-year-old woman with extensive cutaneous
and sigmoid lesions characterized by the presence of CD68+ S100+
cells and emperipolesis suggestive of RDD, along with tibia lesions,
more compatible with ECD. Next generation sequencing for MAP-
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ABSTRACTS
kinase pathway related somatic mutations performed on both skin
and sigmoid biopsies revealed the same MAP2K1 (NM_002755.3) exon
2: c.171G>C; p.K57N mutation. The skin lesions progressed from
small depigmented flat lesions distributed over the patient’s face,
trunk and legs to an excessive number of prominent nodules dur-
ing immunosuppressive treatment with prednisone, hydrochloroquine,
methotrexate and rapamycin. However, a swift and complete remission
of the cutaneous lesions occurred within weeks after cobimetinib was
initiated. Cobimetinib was tapered from daily 60 mg to 20 mg because
of significant adverse cardiac and pulmonary events requiring addi-
tional prednisolone treatment. The complete skin and ossal response
remained up to 9 months after discontinuation of cobimetinib and 6
months after stopping prednisone respectively. However, the rectal
lesion remained present. This case highlights the diagnostic challenge
and added value of molecular testing with respect to clinical decision
making in patients with non-Langerhans cell histiocytosis, manifesting
for example as mixed RDD and ECD . Moreover, our case illustrates
the potential therapeutic efficacy of cobimetinib in the management
of patients with such histiocytic disorders, but also shows that careful
monitoring of toxicity is warranted.
A PEDIATRIC NON-LANGERHANS CELL HISTIOCYTIC LESION
WITH A CLTC::SYK GENE FUSION - A CASE REPORT
Aida Glembocki1 , Bo Ngan1,2 , James Whitlock3 , Oussama Abla3 ,
Robert Siddaway1 , Anthony Arnoldo1 , Jennifer Picarsic4 , Anita
Nagy1,2
1 The Hospital for Sick Children, Division of Pathology, Toronto, Canada;
2 University of Toronto, Department of Laboratory Medicine and Patho-
biology, Toronto, Canada; 3 The Hospital for Sick Children, Division of
Hematology Oncology, Toronto, Canada; 4 Cincinnati Children’s Hospital
Medical Center, Pathology and Lab Medicine, Cincinnati, Ohio, US
Introduction: Non-Langerhans cell histiocytosis (non-LCH) is a diverse
group of diseases. Recently decribed molecular alterations have pro-
vided valuable insights into their pathogenesis and provided potential
therapeutic targets. This abstract presents a case of a pediatric non-
LCH with a CLTC::SYK gene fusion.
Methods: This case study describes the morphological, the immuno-
histochemical and the molecular features of a pediatric juvenile
xanthogranuloma (JXG) family lesion.
Results: The patient is a 6-month-old female infant who presented
with an approximately four week-history of a well-defined soft tissue
lesion on the posterior aspect of the infraspinatus muscle, measuring
up to 2.3 cm on imaging. The biopsy showed solid sheets of predom-
inantly foamy mononucleated histiocytes and focally spindle-shaped
histiocytes, diffusely staining with CD68, CD163, CD14 and vimentin,
and focally with factor XIIIa, p16 and cyclin D1. Other markers,
including CD1a, Langerin, S100, ALK, BRAF, CD117 and MPO were
negative. Touton-type giant cells were not seen. Proliferation index
was low. Cytological atypia or mitotic figures were not seen. TruSight
RNA Pan-Cancer sequencing detected CLTC::SYK gene fusion, which
is an in-frame fusion that preserves the kinase domain of the SYK

ABSTRACTS
gene, suggesting that SYK might be the driver kinase mutation. SYK
gene is a non-receptor tyrosine kinase whose targets can include
the MAPK, PI3K and NF-κB pathways. Oncogenic SYK fusions with
other partners have previously been described in prostate ade-
nocarcinoma and T-cell lymphoma. The overall morphological and
immunohistochemical features are those of a JXG-family lesion, with
predominance of xanthomatous cells but absence of Touton Giant cells.
Four months after the biopsy, there is no clinical sign of regrowth of the
lesion.
Conclusion: We report a novel gene fusion in a pediatric case of non-
LCH, expanding our understanding of molecular mechanisms under-
lying these disorders. Since submission of the abstract, Crowley et al
have reported three JXG-family lesions with the same gene fusion. Fur-
ther studies are needed to explore the prevalence of this gene fusion in
non-LCH and to evaluate its clinical implication for diagnosis, prognosis
and treatment strategies.
PRIMARY HISTIOCYTIC SARCOMA OF THE CENTRAL NERVOUS
SYSTEM IN A PEDIATRIC PATIENT
Sergio Yael Guzman Herrera, Martha Valdés Sanchez
Hospital de Pediatría Centro Médico Siglo XXI, Cuauhtémoc, Ciudad de
México
Purpose: Histiocytic sarcoma is an extremely rare neoplasm in chil-
dren. Derived from the non-Langerhans cell histiocytosis of the
monocyte-macrophage system. The diagnosis is made with immunohis-
tochemical markers; CD68, lysozyme, CD4 and CD163 on the biopsied
tissue. Present the histopathological diagnosis, clinical picture, treat-
ment, evolution and treatment of one patient with an extremely rare
neoplasia in pediatrics where there is no established consensus for its
management.
Methods: It is an extremely rare neoplasm, there is no consensus
for the treatment. It was decided to apply the following chemother-
apy scheme: MORIMOTO scheme with alternate cycles of protocol A
and protocol B. A: Vincristine 1.5 mgm2sc, Cytarabine 100 mgm2sc,
Dexamethasone 9.5 mgm2sc for two cycles. Alternating with pro-
tocol B: Vincristine 1.5 mgm2sc, Cyclophosphamide 250 mgm2sc,
Prednisone 7.5 mgm2sc for one cycle. Subsequently a maintenance
protocol was started: 1. Vincristine, Cytarabine, Dexamethasone,
with a single scheme of Methotrexate 75mgm2sc IM one dose and
Prednisone 46mgm2sc (as a modification of the scheme), and 2. Vin-
cristine 1.5mgm2sc, and Doxorubicin 40mgm2sc, Cyclophosphamide
250mgm2sc, prednisone 46mgm2sc. Finally was complemented with
radiotherapy to the primary tumor.
Results: A head MRI was performed with no report of tumor activ-
ity and surveillance period began on 04.10.23. There is no consensus
on management, it is mentioned that total resection of the tumor is
the gold-standard treatment, and it benefits from the administration
of chemotherapy and radiotherapy.
Conclusions: Primary Histiocytic Sarcoma in the central nervous sys-
tem is a very rare neoplasia at any age and even more in the pediatric
age. So Its diagnosis is by exclusion and based on immunohistochemical
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S15 of S64
techniques. The prognosis varies according to the extent of the dis-
ease. The gold standard in the treatment is the surgical resection of
the tumor. There is no consensus on the best chemotherapy scheme,
so different schemes have been applied.
RESULTS OF THE LANGERHANS CELL HISTIOCYTOSIS (LCH)
GREEK REGISTRY FOR PEDIATRIC PATIENTS WITH BRAF
MUTATION
Emmanuel Hatzipantelis1 , Marina Servitzoglou2 , Natalia Tourkantoni3 ,
Evgenia Papakonstantinou4, Iordanis Pelagiadis5 , Eleni Dana6 , Maria
Ioannidou1 , Demetrios Doganis2 , Loizos Petrikkos7 , Eleni Rigatou3 ,
Vassiliki Tzotzola7 , Athanasios Tragiannidis1 , Eleni Kosmidi6 , Eutixia
Stiakaki5 , Sophia Polychronopoulou7 , Antonis Kattamis3 , Margarita
Baka2 , Vassilios Papadakis7
1 Children’s & Adolescent’s Hematology-Oncology Unit, 2nd Pediatric Clinic,
School of Medicine, Aristotle University of Thessaloniki, AHEPA Univer-
sity General Hospital, Thessaloniki, Greece; 2 Oncology Department, ’P. &
A. Kyriakou’ Children’s Hospital, Athens, Greece; 3 Hematology-Oncology
Unit, First Department of Pediatrics, National and Kapodistrian University
of Athens, “Aghia Sofia” Children’s Hospital, Athens, Greece; 4 Department
of Pediatric Hematology and Oncology, Hippokration Hospital, Thessaloniki,
Greece; 5 Department of Paediatric Hematology-Oncology, University Hos-
pital of Heraklion, Heraklion, Crete, Greece; 6 Pediatric & Adolescent Oncol-
ogy Clinic, “Mitera” Hospital, Athens, Greece; 7 Department of Pediatric
Hematology-Oncology (TAO), “Aghia Sophia” Children’s Hospital, Athens,
Greece
Purpose: The description of characteristics, treatment and outcome of
children with LCH and BRAF mutation in Greece.
Methods: From 2000-2019, 169 patients (62.7% boys) with median
age of 5.46 years, were retrospectively recorded in all 7 Pediatric
Oncology departments. In 51 patients (30.2%) BRAF-V600E mutation
was assessed.
Results: From 169 patients in total, 52 were younger than 2 years,
while 133 (78.7%) presented with single-system disease (SS). Seventy
one (53.4%) children with SS disease received chemotherapy. Two of
them died due to pneumothorax and lymphoma, with an overall sur-
vival (OS) of 98.5%. Thirteen patients relapsed (EFS: 90.2%), with a
mean follow-up time of 6.51 years. Thirty six children (21.3%), with
a median age of 1.7 years had multi-system disease (MS). Twenty
two (59.5%) had risk-organ disease, while 10 (27%) developed dia-
betes insipidus. All MS patients received chemotherapy. Relapse or
resistant disease was observed in 9/36 MS patients (25%), EFS:75%.
One patient died from CMV infection and multiple organ failure. Of
51 patients evaluated for BRAF-V600E mutation, 27 (52.9%) were
found BRAF-V600E+, 21/39 with SS and 6/12 with MS. Overall, 8/27
BRAF+ patients (29.6%) relapsed (EFS:70%). Of the 21 patients with SS
BRAF-V600E+ disease, 5(23%) relapsed, while of 6 MS BRAF-V600E+
patients, 3(50%) relapsed or had refractory disease. All patients with
MS disease and absence of BRAF mutation are in remission. Patients
BRAF-V600E+ had higher risk for relapse (p=0.014) compared to
BRAF-V600E- subjects.

S16 of S64
Conclusions: Although the number of patients tested for BRAF-V600E
mutation was only a percentage of our entire cohort and conse-
quently, relatively small, it becomes evident that the presence of
BRAF-V600 mutation is an important prognostic factor in children with
LCH.
UNDERSTANDING THE EPIGENETIC LANDSCAPE IN
HISTIOCYTIC NEOPLASMS
Oshrat Hershkovitz-Rokah1,2 , Mali Salmon-Divon1,3 , Refael
Meyuchas1,2 , Roei D.Mazor4 , Ofer Shpilberg2,3,4 , Jamal Benhamida5 ,
Mariko Yabe5 , Kseniya Petrova-Drus5 , Omar Abdel-Wahab6 ,
Eli L. Diamond7
1 Department of Molecular Biology, Faculty of Natural Sciences, Ariel Uni-
versity, Ariel, Israel; 2 Translational Research Lab, Assuta Medical Centers,
Tel-Aviv, Israel; 3 Adelson School of Medicine, Ariel University, Ariel, Israel;
4 Clinic of Histiocytic Neoplasms, Institute of Hematology, Assuta Medical
Center, Tel-Aviv, Israel; 5 Department of Pathology, Memorial Sloan Ketter-
ing Cancer Center, New York, NY USA; 6 Molecular Pharmacology Program,
Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New
York, NY USA; 7 Department of Neurology, Memorial Sloan Kettering Cancer
Center, New York, NY USA
Purpose: Histiocytic neoplasms are driven by mutations activating
the MAPK/ERK pathway; however, their epigenetic landscape remains
poorly understood. MicroRNAs (miRNAs) are epigenetic regulators
implicated in cancer development. Moreover, DNA methylation of miR-
NAs affects hematological malignancies development. Our previous
study identified a unique miRNA expression signature in Erdheim-
Chester Disease (ECD) patients. To further understand the biological
mechanisms of ECD, we investigated the involvement of miRNAs,
genes, and their methylation status in ECD, Langerhans cell histiocy-
tosis (LCH), and Rosai-Dorfman disease (RDD).
Methods: Methylation profiles of 14 LCH, 6 ECD, and 10 RDD
patients were determined from histiocytic infiltrated tissues (Illumina
EPIC-methylation array). These were compared to controls, suture
granulomas (n=4), localized inflammatory reactions characterized by
non-neoplastic histiocytic infiltrates. miRNAome data was identified
by NanoString analysis and qRT-PCR.
Results: We identified significant alterations in 23,322 methylation
sites (FDR<0.05, |Δβ|≧20%) between controls and the histiocyto-
sis group, indicating differential epigenetic regulation. ECD and LCH
exhibited a shared methylation signature distinct from RDD. Path-
way analyses revealed that the differentially methylated genes (DMGs)
were involved in inflammatory response, RAS, TNF, and PI3K-mTOR
signaling pathways, linked to histiocytic neoplasms. Specifically, we
found DMG involvement in regulation and generation of non-coding
RNAs. Notably, we observed significant downregulation of the let7-
miRNA family, particularly let7b, in ECD and LCH patients. Subsequent
analysis revealed hypermethylation of specific CpG islands in the let7b
DNA sequence, potentially silencing let7b expression in these dis-
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ABSTRACTS
eases. Given the let7-miRNA family’s role in regulating the MAPK
pathway, this suggests a novel mechanism in the pathogenesis of these
neoplasms.
Conclusions: We provide valuable insights into differential methyla-
tion patterns in histiocytosis neoplasms, highlighting the involvement
of epigenetic modifications in their development and progression. This
enhances our understanding of histiocytosis development and may
contribute to the identification of novel diagnostic and therapeutic
approaches for these patients.
SUCCESSFUL USE OF THALIDOMIDE FOR CUTANEOUS
INDETERMINATE CELL HISTIOCYTOSIS
Hornos, Martin1 ; Rosso, Diego1 , Rojas Bilbao, Erica2 , Manzur,
Graciela1 , Barrios, Paula1 , Coirini, Marcelo3 , Sosa, Soledad1
1 Hospital de Clínicas “José de San Martín” Buenos Aires, Argentina;
2 Instituto de Oncología “Ángel Roffo”, Buenos Aires, Argentina; 3 Hospital de
Niños “Victor J. Vilela” de Rosario, Santa Fe, Argentina
Indeterminate cell histiocytosis was first described in 1985 as a
rare cutaneous disorder characterized by the proliferation of CD1a+,
S100+, and CD207- nonspecific dendritic cells. We present the case
of a 27-year-old male patient, with no significant medical history,
who developed multiple disseminated brown-reddish papules on the
palms, soles, limbs, trunk, and back. The lesions were tender to pal-
pation, non-pruritic, and approximately 1 cm in diameter. A biopsy
was performed, which revealed a histiocytic population that was pos-
itive for CD68, CD163, CD1a, S100, and negative for CD207, BRAF
V600E, and ALK. A PET-CT scan was performed, which showed no
evidence of hypermetabolic uptake areas. With a diagnosis of indeter-
minate cutaneous histiocytosis, the patient underwent treatment with
Methotrexate, Vinblastine, 6-Mercaptopurine, and Methylprednisone
for 9 months, resulting in partial improvement. Following completion
of chemotherapy, the patient experienced a rapid and extensive recur-
rence, leading to referral to our department. A review of the biopsy
confirmed the diagnosis and after informing consent, Thalidomide 300
mg/day was prescribed. Over the following months, there was pro-
gressive reduction in size, coloration, and number of lesions, reaching
a stage of residual pigmentation in most of them. After ten months
of treatment, the patient reported paresthesia in the upper limbs,
prompting the decision to prescribe vitamin B and discontinue Thalido-
mide, resulting in complete resolution of neuropathy. The patient
continued with regular follow-up visits and, to date, has not expe-
rienced any recurrence of lesions despite being off medication. The
cutaneous involvement in this case differed from the typical patterns
observed in Langerhans cell histiocytosis. In this context, Thalidomide
stood out as an effective alternative for the treatment of histiocytic
disorders primarily affecting the skin. Proper monitoring and close
observation of adverse effects are crucial with this medication in
order to prevent the development of potentially irreversible peripheral
neuropathy.

ABSTRACTS
ADULT-ONSET ERDHEIM-CHESTER DISEASE PRESENTING AS
BILATERAL ORBITAL MASSES: A CASE REPORT
Hornos, Martín1 , Diego Rosso1 , Mariela Gomez1 , Erica Rojas Bilbao2 ,
Mariana Gil3
1 Hospital de Clí-nicas “José de San Martín” Buenos Aires, Argentina;
2 Instituto de Oncología “Ángel Roffo”, Buenos Aires, Argentina; 3 Nuevo
Hospital “San Roque”, Córdoba, Argentina
Erdheim-Chester Disease (ECD) is a rare non-Langerhans cell Histiocy-
tosis characterized by CD68+ CD1a- histiocytes systemic infiltration
with main involvement of bone tissue and frequent presence of retro-
orbital tumors. At the time of this report, there have been less than
1000 cases described throughout history. We present the case of a
19-year-old patient with no significant medical history, with bilateral
retro-orbital masses that had developed over four years. These lesions
were accompanied by exophthalmos, conjunctival injection, blurred
vision, and ventilatory insufficiency. A biopsy was performed, which
revealed a foamy histiocytic population that was positive for CD68,
and negative for CD1a, CD207, and the BRAF V600E mutation along
with numerous plasmocytes and lymphoid cells. Diagnostic workup
included laboratory testing, imaging studies, and additional tests in
order to rule out IgG4-related diseases and autoimmune disorders
including a biopsy review. MRI showed a right intraorbital solid mass
of 62 x 30 mm that was compressing the eye leading to proptosis and
a 36 x 12 mm mass in the left orbit. PET-CT scan evidenced hyper-
metabolic lesions in the orbits, calcaneum, astragalus, cuboid, shins,
femur, humerus and radius. An Erdheim-Chester disease diagnosis was
made. Since no vital organs were involved, Interferon-a was admin-
istered. After six months, it failed to achieve a response prompting
us to initiate treatment with Cobimetinib given the absence of BRAF
V600E mutation. Within three months of treatment, the patient had
achieved a marked reduction in tumor size and after six months, exoph-
thalmos and conjunctival irritation were unnoticeable. New PET-CT
imaging only showed a residual tumor image in the lower margin of the
right eye cavity and resolution of most of the bone lesions. Of the few
lesions that persisted, both number, size and SUV units had decreased.
The patient tolerated Cobimetinib well, with no relevant adverse
events.
CHIDAMIDE COMBINED WITH ETOPOSIDE AND
GLUCOCORTICOID IN THE HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS
Junxia Hu1 , Zhao Wang2
1 Department of Haematology, Beijing Friendship Hospital, Capital Medical
University, Beijing, China; 2 Department of Haematology, Beijing Friendship
Hospital, Capital Medical University, Beijing, China
Objective: Hemophagocytic lymphohistiocytosis (HLH) is a fatal exces-
sive inflammatory response syndrome that progresses rapidly and has
a high mortality rate. This study prospectively observed the efficacy
and safety of chidamide combined with etoposide and glucocorticoid
in HLH.
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S17 of S64
Methods: At the mid-term assessment, thirteen HLH patients were
enrolled and treated with chidamide combined with etoposide and glu-
cocorticoid. The primary endpoints were overall response rate (ORR)
and safety.
Results: The results showed that five patients achieved complete
response, ten achieved partial response, and the overall response
rate (ORR) reached 76.9%. Three patients had no response. The main
adverse events (AEs) were grade 3/4 hematologic toxicities such as
neutropenia (23%), anemia (61.5%), and thrombocytopenia (53.8%).
Other main non-hematologic AEs were grade 3/4 infection (23%).
One patient developed thromboembolism in both lower limb and pul-
monary blood vessels. No renal toxicity or treatment-related death
occurred.
Conclusion: Chidamide combined with etoposide and glucocorticoid
can improve the treatment response of HLH patients with good tol-
erance to AEs, suggesting this regimen has potential as a possible
new treatment option for HLH patients. (identifier : NCT05137522,
website: Clinical Trials.gov)
LONG-TERM FOLLOW-UP OF PATIENTS WITH PRIMARY
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WHO RECEIVED
TREATMENT WITH EMAPALUMAB, A FULLY HUMAN
ANTI-INTERFERON GAMMA MONOCLONAL ANTIBODY
Michael Jordan1 , Carl Allen2 , Anupama Rao3 , Carmelo Rizzari4 ,
Simone Cesaro5 , Maria Caterina Putti6 , Julian Sevilla7 , Cristina de
Min8*, Maria Ballabio8*, Veronica Asnaghi8*, Anna Stoltenberg9 , Rad-
mila Kanceva8 , Franco Locatelli10
1 Division of Immunobiology Department of Pediatrics Cincinnati Chil-
dren’s Hospital, Cincinnati, OH USA; 2 Department of Pediatrics Section of
Hematology-Oncology, Baylor College of Medicine Texas Children’s Cancer
Center, Houston, TX USA; 3 Department of Haematology, Great Ormond
Street Hospital for Children, London, UK; 4 Department of Paediatrics, Uni-
versity of Milano-Bicocca, IRCCS San Gerardo dei Tintori, Monza, Italy;
5 Ospedale della Donna e del Bambino, U.O.C. Oncoematologia Pediatrica,
Verona, Italy; 6 Clinic of Pediatric Hematology-Oncology, Department of
Biomedical Sciences, University Hospital of Padova, Padova, Italy; 7 Hospital
Universitario Niño Jesús Servicio de Hemato-Oncología Pediátrica, Madrid,
Spain; 8 Sobi, Basel, Switzerland; 9 Sobi, Stockholm, Sweden; 10 Ospedale
Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome,
Italy
*Former Sobi employee
Purpose: Emapalumab, a fully human IgG1 anti-interferon-gamma
monoclonal antibody, binds free and receptor-bound interferon-
gamma neutralizing its biologic activity. Emapalumab has demon-
strated efficacy in patients with primary hemophagocytic lymphohis-
tiocytosis (pHLH) and has a favorable safety profile with no increase
in the risk of adverse events (AEs) with increasing drug exposure prior
to patients undergoing hematopoietic stem cell transplant (HSCT). This
long-term follow-up study aimed to monitor the long-term safety and
efficacy of emapalumab, including during the period after patients
underwent HSCT.
 15455017, 2023, S7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pbc.30714 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [22/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
S18 of S64 ABSTRACTS

Methods: Long-term follow-up study (NCT02069899) of patients with inhibitors included BRAFV600E inhibitors (56%) and MEK inhibitors
pHLH who had received ≥1 dose of emapalumab in a multicenter, (44%). Overall response was 7/9 (78%), with 4/4 (100%) objective
single-arm, open-label phase 2/3 clinical trial were followed for 1 response rate (ORR) for systemic disease. Further, 5/6 (83%) demon-
year after HSCT or last administration of emapalumab in the parent strated reduced or extinguished peripheral BRAFV600E+ fraction by
study (NCT01818492). Treatment with emapalumab could continue the end of combination therapy. Ataxia rating scores were improved
according to the parent study protocol during follow-up, if a favorable in 2/3 (67%) individuals with clinical neurodegeneration. Common
benefit/risk assessment was established. Endpoints included safety, toxicities during treatment included fever, skin rash, arthralgia, and
1-year survival and HSCT outcomes. cytopenia.
Results: Overall, 37/45 patients who participated in the phase 2/3 Conclusion: Combining therapy was well-tolerated and associated
study entered long-term follow-up, with 22 (59.5%) continuing ema- with clinical and molecular improvement in most patients with
palumab treatment. All patients experienced ≥1 AE during follow- highly refractory systemic LCH and LCH-ND. Further prospec-
up, most commonly infections or infestations. Four patients (10.8%) tive multi-center trials are required to optimize this approach,
had study drug-related AEs, including 1 serious AE (Coombs posi- determine potential for combination therapy to achieve cure, and
tive hemolytic anemia). No drug-related deaths were reported. 33 compare risks and benefits to chemotherapy or MAPK inhibitor
(89.2%) survived to undergo HSCT or until 1 year after last ema- monotherapy.
palumab dose (whichever came first). 28/37 (75.7%) patients were
alive at last observation or 1 year after last emapalumab dose.
29 patients (78.4%) underwent HSCT, including 18 during long- BRAFV600E IS ASSOCIATED WITH HIGHER INCIDENCE OF
term follow-up. Engraftment was achieved in 23 patients (79.3%; SECOND CANCERS IN ADULTS WITH LANGERHANS CELL
95% confidence interval, 61.6-90.2%). Primary or secondary graft HISTIOCYTOSIS
failure occurred in 6 (20.7%) patients. Five (17.2%) patients died
post-HSCT. Paul Kemps1 , AldoAcosta-Medina2,3 , Timo Zondag4 , Jithma
Conclusions: The long-term safety and efficacy outcomes for patients Abeykoon3 , Jelske Borst5 , Eline Steenwijk5 , Elizabeth Feijen6 , Jop
with pHLH treated with emapalumab are favorable and consistent with Teepen6 , Nora Bennani3 , Susan Schram3 , Mithun Shah3 , Caroline
observations made during the phase 2/3 study. Davidge-Pitts7 , Matthew Koster8 , Jay Ryu9 , Robert Vassallo9 ,Oliver
Tobin10 , Jason Young11 , Surendra Dasari12 , Karen Rech13 , Aish-
warya Ravindran14 , Arjen Cleven1,15 , Robert Verdijk1,16 , Carel van
COMBINATION CHEMOTHERAPY AND MAPK PATHWAY Noesel17 , Brian Balgobind18 , Gerrit Joan Bouma19, Peerooz Saeed20 ,
INHIBITION IN REFRACTORY AND CEREBELLAR LCH Jos Bramer6,21 , Ruben de Groen22 , Joost Vermaat22 , Michiel van
de Sande6,23 , Egbert Smit24 , Anton Langerak25 , Tom van Wezel1 ,
Vivekanudeep Karri1,2 , Nader El-Mallawany1,2 , Howard Lin1,2 , Har- SanneTonino26 , Cor van den Bos6,27 , Jan van Laar4,28 , Ronald Go3 ,
shal Abhyankar1,2 , Jennifer Agrusa1,2 , Whitney Stanton1,2 , Olive Astrid van Halteren1,4,6 , Gaurav Goyal3,29
Eckstein1,2 , Nitya Gulati1,2 , Carl Allen1,2 , and Kenneth McClain1,2 1 Department of Pathology, Leiden University Medical Center, Leiden, The
1 Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX Netherlands; 2 Department of Internal Medicine, Mayo Clinic, Rochester,
USA; 2 Division of Pediatric Hematology-Oncology, Department of Pedi- MN USA; 3 Division of Hematology, Mayo Clinic, Rochester, MN USA;
atrics, Baylor College of Medicine, Houston, TX USA 4 Department of Internal Medicine, Section Clinical Immunology, Eras-
Purpose: Though MAPK pathway inhibition (MAPKi) is associated mus MC University Medical Center Rotterdam, Rotterdam, The Nether-
with high response rates in patients with Langerhans cell histio- lands; 5 Department of Pediatrics, Leiden University Medical Center, Lei-
cytosis (LCH), monotherapy may not be curative and efficacy in den, The Netherlands; 6 Princess Máxima Center for Pediatric Oncol-
LCH-associated neurodegeneration (LCH-ND) is not known. Based ogy, Utrecht, The Netherlands; 7 Division of Endocrinology, Mayo Clinic,
on upregulation of Bcl-xL by MAPK activation, we hypothesize that Rochester, MN USA; 8 Division of Rheumatology, Mayo Clinic, Rochester,
MAPKi may render LCH cells more sensitive to chemotherapy-induced MN USA; 9 Division of Pulmonary and Critical Care Medicine, Mayo
cytotoxicity. Clinic, Rochester, MN USA; 10 Department of Neurology, Mayo Clinic,
Methods: We assessed the safety and efficacy of combination therapy Rochester, MN USA; 11 Department of Radiology, Mayo Clinic, Jack-
in 9 patients with refractory systemic disease and LCH-ND. Records of sonville, FL USA; 12 Division of Biomedical Statistics and Informatics,
patients treated with combination therapy at Texas Children’s Hospital Department of Quantitative Health Sciences, Mayo Clinic, Rochester,
from October 2018 to April 2023 were reviewed for clinical responses MN USA; 13 Department of Laboratory Medicine and Pathology, Mayo
as well as peripheral blood/tissue BRAFV600E mutation status, ataxia Clinic, Rochester, MN USA; 14 Department of Pathology, University of
rating scores, and toxicity. Alabama at Birmingham, Birmingham, AL USA; 15 Department of Pathol-
Results: The median age at the start of combination therapy was 7.33 ogy, University Medical Center Groningen, Groningen, The Netherlands;
years (range, 2.03-18.37 years) with a median of 4 treatments prior to 16 Department of Pathology, Erasmus MC University Medical Center Rotter-

this therapy regimen (range, 1-14). Almost all Clofarabine was adminis- dam, Rotterdam, The Netherlands; 17 Department of Pathology, Amsterdam
tered outpatient (typical starting dose 25 mg/m2/day x 5 days). MAPK University Medical Centers, Amsterdam, The Netherlands; 18 Department

ABSTRACTS
of Radiation Oncology, Amsterdam University Medical Centers, Amster-
dam, The Netherlands; 19 Department of Neurosurgery, Amsterdam Uni-
versity Medical Centers, Amsterdam, The Netherlands; 20 Orbital Center,
Department of Ophthalmology, Amsterdam University Medical Centers,
Amsterdam, The Netherlands; 21 Department of Orthopedic Surgery and
Sports Medicine, Amsterdam University Medical Centers, Amsterdam, The
Netherlands; 22 Department of Hematology, Leiden University Medical Cen-
ter, Leiden, The Netherlands; 23 Department of Orthopedic Surgery, Leiden
University Medical Center, Leiden, The Netherlands; 24 Department of Pul-
monology, Leiden University Medical Center, Leiden, The Netherlands;
25 Department of Immunology, Laboratory Medical Immunology, Erasmus
MC University Medical Center Rotterdam, Rotterdam, The Netherlands;
26 Department of Hematology, Amsterdam University Medical Centers,
Amsterdam, The Netherlands; 27 Department of Pediatric Oncology, Emma
Children’s Hospital, Amsterdam University Medical Centers, Amsterdam,
The Netherlands; 28 Department of Immunology, Section Clinical Immunol-
ogy, Erasmus MC University Medical Center Rotterdam, Rotterdam, The
Netherlands; 29 Division of Hematology-Oncology, University of Alabama at
Birmingham, Birmingham, AL USA
The discovery of somatic, MAP kinase pathway-activating mutations
established LCH as a clonal hematologic neoplasm.
Purpose: In pediatric LCH, BRAFV600E is detected in 50-60% of
patients and associated with severe disease forms. In adults, the preva-
lence and clinical associations of BRAFV600E remain incompletely
characterized.
Methods: We analyzed data from BRAFV600E genotyped adults
with LCH collected by two research groups. The combined cohort
comprised a balanced distribution of disease phenotypes, including
multi-system (37%), isolated pulmonary (14%) and single-system non-
pulmonary (49%) LCH. Median age at diagnosis was 41 years (range
18-88). Results BRAFV600E was detected in 74/156 cases (47%);
Unlike in pediatric LCH, BRAFV600E did not correlate with age, dis-
ease extent, sites of disease, first-line therapy subtype, event-free
survival or overall survival. These results were supported by our meta-
analysis of published data. However, BRAFV600E did correlate with an
increased incidence of second primary malignancies (SPM; P = .017);
9/18 patients with SPM, presented with second hematologic malignan-
cies (SHM), which were not confined to patients with MS-LCH. While
none of the patients with SHM had received alkylating agents, 4/4 with
secondary AML had received cladribine. Both BRAFV600E positive
and BRAFV600E negative patients had an elevated risk of SHM when
compared to the age-, sex-, and calendar year-matched general popu-
lation of the Netherlands. In two cases, we detected identical genomic
alterations in separate LCH and SHM samples, suggesting a common
clonal origin. In the first case, a SRSF2P95R mutation was identified in
consecutive LCH (VAF 26%) and AML (VAF 49%) samples. In the sec-
ond case, the same IGH rearrangement was found in separate LCH and
DLBCL samples.
Conclusion: These results demonstrate that prospective collection of
samples from adult LCH patients and genomic analysis beyond the
MAP kinase pathway is needed in order to shed more light on molecular
associations between LCH and additional neoplasms.
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VEMURAFENIB MONOTHERAPY IN BRAF-MUTATED MYELOID
SARCOMA
Ayat Khoraizat1 , Jon Bjørn1 , Trine L. Plesner2 , Daniel El Fassi1,3
1 Department of Hematology, Rigshospitalet Copenhagen University Hos-
pital, Copenhagen, Denmark; 2 Department of Pathology, Rigshopitalet
Copenhagen University Hospital, Copenhagen, Denmark; 3 Department of
Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Purpose: To report the efficacy of vemurafenib monotherapy in a
patient with aggressive BRAF-mutated myeloid sarcoma.
Methods: Case report
Results: In 2019, a 70-year-old female was diagnosed with BRAF-
V600E-mutated multisystem Langerhans cell histiocytosis (LCH) with
a classical immunophenotype (CD1a, S-100 and langerin). She had
lesions in the vulva, perineum, os ilium and the pituitary gland. Vin-
blastine and prednisolone induced remission at the expense of inten-
sive care unit-requiring infection. Biopsy-verified relapse of genital
LCH-lesions mandated radiotherapy in 2022. Two months after end-
of-therapy a single nodule emerged on the patient’s arm. Within a
week multiple aggressively-looking violaceus skin lesions appeared,
and she experienced high-spiking fever and night sweats. She was
anemic, slightly thrombocytopenic, and lactatedehydrogenase and uric
acid levels were markedly elevated (1680 (N:115-255) U/L and 0.78
(N:0.16-0.40) mmol/L, respectively). A skin biopsy was positive for
CD68, CD163 and CD56, and partly-positive for MPO. All LCH mark-
ers as well as CD34, CD4, CD14, CD20, CD23, CD117 and CD123
stained negative. The Ki67 index was around 100%. A bone marrow
analysis revealed few CD56 and CD68 positive cells along with <1%
CD34 positive blasts. But she displayed a highly abnormal karyotype
(49 XX+8+8+8). The BRAF-V600E mutation was verified in skin, bone-
marrow and peripheral blood. A PET-CT showed dispersed uptake in
skin, lymphnodes and bone. Based upon these findings the diagnosis
of a BRAF-mutated myeloid sarcoma was made. Monotherapy with the
BRAF-inhibitor vemurafenib was initiated. By day 5 the skin lesions had
noticeably faded and the patients lactatedehydrogenase level was 414
U/L. PET-CT changes were greatly improved by day 32. Unfortunately,
the patient succumbed to a severe infection by day 35.
Conclusion: We describe a marked response to vemurafenib
monotherapy in aggressive systemic BRAF-mutated myeloid sar-
coma in a patient with previous multisystem LCH. Clonality analysis
between the initial and later lesions is being planned.
COMPREHENSIVE GENETIC ANALYSIS OF MAPK PATHWAY
MUTATIONS AND THEIR CLINICAL IMPLICATIONS IN KOREAN
LANGERHANS CELL HISTIOCYTOSIS PATIENTS
Kyung-Nam Koh, Su Hyun Yoon, Ji Young Kim, Sung Han Kang, Seo
Yeon Kim, Hyery Kim, Ho Joon Im
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan
Medical Center Children’s Hospital, University of Ulsan College of Medicine,
Seoul, South Korea

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Purpose: This study aimed to conduct comprehensive genetic
analysis of Langerhans cell histiocytosis (LCH) patients, focus-
ing on the frequency of MAPK pathway mutations, detailed
mutation profiles of BRAF and MAP2K1 genes, and their correla-
tion with clinical features and prognosis in Korean patients with
LCH.
Methods: Targeted next-generation sequencing was performed
on genomic DNA extracted from formaldehyde-fixed and paraffin-
embedded samples of 45 pathologically confirmed LCH patients at
Asan Medical Center. OncoPanel version 2 was used to capture exons
of 550 cancer-related genes.
Results: The majority of patients exhibited single system (SS) disease
(91.1%), with bone being the most common location (84.4%). Initial
treatment varied, and no patients died during a median follow-up of
81.9 months. OncoPanel assay revealed all patients had MAPK path-
way alterations, including 51.2% with BRAF mutations, 42.2% with
MAP2K1 mutations, 4.4% with RAF1 mutations, and 2.2% with KRAS
mutation. Mutations were mutually exclusive. Detailed mutation pro-
files showed that among BRAF mutations, 18 were point mutations
and 5 were in-frame deletions, while most MAP2K1 mutations were in-
frame deletions, with only 1 having a missense mutation. No significant
differences in clinical presentation between BRAF and MAP2K1 muta-
tion groups were found. However, some differences between BRAF
V600E and non-V600E mutants were observed. Patients with BRAF
mutations were significantly younger than those with MAP2K1 muta-
tion, and genetic mutations were not associated with high-risk features
and relapse-free survival.
Conclusions: Comprehensive genetic analysis detected mutually exclu-
sive MAPK pathway mutations in all LCH patients, including detailed
mutation profiles of BRAF and MAP2K1 genes, as well as rare muta-
tions in the MAPK pathway. These genetic mutations did not predict
the severity of the disease.
PROGNOSTIC SCORING SYSTEM FOR PEDIATRIC
EPSTEIN-BARR VIRUS INFECTION-ASSOCIATED
HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS BASED ON
BASELINE CHARACTERISTICS: A MULTICENTRIC
RETROSPECTIVE STUDY
Qi Kong1*, Min Li2*, Jingshi Wang1 , Lin Wu1 , Dunhua Zhou3 , Minghua
Yang4 , Xiaojun Xu5 , Zhen Tan6 , Xiaoyan Wub , Zhao Wanga
1 Department of Hematology, Beijing Friendship Hospital, Capital Medical
University, Beijing, China; 2 Clinical Epidemiology and EBM Center, National
Clinical Research Center for Digestive Diseases, Beijing Friendship Hospi-
tal, Capital Medical University, Beijing, China; 3 Children’s Medical Center,
Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China;
4 Department of Pediatrics, Third Xiangya Hospital, Central South Univer-
sity, Changsha, Hunan, China; 5 Department of Hematology-Oncology, The
Children’s Hospital of Zhejiang University School of Medicine, Hangzhou,
China; 6 Department of Pediatric Hematology-Oncology, Xinhua Hospital
affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai,
China
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ABSTRACTS
aCorresponding author: Zhao Wang, Department of Hematology, Beijing
Friendship Hospital, Capital Medical University, Beijing, China
bXiaoyan Wu, Department of Pediatrics, Union Hospital, Tongji Medical
College, Huazhong University of Science and Technology, Wuhan, China
Purpose: Pediatric Epstein-Barr virus infection-associated
haemophagocytic lymphohistiocytosis (EBV-HLH) varies in prog-
nosis, but the prognostic scoring system remains vacant. We aimed to
identify high-risk children early and improve their prognosis.
Methods: We analyzed 264 children (0-14 years old) diagnosed with
EBV-HLH from 7 centers in China between January 2015 and Decem-
ber 2018. They were randomly divided into a derivation cohort (185
cases) and a verification cohort (79 cases). Baseline variables asso-
ciated with overall survival (OS) were evaluated by univariate and
multivariate Cox models among patients in the derivation cohort to
identify independent prognostic factors and establish a prognostic
scoring system.
Results: Chronic active Epstein-Barr virus infection (CAEBV) history
(HR 1.82, 95%CI 1.02-3.26, P=0.04), EBV-DNA in plasma > 104 copies
/ml (HR 2.89, 95%CI 1.62-5.16, P < 0.01), pulmonary infection (HR
2.24, 95%CI 1.06-4.75, P=0.04), hemorrhage of digestive tract (HR
2.55, 95%CI 1.35-4.82, P < 0.01) and hypoxemia (HR 3.95, 95%CI
2.15-7.26, P < 0.01) were independent risk factors. Accordingly, we
established the CAEBV history-EBV-DNA copies in plasma-pulmonary
infection-hemorrhage of digestive tract-hypoxemia prognostic scor-
ing system (CEPHO-PSS), which separated patients into a low-risk
group (0-1 points), a middle-risk group (2-3 points) and a high-risk
group (4-8 points). The survival curves of the three groups demon-
strated statistically significant differences (P < 0.0001). Internal and
external verification of the CEPHO-PSS were conducted by receiver
operating characteristic (ROC) curves and calibration curves in the
derivation cohort and verification cohort, respectively, confirming
good accuracy and applicability. The Mortality of patients between
the hematopoietic-stem-cell-transplantation (HSCT) group and the
non-HSCT group in different risk stratifications from the CEPHO-
PSS were compared and presented that patients of the high-risk
group potentially benefited from allogeneic hematopoietic stem cell
transplantation (allo-HSCT) (HR 0.32, 95%CI 0.13-0.8, P<0.05).
Conclusion: The CEPHO-PSS is clinically practical, and may
optimize individual therapy and improve prognosis of pediatric
EBV-HLH.
EFFICACY OF RAPID LEISHMANIA DETECTION BY PCR IN THE
ETIOLOGICAL DIAGNOSIS OF HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS
Qi Kong, Lin Wu, Junxia Hu, Jingshi Wang, Zhao Wang
Department of Hematology, Beijing Friendship Hospital, Capital Medical
University, Beijing, China
Purpose: Visceral leishmaniasis (VL), as a rare cause of hemophagocytic
lymphohistiocytosis (HLH), is easily misdiagnosed or missed, result-
ing in unnecessary treatment. We aimed to facilitate the early and
accurate diagnosis of patients with VL-HLH.

ABSTRACTS
Methods: Retrospectivly collected the clinical records of 9 patients
with VL-HLH admitted in Beijing Friendship hospital from January
2018 to December 2021.
Results: PCR detection was positive in all of the 9 (100%) patients,
while bone marrow morphological examination and serological anti-
body detection showed negative results in 2(22%) and 3 (33%) patients,
respectively. All of the 9 patients (100%) avoided chemotherapy and
achieved complete remission(CR).
Conclusion: Early diagnosis of VL-HLH is vital for patients to avoid
inappropriate and pernicious medicines. PCR has relative high sensitiv-
ity and specificity in the detection of Leishmania and is recommended
for the early diagnosis of VL-HLH.
INDOMETHACIN TREATMENT MODIFY THE EXPRESSION OF
CCR1, CXCR4, AXL, AND RANK AT DIFFERENT STAGES OF
IN-VITRO DIFFERENTIATION OF DENDRITIC CELLS
María Catalina Lava1 , Denise Mariel Risnik1 , Cinthia Mariel Olexen1,2 ,
Diego Alfredo Rosso3 , Eugenio Antonio Carrera Silva2 , Andrea Emilse
Errasti1
1 Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos
Aires, Buenos Aires, Argentina; 2 Instituto de Medicina Experimental, IMEX-
CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina;
3 Hospital de Clínicas General San Martín, Facultad de Medicina, Universi-
dad de Buenos Aires, Buenos Aires, Argentina
Purpose: Indomethacin, a non-selective COX inhibitor (NSAID) is
effective in the treatment of bone LCH. Nevertheless, the specific
mechanism of action involved in this therapeutic benefit is not defined.
We hypothesized that Indomethacin restrain the homing and migra-
tion of Langerhans cells and/or their precursors to the bone. To test
this hypothesis, we analyze the expression of homing receptors CCR1,
CXCR4, AXL and RANK in monocytes and dendritic cells (DC) under
indomethacin treatment. To determine if this effect is extended to
another NSAID, we compare it with Ibuprofen.
Methods: CD14+ monocytes from Peripheral Blood Mononuclear cells
of healthy volunteers were used as precursor cells, and conventional
DC (GM-CSF + IL-4) and inflammatory Langerhans like cells “LC-like”
(IL-4 + GM-CSF + TNFα + TGFβ + dexamethasone) were in-vitro dif-
ferentiated from the monocytes. The treatment was performed with
100uM of Indomethacin or Ibuprofen or vehicle. qPCR and flow cytom-
etry assays were performed to evaluate their effect on gene expression
and proteins, respectively.
Results: Indomethacin significantly reduced RNA expression of RANK
(N=6, P=0.0156), AXL (N=6, P=0.031) and CCR1 (N=8, P= 0.007)
in conventional DC. AXL was reduced in both conventional DC and
“LC-like” cells confirmed by qPCR and flow cytometry. Treatment of
monocytes with Indomethacin reduced the expression of AXL (N=9,
P=0.004) and CXCR4 (N=6, P=0.031), measured by flow cytometry.
By the contrary, RNA expression of RANK was upregulated (N=9,
P=0.0039) when monocytes were treated with Indomethacin. On the
other hand, when conventional DC were treated with Ibuprofen it also
showed a reduction in the RNA expression of CCR1 (N=4, P=0.062)
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S21 of S64
and RANK (N=4, P=0.062). Monocyte treatment with ibuprofen do
not modify AXL expression, but significantly reduces CXCR4 levels
measured by flow cytometry (N=6, P=0.031).
Conclusions: Indomethacin affects cell migration molecules on DC and
their precursors, with some specific differences when compared with
Ibuprofen.
CHARACTERISTICS AND OUTCOMES OF MALIGNANT AND
NON-MALIGNANT CAUSES OF ADULT HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS (HLH): A SINGLE CENTER
RETROSPECTIVE STUDY
Jerry Lee, Aaron Logan
University of California, San Francisco, CA USA
Purpose: to describe the patient characteristics, practice patterns, and
outcomes of patients with adult HLH at the University of California,
San Francisco (UCSF).
Methods: single center retrospective study enrolling patients >18
years old with HLH between 3/2016 and 3/2023. Patients must
meet >five of the HLH-2004 diagnostic criteria and have received
some HLH-directed therapy to be eligible. Minimum follow-up was
3 months. IEC-HS was excluded. Survival outcomes are estimated by
Kaplan-Meier and compared using logrank tests.
Results: there were 42 patients overall (23 mHLH, 19 nmHLH). Of the
mHLH cases, 44% were due to T/NK cell lymphomas; 52% were B cell
lymphomas including 26% Hodgkin. Of the nmHLH cases, most were
due to infection (47%); some were idiopathic (26%) or familial (16%).
Almost all presented with fever, cytopenias, hyperferritinemia, and ele-
vated interleukin-2. 79% of the time, HLH94 was incorporated in the
induction regimen; the remaining utilized steroids and/or chemother-
apy. Only 4 cases proceeded to allogeneic transplantation. Relapse
rates were high, with median RFS being 37 days (23 v 47 days for mHLH
and nmHLH, respectively); median OS was 96 days (86 v 149 days).
RFS/OS was not statistically different between mHLH and nmHLH. Age
was a significant predictor of OS but not RFS. 13 patients were alive at
the time of last follow-up (6 mHLH, 7 nmHLH).
Conclusion: This study serves as the foundation for larger cohort
studies anticipated for University of California medical centers, and
will guide an upcoming investigator-initiated trial for frontline adult
HLH. Poor survival and high relapse rates for both mHLH and
nmHLH emphasize the need for therapeutic advances and further
research.
PRE-THERAPY BRAFV600E+ IN PERIPHERAL BLOOD
IDENTIFIES A NOVEL RISK GROUP IN LANGERHANS CELL
HISTIOCYTOSIS
Howard Lin1,2 , Harshal Abhyankar1 , Vivekanudeep Karri1 ,
Deevyashali Parekh1 , Daniel Zinn1 , Brooks Scull1 , Nader El-
Mallawany1 , Olive Eckstein1 , Nitya Gulati1 , Donald Parsons1,2 ,
Kenneth McClain1 , Carl Allen1,2

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1 Texas Children’s Hospital, Houston, TX USA; 2 Baylor College of Medicine,
Houston, TX USA
Purpose: Langerhans Cell Histiocytosis (LCH) is a myeloprolifera-
tive neoplasia driven by somatic mutations in the mitogen-activated
protein kinases pathway (MAPK). LCH is clinically staged as “high
risk” (e.g. liver, spleen and/or bone marrow involvement, HR) or “low
risk” (LR) due to risk of death. However, defining clinical risk status
may be variable between sites due to differences in imaging tech-
niques or inconsistent histologic protocols. We previously reported
that BRAFV600E+ peripheral blood mononuclear cells (PBMC) were
universally identified in HR LCH and in some cases of multifocal LR
LCH. To determine the clinical significance of BRAFV600E+ PBMC at
diagnosis, we analyzed an extended cohort with longitudinal clinical
evaluations.
Methods: Genomic DNA was isolated from 394 lesion biopsies and
the PBMCs of 332 patients with active LCH before initial therapy. The
percentage of PBMC with the BRAFV600E allele in patients was deter-
mined by quantitative polymerase chain reaction and clinical results
were analyzed from medical records.
Results: Lesion genotypes were 51.9% BRAFV600E and 49.1% not
BRAFV600E. BRAFV600E in LCH lesions was associated with lower
age at diagnosis and higher prevalence of HR disease. However, there
was no difference in EFS between BRAFV600E and alternative muta-
tions (p=0.35). Notably, for the entire cohort, presence of BRAFV600E
in diagnostic PBMC was associated with younger patients, HR dis-
ease and risk of LCH-ND. For PBMC from patients with BRAFV600E+
lesions, 32.5% had detectable BRAFV600E: 100% of HR, 52.6% of mul-
tisystem LR, 18.4% of multi-focal single system LR and 0% of single
lesion. Further, clinical LR PBMC BRAFV600E+ represented a group
at higher risk of treatment failure compared to BRAFV600E-neg LR
(p=0.01).
Conclusion: Results from this study support the potential for pre-
therapy PBMC BRAFV600E to predict clinical risks, inform pathogenic
mechanisms in LCH, and identify LR PBMC BRAFV600E+ as a novel
clinical risk factor.
RETROSPECTIVE ANALYSIS OF CLOFARABINE SALVAGE
THERAPY IN REFRACTORY MULTIFOCAL LANGERHANS CELL
HISTIOCYTOSIS (LCH)
Howard Lin1,2 , Deevyashali Parekh1 , Vivekanudeep Karri1 , Whitney
Stanton1 , Nitya Gulati1 , Jennifer Agrusa1 , Nader El-Mallawany1 , Olive
Eckstein1 , Donald Parsons1,2 , Kenneth McClain1 , Carl Allen1,2
1 Texas Children’s Hospital, Houston, TX USA; 2 Baylor College of Medicine,
Houston, TX USA
Purpose: LCH is a neoplastic inflammatory disorder driven by recur-
rent somatic mutations in the MAPK pathway in myeloid precursors.
Over 50% of patients with systemic LCH are not cured with front-line
therapies and data to guide salvage options are limited. In this study, we
describe 58 patients with relapsed/refractory LCH who were treated
with clofarabine.
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ABSTRACTS
Methods: Data were extracted from clinical records of patients treated
with clofarabine for LCH by Texas Children’s Hospital physicians or
collaborators between May 2011 and 2023.
Results: Patients were treated with a median of two chemotherapeutic
regimens prior to receiving clofarabine; median age was 3.49 (4 months
to 61 years). The typical treatment course was 25mg/m2 daily for 5
consecutive days per month; 19%(11/58) received treatment for less
than 6 months; 26%(15/58) for 6-9 months; and 55%(32/58) for 9-24
months. OS in this cohort was 100%(58/58) and PFS was 75% with
median 2-year follow-up (range: 5 months to 11 years); The objective
response rate (ORR) for all patients was 84% with 9%(5/58) main-
taining stable disease and 7%(4/58) developing progressive disease
during the study period. Patients treated for LCH-associated neurode-
generation had relatively worse outcomes (ORR: 63%) compared to
patients with systemic disease without LCH-ND (ORR: 88%). Patients
treated with clofarabine showed a significant decrease in the amount
of detectable BRAFV600E alleles in their circulating peripheral blood
mononuclear cells. Toxicities included cytopenia, severe vomiting, and
bacterial infections, but the majority tolerated chemotherapy in the
outpatient setting.
Conclusion: Clofarabine monotherapy has activity against LCH in
heavily pretreated patients, the majority of whom achieved durable
remission. Prospective multi-center trials are warranted to determine
long-term efficacy, optimal dosing, and late toxicities of clofarabine and
relative cost and patient reported outcomes compared to alternatives
(e.g. MAPK inhibitors) in patients with relapsed/refractory LCH.
COMBINING VEMURAFENIB AND CHEMOTHERAPY FOR
HIGH-RISK PEDIATRIC LCH - A 5 YEARS PERSPECTIVE
Evelina Lyudovskikh1 , Daria Osipova1 , Irina Kalinina1 , Elena Raykina1 ,
Dina Baidildina1 , Alexander Popov1 , Vladimir Zhogov1 , Alexan-
dra Semchenkova1 , Natalia Kotskaya1 , Ekaterina Cherniak1 , Kirill
Voronin1 , Eugeny Burtsev2 , Gleb Bronin2 , Irina Vlasova2 , Bazarma
Purbueva3 , Olesya Fink3 , Ekaterina Pristanskova3 , Irina Dzhukaeva4 ,
Elena Erega4 , Dmitry Evseev1 , Alexey Maschan1 , Mikhail Maschan1
1 Dmitriy Rogachev National Center for Pediatric Hematology, Oncology
and Immunology, Moscow, Russian Federation; 2 Morozov Children Hospital,
Moscow, Russian Federation; 3 Pirogov Russian Clinical Children Hospital,
Moscow, Russia, Moscow, Russian Federation; 4 Piotrovich Regional Clinical
Children Hospital, Khabarovsk, Khabarovsk, Russian Federation
Purpose: To present updated results of a study on the safety and effi-
cacy of a combination of vemurafenib and chemotherapy in patients
with high-risk Langerhans cell histiocytosis (LCH).
Methods: Twenty-seven patients (15 boys, 12 girls) with BRAF V600E
positive LCH were enrolled from 2018 to 2023. Eighteen patients
with RO+ LCH and 9 patients with RO- LCH were included. Ther-
apy was administered as 1st line in 7, 2nd line in 8, and 3rd and
further - in 12 patients. The treatment regimen consisted of vemu-
rafenib (20 mg/kg/day), cytarabine (Ara-C, 100 mg/m2/12 h, days
1-5), and cladribine (2-CdA, 6 mg/m2/day, days 1-5). Vemurafenib was

ABSTRACTS
used as induction therapy, and 3 courses of Ara-C + 2-CdA followed
after. After that, vemurafenib therapy was stopped. Three courses of
mono 2-CdA therapy were used as maintenance. Minimal residual dis-
ease was monitored by detecting BRAF V600E allelic load in cell-free
DNA in peripheral blood and bone marrow-derived myeloid precursors
(CD34+CD19-) by digital droplet PCR.
Results: All patients except one completed the protocol. At a median
follow-up of 24 months from vemurafenib cessation (range 4.1 - 54
months), the event-free survival was 82 percent (95% Cl 66-100%) in
RO+ and 89% (95% Cl 71-100%) in RO- group. Four patients relapsed
(1 - skin, 2 - bones, 1 - RO). The median time to relapse was 3 months
(range 1 - 8 months). All relapsed patients restarted vemurafenib ther-
apy with a full response. One patient experienced MDS a year after
the cessation of therapy. Apart from that and the common hematologi-
cal toxicity, no Grade 3 or 4 toxicities (CTCAE 5.0) were observed. The
allelic load decreased during the treatment while persisting after the
treatment cessation for months in several cases.
Conclusion: Vemurafenib and Ara-C + 2-CdA combination is safe and
ensures unmaintained remission in an extended cohort.
TRANSAMINASE ACTIVITY IN ADULT HLH PATIENTS -
ANALYSIS FROM THE PALG HLH IN ADULTS DATABASE
Rafal Machowicz1*, Magdalena Witkowska2 , Agnieszka Piekarska3 ,
Piotr Boguradzki1 , Bozena Katarzyna Budziszewska4 , Malgorzata
Razny5 , Wanda Knopinska-Posluszny6 , Edyta Cichocka7 , Wojciech
Sydor8 , Joanna Drozd-Sokolowska1 , Szymon Fornagiel9 , Bartosz
Garus10 , Patrycja Mensah-Glanowska11 , Mateusz Wilk11 , Krzysztof
Madry1 , Renata Guzicka-Kazimierczak12 , Slawomir Rejowski13 ,
Judyta Strzała Gdańsk3 , Patrycja Zielinska14 , Karolina Chromik14 ,
Monika Joks15 , Jagoda Tryc-Szponder15 , Dorota Zdunczyk1 , Adam
Hajduk16 , Marta Sobas17 , Lukasz Bolkun18 , Marta Libura1 , Katarzyna
Brzezniakiewicz-Janus19 , Justyna Gil20 , Malgorzata Paszkowska-
Kowalewska1 , Agata Malenda21 , Mateusz Ziarkiewicz1 , Katarzyna
Popko22 , Wieslaw Wiktor-Jedrzejczak1 , Grzegorz Basak1
1 Department of Hematology, Transplantation and Internal Medicine, Med-
ical University of Warsaw, Warsaw, Poland; 2 Department of Experimental
Hematology, Medical University of Lodz, Poland; 3 Department of Hematol-
ogy and Transplantology, Medical University of Gdansk, Gdansk, Poland;
4 Department of Hematology, Institute of Hematology and Transfusion
Medicine, Warsaw, Poland; 5 Department of Hematology, Rydygier Spe-
cialistic Hospital, Krakow, Poland; 6 Hematology Department, Independent
Public Health Care Ministry of the Interior of Warmia and Mazury Oncol-
ogy Center, Olsztyn, Poland; 7 Nicolaus Copernicus General Hospital. Toruń,
Poland; 8 The Second Chair and Department of Internal Medicine, Collegium
Medicum, Jagiellonian University, Kraków, Poland; 9 Department of Hema-
tology, Jędrzej Åšniadecki Hospital in Nowy Sacz, Poland; 10 Department
of Hematology, Holycross Cancer Center, Kielce, Poland; 11 Department of
Hematology, Collegium Medicum, Jagiellonian University, Krakow, Poland;
12 Department of Hematology, Pomeranian Medical University, Szczecin,
Poland; 13 Department of Hepatology and Internal Medicine, Medical Uni-
versity of Warsaw, Warsaw, Poland; 14 Department of Hematology and Bone
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S23 of S64
Marrow Transplantation, Medical University of Silesia, Katowice, Poland;
15 Department of Hematology and Bone Marrow Transplantation, Poznan
University of Medical Sciences, Poznań, Poland; 16 Department of Internal
Medicine, Connective Tissue Diseases and Geriatrics, Medical University of
Gdansk, Gdansk, Poland; 17 Department of Hematology, Blood Neoplasms
and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw,
Poland; 18 Department of Hematology, Medical University of Bialystok,
Bialystok, Poland; 19 Department of Hematology, Multi-Specialist Hospital,
University of Zielona Gora, Gorzów Wielkopolski, Poland; 20 Department
of Hematology, Markiewicz Memorial Oncology Center Brzozow, Brzo-
zow, Poland; 21 John Paul II Western Hospital in Grodzisk Mazowiecki,
Poland; 22 Department of Laboratory Medicine and Clinical Immunology of
Developmental Age, Medical University of Warsaw, Warsaw, Poland
Purpose: Elevated transaminase activity is one of the characteristic
findings in HLH (hemophagocytic lymphohistiocytosis; hemophago-
cytic syndrome). The aim of this study was to analyze transaminase
activity in adult HLH patients in the context of different triggering
factors, and their effect on survival.
Methods: Data of 120 adult patients from the HLH Database affili-
ated with PALG (Polish Adult Leukemia Group) were analyzed. Non-
parametric tests were used, a p-value <0.05 was considered significant
Results: The majority of patients had elevated transaminase activity
(83,3% AST, 77,5% ALT). AST activity (mean 421 IU/l, median 129 IU/l
IQR: 58-307) was higher than ALT (mean 273 IU/l, median 93 IU/l IQR:
44-180; p=0.017). An AST/ALT ratio (de Ritis ratio) was thus above 1
in 72% of patients: mean 1.76 median 1.55, IQR (0,86-2,27). A very
high correlation between AST and ALT was observed: correlation coef-
ficient r=0.988, p<0.0001. Patients with HLH triggered by malignancy
(n=59) had higher transaminase activities as compared to the rest of
the patients: AST 107 IU/l vs 184 IU/l, p=0.011; ALT 75 IU/l vs 123 IU/l,
p=0.006. Comparing the survival of patients below and above median
activity for AST, as well as ALT, did not reveal any difference. Looking for
the optimal cutoff for survival shown that patients with ALT below 62
IU/l and patients with AST below 203 IU/l had worse survival rates than
ones with values above those thresholds, respectively: HR 0.45 (0.28-
0.72) p=0.00075 and 0.55 (0.32-0.94) p=0.026. De Ritis ratio above 1
or above 2 did not have any influence on survival.
Conclusion: While elevated transaminase activity is a common feature
of HLH, this effect may additionally be modified by the triggering factor.
Elevated transaminase activity is not a good candidate for a prognostic
factor in adult HLH.
A PHASE 1B STUDY OF ELA026, A MONOCLONAL ANTIBODY
TARGETING SIGNAL REGULATORY PROTEIN-α/β1/γ IN
PATIENTS WITH NEWLY DIAGNOSED AND PREVIOUSLY
TREATED SECONDARY HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS
Abishek Maiti1 , Naval Daver1 , Swaminathan Iyer1 , David McCall1 ,
Satyen Gohil2 , Javier Lopez Jimenez3 , Hayley Lane4 , Benjamin Kim4 ,
Kim-Hien Dao4 , Gary Patou4 , Sandip Panicker4 , Kelly Covert4 , Graham
Parry4 , Carl Allen5

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1 University of Texas MD Anderson Cancer Center, Houston, TX USA;
2 University College London Hospitals NHS Foundation Trust, London, UK;
3 Hospital Ramon y Cajal, Madrid, Spain; 4 Electra Therapeutics Inc., South
San Francisco, CA USA; 5 Baylor College of Medicine, Texas Children’s
Hospital, Houston, TX USA
Purpose: ELA026 is under investigation in secondary hemophagocytic
lymphohistiocytosis (sHLH), a life-threatening hyperinflammatory con-
dition that is most often triggered by malignancy, autoimmune dis-
orders, and infectious diseases. There are no approved therapies in
sHLH and current treatment approaches are suboptimal; for exam-
ple, in adult patients with malignancy-associated HLH (mHLH), median
survival is approximately 2 months (Lee et al. 2023). ELA026 is a
monoclonal antibody against signal regulatory protein-α/β1/γ and is
intended to target the activated myeloid and T cells that drive sHLH.
Methods: This is an open-label, single arm, Phase 1B multicenter global
study to evaluate the safety, efficacy, pharmacokinetics, and pharmaco-
dynamics of ELA026 in newly diagnosed and previously treated sHLH
patients, initially 12 years or older (in select countries including the
US, 6 years or older). In Cohort 1, an intra-patient dose escalation
of ELA026 occurs if there are suboptimal biomarker responses in the
absence of a dose limiting toxicity (DLT). Response is evaluated as
described in Locatelli et al. 2020.
Results: Six mHLH patients enrolled in Cohort 1 with median age of
50 years (range 21-67). Three patients were refractory to etoposide-
based therapies and/or anti-cytokine therapies. No DLTs or study
drug-related serious adverse events occurred. Five patients were
deemed evaluable for efficacy based on >1 week of ELA026 expo-
sure (efficacy assessment is pending). All 5 of these patients received
chemotherapy for their malignancies. As of June 27, 2023, 3 patients
are alive and 2 patients have died from complications of malignancy
(median overall survival not reached). Three patients who had peri-
ods of ELA026 monotherapy displayed early progressive monocyte and
lymphocyte reduction with associated changes in C-reactive protein
and other sHLH-associated biomarkers.
Conclusion: Preliminary data suggest ELA026 is well tolerated and
induces early biomarker changes in sHLH patients that warrant further
clinical investigation.
RESPONSE TO TOCILIZUMAB THERAPY IN A PATIENT WITH H
SYNDROME
Sara Makkeyah1 , Reem El-Mazloum1 , Nesrine Radwan2 , Seham
Gohar3
1 Pediatric Hematology-Oncology and Bone Marrow Transplant Unit, Fac-
ulty of Medicine, Ain Shams University, Cairo, Egypt; 2 Pediatric Allergy,
Immunology and Rheumatology Unit, Faculty of Medicine, Ain Shams
University, Cairo, Egypt; 3 Pediatric Hematology Oncology Department,
Children’s Cancer Hospital, Cairo, Egypt
Purpose: H syndrome, also known as histiocytosis-lymphadenopathy-
plus syndrome, and familial Rosai Dorfman disease, is a rare form of his-
tiocytoses characterized by cutaneous hyperpigmentation, induration,
and hypertrichosis with numerous systemic manifestations. Autoin-
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ABSTRACTS
flammation is increasingly recognized in this syndrome. The use of
tocilizumab, a humanized monoclonal anti-human IL-6 receptor (IL-6R)
antibody has been recently reported in a number of cases. We report
a case of genetically proven H syndrome with homozygous SLC29A3
mutation treated with tocilizumab therapy.
Case Presentation: A thirteen-year-old girl presented with fever,
lymphadenopathy, and hepatosplenomegaly. She had features of scle-
rodermatous hyperpigmented skin, hypertrichosis, insulin-dependent
diabetes mellitus, short stature, bilateral sensorineural hearing loss,
and arthritis with flexion deformities involving metacarpal and
metatarsal joints. She also had bilateral peroneal neuropathy and
concentric left ventricular (LV) hypertrophy, both features have not
been previously described in H syndrome. Her laboratory investiga-
tions showed normocytic normochromic anemia, hypoalbuminemia,
elevated C-reactive protein (CRP) and erythrocyte sedimentation rate
(ESR), and a high serum interleukin-6 (IL-6). Biopsy from the inguinal
lymph node was consistent with Rosai-Dorfman disease. Therapy
with tocilizumab was initiated at a dose of 10 mg/Kg intravenously
every 2 weeks. All inflammatory manifestations including fever, lym-
phadenopathy, and hepatosplenomegaly showed rapid response and
resolution. After a period of six months, the girl had marked improve-
ment in skin pigmentation, induration, and hypertrichosis. She also had
a resolution of her LV hypertrophy and improvement of peripheral
neuropathy. However, the impact on arthritis was not prominent.
Conclusion: Tocilizumab appears to improve the autoinflammatory
manifestations, skin changes, and lymphadenopathy in H syndrome
through the blockade of IL-6. However, the neutral effect on some
other systemic manifestations warrants more research into the
pathophysiology of this genetic disease to help tailor more specific
therapy.
RACIAL DIFFERENCES IN DIAGNOSIS AND CLINICAL COURSE
IN ADULTS AND CHILDREN WITH HISTIOCYTIC NEOPLASMS
Priya Marathe, Anne Reiner, Maria Luisa Sulis, Ira Dunkel, Christopher
Forlenza, Joshua Budhu, Raajit Rampal, Eli Diamond
Memorial Sloan Kettering Cancer Center, New York, NY USA
Purpose: Histiocytic neoplasms are diverse disorders with hetero-
geneous clinical phenotypes; there has been little investigation of
differences in diagnosis or clinical trajectory with respect to race. We
analyzed our adult and pediatric cohorts of patients with histiocytic
neoplasms to identify differences by race and thus identify vulnerable
populations.
Methods: This is a retrospective study of adult and pediatric patients
with biopsy-confirmed histiocytic neoplasms including Erdheim-
Chester Disease (ECD), Langerhans Cell Histiocytosis (LCH), and
Rosai-Dorfman Disease (RDD). Demographic characteristics including
age, sex, and race were gleaned from the medical record. Clinical char-
acteristics included diagnosis, time between presentation, diagnosis,
and initiation of therapy, and tumor mutations. White patients were
compared to non-White patients with respect to clinical variables to
reach statistically significant conclusions.

ABSTRACTS
Results: 402 patients (288 adults and 114 children) were included in
the analysis. 328 were White and 74 were non-White. 78 had a diagno-
sis of ECD, 222 had LCH, and 47 had RDD. In the overall cohort, there
were trend-level differences between White and non-White patients
in time from diagnosis to first treatment (0.47 years versus 0.81;
p=0.09) and BRAFV600E versus other mutations (p=0.079). Adult
and pediatric non-White patients were diagnosed younger than White
patients (38 years versus 49; p=0.005 for adults and 0.9 years versus
5.2; p=0.05 for pediatrics). A significantly higher percentage of White
patients had a diagnosis of ECD (23% versus 5.4%; p<0.001) while a
higher percentage of non-White patients had RDD (30% versus 7.6%;
p<0.001).
Conclusion: White and non-White adults differ with respect to his-
tiocytic neoplasm diagnosis. Non-White adults and children may be
diagnosed at a younger age and may have more time elapse between
diagnosis and first treatment. Driver mutations may vary by race,
although additional data is needed. More data from diverse set-
tings will allow for further granulation by race in this important
investigation.
A+A2:K5 TOOL FOR PREDICTING PATHOGENICITY OF
VARIANTS OF UNKNOWN SIGNIFICANCE IN FAMILIAL HLH
GENES
Lauren Meyer1 , Ritu Roy2 , Erica Steen3 , Benjamin Huang2 , Adam
Olshen2 , Kim Nichols4
1 University of Washington, Seattle, WA USA; 2 University of Cal-
ifornia, San Francisco, CA USA; 3 University of California, San
Diego, CA USA; 4 St. Jude Children’s Research Hospital, Memphis,
TN USA
Purpose: Diagnosing familial hemophagocytic lymphohistiocytosis
(FHLH) requires identifying biallelic loss-of-function (LOF) muta-
tions in a disease-associated gene. However, sequencing commonly
identifies variants of unknown significance (VUS) that complicate
clinical decision making. To address this critical gap, we developed
a tool to predict the pathogenicity of missense variants in FHLH
genes.
Methods: We first constructed a training dataset of 707 pathogenic
and 304 benign missense variants from 46 genes underlying non-
FHLH primary immunodeficiencies. We evaluated each variant using
eight tools that predict pathogenicity through assessment of sequence
homology, protein structure, and evolutionary conservation. Using
the score from each tool as predictors, we modeled pathogenicity
using three methods: multivariable logistic regression, elastic net, and
random forests. For the latter two, we optimized model parameters
using repeated cross-validation. We evaluated these models in a val-
idation dataset consisting of 59 pathogenic and 49 benign missense
FHLH gene variants. Finally, we applied our fixed model developed
on the training and validation sets to 4,979 NCBI-reported VUS in
FHLH genes.
Results: All models demonstrated an accuracy between 84% and
86% in the validation set. The multivariable logistic regression model
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S25 of S64
had the best sensitivity, identifying 91% of pathogenic variants in
the training and validation sets. It also demonstrated greater overall
accuracy than any of the individual tools used in model develop-
ment. We selected this model for analysis of the VUS, of which 49%
were predicted to be benign and 51% pathogenic. To further validate
these predictions, we performed a literature search and identified 32
patients with VUS in the PRF1 gene and associated decreased perforin
expression. Our model identified 88% of these variants as pathogenic.
Conclusion: FHLH gene VUS are challenging to interpret. We have
developed a tool with high sensitivity for identification of pathogenic
missense variants, which may help guide clinical decision making for
patients with VUS.
A REAL-WORLD ANALYSIS OF THE HLH/MAS DIAGNOSTIC
EVALUATION IN HOSPITALIZED PEDIATRIC PATIENTS
Lauren Meyer1 , Erica Steen2 , Adam Olshen3 , Kim Nichols4 , Matt
Zinter3
1 University of Washington, Seattle, WA USA; 2 University of California, San
Diego, CA USA; 3 University of California, San Francisco, CA USA; 4 St. Jude
Children’s Research Hospital, Memphis, TN USA
Purpose: Diagnostic criteria for hemophagocytic lymphohistiocytosis
(HLH) and macrophage activation syndrome (MAS) are nonspecific.
This contributes to diagnostic uncertainty, which can delay treatment
or risk exposing patients to unnecessary immunosuppressive ther-
apy. We sought to understand how these challenges manifest in a
real-world setting, with a goal of informing the diagnostic workup.
Methods: We queried the UCSF Electronic Medical Record Search
Engine for HLH/MAS in previously healthy pediatric patients. This
yielded 68 patients with an ICD-10 code for HLH/MAS and 567
without but in whom HLH/MAS was considered on the differential.
Results: Clinical presentations were indistinguishable between these
two groups. Within the “on differential” group, infectious diagnoses
were most common (23%), followed by rheumatologic diseases (20%),
malignancies (9%), and fever of unknown origin (8%). Across the cohort,
the HLH-2004 criteria had a sensitivity and specificity of 65% and 92%
versus 82% and 83% for the H-score. Patients with newly-diagnosed
malignancies had the highest false positivity rate, with 20% testing
positive by HLH-2004 criteria and 34% by H-score. We also evalu-
ated these algorithms in patients assigned an ICD-10 code for sepsis
(n=62). Fifteen and 42% had a false positive result by HLH-2004
criteria and H-score, respectively. Given these high false positivity
rates, we generated an alternative multivariate logistic regression
model to identify patients with HLH/MAS that consisted of cytope-
nias, ferritin, triglycerides, and fibrinogen, all of which were significant
predictors in univariate analyses and independent predictors in the
multivariate analysis. This produced an area under the curve of 0.86
(0.81-0.90).
Conclusion: HLH/MAS is commonly on the differential for hospi-
talized children and cannot be differentiated from disease mimics
by clinical features. Existing diagnostic algorithms showed subopti-
mal specificity, particularly in patients with malignancy and sepsis. A
 15455017, 2023, S7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pbc.30714 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [22/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
S26 of S64 ABSTRACTS

multivariate logistic regression model consisting of basic laboratory Suzhou Municipal Hospital, Suzhou, China; 27 Department of Hematol-
parameters may help triage patients who require further specialized ogy, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China;
testing. 28 Jiangsu Cooperative Lymphoma Group (JCLG) and Jiangsu Histiocytosis
Association Lymphoma Group
Purpose: The most common secondary causes include malignancies,
LYMPHOMA-ASSOCIATED HEMOPHAGOCYTIC infections, and rheumatic diseases. For patients with malignancy-
LYMPHOHISTIOCYTOSIS IN THE ELDERLY: A MULTICENTER related HLH, lymphoma is the most common cause. Treatment for
ANALYSIS older adults with lymphoma-related HLH is challenging. No studies
have focused on older adults with lymphoma-associated HLH. The lym-
Yi Miao1,28 , Jie Zhang2,28 ,Jing Zhang1,28 , Xuzhang Lu3,28 , Bingzong phoma subtypes, presenting features, treatments, and outcomes in
Li4,28 , Chunling Wang5,28 , Miao Sun6,28 , Yun Zhuang7,28 , Yuqing these patients remain unclear.
Miao8,28 , Haiwen Ni9,28 , Xiaoyan Xie10,28 , Jingyan Xu11,28 , Yunping Methods: We did a multicenter analysis of older lymphoma patients
Zhang12,28 , Min Zhao13,28 , Min Xu14 , Wanchuan Zhuang15,28 , Weiy- with HLH for lymphoma subtypes, baseline characteristics, treatment
ing Gu16,28 , Guoqiang Lin17,28 , Haiying Hua18,28 , Jianfeng Zhu19,28 , modalities, outcomes, and prognostic features. Patients older than 60
Maozhong Xu20,28 , Tao Jia21,28 , Zhi Wang22,28 , Lijia Zhai23,28 , Tong- were defined as elderly patients. Younger patients were included for
tong Zhang24,28 , Qiurong Shan25,28 , Qiudan Shen26,28 , Jun Qian27,28 , comparison with their older counterparts.
Jianyong Li1,28 , Wenyu Shi2,28 Results: A total of 173 older adults with lymphoma-associated HLH
1 Department of Hematology, the First Affiliated Hospital of Nanjing Medi- were included. B cell lymphoma was more common in older patients
cal University, Nanjing, China; 2 Department of Oncology, Affiliated Hospital than younger patients (61.3% vs 32%, P<0.0001), while T cell lym-
of Nantong University, Nantong,226001, China; 3 Department of Hematol- phoma was less common in older patients (35.3% vs 65.0%, P<0.0001).
ogy, Affiliated Changzhou Second Hospital of Nanjing Medical University, Aggressive NK cell leukemia (ANKL) and extranodal NK/T cell lym-
Changzhou, China; 4 Department of Hematology, the Second Affiliated Hos- phoma, nasal type (ENKL) were less common in older patients
pital of Soochow University, Suzhou, China; 5 Department of Hematology, (ANKL: older 6.4% vs younger 19.5%, P=0.0001; ENKL: older 5.8%
The First People’s Hospital of Huai’an, Huai’an, China; 6 Department of vs younger 19.5%, P<0.0001). The median survival for older patients
Hematology, Jingjiang People’s Hospital, The Seventh Affiliated Hospital with lymphoma-associated HLH was 92 days. In older patients, those
of Yangzhou University, Jingjiang, China; 7 Department of Hematology, Wu with T/NK lymphomas showed remarkably poorer prognosis (median
Xi People’s Hospital, Wuxi, China; 8 Department of Hematology, Yancheng survival: T/NK 39 days vs. 418 days, P=0.0020). The initial use of
First People’s Hospital, Yancheng, China; 9 Department of Hematology, The etoposide to control HLH did not seems to be associated with supe-
Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, rior outcomes (P=0.7517) in older patients. For older patients with
Nanjing, China; 10 Department of Hematology, Northern Jiangsu People’s B-cell lymphoma, the use of the EPOCH regimen was associated
Hospital Affiliated to Yangzhou University, Yangzhou, China; 11 Department with a higher 60-day survival rate (EPOCH 100% vs. others 68.2%,
of Hematology, Nanjing Drum Tower Hospital, the Affiliated Hospital of P=0.0407).
Nanjing University Medical School, Nanjing, China; 12 Department of Hema- Conclusion: This is the largest cohort describing Lymphoma-associated
tology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China; HLH in the elderly. Our study demonstrated older lymphoma patients
13 Department of Hematology, Wuhu Second People’s Hospital, Wuhu, with HLH showed distinct subtypes. Generally, the prognosis is poor,
China; 14 Department of Hematology, Zhangjiagang First Affiliated Hospital especially for those with T/NK lymphomas. The EPOCH regimen may
of Soochow University, Zhangjiagang, China; 15 Department of Hematol- improve the 60-day survival in older patients with B-lymphoma related
ogy, The Second People’s Hospital of Lianyungang, Lianyungang, China; HLH.
16 Department of Hematology, The First People’s Hospital of Changzhou
and The Third Affiliated Hospital of Soochow University, Changzhou,
China; 17 Department of Hematology, Huai’an Hospital Affiliated to Xuzhou CLINICAL SIGNIFICANCE OF SERUM HIGH-DENSITY
Medical College and Huai’an Second People’s Hospital, Huai’an, China; LIPOPROTEIN CHOLESTEROL AND ITS DYNAMIC CHANGE IN
18 Department of Hematology, Wuxi Third people’s hospital, Wuxi, China; PATIENTS WITH LYMPHOMA-ASSOCIATED HEMOPHAGOCYTIC
19 Department of Hematology, the People’s Hospital of Taizhou, Taizhou, LYMPHOHISTIOCYTOSIS
China; 20 Department of Hematology, The Affiliated Jiangyin Hospital of
Southeast University Medical College, Jiangyin, China; 21 Department of Yi Miao1,28 , Wenyu Shi2,28 ,Jing Zhang1,28 , Xuzhang Lu3,28 , Bing-
Hematology, The First People’s Hospital of Lianyungang, Lianyungang, zong Li4,28 , Chunling Wang5,28 , Miao Sun6,28 , Yun Zhuang7,28 , Yuqing
China; 22 Department of Hematology, Wuxi Second People’s Hospital, Wuxi, Miao8,28 , Haiwen Ni9,28 , Xiaoyan Xie10,28 , Jingyan Xu11,28 , Yunping
China; 23 Department of Hematology, Affiliated Hospital of Yangzhou Uni- Zhang12,28 , Min Zhao13,28 , Min Xu14 , Wanchuan Zhuang15,28 , Weiy-
versity, Yangzhou, China; 24 Department of Hematology, Rudong county ing Gu16,28 , Guoqiang Lin17,28 , Haiying Hua18,28 , Jianfeng Zhu19,28 ,
people’s hospital, Rudong, China; 25 Department of Hematology, Shuyang Maozhong Xu20,28 , Tao Jia21,28 , Zhi Wang22,28 , Lijia Zhai23,28 , Tong-
Traditional Chinese Medicine Hospital, Shuyang, China; 26 Department of tong Zhang24,28 , Qiurong Shan25,28 , Qiudan Shen 26,28 , Jun Qian27,28 ,
Hematology, the Affiliated Suzhou Hospital of Nanjing Medical University, Jianyong Li128

ABSTRACTS
1 Department of Hematology, the First Affiliated Hospital of Nanjing Medi-
cal University, Nanjing, China; 2 Department of Oncology, Affiliated Hospital
of Nantong University, Nantong,226001, China; 3 Department of Hematol-
ogy, Affiliated Changzhou Second Hospital of Nanjing Medical University,
Changzhou, China; 4 Department of Hematology, the Second Affiliated Hos-
pital of Soochow University, Suzhou, China; 5 Department of Hematology,
The First People’s Hospital of Huai’an, Huai’an, China; 6 Department of
Hematology, Jingjiang People’s Hospital, The Seventh Affiliated Hospital
of Yangzhou University, Jingjiang, China; 7 Department of Hematology, Wu
Xi People’s Hospital, Wuxi, China; 8 Department of Hematology, Yancheng
First People’s Hospital, Yancheng, China; 9 Department of Hematology, The
Affiliated Hospital of Nanjing University of Traditional Chinese Medicine,
Nanjing, China; 10 Department of Hematology, Northern Jiangsu People’s
Hospital Affiliated to Yangzhou University, Yangzhou, China; 11 Department
of Hematology, Nanjing Drum Tower Hospital, the Affiliated Hospital of
Nanjing University Medical School, Nanjing, China; 12 Department of Hema-
tology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China;
13 Department of Hematology, Wuhu Second People’s Hospital, Wuhu,
China; 14 Department of Hematology, Zhangjiagang First Affiliated Hospital
of Soochow University, Zhangjiagang, China; 15 Department of Hematol-
ogy, The Second People’s Hospital of Lianyungang, Lianyungang, China;
16 Department of Hematology, The First People’s Hospital of Changzhou
and The Third Affiliated Hospital of Soochow University, Changzhou,
China; 17 Department of Hematology, Huai’an Hospital Affiliated to Xuzhou
Medical College and Huai’an Second People’s Hospital, Huai’an, China;
18 Department of Hematology, Wuxi Third people’s hospital, Wuxi, China;
19 Department of Hematology, the People’s Hospital of Taizhou, Taizhou,
China; 20 Department of Hematology, The Affiliated Jiangyin Hospital of
Southeast University Medical College, Jiangyin, China; 21 Department of
Hematology, The First People’s Hospital of Lianyungang, Lianyungang,
China; 22 Department of Hematology, Wuxi Second People’s Hospital, Wuxi,
China; 23 Department of Hematology, Affiliated Hospital of Yangzhou Uni-
versity, Yangzhou, China; 24 Department of Hematology, Rudong county
people’s hospital, Rudong, China; 25 Department of Hematology, Shuyang
Traditional Chinese Medicine Hospital Shuyang, China; 26 Department of
Hematology, the Affiliated Suzhou Hospital of Nanjing Medical University,
Suzhou Municipal Hospital, Suzhou, China; 27 Department of Hematol-
ogy, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China;
28 Jiangsu Cooperative Lymphoma Group (JCLG)
Purpose: The lipid profile in serum is frequently dysregulated in
lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). We
aimed to explore the clinical significance of serum lipoprotein choles-
terol in lymphoma-associated HLH.
Methods: Patients with lymphoma-associated HLH were included.
Serum levels of baseline low-density lipoprotein cholesterol
(LDL-c) and high-density lipoprotein cholesterol (HDL-c) were
collected. Serum levels of LDL-c and HDL-c after treatment
(first test after treatment, time interval ≥ 14 days) were also
collected.
Results: A total of 169 lymphoma-associated HLH were included. Low
HDL-c (< 1.03 mmol/L) was observed in 161 (95.3%) patients and low
LDL-c (< 2.6 mmol/L) was presented in 145 (85.8%) patients. The best
cutoff of 0.50 mmol/L for HDL-c was determined to predict the 60-
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day survival. Patients with HDL-c ≥ 0.50 mmol/L showed a significantly
higher 60-day survival rate than patients with HDL-c <0.50 mmol/L
(70.9% vs 42.2%, p < 0.001.). Patients with HDL-c ≥ 0.50 mmol/L also
showed longer overall survival (OS) (median OS: 346 days vs 34 days,
p < 0.001). LDL-c showed no significant impacts on 60-day survival
and OS. Dynamic data of HDL-c were available in 69.2% (117) of the
patients. The median interval between the two tests was 18 (IQR:
15-25) days. The level of HDL-c after treatment increased in 80.3%
(94/117) of the patients. The ratio of post-treatment HDL-c/baseline
HDL-c was calculated and the median number was 1.67 (IQR: 1.05-
2.48). The ratio was significantly lower in the patients with T/NK-cell
malignancies than those with B-cell lymphomas (median 1.40 versus
1.97, p < 0.001). For prognosis analysis, patients with a ratio<0.78 had
significantly reduced 60-day survival (42.4% vs 76.6%, P=0.0035) and
OS (median 36 days vs 407 days, P<0.001).
Conclusion: Our study demonstrated serum HDL-c and its dynamic
Change were robust and clinically feasible markers for predicting the
outcomes of patients with lymphoma-associated HLH.
HISTIOCYTIC NECROTIZING LYMPHADENITIS WITH
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A
SINGLE-CENTER ANALYSIS OF 5 CASES
Yi Miao1 , Wenyu Shi2 , Qingqing Chen1 , Jing Zhang1 , Jianyong Li1
1 Department of Hematology, the First Affiliated Hospital of Nanjing Medical
University, Nanjing, China; 2 Department of Oncology, Affiliated Hospital of
Nantong University, Nantong,226001, China
Purpose: Histiocytic necrotizing lymphadenitis (HNL) is a benign, self-
limiting disease that presents with few nonspecific symptoms such
as fever and swollen lymph nodes in the neck. Histiocytic necrotizing
lymphadenitis with hemophagocytic lymphohistiocytosis (HNL-HLH)
is rare and case series have been reported in children. HNL-HLH in
adults has not been systematically analyzed.
Methods: We aimed at exploring the clinical, laboratory, and radio-
logical features and outcomes of adult patients with HNL-HLH. We
collected the clinical data of patients with HNL-HLH admitted to the
First Affiliated Hospital of Nanjing Medical University from October
2010 to June 2015. All the patients underwent lymph node biopsy
and have a pathological diagnosis of HNL. The age, gender, clinical pre-
sentation, lymph node signs, laboratory findings and imaging data, and
pathological findings of the patients were collected.
Results: In this study, we reported five adult patients with HNL-HLH,
including 3 females and 2 males. The median age was 37 years. All
five patients showed enlarged lymph nodes and prolonged fever. Lab-
oratory findings were consistent with the diagnosis of HLH. Serum
lactate dehydrogenase (LDH) and aminotransferase were significantly
elevated in all five patients. 18F-FDG PET/CT showed enlarged lymph
nodes with increased FDG uptake and splenic hypermetabolism could
be present. Hemophagocytosis in the lymph node was present in two
cases. All the patients responded well to corticosteroids and had a good
prognosis. Two of the five patients were diagnosed with systemic lupus
erythematosus (SLE) during the follow-up.

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Conclusion: Our study demonstrated that adult patients with HNL-
HLH showed distinct clinical, laboratory, and radiological features. And
the prognosis is good and patients could be managed with steroids and
supportive care.
THE CLINICAL SIGNIFICANCE AND PROGNOSTIC VALUE OF
SERUM BETA-2 MICROGLOBULIN IN ADULT
LYMPHOMA-ASSOCIATED HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS: ANALYSIS OF A MULTICENTER
COHORT OF 326 PATIENTS
Yi Miao1,28 , Wenyu Shi2,28 , Jing Zhang1,28 , Xuzhang Lu3,28 , Bing-
zong Li4,28 , Chunling Wang5,28 , Miao Sun6,28 , Yun Zhuang7,28 , Yuqing
Miao8,28 , Haiwen Ni9,28 , Xiaoyan Xie10,28 , Jingyan Xu11,28 , Yunping
Zhang12,28 , Min Zhao13,28 , Min Xu14 , Wanchuan Zhuang15,28 , Weiy-
ing Gu16,28 , Guoqiang Lin17,28 , Haiying Hua18,28 , Jianfeng Zhu19,28 ,
Maozhong Xu20,28 , Tao Jia21,28 , Zhi Wang22,28 , Lijia Zhai23,28 , Tong-
tong Zhang24,28 , Qiurong Shan25,28 , Qiudan Shen26,28 , Jun Qian27,28 ,
Jianyong Li128
1 Department of Hematology, the First Affiliated Hospital of Nanjing Medi-
cal University, Nanjing, China; 2 Department of Oncology, Affiliated Hospital
of Nantong University, Nantong,226001, China; 3 Department of Hematol-
ogy, Affiliated Changzhou Second Hospital of Nanjing Medical University,
Changzhou, China; 4 Department of Hematology, the Second Affiliated Hos-
pital of Soochow University, Suzhou, China; 5 Department of Hematology,
The First People’s Hospital of Huai’an, Huai’an, China; 6 Department of
Hematology, Jingjiang People’s Hospital, The Seventh Affiliated Hospital
of Yangzhou University, Jingjiang, China; 7 Department of Hematology, Wu
Xi People’s Hospital, Wuxi, China; 8 Department of Hematology, Yancheng
First People’s Hospital, Yancheng, China; 9 Department of Hematology, The
Affiliated Hospital of Nanjing University of Traditional Chinese Medicine,
Nanjing, China; 10 Department of Hematology, Northern Jiangsu People’s
Hospital Affiliated to Yangzhou University, Yangzhou, China, 11 Department
of Hematology, Nanjing Drum Tower Hospital, the Affiliated Hospital of
Nanjing University Medical School, Nanjing, China; 12 Department of Hema-
tology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China;
13 Department of Hematology, Wuhu Second People’s Hospital, Wuhu,
China; 14 Department of Hematology, Zhangjiagang First Affiliated Hospital
of Soochow University, Zhangjiagang, China; 15 Department of Hematol-
ogy, The Second People’s Hospital of Lianyungang, Lianyungang, China;
16 Department of Hematology, The First People’s Hospital of Changzhou
and The Third Affiliated Hospital of Soochow University, Changzhou,
China; 17 Department of Hematology, Huai’an Hospital Affiliated to Xuzhou
Medical College and Huai’an Second People’s Hospital, Huai’an, China;
18 Department of Hematology, Wuxi Third people’s hospital, Wuxi, China,
19 Department of Hematology, the People’s Hospital of Taizhou, Taizhou,
China; 20 Department of Hematology, The Affiliated Jiangyin Hospital of
Southeast University Medical College, Jiangyin, China; 21 Department
Hematology, The First People’s Hospital of Lianyungang, Lianyungang,
China; 22 Department of Hematology, Wuxi Second People’s Hospital, Wuxi,
China; 23 Department of Hematology, Affiliated Hospital of Yangzhou Uni-
versity, Yangzhou, China; 24 Department of Hematology, Rudong county
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ABSTRACTS
people’s hospital, Rudong, China; 25 Department of Hematology, Shuyang
Traditional Chinese Medicine Hospital<Shuyang, China; 26 Department of
Hematology, the Affiliated Suzhou Hospital of Nanjing Medical University,
Suzhou Municipal Hospital, Suzhou, China; 27 Department of Hematol-
ogy, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China;
28 Jiangsu Cooperative Lymphoma Group (JCLG).
Purpose: To investigate the prognostic role of serum beta-2 microglob-
ulin (B2M) in adult lymphoma-associated hemophagocytic lymphohis-
tiocytosis (HLH).
Methods: The clinical and laboratory characteristics of adult patients
in a multicenter cohort with lymphoma-associated HLH who had base-
line serum B2M levels between August 2009 and June 2023 were
retrospectively analyzed.
Results: A total of 326 cases were included and the median serum
B2M level was 5.19 mg/L. The optimal cut-off value of serum B2M for
predicting overall survival (OS) was 8.73 mg/L (p < 0.0001). Patients
with higher B2M had significantly decreased OS compared with those
with lower B2M (median OS: 21 days vs. 236 days, P < 0.0001). The
subgroup with B2M level > 8.73 mg/L was older and had a higher pro-
portion of stage IV. Patients with higher levels of B2M showed lower
levels of platelets, albumin, and fibrinogen, and higher levels of cre-
atinine. A moderate correlation between creatinine and serum B2M
was found (Spearman’s ρ = 0.417, p < 0.001). The multivariate analysis
showed that the high levels of serum B2M (> 8.73 mg/L) and creati-
nine (≥ 133 μmol/L), decreased fibrinogen (≤ 1.5 g/L), agranulocytosis
(< 0.5×109/L), severe thrombocytopenia (< 50×109/L), and increased
serum Epstein-Barr virus DNA were found to have significant prog-
nostic values in all patients. Finally, a prognostic scoring system was
established based on serum B2M levels as well as five other indepen-
dent prognostic factors and divided the patients into three groups with
significant prognostic differences (median survival: low-risk [score ≤ 1]
428 days vs. intermediate-risk [score = 2] 102 days vs. high-risk [score
≥ 3] 18 days, P < 0.0001).
Conclusion: This study confirmed that the serum B2M level can be
a simple and independent prognostic factor in lymphoma-associated
HLH and established a prognostic scoring system to predict patients’
survival.
DIGITAL SPATIAL PROFILING OF THE MICROENVIRONMENT IN
LANGERHANS CELL HISTIOCYTOSIS (LCH) LESIONS
Jenee Mitchell1,2 , George Kannourakis1,2
1 Fiona Elsey Cancer Research Institute, Ballarat, Australia; 2 School of
Science, Psychology and Sport, Federation University, Mt Helen, Australia
Purpose: Langerhans cell histiocytosis (LCH) is a rare disease involv-
ing inflammatory lesions that mostly affect children but can also
occur in adults. Lesions comprise myeloid lineage ’LCH’ cells that
of often harbor mitogen-activated protein kinase cell-signaling pathway
mutations, along with immune cells such as T cells and an inflam-
matory cytokine milieu. This composition suggests that both LCH
cells and T cells contribute to the local inflammation. Our study
aimed to understand which T cell and LCH cell associated proteins

ABSTRACTS
are upregulated in response to microenvironmental factors in LCH
lesions.
Methods: Multiplex digital spatial profiling (DSP) is a novel proteomics
approach that allows for high-throughput quantitative and spatial anal-
ysis of formalin-fixed, paraffin-embedded tissue samples. Using DSP,
we conducted a deep characterization of LCH lesion tissue (n =4). We
segmented regions of interest (ROIs) by expression of CD3 and CD1a
and used a 72-protein immuno-oncology panel to examine expres-
sion of proteins adjacent to T cells (CD3+) in CD3 rich areas and in
CD1a (LCH cell) rich areas, and expression of LCH cell (CD1a) adjacent
proteins in CD3 rich areas and CD1a rich areas.
Results: We found 14 proteins significantly upregulated adjacent to T
cells in CD1a rich regions of tissue and 15 proteins significantly upreg-
ulated adjacent to LCH cells in CD3 rich regions of tissue. Additionally,
using complete ROIs we tested for differences between lesions with
presence or absence of detectable BRAFV600E mutation and found
several proteins significantly upregulated in each group. Significance
was based on a fold change >2 and p <0.05.
Conclusion: This study highlights proteins that are potentially impor-
tant in LCH pathogenesis. Further study into these associations is
needed to determine whether the proteins or their associated path-
ways are suitable prognostic indicators or therapeutic targets to
benefit patients.
A CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS THAT
WAS MISDIAGNOSED AS ROSAI DORFMAN DISEASE
Maha Mohammed1 , Marwa Tolba2 , Salwa AbdelKader2 , Omnia El-
Rashidy1 , Sara Makkeyah2
Pediatric Neurology Unit, Faculty of Medicine, Ain Shams University, Cairo,
Egypt; 2 Pediatric Hematology-Oncology and Bone Marrow Transplant Unit,
Faculty of Medicine, Ain Shams University, Cairo, Egypt
Purpose: Rosai-Dorfman disease (RDD), is a lymphoproliferative disor-
der that belongs to the rare group of non-Langerhans cell histiocytoses.
Central nervous system RDD represents only 10% of extra-nodal dis-
ease and it typically affects the dura rather than brain parenchyma.
We report a patient who presented with multiple brain parenchy-
mal lesions, initially diagnosed as RDD and showed partial response
to combined therapy with cladribine (CdA) and cytarabine (Ara-C)
then proven to have genetic hemophagocytic lymphohisteocytosis
(HLH).
Case Presentation: A 5-year-old boy presented with fever and right
sided hemiparesis associated with ipsilateral lower motor neuron
lesion facial nerve palsy. He had no history of preceding trauma or
ear infection and no constitutional symptoms. On physical exam-
ination, the boy had no lymphadenopathy. His gait was unsteady.
MRI Brain revealed multiple well defined intra-axial lesions that
attained high signal intensity (SI) in T2 and FLAIR (Fluid attenu-
ated inversion recovery) sequences and low SI in T1 images at right
frontal, bilateral temporal, left occipital and right cerebellar pedun-
cle. Biopsy from the temporal lesion confirmed the diagnosis of RDD
with histopathology showing a lymph-histiocytic rich lesion with non-
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prominent emperipolesis, and immunohistochemical staining positive
for S100 and CD68, Cyclin D1 patchy positive staining of large histio-
cytoid cells, and GMA weak patchy positive staining. The boy showed
initial partial response to steroid then intravenous CdA/Ara-C. After
three cycles of CdA/Ara-C, the patient developed systemic symptoms
of HLH; fever, elevated liver enzymes, jaundice, cytopenia, hyper-
triglyceridemia, hyperferritinemia, and low fibrinogen level. A whole
exome sequencing revealed a homozygous variant of unknown sig-
nificance in UNC13D gene suggesting the diagnosis of familial HLH
type 3.
Conclusion: our case report highlights the overlap between CNS
lesions in RDD and HLH and suggests that genetic testing in case of
overlapping symptoms and partial response to treatment might be
warranted.
CIRCULATING CELL FREE DNA BRAFV600E LEVELS AS A
BIOMARKER OF DISEASE STATUS IN A COHORT OF PEDIATRIC
PATIENTS WITH LCH INCLUDING A PATIENT WITH RELAPSED
PITUITARY INVOLVEMENT
Sonia Morales1 , Carol Brown1 , Natalie Johnson1 , Kirsten Kasper2 , Keri
Zabokrtsky2 , Lilibeth Torno1
1 Hyundai Cancer Institute at Children’s Healthcare of Orange County
(CHOC Children’s), Orange, CA USA; 2 Hyundai Cancer Genomics Center,
Children’s Healthcare of Orange County (CHOC Children’s), Orange, CA USA
Background: Langerhans cell histiocytosis (LCH) is a myeloid neo-
plasm characterized by an accumulation of langerin positive cells.
The BRAFV600E mutation has been associated with high-risk disease,
recurrences and poorer outcomes. Circulating cell-free DNA (ccf DNA)
has been used as a measure of response in other diseases. We report
longitudinal changes in ccf BRAFV600E in a cohort of patients and the
detection of ccf BRAFV600E in a patient with recurrence localized to
both bone and pituitary.
Methods: ccf BRAFV600E collections on patients with newly diag-
nosed/refractory/recurrent disease were performed at enrollment, 6
weeks and then every 3 months from 6/2021 to 5/2023. cfDNA
by Digital Droplet PCR was performed at ARUP laboratories.
Research reported was supported by Children’s Healthcare of Orange
County.
Results: Eighteen patients diagnosed at <18 years of age (median age
of 7 yrs) and predominantly Hispanic (67%) with BRAFV600E-mutated
LCH were included in this observational study. Eighty-two percent
had recurrent/refractory disease at the start of the study. Thirty nine
percent had multisystem (MS) disease and 22% with risk organ involve-
ment (RO+MS). One patient with MS disease had detectable disease
at start of study (28.00 copies/mL; 1.27 mutant allele frequency), ulti-
mately became undetectable, with imaging suggestive of stable disease
and laboratory markers. Another patient with RO+MS without pitu-
itary stalk involvement at diagnosis, had detectable ccf BRAFV600E
(2.00 copies/mL;0.22 mutant allele frequency) at the time of disease
recurrence at the pituitary stalk and a 7 mm parietal calvarial bone
lesion.
 15455017, 2023, S7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pbc.30714 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [22/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
S30 of S64 ABSTRACTS

Conclusions: Our data suggests that BRAFV600E in cfDNA may be Results: We found 9 cases of RDD (5 males, 4 females) with a median
useful as a biomarker to detect relapse in high-risk patients with age at diagnosis of 8 years and 3 months (range, 9 months to 15 years
LCH. This may be a useful marker in those with Non isolated pitu- 5 months). As underlying diseases, one patient each had osteogenesis
itary involvement. The use of serial monitoring for the presence of ccf imperfecta and atopic dermatitis. Two had nodal lesions only, three had
BRAFV600E needs to be performed in a larger prospective study for a extra-nodal lesions only (one each in bone, dura mater and soft tissue),
larger time frame. and four had both. Two had spontaneous regression without treatment.
Three were treated with PSL, one with PSL/2CdA, one with multiagent
chemotherapy, one with multiagent chemotherapy and trametinib, and
PEDIATRIC ROSAI-DORFMAN DISEASE IN JAPAN one with surgery and radiation. Two had complicated with glomeru-
lonephritis. Somatic mutations were found in 5 of the 6 cases analyzed
Akira Morimoto1 , Atsuko Nakazawa2 , Takahiro Ueda3 , Chitose (2 in MAP2K1, 1 in KARS, 1 in BRAF and 1 in TSC1). With a median
Ogawa4 , Naoki Sakata5 , Keisuke Sugimoto5 , Jotaro On6 , Taro follow-up of 4 years and 9 months, 2 died of disease and 7 survived
Yoshida7 , Naoki Otsuki8 , Yuichi Taneyama9 , Nobuyuki Hyakuna10 , (6 in CR and 1 on disease). Both of the two who died were positive for
Takashi Ishihara11 , Akihiko Matsumine12 , Yoko Shioda13 , Yozo MAP2K1 mutation.
Nakazawa14 , Takahiro Yasumi15 , Takehiko Doi16 , Kenichi Sakamoto17 , Conclusion: The majority of children with RDD carry oncogenic muta-
Yuhki Koga18 , Takeshi Asano19 tions. Glomerulonephritis may be noted as a complication of RDD.
1 Division of Pediatrics, Showa Inan General Hospital, Komagane, Japan; The relationship between gene mutations and prognosis should be
2 Department of Clinical Research, Saitama Children’s Medical Center, investigated.
Saitama Japan; 3 Department of Pediatrics, Nippon Medical School Hospital,
Tokyo, Japan; 4 Department of Pediatric Oncology, National Cancer Cen-
ter Hospital, Tokyo, Japan; 5 Department of Pediatrics, Faculty of Medicine, LONG-TERM FOLLOW-UP AND LATE COMPLICATIONS IN
Kindai University, Osaka-Sayama, Japan; 6 Department of Neurosurgery, CHILDREN WITH LCH UNDER THE AGE OF 24 MONTHS
Brain Research Institute, Niigata University, Niigata, Japan; 7 Department

of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Maria Moschovi1 , Panagiota Kourou1 , Ioannis Zarkos1 , Archontis
Japan; 8 Department of Otorhinolaryngology, Kindai University Faculty of Zampogiannis1 , Natalia Tourkantoni1 , John Nikas2 , Christopoulos
Medicine, Osaka-Sayama, Japan; 9 Department of Hematology/Oncology, Nickolaos3
Chiba Children’s Hospital, Chiba, Japan; 10 Department of Pediatrics, 1 Hematology/Oncology unit, 1st Department of Pediatrics, University
University of the Ryukyus Hospital, Nishihara, Japan; 11 Department of of Athens, Pediatric Oncology Unit “MARIANNA V VARDINOGIANNIS-
Pediatrics, Nara Medical University, Kashihara, Japan.; 12 Department of ELPIDA”, Athens, Greece; 2 Radiology Department, “Agia Sofia” Children’s
Orthopaedic Surgery, University of Fukui, Fukui, Japan; 13 Children’s Cancer Hospital, Athens, Greece; 3 Surgical Department, “Agia Sofia” Children’s
Center, National Center for Child Health and Development, Tokyo, Japan; Hospital, Athens, Greece
14 Department of Pediatrics, Shinshu University School of Medicine, Mat- Purpose: Patients under age of 24 months usually present with multi-
sumoto, Japan; 15 Department of Pediatrics, Kyoto University Graduate system LCH. The outcome is poor in this type of LCH. The long-term
School of Medicine, Kyoto, Japan; 16 Department of Pediatrics, Grad- follow-up and the complications of LCH in children younger than 24
uate School of Biomedical and Health Science, Hiroshima University, months of age was the aim of our study.
Hiroshima, Japan; 17 Department of Pediatrics, Shiga University of Med- Methods: Eleven children, who were diagnosed with LCH in the first
ical Science, Otsu, Japan; 18 Department of Pediatrics, Graduate School two years of age and treated in our Unit, were enrolled in this study.
of Medical Sciences, Kyushu University, Fukuoka, Japan; 19 Department The age ranged from 26 days to 24 months (mean: 10 month). All
of Pediatrics, Nippon Medical School, Chiba Hokusoh Hospital, Inzai, patients were treated according to the LCH protocol and completed
Japan the chemotherapy regiment at least 12-17 years ago. All patients
Background: Rosai-Dorfman disease (RDD) is a rare histiocytosis char- remain in follow up.
acterized by accumulation of S100+, CD68+ and CD1a- histiocytes Results: Five patients presented with multisystem disease in the
with emperipolesis. It predominantly occurs in black adolescents (mean first 6 months of life, including intestine involvement, three cases
age 20 years), but is rare in Japanese children. Recently, oncogenic had multiple bone lytic lesions in rare sites, one case had peri-
mutations in MAPK pathway genes have been reported, especially in orbital mass and two cases had juvenille xanthogranuloma in
adults. the first month of life. All achieved second remission. Two cases
Methods: We conducted a nationwide retrospective survey of child- presented with esophageal varices 10 years after the diagno-
hood RDD in Japan. We confirmed the diagnosis of RDD by central sis of LCH. Biochemical profile within normal. Sclerotherapy was
pathological review and collected clinical information. In addition, we performed.
performed targeted sequencing of 146 genes associated with carcino- Conclusion: Although children with LCH under the age of 24 months
genesis in cases with sufficient DNA from paraffin sections of tumor have a poor outcome, the new treatment protocol achieve a higher
tissues and identified somatic mutation designated as pathogenic or survival rate for the patient group. Reactivation of the disease is still
likely pathogenic by ClinVar. high but reactivated cases had a second chance for stable remission.

ABSTRACTS
Esophageal varices remain the main late complication even 10-years
post therapy.
CLINICAL MANIFESTATIONS, TREATMENT, AND OUTCOMES IN
ISOLATED CENTRAL NERVOUS SYSTEM HISTIOCYTIC
NEOPLASMS
Nabeela Nathoo1 , Joon Uhm1 , Alyx Porter2 , Julie Hammack3 , Kurt
Jaeckle3 , Maciej Mrugala2 , Brian Crum1 , Sean Pittock1,4 , Gaurav
Goyal5 , Jason Young6 , Matthew Koster7 , Robert Vassallo8 , Jay Ryu8 ,
Caroline Davidge-Pitts9 , Corrie Bach10 , Aishwarya Ravindran11 , Julio
Sartori Valinotti12 , Nora Bennani13 , Mithun Shah13 , Karen Rech14 ,
Ronald Go13 , Oliver Tobin1,4 , Mayo Clinic-University of Alabama at
Birmingham Histiocytosis Working Group
1 Department of Neurology, Mayo Clinic, Rochester, MN USA; 2 Department
of Neurology, Mayo Clinic, Phoenix, AZ USA; 3 Department of Neurol-
ogy, Mayo Clinic, Jacksonville, FL USA; 4 Center for Multiple Sclerosis and
Autoimmune Neurology, Mayo Clinic, Rochester, MN USA; 5 Division of
Hematology-Oncology, University of Alabama at Birmingham, Birmingham,
AL USA; 6 Department of Radiology, Mayo Clinic, Jacksonville, FL USA;
7 Division of Rheumatology, Mayo Clinic, Rochester, MN USA; 8 Division of
Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN USA;
9 Division of Endocrinology, Mayo Clinic, Rochester, MN USA; 10 Division
of Radiology, Mayo Clinic, Rochester, MN USA; 11 Division of Laboratory
Medicine- Hematopathology section, Department of Pathology, The Uni-
versity of Alabama at Birmingham, Birmingham, AL USA; 12 Department of
Dermatology, Mayo Clinic, Rochester, MN USA; 13 Division of Hematology,
Mayo Clinic, Rochester, MN USA; 14 Division of Hematopathology, Depart-
ment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
USA
Purpose: Central nervous system (CNS) involvement in histiocytic neo-
plasms such as Langerhans cell histiocytosis (LCH), Erdheim-Chester
disease (ECD), and Rosai-Dorfman disease (RDD) has been well-
described in those with systemic manifestations. We aimed to describe
the frequency and clinical manifestations of isolated CNS histiocytic
neoplasms.
Methods: This was a retrospective observational study of all adult
patients (age ≥ 18 years) diagnosed with histiocytic neoplasms at a ter-
tiary care referral center from January 1, 1996 to February 28, 2023.
Inclusion criteria were as follows: 1) diagnosis of a histiocytic neo-
plasm based on biopsy and appropriate clinical phenotype; 2) isolated
CNS involvement without other organ systems based on whole body
positron emission tomography or computed tomography of the chest,
abdomen, pelvis along with bone scan, if available; and 3) sufficient
medical records for review.
Results: Isolated CNS involvement was seen in 15 of 384 cases
(3.9%) of confirmed histiocytic neoplasms. This included 5 of 236
(2.1%) with LCH, 4 of 102 (3.9%) with ECD, and 6 of 46 (13.0%)
with RDD. Headache (7/15, 47%), diabetes insipidus (7/15, 47%),
and weakness (6/15, 40%) were the 3 most common neurological
symptoms. All 5 LCH patients presented with diabetes insipidus with
endocrinologic findings related to having pituitary and/or hypothala-
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mic involvement. Two of 4 ECD patients also had diabetes insipidus.
Seizure was present in 4 of 6 RDD patients. BRAF V600E mutation
was present in 4 of 10 patients tested: 3 with ECD and 1 with LCH.
Management was individualized to patients with 57% showing clini-
cal response and 71% showing radiologic response at 3 months since
diagnosis.
Conclusion: Isolated CNS involvement in histiocytic neoplasms is rare
and may occur most frequently with RDD. The presence of diabetes
insipidus and persistently enhancing lesions on brain or spine magnetic
resonance imaging should raise consideration of histiocytic neoplasms.
CUTANEOUS NON-LANGERHANS CELL HISTIOCYTOSIS WITH
HISTOPATHOLOGY FEATURES OF ROSAI-DORFMAN DISEASE
WITH AN ONCOGENIC IRF2BP2::NTRK1 FUSION
Bo-Yee Ngan1 , Rose Chami1 , Cynthia Hawkins1 , Anthony Arnoldo1 ,
Oussama Abla2
1 Division of Pathology, Department of Pediatric Laboratory Medicine, The
Hospital for Sick Children, Toronto, ON, Canada; 2 Division of Hematol-
ogy/Oncology, Department of Pediatrics. The Hospital for Sick Children,
Toronto, ON, Canada
Purpose: Cutaneous Rosai-Dorfman disease (RDD) is a rare non-
Langerhans cell histiocytosis with unknown etiology. According to
the SHML registry, 16% frequency occur in skin and soft tissues.
Apart from the familial type with germline SLC29A3 mutation, some
RDD have NRAS, KRAS, MAP2K1, BRAF and ARAF mutations. We
report a case where an oncogenic IRF2BP2::NTRK1 fusion was
identified.
Methods: A 16-year-old boy underwent a biopsy of single skin
nodule that developed on the scalp. Lesion was slow growing
and he was asymptomatic. Systemic involvement was absent. He
had no lymphadenopathy and his blood work was normal. Com-
bined histopathology, immunopathology and molecular analysis were
used.
Results: Skin biopsy showed the full thickness of the dermis, from the
papillary dermis to the deep reticular dermis, contained an extensive
infiltrate of medium to large macrophages/histiocytes. Some were
multinucleated. Some of these macrophages exhibit emperipolesis.
Immunohistochemistry (IHC) with activated macrophage marker
CD163 was positive. They are S100+; but Langerin, CD1a Fac-
tor XIIIa and BRAF were negative. Nuclei-acids were extracted
from the paraffin embedded tissues and underwent Targeted
Next Generation Sequencing using Tru-sight RNA Seq platform.
An oncogenic IRF2BP2::NTRK1 fusion transcript was detected;
other RDD associated somatic genes mutations were screened and
were negative. The functional significance of the fusion was vali-
dated using IHC staining for NTRK and the RDD cells were nuclear
positive.
Conclusions: This is the first example of oncogenic IRF2BP2::NTRK1
fusion in cutaneous RDD. Another example of this fusion gene was
reported by Chan WH et.al. (JAAD Case Reports 2020;6:1156-8) in a
case of progressive nodular histiocytosis xanthogranulomatosis after

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autologous hematopoietic cell transplantation for large B cell lym-
phoma. The clinical, histopathology and IHC features were entirely dif-
ferent than our patient. We conclude that the molecular abnormalities
of non-Langerhans Cell Histiocytosis are heterogeneous and highlight
that oncogenic IRF2BP2::NTRK1 fusion can occur in cutaneous RDD.
HOW TO TREAT DIFFICULT HISTIOCYTOSES: EXPERIENCE OF
THE UK HISTIOCYTOSIS ADVISORY PANEL
Trung Nguyen1 , Olga Slater2 , Vasanta Nanduri3 , Simon Bomken4 ,
Robin Dowse5 , Cor van den Bos6 , Hugh Bishop7 , Talha Munir8 ,
Mark Bishton9 , Nikesh Chavda10 , Kristian Bowles11 , Christopher
McNamara1 , Satyen Gohill1 , Matthew Collin12
1 University College London Hospitals, London, UK; 2 Great
Ormond Street Hospital, London, UK; 3 Watford General Hospital,
London, UK; 4 Great North Children’s Hospital, Newcastle, UK; 5 Royal
Marsden Hospital, London, UK; 6 Princess Máxima Center for Pediatric
Oncology, Utrecht, Netherlands; 7 Royal Aberdeen Children’s Hospital,
Aberdeen, UK; 8 St James’s University Hospital, Leeds, UK; 9 Nottingham
City Hospital, Nottingham, UK; 10 University Hospitals Bristol and Weston,
Bristol, UK; 11 Norfolk and Norwich University Hospital, Norwich, UK;
12 Northern Centre for Cancer Care, Newcastle, UK
Purpose: The UK Histiocytosis Advisory Panel (UKHAP) was formally
established in 2013 to provide advice for management of paediatric
patients with histiocytic disorders. It has since expanded to include
both paediatric and adult clinicians with a special interest in histiocytic
disorders and discusses patients of all ages. Recently, there has been
significant increase in the number of referrals. We present an overview
of the most recent two-year period.
Methods: Patients were referred by treating clinicians at diagnosis,
during management, or at time of refractory or reactivated dis-
ease. Meetings were held via teleconferencing fortnightly. Referring
clinicians were invited to present their cases and treatment recommen-
dations were made by the UKHAP.
Results: During the two-year period from 1 July 2021 to 30 June
2023, 262 cases were referred from 71 institutions: 64 institu-
tions within the United Kingdom and Ireland, and 7 institutions
from the Netherlands, Switzerland, Serbia, Croatia, Malta, Israel and
India. Patient age ranged from 4 weeks to 89 years, with 31.7%
(83/262) being paediatric-aged and 68.3% (179/262) being adult-
aged (mean age 34.3 years). Langerhans cell histiocytosis repre-
sented 46.7% of cases (122/262); Erdheim-Chester disease 17.4%
(46/262); Rosai-Dorfman disease 11.2% (29/262); histiocytic sarcoma
8.7% (23/262); juvenile xanthogranuloma 6.2% (16/262); other non-
Langerhans dendritic cell neoplasms 6.2% (16/262); ALK-positive
histiocytosis 1.7% (4/262); and other entities 2.1% (5/262). Treatment
recommendations were made by the UKHAP in all cases, although
responsibility for final treatment decisions remained with referring
clinicians.
Conclusion: Decision-making in histiocytic disorders can be com-
plex, particularly when standard-of-care options are exhausted or
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ABSTRACTS
optimal treatment is unclear. The UKHAP provides expert-based
recommendations to improve patient outcomes across all ages.
Future directions include review of patients receiving inhibitors for
improving access to treatment, ongoing follow-up for outcome anal-
ysis, continued recruitment of patients discussed in the UKHAP
to the UK Histiocytosis Registry, and expansion of international
membership.
SOLITARY BONE LESIONS IN CHILDREN WITH LANGERHANS
CELL HISTIOCYTOSIS: A SURGICAL DISEASE OR NOT?
Suheyla Ocak1 , Ayse Kalyoncu Ucar2 , Sebuh Kurugoglu2 , Nil
Comunoglu3 , Mahmut Kursat Ozsahin4 , Baris Kucukyoruk5 , Ali
Metin Kafadar5
1 Istanbul Universsity- Cerrahpasa, Cerrahpasa Faculty of Medicine, Depart-
ment of Pediatric Hematology and Oncology, Istanbul, Turkey; 2 Istanbul
Universsity- Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of
Pediatric Radiology, Istanbul, Turkey; 3 Istanbul Universsity- Cerrahpasa,
Cerrahpasa Faculty of Medicine, Department of Pathology, Istanbul, Turkey;
4 Istanbul Universsity- Cerrahpasa, Cerrahpasa Faculty of Medicine, Depart-
ment of Orthopedics, Istanbul, Turkey; 5 Istanbul Universsity- Cerrahpasa,
Cerrahpasa Faculty of Medicine, Department of Neurosurgery, Istanbul,
Turkey; 5 Istanbul Universsity- Cerrahpasa, Cerrahpasa Faculty of Medicine,
Department of Neurosurgery, Istanbul, Turkey
The aim of the study is to present clinical and prognostic features chil-
dren with single bone lesion LCH treated in our institution. Between
2000- 2023, 64 children (20 girls, 44 boys) with monostotic LCH were
admitted to our department. Median age on diagnosis was 7,4 years
(range 1,7-15,9 yrs.). All but 2 children had either pain or swelling
on the lesion site. Standard baseline laboratory evaluation with CT
or MRI of the primary lesion were performed. All but 3 patients had
histologic confirmation of LCH. The lesions were in calvarium (n=32),
craniofacial bones (n=13), extremities (n=10), vertebra (n=4), pelvic
bones and thoracic cage (n=5). The surgical resection/curettage was
the most common first-line treatment (43/64 cases). Overall, 27/32
children had non-cns risk calvarial lesions and 8 small lesions located
on the long bones had surgical intervention. After biopsy or surgical
resection, 15 children received chemotherapy (vinblastine and pred-
nisolone) for 6-12 months. Wait and watch strategy was resulted in
spontaneous regression of the lesion in 5 children (without biopsy
in 3) in 9-12 months. In 6 children, local or distant bony recurrence
was observed and treated with chemotherapy. The median follow-
up duration was 5,3 years (3 months-18,3 years). At last control
56 patient were alive with no active bone lesion. Scoliosis, diabetes
insipidus and neurodegenerative LCH were developed in 3, 2 and 1
children, respectively. The growing data supports the treatment of
monostotic bone lesion in LCH by conservative methods. In Turkey,
the primary treatment of bone lesions in LCH are mostly at the sur-
geons’ discretion. Our results showed that awareness for the new
treatment approaches for monostotic LCH should be increased in our
country.

ABSTRACTS
CENTRAL NERVOUS SYSTEM INVOLVEMENT IN LANGERHANS
CELL HISTIOCYTOSIS: DIFFERENT SHADES OF THE DISEASE
Suheyla Ocak1 , Ayse Kalyoncu Ucar2 , Sebuh Kurugoglu2 , Osman
Kızılkılıc3 , Nil Comunoglu4 , Serhat Guler5
1 Istanbul University- Cerrahpasa Faculty of Medicine, Department of Pedi-
atric Hematology and Oncology,Istanbul, Turkey; 2 Istanbul University- Cer-
rahpasa Faculty of Medicine, Department of Pediatric Radiology, Istanbul,
Turkey; 3 Istanbul University- Cerrahpasa Faculty of Medicine, Department
of Neuroradiology, Istanbul, Turkey; 4 Istanbul University- Cerrahpasa Fac-
ulty of Medicine, Department of Pathology, Istanbul, Turkey; 5 Istanbul
University- Cerrahpasa Faculty of Medicine, Department of Pediatric Neu-
rology, Istanbul, Turkey
Central nervous system involvement in Langerhans Cell Histiocytosis
(CNS-LCH) can occur as isolated LCH of the brain, in the setting of
MS-LCH or in the form of neurodegeneration. As the disease has a
wide clinical and radiological heterogeneity, diagnosis and treatment
is challenging. Herein, 5 children with CNS LCH are presented. Since
2018, 4 girls,1 boy (age range 10-14 years) were diagnosed with CNS -
LCH other than isolated pituitary stalk involvement. Three children had
previous diagnoses of LCH in the form of Pulmonary involvement (#1),
Multisystem Disease (#2) and CNS-Risk bone disease (#5). Patients #2,
#3 and #5 had Diabetes Insipidus on admission. Headache and cogni-
tive deterioration were the main complaints of 4/5 patients and gait,
and speech disturbances were the presenting symptoms in one. Two
children were diagnosed 2 and 4 years after the onset of symptoms, one
child had CNS involvement 5 year after the primary diagnosis. Radi-
ologically typical imaging findings in posterior fossa structures were
noted in all. In one patient choroid plexus involvement was present.
Based on the clinical and radiological findings, 2 children received IVIG,
1 child received systemic chemotherapy, 1 child received systemic
chemotherapy and targeted therapy. Patient #5 was given supportive
treatment due to familial disproval of any systemic therapy. Treat-
ment resulted in slight clinical improvement on neurological scales with
stable radiological findings in 2 patients, stable clinical and radiologi-
cal disease in one patient. In patient #5 both clinical and radiological
improvement were noted on follow-up. Due to its rarity and low level
of awareness, the time to diagnosis of CNS-LCH was long in 3 of
our patients with more pronounced clinical and radiological presen-
tations. A standard algorithm for surveillance and diagnosis of CNS
involvement is necessary in children with LCH.
CLINICAL UTILITY OF DEXAMETHASONE PALMITATE IN
CHILDREN WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
FOLLOWING ALLOGENEIC HEMATOPOIETIC CELL
TRANSPLANTATION
Rintaro Ono1 , Kenichi Sakamoto2 , Takehiko Doi3 , Ryu Yanagisawa4 ,
Akira Morimoto5,6 , Hirokazu Kanegane7 , Yozo Nakazawa8 , Yoko
Shioda9
1 Department of Pediatrics, St. Luke’s International Hospital, Tokyo,
Japan; 2 Department of Pediatrics, Shiga University of Medical Science,
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S33 of S64
Shiga, Japan; 3 Department of Pediatrics, Hiroshima University Graduate
School of Biomedical and Health Sciences, Hiroshima, Japan; 4 Division
of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan;
5 Department of Pediatrics, Jichi Medical University School of Medicine,
Tochigi, Japan; 6 Department of Pediatrics, Showa Inan Hospital, Koma-
gane, Japan; 7 Department of Child Health and Development, Gradu-
ate School of Medical and Dental Sciences, Tokyo Medical and Den-
tal University (TMDU), Tokyo, Japan; 8 Department of Pediatrics, Shin-
shu University School of Medicine, Matsumoto, Japan; 9 Children’s Can-
cer Center, National Center for Child Health and Development, Tokyo,
Japan
Post-transplant hemophagocytic lymphohistiocytosis (PT-HLH) is a
severe complication of allogeneic hematopoietic cell transplantation
(HCT). Although systemic corticosteroids and low-dose etoposide
(ETP) have been used to treat PT-HLH, no standard treatment has
been established. Dexamethasone palmitate (DP) contains a combina-
tion of dexamethasone and a lipid emulsion and is selectively taken up
by activated macrophages. As few case reports have demonstrated the
usefulness of DP for PT-HLH, we conducted a nationwide survey in
facilities participating in the Japanese Pediatric Leukemia/Lymphoma
Study Group. A total of 23 (14 boys and 9 girls; median age, 5 years)
DP-treated pediatric patients with PT-HLH diagnosed within 30 days
after HCT were identified. The median time to PT-HLH diagnosis after
HCT was 18 (range, 7-30) days. Of the 23 patients, 15 received DP
therapy without ETP (DP first group), 3 received DP therapy in con-
currence with ETP (DP concurrent group), and 5 received DP therapy
after ineffective ETP therapy (DP delayed group). DP therapy was
assessed as effective for HLH by their attending physicians in 14 of
15 (93%), 2 of 3 (67%), and 2 of 5 (40%), and graft failure developed
in 3, 2, and 1 patients in each group, respectively. DP-related adverse
events were few, with only three infectious events. Thus, DP would be
effective against PT-HLH without ETP and may be effective to some
extent even for ETP-refractory PT-HLH. Further prospective studies
are warranted.
CLINICO-GENOMIC ASSOCIATIONS IN PEDIATRIC
LANGERHANS CELL HISTIOCYTOSIS - A COHORT STUDY
Daria Osipova, Elena Raykina, Evelina Lyudovskikh, Yulia Kozlova, Irina
Kalinina, Dmitry Evseev, Michael Maschan
Dmitry Rogachev National Medical Research Center Of Pediatric Hematol-
ogy, Oncology and Immunology, Moscow, Russia
Purpose: Somatic BRAF V600E mutation is detected in 60% of patients
with LCH. In addition to BRAF V600E, the most common alterations in
LCH are in MAP2K1 and BRAF exon12 in-frame deletions. These muta-
tions are associated with different LCH presentations and affected
organs. In this study we evaluated clinic-genomic associations in the
pediatric LCH cohort.
Methods: mutant-specific PCR and Sanger sequencing (99 patients)
were used to detect the BRAF V600E mutation in FFPE samples.
For BRAF-negative patients (58/99) - NGS was performed using a
customized targeted gene panel.

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Results: Among 58 BRAF-negative patients, 13 BRAF exon12 in-
frame deletions, 21 MAP2K1 alterations, 3 low-level BRAF V600E,
1 BRAF V600A, 2 KRAS, 2 HRAS, 1 NRAS variants were deter-
mined. In 15 patients no significant genetic variants were identified.
Among patients with single system disease 4 had BRAF V600E, 3
- BRAF 12ex del, 4 - MAP2K1; in patients with multisystem dis-
ease without risk organ involvement (MS RO-) 15 had BRAF V600E
and 9 - 12ex del, 14 - MAP2K1; in MS RO+ patients 25 had
BRAF V600E and 1 - 12ex del, 3 - MAP2K1. Skin involvement
was found in 30 patients with BRAF V600E, in 7 patients with
BRAF 12ex del, 5-MAP2K1. Bones involvement - in 36 patients with
BRAF V600E, 10 with BRAF 12ex del, 15-MAP2K1. Lungs involve-
ment - in 9 patients with BRAF V600E, 8 with BRAF 12ex del,
6-MAP2K1.
Conclusions: Analysis of our cohort showed that BRAF V600E is sig-
nificantly associated with multisystem form of LCH with risk organ
involvement (p=0.009). No significant differences in bones involve-
ment were identified, but the deletions in the 12th exon of BRAF
are significantly associated with lungs involvement compared to the
BRAF V600E group (p=0.049), and patients with BRAF V600E are
more likely to have skin involvement compared to MAP2K1 group
(p=0.027).
SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA
ASSOCIATED WITH HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS: A SYSTEMATIC REVIEW
Wenxin Ou, Yunze Zhao, Ang Wei, Honghao Ma, Liping Zhang,
Hongyun Lian, Qing Zhang, Dong Wang, Zhigang Li, Tianyou Wang, Rui
Zhang
Beijing Children’s Hospital Capital Medical University, China
Purpose: To review the clinical features of subcutaneous
panniculitis-like T-cell lymphoma complicated with hemophagocytic
lymphohistiocytosis(SPTCL-HLH).
Methods: We searched the Web of Science, Embase, Cochrane
Library, and PubMed databases. The keywords were subcutaneous
panniculitis-like T-cell lymphoma and hemophagocytic lymphohistio-
cytosis or hemophagocytic syndrome.
Results: A total of 45 reports, including 63 patients with SPTCL-HLH,
were included. Twelve patients detected gene mutations, includ-
ing 11 with the HAVCR2 gene mutation and 1 with the STXBP2
gene mutation. Compared with the wild-type group, patients in the
mutated group were younger(25.16±13.68 years vs. 14.55±9.06
years, P=0.017), and the autoantibody positive rate was higher(12.5%
vs. 71.4%, P=0.006). Four patients were treated with anthracycline-
based chemotherapy after controlling HLH, with an overall response
rate(ORR) of 100%. The main treatment target of 17 patients was to
control HLH, yielding an ORR of 88.2%. The corticosteroid monother-
apy experienced a higher recurrence rate than the corticosteroids
plus other immunoregulatory therapy(66.7% vs. 0.0%, P=0.029). Eigh-
teen patients received initial anthracycline-based chemotherapy, and
50.0% reached remission. The ORR of initial chemotherapy aiming
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ABSTRACTS
at controlling HLH was higher than those of anthracycline-based
chemotherapy(88.2% vs. 50.0%, P=0.015). The ORR was higher in
patients initially controlled for HLH versus chemotherapy without
HLH control first(90.5% vs. 61.5%, P=0.024). Sixteen patients received
stem cell transplantation(SCT). Fifteen patients, including 5 with
relapsed/refractory SPTCL-HLH, responded well and survived after
SCT. There was a difference in the OS rate among patients of differ-
ent age, and patients aged 40 to 60 had the lowest 2-year OS rate
(66.7%±19.2%).
Conclusion: Patients with HAVCR2 gene mutations are younger
and likely to be misdiagnosed with autoimmune diseases. Initial
treatment of corticosteroids plus immunoregulatory attaches signifi-
cance to avoiding aggressive therapies. Intensive anthracycline-based
chemotherapy can also induce long-term remission for aggressive dis-
ease. SCT is still a reliable strategy. Older patients with SPTCL-HLH
may be associated with a lower survival rate.
EFFICACY OF CYTARABINE MONOTHERAPY AND CYTARABINE
PLUS CLADRIBINE IN PEDIATRIC REFRACTORY/RELAPSED
LANGERHANS CELL HISTIOCYTOSIS
Wenxin Ou, Honghao Ma, Ang Wei, Lei Cui, Liping Zhang, Hongyun
Lian, Ying Yang, Dong Wang, Li Li, Junye Du, Li Zhang, Zhigang Li,
Tianyou Wang, Rui Zhang
Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncol-
ogy; National Key Discipline of Pediatrics (Capital Medical University); Key
Laboratory of Major Disease in Children, Ministry of Education; Beijing Chil-
dren’s Hospital, Capital Medical University, National Center for Children’s
Health, China
Purpose: Objective To analyze the efficacy and safety of
Cytarabine(Ara-C) monotherapy and Ara-C combined with
Cladribine(2-CDA) in pediatric refractory/relapse(R/R) Langerhans
cell histiocytosis(LCH) treatment.
Methods: We retrospectively analyzed children with R/R LCH, who
accepted Ara-C monotherapy and Ara-C plus 2-CDA treatment in
the same period at Beijing Children’s Hospital, from January 2014 to
December 2019.
Results: A total of 190 children were enrolled, including 96 of
Ara-C monotherapy and 94 of Ara-C plus 2-CDA treatment. At
diagnosis, circulating cell-free BRAFV600E was positive in 61 of
127(48.03%) patients. The overall response rate(ORR) for monother-
apy was lower than that of combination therapy(P=0.273). The 3-
year event free survival(EFS) rate for combination treatment was
higher than that of monotherapy(P=0.024). The 3-year EFS of com-
bination treatment in the MS-RO+ group was higher than that of
monotherapy, but there was no significant difference in 3-year EFS
between the SS-RO- and the MS-RO- group(P=0.047, 0.280 and
0.280). The incidence of myelosuppression and gastrointestinal reac-
tions during monotherapy was lower than that during combination
treatment(P<0.001 and P<0.001). All patients had no chemotherapy-
related deaths. The recovery rate of abnormal pituitary MRI signal
in patients without diabetes insipidus was lower in the Ara-C group

ABSTRACTS
than in the 2-CDA+Ara-C group(P=0.053). Compared to monother-
apy, the symptoms and imaging abnormalities of children with dia-
betes insipidus improved after combination treatment(P=0.066 and
0.526). The thickening signal of pituitary stalk improved or returned
to normal during the two therapies(P=1.000). The cure rate in chil-
dren with pulmonary involvement after combination treatment was
higher(P=0.003).
Conclusion: Compared to Ara-C monotherapy, the 3-year EFS is higher
in Ara-C plus 2-CDA treatment, especially in the MS-RO+ group. All the
side effects are mild to tolerate, but the incidence of myelosuppression
and gastrointestinal reactions in monotherapy is lower. Combination
therapy is more effective in children with lung or pituitary involvement,
especially with diabetes insipidus.
LIVER INVOLVEMENT OF CHILDREN WITH LANGERHANS CELL
HISTIOCYTOSIS
Wenxin Ou, Xinshun Ge, Ang Wei, Honghao Ma, Liping Zhang, Hongyun
Lian, Lei Cui, Dong Wang, Zhigang Li, Tianyou Wang, Rui Zhang
Beijing Children’s Hospital Capital Medical University, China
Purpose: To analyze the features and prognosis of liver involvement in
children with Langerhans cell histiocytosis(LCH).
Methods: We enrolled children with LCH at Beijing Children’s Hospital
between 2016 and 2022. They were divided into the liver group and
the non-liver group based on liver involvement. According to bile duct
involvement, hepatic LCH were further divided into the bile duct group
and the non-bile duct group.
Results: A total of 899 children with LCH were included, including
130 in the liver group and 769 in the non-liver group. The incidence
of fever, rash, splenomegaly, ear discharge, polyuria and polydipsia
in the liver group was higher than in the non-liver group(P<0.001,
<0.001, <0.001, <0.001, and 0.013), and the mutation abundance of
serum cell-free BRAFV600E was also higher(P<0.001). Liver biopsies
demonstrated periductal infiltration of inflammatory cells and Langer-
hans cells. A total of six children died, and they were all in the liver
group. The 2-year overall survival rate(OS) and liver-related event-free
survival rate(EFS) in the liver group were lower than in the non-
liver group(P<0.001 and 0.002). EFS of patients with hepatic LCH
was lower after first-line treatment than after second-line(cytarabine
with/without cladribine) or targeted therapy(P=0.011). The 2-year OS
and liver-related EFS in the bile duct group were also lower than in the
non-bile duct group(P=0.036 and <0.001). In our study, four patients
received liver transplantation because of liver cirrhosis, and the last
evaluation was AD-Better. One patient had disease reactivation 18
months post-transplant.
Conclusion: LCH patients with liver involvement are more likely to
have multisystem involvement, and the mutation abundance of serum
cell-free BRAFV600E is higher. Langerhans cells show a marked affin-
ity for the bile ducts. LCH with liver involvement, especially biliary
involvement, suggest a poor prognosis. The second-line or targeted
therapy may be an effective chemotherapy regimen for LCH with liver
involvement.
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CLINICAL CHARACTERISTICS OF PERIPHERAL LYMPHOCYTE
SUBTYPES IN CHRONIC ACTIVE EPSTEIN-BARR VIRUS
INFECTION
Wenxin Ou, Ang Wei, Yunze Zhao, Honghao Ma, Liping Zhang,
Hongyun Lian, Qing Zhang, Dong Wang, Zhigang Li, Tianyou Wang, Rui
Zhang
Beijing Children’s Hospital Capital Medical University, China
Purpose: To analyze the clinical characteristics of peripheral Epstein-
Barr virus (EBV)-infected lymphocyte subtypes in children with chronic
active EBV infection (CAEBV).
Methods: The levels of peripheral EBV infection of CD4+T cells,
CD8+T cells, and CD56+NK cells were determined by flow cytome-
try and qPCR in hospitalized patients with CAEBV from July 2017 to
July 2022, and their association with clinical features was analyzed
retrospectively.
Results: A total of 112 children with CAEBV were evaluated in the
study, including 56 with HLH. Of them, CD4+ type, CD8+ type, and
CD56+ type was defined in 44, 21, and 47 patients, respectively.
Patients with CD8+T-cell type had a significantly higher frequency of
rash, while hepatomegaly was more common in patients with CD4+T-
cell type. There was no significant difference in pathologic grade or
incidence rate of HLH among different subtypes of CAEBV. At the
end of follow-up, 15 children had died, with a median follow-up time
of 3.36 years. Generally, the 3-year overall survival rate (OS) was
79.3%±6.1%, and patients with CD8+T-cell type had the lowest OS
rate (P=0.017). Meanwhile, Patients with grade III had a lower 3y-
OS rate than those with grade I (P=0.020). As for treatment, patients
treated with chemotherapy and hematopoietic stem cell transplanta-
tion had a better prognosis (P=0.001). In multivariate analysis, rash,
HLH, CD8+T-cell type, and no decrease of plasma EBV-DNA after
treatment were indicated as independent factors of poor prognosis
(P=0.002, 0.024, 0.022, and 0.012, respectively).
Conclusion: In children with CAEBV, the rash was more frequent in
patients with CD8+T-cell type, whereas patients with CD4+T-cell type
were more likely to develop hepatomegaly. There was no significant
difference in pathologic grade or incidence rate of HLH among dif-
ferent subtypes of CAEBV. Patients with CD8+T-cell type had a poor
prognosis despite receiving chemotherapy or further HSCT.
CYTOKINE RELEASE SYNDROME IN CHILDREN WITH VIRAL
LOWER RESPIRATORY TRACT INFECTIONS AT A TERTIARY
CARE CENTER IN EASTERN INDIA: RETROSPECTIVE
OBSERVATIONAL STUDY
Priyankar Pal1 , Jigna N Bathia1 , Maria Arjumand2 , Pratiksha Khatua3
1 Pediatric Rheumatology, Institute of Child Health, Kolkata, India; 2 Pedi-
atric Medicine, Institute of Child Health, Kolkata, India; 3 Pediatric Infectious
Diseases, Institute of Child Health, Kolkata, India
Purpose: Infection as a cause of hypercytokinemia is now increasingly
seen. In the recent upsurge of viral lower respiratory tract infec-
tions (LRTI), especially adenovirus, many patients were noted to suffer

S36 of S64
from CRS. Not all satisfied the HLH 2004 criteria but required anti-
inflammatory therapies. With no available guidelines we intend to
describe our experience in such patients.
Methods: Retrospective observational study on children with CRS
due to viral LRTI, admitted from January 2023 to March 2023, at
Institute of Child Health, Kolkata. CRS was diagnosed on basis of con-
tinuous fever, multisystem involvement, falling platelets, transaminitis
and elevated ferritin with negative cultures. RESULTS :20 patients
were included. 14 had Adeno virus, 1 for human metapneumovirus
and 1 Corona 229e. 13 were males, 7 were females. All had contin-
uous fever, 17 had tachypnoea, 17 had CNS involvement (irritability,
lethargy or seizures), 15 had oedema, 19 had hepatomegaly and 9 had
splenomegaly. The median age was 36 months, median day of fever at
admission was 4 days, median day of fever at diagnosis was 13 days.
Median investigations at diagnosis was Hb 9.15 mg/dl, total leuko-
cyte count 4490/cmm, absolute neutrophil count 2088, platelet 1.15
lakhs/cmm, CRP 27.6 mg/L, SGOT 116.5 U/l, Albumin 3.05g/l, Ferritin
2954 ng/ml, triglyceride 162mg/dl. CRP was noted to be normal at diag-
nosis in 7 patients. 18 patients received intravenous dexamethasone, 1
hydrocortisone and 1 required no intervention. Fever was the first to
respond to therapy. Encephalopathy and oedema subsided 4 to 5 days
after initiation of therapy.
Conclusion: High degree of suspicion is required to diagnose CRS.
Criteria of HLH-2004 maybe not fulfilled. Multisystem involvement,
trends in cytopenia with rising ferritin, transaminitis and fall in albumin
helps in early identification. CRP may not always be raised. Early iden-
tification and initiation of immunosuppression is the key to a successful
outcome.
HIGH PREVALENCE OF VULVAR AND HEPATIC
MANIFESTATIONS IN A SERIES OF 18 HISTIOCYTOSIS
PATIENTS WITH BRAF DELETION MUTATIONS
Matthias Papo1 , Julien Haroche1 , Malik Da Silva2 , Zofia Hélias-
Rodzewicz2 , Vsevolod Potapenko3 , Suzanna Bota4 , Vanessa Leguy
Seguin5 , Stephane Dominique6 , Marion Campana7 , Visal Keo8 , Zahir
Amoura1 , Jean-François Emile2
1 Internal medicine, Pitié Salpêtrière Hospital, Sorbonne University, Paris,
France; 2 Anatomopathology Laboratory, Ambroise Paré Hospital, APHP,
Paris-Saclay University, Boulogne-Billancourt, France; 3 Municipal educa-
tional hospital №31, Saint-Petersburg, Russia; 4 Pneumology Department,
Charles Nicol Hospital, Rouen, France; 5 Internal medicine Department,
François Mitterand Hospital, Dijon, France; 6 Pneumology Department,
Charles Nicol Hospital, Rouen, France; 7 Pneumology Department, Source
hospital, Orléans, France; 8 Internal medicine departement, Bayonne hospi-
tal, Bayonne France
Introduction: L-group histiocytosis (Erdheim-Chester disease ( ECD)
and Langerhans-cell histiocytosis (LCH)) are multi-system diseases
characterized by histiocyte infiltration in several organs. These his-
tiocytes frequently harbor activating somatic mutations of the MAP
Kinase pathway. Many of these mutations are frequently associated
with a specific phenotype. Our objective was to describe character-
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ABSTRACTS
istics of patients with histiocytosis and a particular BRAF-deletion
mutation.
Methods: We performed a retrospective multi-center study.
Patients were identified through the Histiocytosis national referral
center pathology laboratory in Ambroise-Paré Hospital (Boulogne-
Billancourt) in which all suspected diagnosis of histiocytosis samples
are sent for proofreading and sequencing. Samples are sequenced with
a specific panel next generation sequencing. We identified patients
with BRAFdel mutations and contacted the centers for clinical,
morphological, and biological datas.
Results: Twenty-four patients with a BRAFdel mutation were identi-
fied. Data were available for 18 of them. Most patients (n=17) had
LCH (one with an ECD component) and one had an ECD. Median age
at diagnosis was 50 years (IQR 35-78). The most frequent manifesta-
tions were hepatic (n=8, 44%) and vulvar (8/10 female gender patients,
80%). Other manifestations were cystic interstitial lung disease (n=6),
lytic bone lesions (n=7), diabetes insipidus (n=6), panhypopituitarism
(n=3), pachymeningitis (n=2), long bone osteosclerosis (n=1), perire-
nal infiltration (n=1), salivary gland infiltration (n=1) and digestive
track infiltration (n=1). Hepatic manifestation was sclerosing cholan-
gitis in all cases, and 5/6 patients had histiocytic infiltration in liver
biopsy. Two patients received cobimetinib, that resulted in partial
remission and stable disease at 6 months. After a median follow-
up of 43 (IQR 11-315 months), one patient had died from unknown
cause.
Conclusion: BRAF-deletion mutations in histiocytoses are associated
with a specific LCH pattern with high prevalence of hepatic and vul-
var involvements. These manifestations should be carefully screened
in these patients.
EXPANDED ASSESSMENTS OF GERMLINE GENETIC VARIANTS
IDENTIFY ADDITIONAL ANCESTRY-SPECIFIC RISK LOCI FOR
LANGERHANS CELL HISTIOCYTOSIS
Erin Peckham-Gregory1,2,3 , Priya Shetty1,2,4 , Erik Stricker1,2 , Danielle
Mitchell1,2 , Howard Lin1,2 , Brooks Scull1,2 , Erik Ehli5 , Christel Davis5 ,
Kenneth McClain1,2 , Philip Lupo1,2,3 , Carl Allen1,2,6 , and Michael
Scheurer1,2,3
1 Texas Children’s Cancer and Hematology Center, Texas Children’s Hospital,
Houston, TX USA; 2 Department of Pediatrics, Section of Hematology-
Oncology, Baylor College of Medicine, Houston, TX USA; 3 Center for
Epidemiology and Population Health, Baylor College of Medicine, Houston,
TX USA; 4 Department of Medicine, Baylor College of Medicine, Houston, TX
USA; 5 Avera Institute for Human Genetics, Sioux Falls, SD USA; 6 Program in
Translational Biology and Molecular Medicine, Baylor College of Medicine,
Houston, TX USA
Purpose: LCH is known to be driven by somatic MAPK mutations and
exhibit higher incidence among some populations (e.g., Hispanic) more
than others. Mechanisms underlying germline risk in LCH remains
largely unknown. We previously identified a risk variant in SMAD6
associated with a 3-fold increase in LCH risk. This study further
elucidates the role of SMAD6 variation on LCH risk.

ABSTRACTS
Methods: Independent of our discovery GWAS, we sequenced SMAD6
in 466 additional LCH cases and compared them to aggregate-level
SMAD6 data from ∼15,694 non-cancer controls in gnomAD v2.1.1. In
parallel, we conducted a GWAS of 319 of those cases and 9,921 con-
trols from the ADDHealth study. Analyses were conducted in Plink and
STATAv17.1.
Results: The case-control study of targeted SMAD6 identified 49
SMAD6 variants associated with LCH (P-values ranging from 4.54x10-
28 to 2.9x10-4), including our original GWAS locus. The linkage
disequilibrium between the top 5 variants varied across ancestral
groups. All cases with two copies of the alternate alleles in the top 2
SNPs had BRAF V600E+ lesions. From the new GWAS, 31 novel loci
were associated with LCH at P-value=5x10-8. Principal components
(PC) analysis revealed that an ancestral population for Hispanics is
significant at SMAD6 loci surrounding our discovery hit, suggesting
that this may be an ancestry-specific variant.
Conclusion: We identified additional support that inherited genetic
variation impacts LCH risk, and that variant-specific risk may differ by
ancestral group. We are analyzing newly generated SMAD6 targeted
sequence and GWAS data in an independent set of case-parent trios
(n=185) to integrate with the findings reported here. Next steps aim
to determine the role of variants on clinical characteristics (e.g., ances-
try, age at onset, BRAF V600E). Our work suggests an important and
complex role of germline variants and ancestry in LCH pathogenesis.
OUTCOME OF 148 PATIENTS WITH FAMILIAL
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM THE
ITALIAN REGISTRY
Francesco Pegoraro1,2 , Aurora Chinnici2,3 , Linda Beneforti2,3 ,
Michele Tanturli4 , Irene Trambusti2,5 , Carmela De Fusco6 , Con-
cetta Micalizzi7 , Fabio Timeus8 , Simone Cesaro9 , Stefania Gaspari10 ,
Fabiola Dell’Acqua11 , Alessandra Todesco12 , Maurizio Aricò13 , Claudio
Favre2 , Annalisa Tondo2 , Maria Luisa Coniglio2 , Elena Sieni2
1 Department of Health Sciences, University of Florence, Florence, Italy;
2 Pediatric Hematology Oncology, Meyer Children’s Hospital IRCCS, Flo-
rence, Italy; 3 Department of Neurosciences, Psychology, Drug Research
and Child Health (NEUROFARBA), University of Florence, Florence, Italy;
4 Department of Experimental and Clinical Biomedical Sciences “Mario
Serio”, University of Florence, Florence, Italy; 5 Department of Clinical and
Experimental Medicine, University of Pisa, Pisa, Italy; 6 Pediatric Oncology,
AORN Santobono-Pausilipon, Pausilipon Hospital, Naples, Italy; 7 Pediatric
Hematology Oncology IRCCS Istituto Giannina Gaslini, Genova, Italy;
8 Pediatric Hematology Oncology, Stem Cell Transplantation and Cell Ther-
apy Division, A.O. Cittí della Salute e della Scienza-Ospedale Infantile
Regina Margherita, Turin, Italy; 9 Paediatric Haematology Oncology, Depart-
ment of Mother and Child, Azienda Ospedaliera Universitaria Integrata,
Verona, Italy; 10 Pediatric Hematology Oncology, Cellular and Gene Ther-
apy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; 11 Department
of Pediatrics, Fondazione MBBM, University of Milano-Bicocca, Monza,
Italy; 12 Pediatric Hemato Oncology, University of Padua, Padua, Italy;
13 Pediatrics, S. Spirito Hospital, Local Health Unit of Pescara, Pescara, Italy
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S37 of S64
Familial hemophagocytic lymphohistiocytosis (FHL) is a severe, life-
threatening hyperinflammatory syndrome that requires hematopoi-
etic stem cell transplantation (HSCT) as the only curative treatment.
We investigated the clinical presentation and outcome in a large cohort
of patients with FHL (diagnosed 2007-2022) enrolled in the Italian HLH
Registry of the Meyer Children’s Hospital (Florence, Italy). Genetic
diagnoses of the 148 included patients were: FHL2, n=48 (32.4%);
FHL3 n=41 (27.7%); FHL4 n=2 (1.4%); FHL5 n=16 (10.8%); XLP-
1 and XLP-2 n=12 each (8.1%); GS2 n=9 (6.1%); CHS n=8 (5.4%).
One-third of patients (n=93, 62.8%) fulfilled the HLH-2004 criteria.
The most frequent presenting features were: fever (n=130, 87.8%),
splenomegaly (n=121, 81.8%) and bi-cytopenia (n=98, 66.2%). Neu-
rological involvement was detected in 49 patients (33.1%), and liver
enzymes abnormalities in 73 (49.3%). Most patients (n=111, 75%)
received first-line chemotherapy as per HLH-94 (20%), HLH-2004
(51%) and Euro-HIT (5%), while 18 (12.2%) received only steroids and
19 (12.8%) did not receive any treatment. Out of patients receiving
chemotherapy, 65 (58.6%) achieved complete response (CR) and 21
(18.9%) partial response (PR). Thirty-three patients (22%) reactivated,
and 91 (61.5%) received HSCT, 77 of whom survived and were alive at a
median follow-up of 67 months (34-106). Overall, 98 patients (66.2%)
were alive after a median follow-up of 30 months (IQR 5.5-73.5). Unad-
justed predictors of non-response were age <6 months, low platelets
(<20,000/uL), hyperferritinemia (>5,000 ng/mL) and high bilirubin lev-
els (>2 mg/dL); predictors of pre-transplant mortality were high ferritin
and bilirubin levels, while predictors of overall mortality were age
<6 months and high bilirubin levels. At multivariable analysis, high
bilirubin levels were confirmed as a predictor of pre-transplant mor-
tality (OR 4.29, 95%CI 1.25-15.7; p=0.022). Despite recent advances
in therapeutic management, FHL remains a life-threatening condition
that requires additional efforts to develop novel treatments. Liver
involvement is the main predictor of poor survival.
CLINICAL PHENOTYPE AND SURVIVAL OF 62 PATIENTS WITH
MIXED HISTIOCYTOSIS OF THE L-GROUP
Francesco Pegoraro1,2 , Mathias Papo3 , Francesco Peyronel4,5 , Irene
Trambusti1 , Elena Sieni1 , Fleur Cohen-Aubart3 , Zahir Amoura3 , Jean-
Francois Emile6 , Augusto Vaglio4,5 , and Julien Haroche3
1 Oncology and Hematology Unit, Meyer Children’s Hospital IRCCS, Flo-
rence, Italy; 2 Department of Health Sciences, University of Firenze,
Firenze, Italy; 3 Assistance Publique-Hôpitaux de Paris, Service de Médecine
Interne2 , Centre National de Références des Histiocytoses, Hôpital Pitié-
Salpêtrière, Sorbonne Université, 47-83, Boulevard de l’Hôpital, 75651,
Paris Cedex 13 , France; 4 Nephrology and Dialysis Unit, Meyer Children’s
Hospital IRCCS, Florence, Italy; 5 Department of Biomedical Clinical and
Experimental Sciences, University of Florence, Florence, Italy; 6 EA4340
BECCOH, Université de Versailles SQY, Service de Pathologie, Hôpital
Ambroise Paré, AP-HP, Boulogne, France
Purpose: To analyze the phenotype and outcome of patients with
mixed Erdheim-Chester disease (ECD) and Langerhans-cell histiocyto-
sis (LCH) and compare them to patients with ECD alone.

S38 of S64
Methods: We analyzed patients with mixed ECD-LCH followed at two
ECD referral centers in France (Paris) and Italy (Florence) and a well-
phenotyped cohort of 197 ECD patients.
Results: The median age at ECD and LCH diagnosis of the 62 included
patients was 56 (IQR 42-66) and 55 (IQR 33-65) years, respec-
tively. Typical ECD features included long bone osteosclerosis (n=56,
90%), peri-renal and peri-aortic infiltration (n=36, 58%, each), cardiac
involvement (n=22, 35%), and xanthelasma (n=22, 35%), while typical
LCH features mostly included lytic bone lesions (n=41, 66%), cuta-
neous involvement (n=24, 39%), and lymph-node infiltration (n=10,
16%). Shared features, such as central nervous system (CNS, n=29,
47%), hypothalamic/pituitary (n=29, 47%), and facial/orbit (n=28,
45%) involvement, were also frequently found. Compared to patients
with ECD alone, patients with mixed ECD-LCH were more frequently
females (50% vs. 27%, p=0.002), and had significantly higher rates
of long bone (90% vs. 74%, p=0.012), CNS (47% vs. 32%, p=0.047),
and hypothalamic/pituitary (47% vs. 25%, p=0.001) involvement. The
frequency of the BRAFV600E mutation was significantly higher in
patients with mixed ECD-LCH (n=49, 76%), compared to patients
with ECD alone (48%, p=0.001). First-line treatments mostly included
interferon-alpha and targeted treatments. The overall response rate
at the first targeted treatment with BRAF and/or MEK inhibitors was
82% (32/39). After a median follow-up of 72 months, 21 patients (34%)
died, but no significant difference in survival probability was found as
compared to ECD patients (log-rank test p=0.161).
Conclusion: Patients with mixed ECD-LCH present more frequently
with long bone, CNS, and hypothalamic/pituitary involvement, and with
BRAFV600E mutation, than patients with ECD alone. They respond
well to targeted treatments and their survival is similar to ECD
alone.
PEDIATRIC ERDHEIM-CHESTER DISEASE IN THE MOLECULAR
ERA
Francesco Pegoraro1,2 , Martina Mazzariol3,4 , Irene Trambusti2,5 ,
Sameer Bakhshi6 , Saumyaranjan Mallick7 , Ira J. Dunkel8 , Cor van
den Bos9 , Özlem Tezol10 , Shijun Shan11 , Suheyla Ocak12 , Flavio
Giordano13,14 , Carmela De Fusco15 , Stefania Gaspari16 , Anna Maria
Buccoliero17 , Maria Luisa Coniglio2 , Elisa Buti4 , Paola Romagnani4,18 ,
Jennifer Picarsic19 , Jean Donadieu20 , Eli L. Diamond21 , Jean-François
Emile22 , Elena Sieni2*, Julien Haroche23*, Augusto Vaglio4,18*
1 Department of Health Sciences, University of Florence, Florence, Italy;
2 Hematology and Oncology Unit, Meyer Children’s Hospital IRCCS, Flo-
rence, Italy; 3 Department of Medical Sciences, University of Turin, Turin,
Italy; 4 Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Flo-
rence, Italy; 5 Department of Clinical and Experimental Medicine, University
of Pisa, Pisa, Italy; 6 Department of Medical Oncology, All India Institute
of Medical Sciences, New Delhi, India; 7 Department of Pathology, All India
Institute of Medical Sciences, New Delhi, India; 8 Department of Pedi-
atrics, Memorial Sloan Kettering Cancer Center, NY USA; 9 Department of
Hemato-Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht,
The Netherlands; 10 Mersin University Faculty of Medicine, Department of
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ABSTRACTS
Pediatrics, Mersin, Turkey; 11 Department of Dermatology, No. 1 Hospital
of China Medical University, Shenyang, China; 12 Department of Pediatric
Hematology-Oncology, Istanbul University Cerrahpasa, Cerrahpasa Fac-
ulty of Medicine, Istanbul, Turkey; 13 Department of Neurosurgery, Meyer
Children’s Hospital IRCCS, Florence; Italy; 14 NEUROFARBA Department,
University of Florence, Italy; 15 Department of Oncology, AORN Santobono-
Pausilipon, Pausilipon Hospital, Naples, Italy; 16 Department of Pediatric
Hematology/Oncology, Cellular and Gene Therapy, Bambino Gesù Chil-
dren’s Hospital, IRCCS, Rome, Italy; 17 Pathology Unit, Meyer Children’s
Hospital IRCCS, Florence, Italy; 18 Department of Biomedical, Experimen-
tal and Clinical Sciences “Mario Serio”, University of Florence, Florence,
Italy; 19 Cincinnati Children’s Hospital Medical Center, University of Cincin-
nati School of Medicine, Cincinnati, OH USA; 20 Pediatric Oncology and
Hematology, Armand-Trousseau Hospital, APHP, EA4340-BECCOH, Refer-
ral Center for Histiocytoses UVSQ, Paris, France; 21 Department of Neurol-
ogy, Memorial Sloan Kettering Cancer Center, New York, NY USA; 22 EA4340
BECCOH, Université de Versailles SQY, Service de Pathologie, Hôpital
Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne, France;
23 Department of Internal Medicine, Institut E3M French Reference Centre
̑
for Histiocytosis, Pitié-Salpetrière Hospital, Assistance Publique-Hôpitaux
de Paris, Sorbonne Université, Paris, France
*These authors share senior authorship
Erdheim-Chester disease (ECD) is a rare histiocytosis that almost
exclusively affects adults. Childhood-onset ECD is anecdotal, and its
clinical and molecular characterization limited. We analyzed patients
with biopsy-proven ECD. Inclusion criteria were a) age at onset
<18y; b) >1 typical ECD localization (long-bone; peri-renal; large-
vessel; cardiac; xanthelasma); c) BRAF status; d) follow-up >6 months.
Among the 21 included patients, the main clinical manifestations
included systemic symptoms, polyuria/polydipsia, bone pain, and neu-
rological deficits. The most frequently affected sites were the bones
(86%), the facial/orbital area (67%), the central nervous system
(CNS, 62%), and the hypothalamic-pituitary region (57%). Less fre-
quent lesions were detected at skin (43%), peri-renal (24%), and
peri-aortic, cardiac, or pulmonary level (14% each). Eight patients
(38%) had clinical and/or pathology findings consistent with mixed
ECD/LCH, and they had higher frequency of systemic symptoms and
diabetes insipidus. Twelve patients (57%) harbored the BRAFV600E
mutation and presented more frequently with exophthalmos. First-
line treatment regimens included chemotherapy (38%), interferon-α
(29%), and targeted approaches (BRAF/MEK/mTOR inhibitors; 29%).
Ten patients (48%) required >1 line of treatment due to toxicity
or disease progression. Best objective responses were reported in
patients receiving BRAF/MEK inhibitors (100%) and interferon-α (5/8).
After a median follow-up of 49 months, two patients died (one for
chemotherapy-related toxicity and the other for unknown causes),
and the remaining 19 had either stable disease (n=2) or response
(n=17). Ten patients (48%) had treatment-related side effects, which
required treatment discontinuation in eight. Most patients experi-
enced long-term sequelae (mostly endocrine, renal, ocular, and neu-
ropsychiatric). Pediatric ECD is a rare and challenging condition
that mimics its adult counterpart. However, localizations such as the
facial/orbital area, the CNS, and the hypothalamic/pituitary axis are

ABSTRACTS
more common in children, as it is for mixed ECD/LCH. Targeted treat-
ments used for adult ECD are effective in the pediatric population
as well.
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN CHILDREN
WITH LANGERHANS HISTIOCYTOSIS (LCH) - THE
HISTIOCYTOSIS STUDY GROUP OF THE HELLENIC SOCIETY OF
PEDIATRIC HEMATOLOGY-ONCOLOGY EXPERIENCE
Loizos Petrikkos1 , Marina Servitzoglou2 , Vasiliki Tzotzola1 ,
Dimitrios Doganis2 , Margarita Baka2 , Sophia Polychronopoulou1 ,
Vassilios Papadakis1
1 Department of Paediatric Haematology-Oncology (T.A.O.), «Aghia Sophia»
Children’s Hospital, Athens, Greece; 2 Oncology Department, “P&A Kyri-
akou” Children’s Hospital, Athens, Greece
Purpose: Presentation of Hemophagocytic Lymphohistiocytosis (HLH)
concurrent with Langerhans Histiocytosis (LCH) in children registered
by the Histiocytosis Study Group of the Hellenic Society of Pediatric
Hematology-Oncology (HSG-HeSPHO).
Methods: 169 LCH patients were retrospectively evaluated in 7 ref-
erence centers (2000-2019). Boys/Girls: 106/63(1.7:1). Median/mean
age at diagnosis: 4.8/5.6years (0-20.5, 52 patients<2years). Single-
system disease(SS)/Multisystem(MS) disease: 133/36 patients.
According to current criteria, HLH was documented in 3/169 (1.8%)
patients (female/male: 2/1, aged 1.04, 1.08 and 1.33 years).
Results: All 3 children presented with severe MS-LCH (confirmed by
skin biopsy). One of them recurred following spontaneous complete
regression of congenital cutaneous histiocytosis, inititally presenting
at 3 months-old. He was recently treated for leishmaniasis, with par-
asite eradication but persistence of hemophagocytosis. In all patients:
high-risk organ involvement (liver, spleen in addition to hematopoi-
etic) with hemophagocytosis (myelogram). Bone lesions: 2/3 (both
with CNS-risk foci). Diabetes insipidus: 0/3. Two patients were evalu-
ated for BRAF-V600E-mutation: both positive (total cohort’s positivity:
27/51). One patient initially received Prednisolone/Vinblastine (HS-
LCH-IV-protocol) with remission of both LCH and hemophagocytosis,
but with leishmaniasis’ recurrence, and received a second course of
liposomal-amphotericin-B, with good response. Disease was refractory
to the frontline treatment in the other 2 patients. Due to persis-
tent hemophagocytosis (bone marrow), one received Dexametha-
sone/Etoposide/Cyclosporin (HLH-2004-protocol) for 4 weeks with-
out response and the second Vincristine/Cytarabine/Dexamethasone,
with partial response at 6 weeks. Both received third-line therapy with
good response, one: high-dose Cytarabine pulses and the second: Clan-
dribine/Cytarabine. All three patients completed maintenance therapy
according to LCH-protocols and remain in remission for 11.3, 7.2 and
3.6 years from initial diagnosis.
Conclusion: The HLH rate among LCH patients in this cohort (HSG-
HeSPHO) was 1.8% (8.3% in MS-LCH) with severe clinical presentation.
Early recognition of HLH in LCH patients often requires different ther-
apeutic management for both entities in order to achieve optimal
immediate and long-term outcome.
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SUCCESSFUL TREATMENT OF REFRACTORY LANGERHANS
CELL HISTIOCYTOSIS IN AN ADULT WITH ANTI-CD207 CAR
T-CELL THERAPY
Yubo Pi, Jingshi Wang, Na Wei, Lin Wu, Zhihui Li, Huihui Zhang, Yi Tan,
Jia Zhang, Chaofan Wu, Zhao Wang
Department of Hematology, Beijing Friendship Hospital, Capital Medical
University, Beijing, China
Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid
neoplasia characterized by clonal proliferation of CD207+ / CD1a+
Langerhans cells (LCs) and wide-ranging organ involvement. Over the
last decade, randomized trials and novel approaches have provided sig-
nificant improvements in the treatment of LCH, but there is still no
standard of care for relapsed/refractory LCH. A 33-year-old woman
with left neck mass for 11 year was diagnosed with LCH involving
thyroid gland, salivary gland, cervical lymph nodes, and lung. The com-
bination of prednisolone and etoposide was administered intensively
for 12 weeks, followed by a less intensive maintenance therapy for 12
months. She achieved partial response, and was followed up regularly.
Five year after systemic chemotherapy, she experienced enlarge-
ment of left neck mass and could not tolerate further chemotherapy
due to recurrent lung infection. The patient’s disease progressed
rapidly with new perineal mass (16.1×3.7×3.7 cm), and further BRAF
V600E mutation testing was negative. Meanwhile, we developed autol-
ogous CD207-targeted chimeric antigen receptor-modified T cells
(CD207-CAR T-cells) for the treatment of relapsed/refractory LCH.
The patient then received a lymphodepletion therapy regimen (flu-
darabine 25 mg/m2 and cyclophosphamide 250 mg/m2) for three
days before receiving anti-CD207 CAR T-cell therapy. Then, human-
ized anti-CD207 CAR T-cells were infused at a dose of 3 × 106/kg.
Within first two weeks of infusion, the size of her perineal mass
already decreased to 7.2×3.4×3.3 cm. She experienced no appar-
ent adverse effects, except for grade 2 leukopenia. The expansion of
humanized anti-CD207 CAR T-cells was still being monitored. Anti-
CD207 CAR T-cell therapy might be an alternative treatment option
for relapsed/refractory LCH patients.
A STUDY OF PATIENT-REPORTED OUTCOME MEASURES OF
HEALTH-RELATED QUALITY OF LIFE AMONG PATIENTS WITH
HISTIOCYTIC NEOPLASMS
David Pottinger1 , Matt Slief1 , Ene Enegola2 , Jithma Abeykoon3 ,
Saurabh Zanwar3 , Gordon Ruan3 , Rachelle Rouse3 , Baylie Brook4 ,
Deanna Fournier5 , Kathleen Brewer6 , Aishwarya Ravindran7 , Diana
Morlote7 , Anita D’Souza8 , Ronald Go3 , Gaurav Goyal9
1 Department of Internal Medicine, University of Alabama at Birming-
ham, Birmingham, AL USA; 2 Department of Epidemiology, School of
Public Health, University of Alabama at Birmingham, Birmingham, AL
USA; 3 Division of Hematology, Mayo Clinic, Rochester, MN USA; 4Divi-
sion of Hematology-Oncology Nursing, University of Alabama at Birming-
ham, Birmingham, AL USA; 5 Histiocytosis Association, Pitman, NJ USA;
6 Erdheim-Chester disease Global Alliance, DeRidder, LA USA; 7 Division of

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Hematopathology, University of Alabama at Birmingham, Birmingham, AL
USA; 8 Division of Hematology/Oncology, Department of Medicine, Medi-
cal College of Wisconsin, Milwaukee, WI USA; 9 Division of Hematology-
Oncology, University of Alabama at Birmingham, Birmingham, AL USA
Purpose: There is a lack of data on health-related quality of life
(HRQoL) in patients with histiocytic neoplasms.
Methods: We enrolled participants from 2 histiocytosis centers and
an international conference from August 2022-April 2023 to com-
plete the PROMIS (Patient-Reported Outcomes [PROs] Measurement
Information System) 29+2 profile v2.1, which captures 8 domains of
HRQoL. We calculated summary T-scores for physical health (PH) and
mental health (MH), and additionally focused on pain interference.
T-scores were compared to the US population mean of 50 (SD 10),
and a difference of 3 (SD 0.3) was considered clinically meaningful.
T-scores were also compared between sub-cohorts using analysis of
variance.
Results: 77 individuals were included: Erdheim-Chester Disease
(ECD) (n=33), Langerhans Cell Histiocytosis (LCH) (n=21), and Rosai-
Dorfman Disease (RDD) (n=18). Median age at diagnosis was 50y
(9-79). Median age at survey was 54y (18-82). Disease extent included
unifocal (n=13), single system multifocal (ss-M, n=11), single sys-
tem lung (ss-L, n=4), multisystem (n=48) disease, or unknown (n=1).
The most commonly involved organs included bone (n=44), kidney
(n=24), skin (n=24), CNS (n=24), and pituitary (n=19). PH score was
reduced in ECD (-7.4, SD 0.74) and LCH (-4.5, SD 0.45). MH score was
reduced in LCH (-3.6, SD 0.36) but not in ECD or RDD. Bone involve-
ment was associated with worse PH score (-5.9, 95%CI -10.9, -1.1,
[p=0.02]), MH score (-6.4, 95%CI -11.1, -1.7, [p=0.01]), and pain
interference (5.6, 95%CI 0.6, 10.6, [p=0.03]) compared with bone-
uninvolved disease. CNS involvement was associated with worse PH
score (-5.6, 95%CI -10.7, -0.4, [p=0.03]) than CNS-uninvolved dis-
ease. Finally, ss-L LCH and multisystem histiocytosis of any type were
associated with worse PH score compared with unifocal/ss-M disease
(p=0.02).
Conclusions: We found significantly impaired HRQoL in a large
cohort of patients with histiocytosis. Bone and CNS involvement,
multisystem disease, and ss-L LCH were associated with worse
HRQoL.
STEROID-RELATED, LIFE-THREATENING UPPER
GASTROINTESTINAL HEMORRHAGE IN AN INFANT WITH
MULTI-SYSTEM LANGERHANS CELL HISTIOCYTOSIS
Rachel Foster, Elizabeth Collyer, Benjamin Padilla, Michael Henry
Phoenix Children’s, Phoenix, AZ USA
Purpose: To describe the presentation of an infant with multi-system
Langerhans Cell Histiocytosis (LCH) who presented with acute, life-
threatening upper gastrointestinal hemorrhage after treatment with
corticosteroids and vinblastine.
Methods: This patient showed signs of illness shortly after birth with
decreased oral intake and a diffuse purpuric rash. He was admitted for
failure to thrive, diarrhea, and anasarca. A skin biopsy was performed,
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ABSTRACTS
and the results were consistent with Langerhans Cell Histiocytosis
(LCH), B-RAF V600E positive. A staging workup revealed multi-system
involvement, including bone marrow. He developed respiratory fail-
ure and hypovolemic shock secondary to protein-losing enteropathy
from suspected LCH gastrointestinal mucosal involvement. Treatment
was started per LCH-III with vinblastine and methylprednisolone,
and he initiated hemodialysis for severe fluid overload and acute
kidney injury. Gastroprophylaxis consisted of an H2-antagonist. Sig-
nificant hematemesis complicated his hospital course, and endoscopy
showed severe peptic ulcer disease. He was treated with octreotide,
vasopressors, recombinant factor VIIa, tranexamic acid, and blood
products to control the bleeding. He underwent arterial embolization
and sleeve gastrectomy due to life-threatening upper gastrointestinal
hemorrhage. He then developed direct hyperbilirubinemia, requiring
a 50% dose reduction of vinblastine. After two weeks of treat-
ment, his response was suboptimal, so his treatment was switched
to cytarabine and trametinib and eventually to trametinib monother-
apy. After 11 months of treatment, his PET/CT has been negative
for disease, and circulating cell-free BRAF V600E has decreased
steadily.
Results: This infant developed steroid-related, life-threatening upper
gastrointestinal hemorrhage during treatment for multi-system LCH,
requiring arterial embolization and sleeve gastrectomy.
Conclusion: This report is a cautionary tale to consider when
treating infants for LCH with corticosteroids and vinblastine. The
treating provider should always use gastroprophylaxis and con-
sider the possibility of upper gastrointestinal hemorrhage in patients
receiving corticosteroid therapy. Liver involvement may cause direct
hyperbilirubinemia, which may prevent full-dose administration of
vinblastine.
NEURODEGENERATIVE DISEASE IN HISTIOCYTOSIS PATIENTS -
DIAGNOSTICS AND TREATMENT - THE OWN EXPERIENCES
Anna Raciborska1 , Zofia Małas1 , Andrzej Tysarowski2 , Katarzyna
Seliga2 , Elżbieta Michalak3 , Jadwiga Weclawek-Tompol4 , Carlos
Rodriguez-Galindo5
1 Department of Oncology and Surgical Oncology for Children and Youth,
Mother and Child Institute, Warsaw, Poland; 2 Department of Cancer of
Molecular and Genetic Diagnostics, Maria Sklodowska-Curie, National
Research Institute of Oncology, Warsaw, Poland; 3 Department of Pathology,
Mother and Child Institute, Warsaw, Poland; 4 Clinical Department of Paedi-
atric Bone Marrow Transplantation, Oncology, and Haematology, Wroclaw
Medical University, Poland; 5 Departments of Global Pediatric Medicine and
Oncology, St. Jude Children’s Research Hospital, Memphis, TN USA
Purpose: Neurodegenerative disease (ND) is one of the most severe
complications connected with histiocytoses. Currently, the manage-
ment of ND secondary to histiocytosis is not well determined. Here, we
present our experience in the management of histiocytic-determined
neurodegenerative disease.
Methods: Six patients (5 with LCH, 1 with JXG) were diagnosed and
treated due to secondary ND between 2020 and 2023. All patients

ABSTRACTS
had a molecular test from the tissue and all patients had evaluation
and monitoring of ctDNA status in the peripheral blood. In all patients,
the neurofilaments level was measured in CSF. All patients received the
dedicated treatment. Factors predictive of outcomes were analyzed.
Results: Median age at the time of diagnosis of ND was 5 years.
The median time from diagnosis to ND was 2.75 years. Two pts
used wheelchairs, and 4 were without any neurological disturbances.
All had changes in CNS-MRI. BRAFv600e mutation was detected in
tissue in 4 patients, and in both tissue and peripheral blood in 3
patients. Neurofilaments range was 271,7 - 22800pg/ml before the
treatment started. TKI was started in 4 patients, and systemic treat-
ment was applied to 2 patients. IVG was given in 5 patients, in 3
parallel with TKI. OS in the entire group was 100%. One patient
progressed on Vemurafenib and was transferred to Dabrafenib with
Trametinib with a good response. PR was observed in 4 patients
(one of them left the wheelchair), and 2 are stable. Neurofilaments
range was 140,9 - 20852pg/ml and decreased in treated patients.
In 1 patient BRAFv600e-positive cells monitored by ctDNA are still
detectable.
Conclusion: Qualification for treatment management should be based
not only on clinical status and evaluation of the single imaging find-
ings, but also close monitoring follow-up of the CNS-MRI, neurofila-
ments status, and estimation of mutation in ctDNA in the peripheral
blood.
CHEST RADIOGRAPHIC CHANGES IN PATIENTS WITH
PULMONARY LANGERHANS CELL HISTIOCYTOSIS
Elzbieta Radzikowska, Iwona Bestry, Małgorzata Sobiecka, Jacek
Wakuliński, Renata Langfort, Katarzyna Błasińska Maria Jeśkiewicz
National Tuberculosis and Lung Diseases Research Institute, Warsaw,
Poland
Purpose: The high-resolution computed tomography (HRCT) is the
most important tools in PLCH diagnosis. The disease belongs to the
group of smoking-related disorders, therefore despite radiological
lesions characteristic for PLCH also findings of the other conditions
are present. The aim of this study was to evaluate the HRCT findings
in PLCH patients.
Material: 129 PLCH patients hospitalized at the NTLDRI were ana-
lyzed. The mean age of patients was (39.1 ± 14.1 years), and 96% were
tobacco and 13% were marijuana smokers.
Results: Cysts (89%), nodules (73%), interface sign (32%), emphy-
sema (31%), reticular lesions (22%), cavitary nodules (21%), hilar and
mediastinal lymphadenopathy (16%), ground glass opacities (11%),
dilatation of the pulmonary artery trunk (9%), bronchiectasis (7%) and
honeycomb (1%) were the lesions visualized on chest HRCT. Nod-
ules less than 5, 5-10 and over than 10mm in diameter were seen
respectively in 74%, 24%, 2% of patients. Thin-walled, thick-walled,
and lacunar cysts were visualized in 89%, 43% and 60% of patients,
respectively. Low, medium, and large intensity nodules were observed
in 74%, 24% and 2% of patients, respectively. The presence of small,
medium, high, and very high intensity of cysts was visualized in 26%,
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29%, 26% and 19% of patients, respectively. Involvement of the supra-
diaphragmatic parts of the lungs was observed in 26% of patients. A
negative correlation was found between the severity of cysts and nod-
ules (R=-0.319; p=0.0002). The interface sign was more frequently
observed in patients with higher than in lower number of cysts (17±3.9
vs. 9.5±6.4; p=0.00). Male compared to females were characterized by
a higher prevalence of emphysema (44% vs.19%; p=0.002) and cysts
(13.3±6.4 vs.10.6±6.7; p=0.022).
Conclusions: The most frequently noticed findings in HRCT were cysts,
nodules, interface sign, emphysema, reticular lesions, and cavitary nod-
ules. There was a negative correlation between severity of cysts and
nodules.
CORRELATION OF CHEST RADIOGRAFIC CHANGES
VISUALIZED BY COMPUTED TOMOGRAPHY WITH
PULMONARY FUNCTION TESTS IN PATIENTS WITH
PULMONARY LANGERHANS CELL HISTIOCYTOSIS
Elzbieta Radzikowska
National Tuberculosis and Lung Diseases Research Institute, Warsaw,
Poland
Purpose: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare dis-
ease characterized by proliferation of Langerhans cells burdened with
mutations of mitogen-stimulated kinase pathway genes accompanied
by the inflammatory infiltrates. In PLCH the high-resolution computed
tomography (HRCT) and pulmonary function tests have an outstanding
role in diagnosis, assessment of extension and activity of the disease.
The goal of this study was to analyze the radiological findings with
pulmonary function parameters in PLCH patients.
Material: The study retrospectively evaluated 129 (53% women)
patients hospitalized at the Institute of Tuberculosis and Lung Diseases
in Warsaw, Poland, between 2007-2021 with confirmed PLCH diag-
nosis. The mean age of patients at the time of diagnosis was 39.1 (±
14.1) years, and 96% of them were tobacco and 13% were marijuana
smokers.
Results: Statistically significant negative correlation between inten-
sity of cysts and: forced vital capacity % predicted (FVC% pred.)
(R=-0,262; R=0,0029), forced expiratory volume in one second % of
predicted (FEV1% pred.) (R=-0,408; p<0,0000), and FEV1%/VC (R=-
0,343; p=0,0001), and diffusion capacity for carbone monoxide (TLco)
(R=-0,540; p 0,0000) was found. In contrary to the positive corre-
lation between intensity of cysts and residual volume % predicted
(RV% pred.) (R=0,378; p 0,0000). There was no correlation between
intensity of nodules and ventilatory parameters. Higher intensity of
cysts was revealed in patients with bronchial obstruction in compari-
son to patients without this symptom (14,76 ± 6,30 vs 10,04 ± 6,29;
p=0,0000), but intensity of nodules was lower (3,54 ± 3,20 vs 5,0
± 3,46; p=0,0198). In patients with restriction pattern of ventilatory
impairment no correlation between intensity of cysts and nodules was
present.
Conclusions: In PLCH patients a negative correlation between
severity of cystic lesions: and FVC% pred, FEV1% pred., and TLco, and

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positive with RV % pred was found. Patients with bronchial obstruction
displayed higher intensity of cysts.
MULTIPLE ADULT XANTHOGRANULOMA (MAXG): A DISTINCT
ENTITY
Vyshnavi Rallapalle1 , Tanvi Bhadkamkar1 , Ronald S. Go2 , Jithma P.
Abeykoon2 , Karen L. Rech3 , Boni Elewski4 , Aishwarya Ravindran5 ,
Gaurav Goyal6
1 Department of Medicine, Heersink School of Medicine, University of
Alabama at Birmingham, Birmingham, AL USA; 2 Division of Hematology,
Mayo Clinic, Rochester, MN USA; 3 Division of Hematopathology, Mayo
Clinic, Rochester, MN USA; 4 Department of Dermatology, University of
Alabama at Birmingham, Birmingham, AL USA; 5 Division of Hematopathol-
ogy, University of Alabama at Birmingham, Birmingham, AL USA; 6 Division
of Hematology-Oncology, University of Alabama at Birmingham, Birming-
ham, AL USA
Purpose: Juvenile xanthogranuloma (JXG) is a rare non-Langerhans
cell histiocytosis, which by definition affects the pediatric population.
There is a lack of data on adults with multiple xanthogranulomas
(MAXG). The prevailing Histiocyte Society classification defines adult
xanthogranuloma (AXG) as usually being a solitary lesion.
Methods: Herein, we present a case of an adult with progressive MAXG
along with a comprehensive review of published cases with MAXG (age
≥18y) through PubMed.
Results: A 49y old male presented to the histiocytosis clinic due
to multiple, progressive, papular lesions on the face, right eyelid,
trunk, abdomen, back, and right foot over the past 3 years. Full
body PET/CT showed multifocal FDG avid skin lesions without any
extra-cutaneous lesions. Comprehensive NGS testing revealed no
pathogenic mutations. On PubMed review, we found 48 cases with
MAXG reported from 1963-2023 in English language. The median
age at diagnosis was 49.5y (range, 19-81), with a 1.5:1 male to
female predominance. Sites of cutaneous involvement included the
trunk(70%), face(59%), arms(45%), and legs(41%), and three cases
had extra-cutaneous involvement of the upper airway, lungs/sclera,
and pituitary gland/brain. Touton giant cells were a frequently
reported histopathologic finding (97%). 8 cases underwent BRAF
testing: 4 had BRAF fusions and 1 was BRAFV600E. 11/48(23%)
had an associated malignancy, including myeloid(n=4), lymphoid(n=4),
histiocytic(n=2), and solid organ(n=1) neoplasms. The most common
initial treatments involved observation(44%), chemotherapy(17%),
and isotretinoin(11%), with variable responses to each. 2 patients
received second-line treatments with CO2 laser and IVIG, respec-
tively, resulting in a response. The median follow-up duration was
12mo(1-180) with one patient dying due to bronchial asthma at 180
months.
Conclusion: MAXG is an ultra-rare condition that is distinct from
JXG, warranting further investigation to develop better diagnostic
criteria and treatment options. Although MAXG may lack systemic
involvement, it is important to evaluate patients to rule-out concurrent
malignancies.
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ABSTRACTS
PD-L1 EXPRESSION IN MALIGNANT HISTIOCYTOSIS: CLINICAL
CORRELATES AND OUTCOMES
Aishwarya Ravindran1 , Liuyan Jiang2 , Gordon Ruan3 , Jithma
Abeykoon3 , Saurabh Zanwar3 , Gaurav Goyal1 , Ronald Go3 , Karen
Rech3
1 University of Alabama at Birmingham, Birmingham, AL USA; 2 Mayo Clinic,
Jacksonville, FL USA; 3 Mayo Clinic, Rochester, MN USA
Purpose: Malignant Histiocytoses (Histiocytic Sarcoma, Langerhans
cell sarcoma (LCS), interdigitating dendritic cell sarcoma) are aggres-
sive neoplasms, classified under ’M’ group per Histiocyte Society classi-
fication. Previously, we reported LCS showing >95% PD-L1 expression,
resulting in near-complete remission three years post-Pembrolizumab
therapy (Zanwar et al. Haematologica.2022). In this study, we analyzed
PD-L1 expression in MH.
Methods: Upon IRB approval, we identified eighteen MH
patients between 2009-2023. The slides were re-reviewed by >2
hematopathologists using two criteria: i) positive for >2 macrophage
or dendritic/Langerhans cell markers, ii) anaplasia. Each case was
categorized as unifocal or multifocal (≥ 1 site biopsy-proven; other
sites suspicious on imaging) at diagnosis. PD-L1 immunostain (clones:
22C3 or SP263) was performed on formalin-fixed paraffin-embedded
tissue, with a semi-quantitative manual assessment of positive tumor
cells.
Results: Median age was 63 years (range: 26 -90); 67% were male.
Both nodal and extranodal sites were involved. Thirteen had multifocal
disease, three unifocal, and two were unknown. Five were secondary
MH clonally related to B-cell lymphoma. Median follow-up was 34.5
months (95%CI: 16.1 - 39), and median survival was 33.9 months
(95%CI: 5.2 to 42). PD-L1 was negative in 6 cases, and positive (>1%)
in 12, of which 28% showed 1-5%, 28% with 6-50%, and 11 with
>50% expression. Ten of 13 multifocal MH showed positive PD-L1
compared to 0 of 3 in unifocal MH (P: 0.0357). Among multifocal MH,
PD-L1 expression did not correlate with Ki67, primary/secondary MH
or survival. Four patients received immune checkpoint inhibitors (3
Pembrolizumab, 1 Nivolumab); 2 of these patients (secondary, mul-
tifocal) died of disease, and 2 (primary, multifocal) showed partial
clinical/radiologic response.
Conclusion: PD-L1 expression in MH is associated with multifocal dis-
ease. As MH can show response to immune-checkpoint inhibitors,
multivariate analysis of a larger MH cohort is needed to explore
sustainability and efficacy of anti-PD1 therapies.
MONOCYTE DISTRIBUTION CHANGES AND RELAPSE-FREE
SURVIVAL IN ADULT HISTIOCYTOSES
Jerome Razanamahery1 , Maxime Samson1 , Julien Guy1 , Jessica
Racine1 , Celine Row1 , Stephanie Francois1 , Jean-Francois Emile2 ,
Fleur Cohen-Aubart3 , Sylvain Audia1 , Julien Haroche3 , Bernard
Bonnotte1
1 Dijon University Hospital, Dijon, France; 2 Ambroise Pare Hospital, Paris,
France; 3 Pitie Salpetriere Hospital, Paris, France

ABSTRACTS
Purpose: In a previous report, we identified a specific monocyte
subset distribution in histiocytosis patients who had a metabolic
response. The aim was to confirm these findings through a prospective
study.
Methods: We conducted a one-year trial involving adult patients with
histiocytosis where blood sampling and PET-CT were performed every
6 months. Blood samples included complete blood count with flow
cytometry analysis for monocyte subsets, liver and kidney functions,
lipid test, C-reactive protein, and VEGF-A. Disease progression on
PET-CT or worsening of skin assessment for isolated cutaneous histi-
ocytosis was considered as a relapse. Patients achieving complete or
partial metabolic response on PET-CT were considered as responders,
while non-responders had stable or progressive metabolic disease.
Results: Nineteen patients were included in the study with the follow-
ing distribution: 8 Erdheim-Chester Disease (ECD) (4 with BRAFV600E
mutation), 6 Langerhans cell histiocytosis (LCH) (2 with BRAFV600E
mutation), 1 mixed LCH/ECD with BRAFV600E mutation, and 4 Rosai-
Dorfman Disease (2 with MAP2K1 mutation). At inclusion, responder
patients had a lower percentage of “intermediate” monocytes (p=0.04)
and lower levels of C-reactive protein (p=0.04). Throughout the follow-
up period, 7 patients (4 LCH, 2 ECD, 1 “ECD/LCH”) relapsed. The
relapse group exhibited a higher proportion of patients who received
conventional therapy at the beginning of the study (p=0.05). At 6
months, relapsers had lower lymphocyte counts (p=0.04), while all
other characteristics were similar at one year. The only factor asso-
ciated with relapse-free survival was the decrease in intermediate
monocytes during the first 6 months (p=0.004). Pearson correlation
analysis showed a negative correlation between relapse-free survival
and LCH (p=0.011).
Conclusion: Repeated analyses by flow cytometry can be a
valuable tool for patient management, as the reduction of inter-
mediate monocytes is associated with relapse-free survival in
histiocytoses.
CORRELATING THE PRESENCE OF ALTERNATIVE DRIVER
MUTATIONS IN ROSAI DORFMAN DISEASE WITH TREATMENT
FAILURES TO TARGETED THERAPIES: CASE PRESENTATION
AND REVIEW OF LITERATURE
Samuel Reynolds1 , Sabrina Wilcox2 , Qing Li1 , Azra Zareen Ahmed1
1 University of Michigan Division of Hematology, Ann Arbor, MI USA;
2 University of Michigan Division of Medicine and Pediatrics, Ann Arbor, MI
USA
Introduction: Rosai Dorfman disease (RDD) is a non-Langerhans cell
histiocytic disorder characterized histologically by the presence of
large, pale histiocytes in various tissues and the engulfment of intact
hematopoietic stem cells within their cytoplasm, better known as
emperipolesis. Patients with RDD are also commonly diagnosed with
BRAFV600E (and related) Ras/MAP Kinase pathway driver mutations.
And while such alterations are most well-studied in non-Langerhans
cell histiocytic disease, research into alternative driver mutations is
underexplored.
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Patient Case: A 43 year-old female with intractable pain in her left
mandible over a 3-month period presented to our center for consul-
tation. Focused CT imaging identified a mass with osseous erosion of
the left mandibular alveolar ridge; biopsy that followed was consistent
with extra-nodal Rosai Dorfman Disease and allele-specific sequenc-
ing confirmed a BRAF c.1799T>A V600E mutation. Cobimetinib was
first initiated but her locoregional lymphadenopathy progressed after
6 months of therapy, prompting transition to dabrafenib, which she
now continues under close surveillance.
Discussion: Even in the modern area of non-immunosuppressive MAP
Kinase pathway-targeted small molecule inhibitors, disease progres-
sion is still common in RDD. One working theory from our group based
on a previously-proposed model from Papo et al. in 2019 is that TET2
alterations in myeloid stem cell progenitors followed by the acqui-
sition of a second BRAF mutation drives a more aggressive clinical
phenotype. A more complete understanding of the impact of alter-
ations in various epigenetic regulators (including TET2, ASXL1) and
splicing factors (EZH2, SRSF2) is required to not only predict treat-
ment failures with Ras/MAP Kinase pathway-targeting agents but also
identify potential new targets in RDD and related histiocytic diseases.
Expanded, integrated whole exome and transcriptome sequencing,
accordingly, is currently underway at The University of Michigan in
our cohort of 35 patients (including the presented patient) and will be
reported with this case upon completion.
DIABETES INSIPIDUS AS A CONSEQUENCE OF LANGERHANS
CELL HISTIOCYTOSIS - CORRELATION WITH THE INITIAL
LOCALIZATION OF THE DISEASE
Efthymia Rigatou1 , Marina Servitzoglou2 , Loizos Petrikkos3 , Kleoniki
Roka1 ,Anna Kontogeorgou1 ,Emmanouil Chatzipantelis4 , Evgenia
Papakonstantinou5 , Iordanis Pelagiadis6 , Helen Dana7 , Demetrios
Doganis2 , Natalia Tourkantoni1 , Vassiliki Tzotzola3 , Athanassios
Tragiannidis4 , Helen Kosmidis7 , Eftychia Stiakaki6 , Antonios
Kattamis2 , Sophia Polychronopoulou3 , Margaret Baka1 , Vassilios
Papadakis3
1 University Pediatric Oncology-Hematology Unit, (UPOHEM) First Depart-
ment of Pediatrics, National and Kapodistrian University of Athens, “Aghia
Sofia” Children’s Hospital, Athens, Greece; 2 Oncology Department, ’P. &
A. Kyriakou’ Children’s Hospital, Athens, Greece; 3 Department of Pediatric
Hematology-Oncology (TAO), “Aghia Sophia” Children’s Hospital, Athens,
Greece; 4 Children’s & Adolescent’s Hematology-Oncology Unit,2nd Pedi-
atric Clinic, School of Medicine, Aristotle University of Thessaloniki, AHEPA
University General Hospital, Thessaloniki, Greece; 5 Department of Pediatric
Hematology and Oncology, Hippokration Hospital, Thessaloniki, Greece;
6 Department of Paediatric Hematology-Oncology, University Hospital of
Heraklion, Heraklion, Crete, Greece; 7 Pediatric & Adolescent Oncology
Clinic, “Mitera” Hospital, Athens, Greece
Purpose: Langerhans Cell Histiocytosis (LCH) has particular predilec-
tion of hypothalamo-pituitary axis involvement. Diabetes insipidus (DI)
is the most frequent permanent consequence of LCH occurring in
5-25% of patients. Our aim was to analyze the incidence of DI in

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LCH patients in the Greek registry and correlate DI with LCH initial
localization.
Methods: We retrospectively analyzed data from the Greek registry of
LCH patients treated in all 7 Greek pediatric oncology centers, during
the period 2000-2019.
Results: A total of 177 patients (median age 5.5years) were enrolled.
Upon diagnosis, 14/177 patients (7.9%) had DI and boys/girls cases
was 9/5. Multisystem disease including skeletal /scull involvement pre-
sented in 10/14 patients (71.4%), whereas 7/14 (50%) had Central
Nervous System (CNS) risk lesions. DI as initial symptom was found in
8/14 (57.1%) patients. A positive correlation was found in regards to
CNS risk location and DI: 4/8 (50%). Ten children were initially treated
with systemic chemotherapy (prednisolone/vinblastine) due to local-
ization of multisystem disease, and one with prednisolone/vinblastine
and VP16.Median duration of treatment was 12 months. All children
are alive with permanent DI (mean follow up 3.2 years). Relapse has
occurred in 3/14 patients (21.4%) in median time from diagnosis of 32
months. Notably, in all (3/3) relapsed patients DI was not the initial
symptom at diagnosis. Moreover, 2/3 (66.6%) had multisystem disease
and CNS risk bone lesions.
Conclusions: In the current Greek LCH registry, DI presented in 7.9%
of patients. The majority of the patients had skull bone involvement
and CNS risk lesions. More than half had DI as an initial symptom
of the disease, and in 50% of patients its occurrence was related to
CNS risk bone involvement. CNS risk lesions and multisystem disease
characterized relapsed patients.
TARGETABLE JUVENILE XANTHOGRANULOMA DETECTED BY
IMMUNOHISTOCHEMISTORY-BASED SCREENING SYSTEM
Kenichi Sakamoto1,2 , Kudo Ko3 , Atsuko Nakazawa4 , Takako Yoshioka5 ,
Akira Morimoto6 , Yoko Shioda2
1 Department of Pediatrics, Shiga University of Medical Science, Otsu,
Japan; 2 Children’s Cancer Center, National Center for Child health and
Development, Tokyo, Japan; 3 Department of Pediatrics, Hirosaki Univer-
sity School of Medicine, Hirosaki, Japan; 4 Department of Clinical Research,
Saitama Children’s Medical Center, Saitama, Japan; 5 Department of Pathol-
ogy, National Center for Child Health and Development, Tokyo, Japan;
6 Department of Pediatrics, Jichi Medical University School of Medicine,
Shimotsuke, Japan
Purpose: Juvenile xanthogranuloma (JXG) is a rare histiocytosis char-
acterized CD1a- and CD207-negative, CD68- and CD163-positive
histiocytes accumulation, usually developing in childhood, especially
first year of life. Although more than 90% patients have only cuta-
neous lesions, 5-10% patients have extra-cutaneous lesions. Some of
JXG patients with extra-cutaneous lesions have an aggressive clinical
course and poor prognosis. Recently, comprehensive genomic analysis
revealed that some patients with JXG have targetable tyrosine kinase
gene mutation and get a benefit of tyrosine kinase inhibitor (TKI).
Therefore, a rapid diagnostic method for TKI selection compared to
comprehensive genomic analysis is desired. We report here the results
of immunohistochemistry (IHC) based screening system for JXG.
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ABSTRACTS
Methods: We analyzed 30 patients diagnosed JXG (median age at diag-
nosis: 1.7 year [range, 0.1 - 7.0]). IHC was performed using CD1a,
CD207, CD68, CD163, ALK, panTRK, BRAFV600E(VE1) antibodies.
We performed fluorescence in situ hybridization (FISH) analysis in
cases positive for ALK or panTRK immunostaining and/or next gener-
ation sequencing (NGS) panels to confirm molecular targets.
Results: Twelve patients had cutaneous lesions only and eighteen
patients had extra-cutaneous lesions including iris (n=4), central ner-
vous system (CNS) (n=5), liver/spleen (n=9), lung (n=5), kidney (n=2),
pancreas (n=1), stomach (n=1). IHC and/or FISH result suggested
that seven cases had targetable gene mutation (four cases with ALK-
positive, two with pan TRK-positive, and one with VE-1 positive).
Among the cases performed NGS panel analysis, we confirmed the
kinase-fusion gene in three cases (KIF5B::ALK [n=2), TPM3::NTRK1[n-
=1)). Five of seven patients have multi-organ involvement and two of
them have isolated CNS involvement. Chemotherapy was performed
9 patients with extra-cutaneous lesions, and 2 patients received TKI
(ALK-inhibitor [n=1], NTRK-inhibitor [n=1]). None of patients with
only cutaneous lesions received chemotherapy.
Conclusions: IHC-based screening systems in JXG potentially enable
rapid TKI selection, especially in ALK and NTRK fusion gene-positive
cases.
HLH AS A POTENTIAL RED FLAG OF INBORN ERRORS OF
IMMUNITY IN CHILDREN BEYOND FAMILIAL-HLH: A
SYSTEMATIC REVIEW
Walter Maria Sarli1,2 , Silvia Ricci1,2 , Lorenzo Lodi1,2 , Clementina
Canessa2 , Francesca Lippi2 , Donata Dini3 , Marta Ferrari3 , Laura
Pisano3 , Elena Sieni4 , Giuseppe Indolfi3,5 , Massimo Resti3 , Chiara
Azzari1,2
1 Department of Health Sciences, University of Florence, Florence, Italy;
2 Immunology Division, Section of Pediatrics, Meyer Children’s Hospital
IRCCS, Florence, Italy; 3 Department of Pediatrics, Meyer Children’s Hos-
pital IRCCS, Florence, Italy; 4 Pediatric Hematology-Oncology Department,
Meyer Children’s Hospital IRCCS, Florence, Italy; 5 Department Neurofarba,
University of Florence, Florence, Italy
Purpose: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and
life-threatening condition characterized by a severe impairment of the
immune homeostasis. While Familial-HLH (FHL) is a known cause, the
involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH
remains understudied. This systematic review aimed to assess the clin-
ical features, triggers, laboratory data, treatment, and outcomes of
pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasiz-
ing the importance of accurate identification and management.
Methods: A systematic for studies meeting inclusion criteria search
was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central.
Quality assessment was performed through JBI criteria.
Results: A comprehensive search yielded 108 records meeting inclu-
sion criteria, involving 178 patients. We identified 46 different IEI
according to IUIS 2022 Classification. Combined immunodeficiencies,
immune dysregulation disorders, and phagocyte defects were the IEI

ABSTRACTS
most frequently associated with HLH. In 75% of cases, HLH preceded
the IEI diagnosis, often with an unrecognized history of severe infec-
tions. Triggers reflected the specific infection susceptibilities within
IEI groups. Liver and central nervous system involvement were less
common than in FHL cases. Treatment approaches and outcomes var-
ied, with limited long-term follow-up data, limiting the assessment of
therapeutic efficacy across IEI groups.
Conclusion: A comprehensive evaluation encompassing immunolog-
ical, infectious, and genetic aspects is essential in pediatric HLH.
Relying solely on FHL or EBV susceptibility disorders tests is insuf-
ficient, as diverse IEI can contribute to HLH. Early recognition of
HLH as a potential warning sign can guide timely diagnostic investi-
gations and facilitate tailored therapeutic interventions for improved
outcomes.
GENOMIC FEATURES OF HISTIOCYTIC NEOPLASMS IN ADULTS
Aki Sato1 , Nozomi Yusa2 , Miho Ogawa3 , Hiroyuki Takamori3 , Eigo
Shimizu4 , Koji Jimbo1 , Kazuaki Yokoyama1 , Yasunori Ota5 , Seiya
Imoto4 , Yasuhito Nannya1,3 , Arinobu Tojo6
1 Department of Hematology and Oncology, Institute of Medical Science
Research Hospital, University of Tokyo, Tokyo, Japan; 2 Department of
Applied Genomics, Institute of Medical Science Research Hospital, Univer-
sity of Tokyo, Tokyo, Japan; 3 Division of Hematopoietic Disease Control,
Institute of Medical Science, University of Tokyo, Tokyo, Japan; 4 Division
of Health Medical Intelligence, Human Genome Center, Institute of Medi-
cal Science, University of Tokyo, Tokyo, Japan; 5 Department of Diagnostic
Pathology, Institute of Medical Science Research Hospital, University of
Tokyo, Tokyo, Japan; 6 Institute of Innovation Advancement, Tokyo Medical
and Dental University, Tokyo, Japan
Purpose: Histiocytic neoplasms are rare diseases of clonal haematopoi-
etic cell origin, that are marked by diverse mutations in the mitogen-
activated protein kinase (MAPK) pathway. In Japan, the genetic profiles
in adult histiocytic neoplasms have not been evaluated. Target therapy,
such as BRAF or MEK inhibitor, have not been approved.
Methods: We retrospectively analyzed the data of patients referred to
our hospital between April 2005 and March 2023.
Results: Seventy-five patients or seventeen patients were diagnosed
with Langerhans cell histiocytosis (LCH) or other type of histiocyto-
sis (non-LCH), including Erdheim-Chester disease (ECD) (n=5), mixed
LCH/ECD (n=4), Langerhans cell sarcoma (n=3), histiocytic sarcoma
(n=2), Rosai-Dorfman disease (n=2) and Indeterminate cell histi-
ocytosis (n=1), respectively. Molecular profiling with tumor tissue
whole-exome sequencing, PCR sequencing and/or immunohistochem-
istry and/or plasma cell-free DNA (cfDNA) PCR was attempted for
all 55 LCH patients or 17 non-LCH patients, and yield at least one
valid result for the MAPK pathway mutation for 23 (41.8%) patients
or 14 (93.3%) patients, respectively. Furthermore, BRAF V600E in
plasma cfDNA (BRAF V600E) analysis of 41 LCH patients revealed
that 11 (26.8%) were positive, and the OS probability at 5 years post-
diagnosis of patients with or without plasma cfBRAF V600E mutation
was 74.1% (95% CI: 28.9-93.0) vs. 100% (95% CI: 88.4-100.0), p =
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S45 of S64
0.017, respectively. Among fourteen cases of non-LCH, 9 cases (64.3%)
did not response the first systemic therapy. Severe resistant case with
histiocytic sarcoma responded to MEK-inhibitors.
Conclusion: Based on this result that cfBRAF V600E was associated
with shorter OS in patients with LCH, and more than 90% of non-LCH
cases, for which standard treatment have not been established, possess
MAPK pathway mutation, target therapy is expected to be developed
as an effective treatment for these patients.
MONOCYTE-SPECIFIC BRAFV600E EXPRESSION
RECAPITULATES ERDHEIM-CHESTER PHENOTYPE WITH
ACCUMULATION OF DYSFUNCTIONAL MACROPHAGES
Brooks Scull1 , Matthias Wilk6 , Ryan Fleischmann1 , Dustin Neubauer1 ,
Kenneth McClain1,2 , Miriam Merad6 , Florent Ginhoux3,4,5 , Carl
Allen1,2
1 Division of Pediatric Hematology-Oncology, Department of Pediatrics,
Baylor College of Medicine, Houston, TX USA; 2 Texas Children’s Cancer
Center, Texas Children’s Hospital, Houston, TX USA; 3 Shanghai Institute of
Immunology, Department of Immunology and Microbiology, Shanghai Jiao
Tong University School of Medicine, Shanghai200025, China; 4 Singapore
Immunology Network, Agency for Science, Technology and Research, Singa-
pore 138648, Singapore; 5 Translational Immunology Institute, SingHealth
Duke-NUS Academic Medical Centre, Singapore, Singapore; 6 Precision
Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine
at Mount Sinai, New York, NY USA
Purpose: Histiocytic disorders share the feature of recurrent common
MAPK pathway mutations, but develop a wide range of clinical fea-
tures. Mechanisms underlying heterogenetity in histiocytic disorders is
not known. We have developed Cre-inducible mouse models in which
BRAFV600E is enforced at distinct stages of myeloid cell differentia-
tion. We previously recapitulated a LCH-like phenotype with enforced
expression of BRAFV600E in CD11c+ cells. In this study, we enforce
BRAFV600E using MS4A3 that is expressed exclusively in monocytes
and monocyte-derived cells.
Methods: BRAFV600E expression and reported labeling was enforced
through Cre-mediated recombination to create BRAFV600ECD11c
and BRAFV600EMS4A3 mice. Immune subtypes were assessed
by CyTOF. Gene expression was performed on reported sorted
cells collected from spleen, liver, and lung. Ingenuity Pathway
Analysis (IPA) was used to analyze sorted BRAFV600ECD11c and
BRAFV600EMS4A3 specific cells and control reporter cells.
Results: Kinetics of organomegaly, histiocytic infiltration, and sys-
temic inflammation were much slower and less pronounced in the
BRAFV600EMS4A3 mice compared to BRAFV600ECD11c mice.
Notably, BRAFV600EMS4A3 demonstrated increased enrichment of
cells with macrophage features in spleen, liver and bone marrow and
decreased inflammatory infiltrate compared to BRAFV600ECD11c
mice. IPA on BRAFV600EMS4A3 specific cells identified signif-
icantly decreases in pathways associated with cell mobility and
phagocytosis compared to control counterparts and compared
to BRAFV600ECD11c histiocytes. These pathways include focal

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adhesion kinase (FAK)/paxillin signaling and RAC signaling that
regulate cell mobility and immune cell recruitment.
Conclusion: A later onset ECD-like phenotype is created when
BRAFV600E is driven specifically in monocyte-derived cells com-
pared to pan-CD11c+ expression. This study demonstrates a criti-
cal role for ontogeny in pathogenesis of histiocytic disorders. Fur-
ther, expression of BRAFV600E in monocytes leads to accumulation
of macrophages that show dysfunctional migration and relatively
decreased immune cell recruitment. In addition to illuminating bio-
logical mechanisms in MAPK-activated monocytes, this study pro-
vides an ECD-like model for pre-clinical testing of novel therapeutic
strategies.
DEVELOPMENT OF CONCOMITANT TUMORAL AND
NEURODEGENERATIVE CENTRAL NERVOUS SYSTEM
LANGERHANS CELL HISTIOCYTOSIS LESIONS IN A PATIENT
WITH A PREVIOUS SOFT-TISSUE BRAFV600E LCH DUE TO
VACCINES
Maria Jose Serer1 , Eric Warriner1 , Daniela Fortunati1 , Maria Belen
Popon1 , Marianela Viso1 , Giulia Racca1 , Michelle Schvartz1 , Adriana
Rose1 , Fabiana Lubieniecki2 , Gabriela Lamas2 , Laura Galluzzo2 , Carina
Santacruz2 , Jorge Braier1 , Francisco Maldonado3 , Daniel Alderete1 ,
Guido Felizzia1 .
1 Hematology /Oncology, Hospital Nacional de Pediatrí-a “Prof. Dr. J. P. Gar-
rahan”, Buenos Aires, Argentina; 2 Pathology and 3Neuroradiology Depart-
ments, Hospital Nacional de Pediatrí-a “Prof. Dr. J. P. Garrahan”, Buenos
Aires, Argentina
Purpose: To report a case with previous localized soft tissue Langer-
hans cell histiocytosis due to vaccines, that developed central nervous
system Langerhans cells Histiocytosis (CNS-LCH) with tumoral and
neurodegenerative lesions.
Results: a 22-month-old male patient, with previous localized soft
tissue (deltoid region and thigh) LCH BRAF V600E positive at the
age of 6 months, who received treatment with excisional biopsy and
Indomethacin for eighteen months, developed diabetes insipidus three
months after stopping treatment. The magnetic resonance imaging
(MRI) showed findings compatible with tumoral and neurodegener-
ative (ND) lesions: Absence of normal bright signal in the posterior
pituitary gland on T1-weighted image, along with thickening (5 mm)
of the pituitary stalk, and enhancement of the enlarged pineal gland
after gadolinium administration; confluent lesions with increased sig-
nal on T2 and FLAIR in the dentate nuclei, cerebellar hemispheres and
peduncles (typically associated with ND lesions). Additionally, there
was enhancement in the cortical-subcortical region of both cerebellar
hemispheres following intravenous contrast administration, partially
corresponding to areas of abnormal signal on T2-FLAIR. Due to the rar-
ity of this clinical and neuroradiologic presentation a stereotaxic biopsy
of the brain parenchyma was performed. The samples showed chronic
inflammatory processes with immunochemistry CD1a and CD207 neg-
ative but RT-PCR BRAFV600E positive. Lumbar puncture was not
performed. Treatment with cladribine 5 mg/m2/day for 5 days course
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ABSTRACTS
was started and a revaluation with MRI after two courses will be done.
In case of no response, target therapy with Vemurafenib will be started.
Conclusion: There is no consensus about the best approach in patients
with isolated CNS-LCH. More evidence is needed about this kind of
patients to prevent a late and serious neurological sequelae of the
disease.
SEVERE GASTROINTESTINAL INVOLVEMENT IN A PATIENT
WITH HIGH RISK BRAF V600E+ LANGERHANS CELL
HISTIOCYTOSIS, A CASE REPORT
Maria Jose Serer1 , Eric Warriner1 , Daniela Fortunati1 , Maria Belen
Popon1 , Marianela Viso1 , Giulia Racca1 , Michelle Schvartz1 , Adriana
Rose1 , Laura Galluzzo2 , Karina Santacruz2 , Nilda Gonzalez Roibon2 ,
Strambach Julieta3 , Ramiro Mascardi4 , Valeria Fedrizzi5 , Jorge Braier1 ,
Guido Felizzia1
1 Hematology /Oncology, Hospital Nacional de Pediatría “Prof. Dr. J. P.
Garrahan”, Buenos Aires, Argentina; 2 Pathology, Hospital Nacional de Pedi-
atría “Prof. Dr. J. P. Garrahan”, Buenos Aires, Argentina; 3 Surgery, Hospital
Nacional de Pediatría “Prof. Dr. J. P. Garrahan”, Buenos Aires, Argentina;
4 Pharmacy Hospital Nacional de Pediatría “Prof. Dr. J. P. Garrahan”, Buenos
Aires, Argentina; 5 Pediatric Departments. Hospital Nacional de Pediatría
“Prof. Dr. J. P. Garrahan”, Buenos Aires, Argentina
Purpose: To report the case of an infant male diagnosed with high risk
multisystem Langerhans cell histiocytosis (MS-LCH) BRAFV600E, with
extensive and severe gastrointestinal involvement.
Results: Six-month-old boy, with previous diagnosis of isolated cuta-
neous LCH since two-month-old, confirmed by skin biopsy with
positive CD1a and CD207 immunohistochemical (IHC) staining and
BRAFV600E mutation, progressed with hepatic, spleen, bone and
gastrointestinal compromise with chronic diarrhea and severe hypoal-
buminemia. He started treatment with prednisone and vinblastine.
After two weeks acute abdominal pain and intussusception was diag-
nosed, which required a laparoscopic surgery with devagination and
a five-centimeters gastrointestinal resection. Morphology was not
consistent with LCH besides a small group of cells showed some pos-
itivity for CD1a, but BRAFV600E analysis was positive. Toxicity due
to vinblastine could not be ruled out so a second line chemotherapy
regimen with cytarabine and prednisolone was initiated. The patient
continued with permanent bilious discharge by nasogastric tube so
a second exploratory surgery and an upper-digestive endoscopy was
performed. These showed intestinal bleeding with extensive ulcer-
ation and a severe stenosis in the third portion of the duodenum.
A jejunostomy was performed. Histopathological report described
severe duodenitis. IHC stains were positive for CD207 and S100, and
negative for CD1a. BRAFV600E was positive by RT-PCR. After two
cycles of chemotherapy the patient progressed with hematologic dys-
function (severe anemia with blood cell transfusions). Target-therapy
with Vemurafenib by jejunal tube was started and good response
was observed. Initial Disease Activity Score (DAS)=11 points. After
a week of treatment, the patient markedly improved with DAS=4
points.

ABSTRACTS
Conclusion: Despite the lack of information regarding gastrointesti-
nal absorption of vemurafenib, the patient achieved a good response.
There are no clear guidelines for these severe cases. The use of BRAF-
inhibitors should be considered as a first-line-treatment due to the high
rates of response described in the literature.
DEVELOPMENT OF LANGERHANS CELL SARCOMA IN A
PATIENT WITH ACUTE LYMPHOID LEUKEMIA. A
TRANSDIFFERENTIATION CASE REPORT
Maria Jose Serer1 , Carla Pennella1 , Myriam Guitter1 , Diego Rosso2,3 ,
Laura Galluzzo4 , Maria Centeno4 , Carina Santa Cruz4 , Jorge Rossi5 ,
Jorge Digiorge6 , Guido Felizzia1 , Jorge Braier1 , Maria Sara Felice1
1 Hematology /Oncology, Hospital Nacional de Pediatría “Prof. Dr. J. P. Gar-
rahan”, Buenos Aires, Argentina; 2 Department of Pediatrics. Hospital de
Clínicas “José de San Martín”, Buenos Aires, Argentina. 3 Oncology Depart-
ment. Hospital General de Niños “Pedro Elizalde”, Buenos Aires, Argentina;
4 Pathology, Hospital Nacional de Pediatría “Prof. Dr. J. P. Garrahan”, Buenos
Aires, Argentina; 5 Immunology and 6 Molecular Departments. Hospital
Nacional de Pediatría “Prof. Dr. J. P. Garrahan”, Buenos Aires, Argentina
Purpose: To report a case about a child diagnosed with T Acute Lym-
phoblastic Leukemia (ALL), who developed Langerhans cell sarcoma
(LCS) during maintenance phase.
Results: A 20 month-old healthy boy was diagnosed with T-cortical
ALL, intermediate-risk group with central nervous system compro-
mise. Flow-cytometry of initial bone marrow (BM) aspirate was pos-
itive for cCD3, CD3s, CD2, CD7, CD1a, CD79, HLA-DR, nTdt; and
multiplex ligation-dependent probe amplification detected deletion
of CDKN2A/B and ERG duplication. Chemotherapy was based on
ALLIC-BFM-2009 protocol and the patient presented prednisone-
good-response, MRD-on-day 15, 0.3% and achieved complete remis-
sion after induction (MRD:0.26%). Maintenance phase began, along
with cranial radiotherapy. Five months later, disseminated papular skin
lesions appeared. A biopsy was performed, leading to a diagnosis of
LCS, confirmed by positive immunohistochemical staining for CD1a, S-
100 protein, CD207, and a Ki index of 50%. Flow-cytometry showed
histiocytic markers. Analysis of IGH-TCR rearrangements revealed
identical amplification products of the same size and identical DNA-
sequence were detectable in diagnostic BM and skin biopsy. Disease
staging was performed. Treatment with corticosteroids and cladrib-
ine was initiated without response. Thalidomide was administered for
6 weeks, resulting in signs of improvement, but lesions progressed in
an infectious context. A six-week course of prednisone plus vinblas-
tine was added without improvement. Subsequently, Next Generation
Sequencing (NGS) (FoundationOne Heme®test) identified an NRAS-
G13R mutation. The patient started target-therapy with Trametinib,
showing an excellent response. Other genomic findings included BRAF-
G466R, CKN2A/B loss, NOTCH1-K2472>G and MUTYH-G382D. The
patient remains disease-free at +21-months from diagnosis of ALL.
Conclusion: It is important to highlight the clonal identity between
both entities, that could be explained by a transdifferentia-
tion process. Despite the lack of information regarding this
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S47 of S64
unusual disease, identifying possible mutations with NGS might
be considered the best strategy to find out and adequate target
treatment.
LANGERHANS HISTIOCYTOSIS IN CHILDREN BELOW THE AGE
OF 2 YEARS: CLINICAL CHARACTERISTICS AND OUTCOME
Marina Servitzoglou1 , Efthymia Rigatou2 , Loizos Petrikkos3 ,
Emmanouil Hatzipantelis4 , Evgenia Papakonstantinou5 , Iordanis
Pelagiadis6 , Helen Dana7 , Natalia Tourkantoni2 , Demetrios Doganis1 ,
Vassiliki Tzotzola3 , Athanassios Tragiannidis4 , Helen Kosmidis7 ,
Eftychia Stiakaki6 , Antonios Kattamis2 , Sophia Polychronopoulou3 ,
Margaret Baka1 , Vassilios Papadakis3
1 Oncology Department, Children’s Hospital ’P. & A. Kyriakou’, Athens,
Greece; 2 Hematology-Oncology Unit, First Department of Pediatrics,
National and Kapodistrian University of Athens, “Agia Sofia” Children’s
Hospital, Athens, Greece; 3 Department of Pediatric Hematology-Oncology
(TAO), “Agia Sophia” Children’s Hospital, Athens, Greece; 4 Children’s &
Adolescent’s Hematology-Oncology Unit,2 nd Pediatric Clinic, School of
Medicine, Aristotle University of Thessaloniki, AHEPA University General
Hospital, Thessaloniki, Greece; 5 Department of Pediatric Hematology and
Oncology, Hippokration Hospital, Thessaloniki, Greece; 6 Department of
Paediatric Hematology-Oncology, University Hospital of Heraklion, Her-
aklion, Crete, Greece; 7 Pediatric & Adolescent Oncology Clinic, “Mitera”
Hospital, Athens, Greece
Purpose: To present the results of children with Langerhans Histiocy-
tosis (LCH) diagnosed below the age of 2 and treated in all 7 Oncology
Departments of Greece.
Methods: Between 2000-2019, 52/169 (30.8%) children with LCH in
Greece were diagnosed below 2 years of age. Data was retrospectively
collected. We describe the clinical characteristics and outcome of this
cohort.
Results: Median age at diagnosis was 12.16 months (range, 0.0-
24.2), boys/girls’ ratio 28/24 (1.16:1). With single system disease (SS)
presented 31/52 children (59.6%), median age 7.3 months (range: 0-
22.2). The site of involvement was 13/31 (42%) bone, 15/31 (48.4%)
skin, 1/31 lymph nodes, 1/31 liver, 1/31 mediastinum. Six (6/13;
46.1%) children with bone disease were CNS-Risk+, none had Dia-
betes Insipidus. Thirteen children were initially treated with sys-
temic chemotherapy (Prednisone/Vinblastine) due to localization or
multifocal disease, while the remaining were assigned to follow-up.
Relapse has occurred in 5/31 (9.7%) children, all previously treated
with chemotherapy (time to relapse: 7.87-22.8 months) and have
received second line treatment. All children are alive in remission, at
a mean follow-up time of 3.2 years (range: 0.5-19.2). Multisystem dis-
ease (MS) had 21/52 (38.5%) children, median age at diagnosis 12.6
months (range: 0-23.6). Patients had 2-5 systems involved, mainly
bone (19/21, 90.5%), skin (16/21, 76.2%), hematopoietic system (8/21),
lymph nodes (6/21), lungs (5/21), liver (5/21), spleen (5/21) and bowel
(3/21). Among children with bone involvement, 6/19 were CNS-Risk+,
while 3 had Diabetes Insipidus at diagnosis. All received chemother-
apy with Prednisolone/Vinblastine, one plus Etoposide. Relapse or

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refractory disease was observed in 5/21 (23.8%) children. Over-
all survival was 100%, with a mean follow-up time of 9.1 years
(range: 0.6-20.5).
Conclusion: Skin is the most common site of SS. Younger children
with LCH have a higher prevalence of MS, but still maintain excellent
prognosis, with the use of current treatment protocols.
CLINICAL CHARACTERISTICS AND EFFICACY ANALYSIS OF
XLP-2 RELATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS,
A RETROSPECTIVE STUDY
Lin Shi, Jingshi Wang, Zhao Wang
Department of Hematology, Beijing Friendship Hospital, Capital Medical
University, Beijing, China
Purpose: To explore the clinical characteristics and efficacy of X-linked
lymphoproliferative disease 2(XLP-2) associated hemophagocytic lym-
phohistiocytosis.
Methods: This study analyzed the clinical data of 13 patients with XLP-
2 related hemophagocytic syndrome. Retrospective analysis of Clini-
cal characteristics, EBV infection, efficacy under different treatment
methods, and long-term survival.
Results: Thirteen patients with XLP-2 related hemophagocytic syn-
drome, all male, with a median age of 5.3 years (1-26 years), 12 with
fever, 4 with splenomegaly, and 2 with central nervous system symp-
toms. 10 cases (76.92%) had EBV infection, and 2 cases (15.38%)
had EBV involvement in the central nervous system. Among them, 5
patients completed the detection of EBV-infected lymphocyte subpop-
ulations, 2 patients only infected with B cells, 3 patients mainly infected
with B cells, and the effective rate of Rituximab treatment reached
100%. Ten cases (76.92%) without allogeneic hematopoietic stem cell
transplantation and all survived for a long time. Three cases (23.78%)
with allogeneic hematopoietic stem cell transplantation, of which one
died of disease progression.
Conclusion: Not all XLP-2 related HPS patients require allo-
geneic hematopoietic stem cell transplantation. Rituximab has
excellent efficacy in XLP-2 related HPS patients with EBV infects
B cells.
LOSS-OF-FUNCTION OF ENT3 DRIVES HISTIOCYTOSIS AND
INFLAMMATION THROUGH TLR-MAPK SIGNALING
Ruth Shiloh1,2 , Ruth Lubin3 , Odeya David4,5,6 , Ifat Geron1,2 ,
elech Okon7 , Idit Hazan3 , Marketa Zaliova8 , Gil Amarilyo7,9 , Yehudit
Birger1,2 , Yael Borovitz7,10 , Dafna Brik1 , Arnon Broides5,6,11 , Sarit
Cohen-Kedar2,12 , Liora Harel7,13 , Eyal Kristal5,6,11 , Daria Kozlova7,14 ,
Galina Ling5,6 , Mika Shapira Rootman15 , Noa Shefer Averbuch7,16,17 ,
Shiri Spielman7,18 , Jan Trka8 , Simon Yona3 , Shai Izraeli12,7,19 ,
Elitzur1,7
1 The Rina Zaizov Division of Pediatric Hematology-Oncology, Schnei-
der Children’s Medical Center, Petach Tikva, Israel; 2 Felsenstein Medical
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ABSTRACTS
Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petach
Tikva, Israel; 3 The Institute of Biomedical and Oral Research, Hebrew Uni-
versity, Jerusalem, Israel; 4 Pediatric Endocrinology Unit, Soroka University
Medical Center, Beer Sheva, Israel; 5 Pediatric Ambulatory Center, Soroka
University Medical Center, Beer Sheva, Israel; 6 Joyce and Irving Gold-
man Medical School, Faculty of Health Sciences, Ben Gurion University
of the Negev, Beer Sheva, Israel; 7 Faculty of Medicine, Tel Aviv Univer-
sity, Tel Aviv, Israel; 8 CLIP, Department of Paediatric Haematology and
Oncology, Second Faculty of Medicine of Charles University Prague and
University Hospital Motol, Prague, Czech Republic; 9 Pediatric Rheuma-
tology Unit, Schneider Children’s Medical Center, Petach Tikva, Israel;
10 Institute of Nephrology, Schneider Children’s Medical Center, Petach
Tikva, Israel; 11 Pediatric Immunology Clinic, Soroka University Medical Cen-
ter, Beer Sheva, Israel; 12 Division of Gastroenterology, Rabin Medical Center,
Petach Tikva, Israel, 13 Pediatric Rheumatology Unit, Schneider Children’s
Medical Center, Petach Tikva, Israel; 14 Department of Pathology, Rabin
Medical Center, Beilinson Campus, Petach Tikva, Israel; 15 Department of
Radiology, Rambam Health Care Campus, Haifa, Israel; 16 Pediatric Genet-
ics Clinic, Schneider Children’s Medical Center of Israel, Petach Tikva,
Israel; 17 The Jesse Z and Sara Lea Shafer Institute for Endocrinology and
Diabetes, National Center for Childhood Diabetes, Schneider Children’s
Medical Center of Israel, Petach Tikva, Israel; 18 Department of Pedi-
atrics A, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center,
Ramat Gan, Israel; 19 Beckman Research Institute, City of Hope, Duarte,
CA USA
Purpose: Activation of extracellular signal-regulated kinase (ERK)
is considered a universal driver of histiocytosis and somatic alter-
ations in mitogen-activated protein kinase (MAPK) cascade genes are
identified in most cases. However, in rare histiocytoses, somatic alter-
ations in MAPK cascade genes are less common, and the underlying
mutation frequently remains unknown. This suggests the existence
of alternative pathways leading to histiocytosis. H syndrome is an
inflammatory genetic disorder caused by germline loss-of-function
mutations in SLC29A3, encoding the lysosomal equilibrative nucle-
oside transporter 3 (ENT3). Patients with H syndrome are predis-
posed to develop Rosai-Dorfman Disease (RDD)-like histiocytosis by
an unknown mechanism. Identifying the dysregulated signaling path-
ways in H syndrome may shed light on novel pathways leading to
histiocytosis.
Methods: We assembled a cohort of patients with H syndrome and
performed elaborate analysis of their cells, combining single-cell RNA
sequencing, multi-parameter flow cytometry and functional assays.
Results: Our results suggest a model in which impaired nucleoside
Elim- trafficking aberrantly activates nucleoside-sensing toll-like recep-
tors (TLR7/8), leading to persistent activation of ERK, inflammatory
cytokine secretion and histiocytosis in the absence of somatic muta-
tions in MAPK cascade genes. Treatment with the MEK inhibitor
trametinib led to the resolution of a histiocytic tumor in one of our
Sarah patients, suggesting that patients with H syndrome may benefit from
MAPK-directed therapy.
Conclusion: These results demonstrate a yet-unrecognized link
between a defect in a lysosomal transporter and pathological

ABSTRACTS
activation of MAPK signaling, establishing a novel pathway leading to
histiocytosis.
CHRONIC HEALTH CONDITIONS AFTER CHILDHOOD
LANGERHANS CELL HISTIOCYTOSIS: RESULTS FROM THE
SWISS CHILDHOOD CANCER SURVIVOR STUDY
Tomáš Sláma1,2 , Luzius Mader1 , Maša Žarković1,3 , Reta Malär4 ,
Alexandra Schifferli5 , Nicolas Xavier von der Weid5 , Claudia Elisabeth
Kuehni*1,6 , Christina Schindera*1,5
1 Childhood Cancer Research Group, Institute of Social and Preventive
Medicine, University of Bern, Switzerland; 2 Graduate School for Cellular
and Biomedical Sciences, University of Bern, Switzerland; 3 Graduate School
for Health Sciences, University of Bern, Switzerland; 4 Department of Pae-
diatrics, Cantonal Hospital Graubuenden, Chur, Switzerland; 5 Division of
Pediatric Oncology/Hematology, University Children’s Hospital Basel, Uni-
versity of Basel, Basel, Switzerland; 6 Pediatric Oncology, Inselspital, Bern
University Hospital, University of Bern, Switzerland
*These authors contributed equally to this work (shared last authorship)
Purpose: The prognosis of Langerhans cell histiocytosis (LCH) is gen-
erally favourable, but some LCH survivors experience chronic health
conditions (CHC) resulting from this disease. Since a comprehensive,
population-based description of chronic health conditions among LCH
survivors is lacking, we evaluated the spectrum and prevalence of
chronic health conditions among LCH survivors compared with siblings
of childhood cancer survivors and identified factors associated with
chronic health conditions.
Methods: The Swiss Childhood Cancer Survivor Study sent ques-
tionnaires to all ≥5-year LCH survivors registered in the Swiss
Childhood Cancer Registry who were diagnosed between 1976
and 2015. The sibling cohort received a similar questionnaire. We
standardized siblings on sex, age at study, migration background,
and Swiss language region based on the distribution in survivors.
We compared CHC prevalence between survivors and siblings and
used logistic regression adjusted for sex and age to identify CHC
determinants.
Results: We included 123 LCH survivors (response rate 69%) with a
median time since diagnosis of 13 years (interquartile range [IQR] 9-20)
and median age at study of 20 years (IQR 15-26). LCH survivors were
more often male (63%). We also included 866 siblings. Fifty-nine per-
cent of LCH survivors had at least one CHC while only 48% of siblings
had at least one CHC (p=0.02). Cardiovascular (13% vs. 6%), endocrine
(15% vs. 1%), musculoskeletal (22% vs. 12%), and digestive (15% vs. 8%)
CHC were more prevalent in LCH survivors than siblings (all p<0.05).
Factors most strongly associated with occurrence of CHC were multi-
system LCH, multifocal bone involvement, and involvement of pituitary
gland.
Conclusions: More than half of long-term LCH survivors suf-
fered from one or more CHC. Clinicians in paediatric cancer
follow-up programs should be aware of possible cardiovascu-
lar, endocrine, musculoskeletal, and digestive conditions in LCH
survivors.
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THE MITOCHONDRIAL NETWORK MORPHOLOGY AS A
POTENTIAL INDICATOR OF DRUG RESISTANCE IN PRIMARY
CELL LINES DERIVED FROM HISTIOCYTIC LESIONS
Agnieszka Smieszek1 , Zofia Małas2 , Klaudia Marcinkowska1 , Mateusz
Sikora3 , Jadwiga Węcławek-Tompol4 , Carlos Rodriguez-Galindo5 ,
Anna Raciborska2
1 Department of Pharmacology and Toxicology, Faculty of Veterinary
Medicine, Wroclaw University o Environmental and Life Sciences, Nor-
wida 31, 50-375 Wroclaw, Poland; 2 Department of Oncology and Surgical
Oncology for Children and Youth, Institute of Mother and Child, Kasprzaka
17a, 01-211 Warsaw, Poland; 3 Department of Experimental Biology, Fac-
ulty of Biology and Animal Science, Wroclaw University of Environmental
and Life Sciences, Norwida27B, 50-375 Wroclaw, Poland; 4 Clinical Depart-
ment of Paediatric Bone Marrow Transplantation, Oncology and Haematol-
ogy, Wroclaw Medical University, Poland; 5 Departments of Global Pediatric
Medicine and Oncology, St. Jude Children’s Research Hospital, Memphis, TN
USA
Purpose: Mitochondria are organelles essential in cellular energy pro-
duction, metabolism, and apoptosis. The alterations in mitochondrial
dynamics are most currently analyzed regarding the biology of cancer
cells. Recently, the mitochondrial network organization has been asso-
ciated with drug resistance of various cancers. This study compared
the mitochondrial network development and mitochondria morpho-
types in three primary cell lines originating from histiocytic lesions
(pc-HL). The study aimed to correlate information about mitochondria
dynamics with cells’ response to inhibitors of B-Raf protein (BRAF) and
mitogen-activated protein kinase kinase (MEK), i.e. vemurafenib and
trametinib.
Methods: The microphotographs from the confocal imaging (magnifi-
cations 630× and 1000×) were used to reconstruct the mitochondrial
network and test its morphology. The images were processed with
Fiji software (ImageJ 1.52n, National Institute of Health, USA). The
three-dimensional (3D) reconstructions of the mitochondrial com-
plexity were performed using Leica Application Suite X (version
3.5.2.18963, Leica Microsystems CMS, Germany). Mitochondria were
also identified using MicroP software (ver. 1.1.11b, Biomedical Image
Informatics Lab, Taiwan). Analysis was complemented with an evalu-
ation of mitochondrial membrane potential. Cells were stained with
Muse® Mitopotential Assay Kit and measured using Muse Cell Ana-
lyzer (Luminex/Merck, Poznan, Poland). The transcript levels were
determined using RT-qPCR.
Results: The results showed that obtained pc-HL are metabolically
active, showing high polarization of mitochondria membrane and a
well-developed mitochondrial network with some distinctive mor-
photypes noted. The detailed analysis of mitochondria morphology
showed that the pc-HL resistant to trametinib had globular mitochon-
dria, showing sensitivity to vemurafenib. All tested pc-HL showed high
mRNA expression for fission (FIS), PTEN-induced kinase 1 (PINK1) and
mitofusin-1 (MNF1), simultaneously showing lowered accumulation of
transcripts for mitofusin-2 (MNF2), and Parikn (PRKN).
Conclusions: Analyzing mitochondrial network morphology and activ-
ity in primary cell lines from histiocytic lesions may provide important

S50 of S64
information regarding their drug sensitivity. However, more studies are
essential in this field.
EXPRESSION PROFILE OF ONCOGENIC NON-CODING RNAS IN
CELLS DERIVED FROM HISTIOCYTIC LESIONS
Agnieszka Smieszek1 , Zofia Małas2 , Klaudia Marcinkowska1 , Aleksan-
dra Pawlak1 , Jadwiga Węcławek-Tompol3 , Carlos Rodriguez-Galindo4 ,
Anna Raciborska2
1 Department of Pharmacology and Toxicology, Faculty of Veterinary
Medicine, Wroclaw University o Environmental and Life Sciences, Nor-
wida 31, 50-375 Wroclaw, Poland; 2 Department of Oncology and Surgical
Oncology for Children and Youth, Institute of Mother and Child, Kasprzaka
17a, 01-211 Warsaw, Poland; 3 Clinical Department of Paediatric Bone
Marrow Transplantation, Oncology and Haematology, Wroclaw Medical
University, Poland; 4 Departments of Global Pediatric Medicine and Oncol-
ogy, St. Jude Children’s Research Hospital, Memphis, TN USA
Purpose: Non-coding RNAs play critical roles in various cellular pro-
cesses by regulating gene expression and substantially impacting cell
survival, growth and proliferation. Currently, much attention is paid to
their role in the initiation of oncogenesis and progression, invasion and
metastasis of various cancers, as they may serve as diagnostic biomark-
ers and therapeutic targets. The study aimed to determine the levels
of both long non-coding RNAs (lncRNAs) and small non-coding RNAs
(miRNAs) with oncogenic potential.
Methods: The total RNA was isolated from primary cell lines derived
from histiocytic lesions and from normal cells of mesenchymal ori-
gin. The RNA was extracted from cells using the phenol-chloroform
method. For this purpose, at passage three, the cells (1x106) were
homogenized with 1 ml of TRI Reagent®(Merck). RNA preparations
were purified from genomic DNA by DNAse I treatment (Precision
DNAse kit, Primerdesign), while cDNA synthesis for ncRNA detection
was performed using the Mir-X ™ miRNA First-Strand Synthesis Kit
(Takara Clontech Laboratories). Transcripts accumulation was moni-
tored in real-time on CFX Connect Real-Time PCR Detection System
(Bio-Rad) using SensiFast SYBR & Fluorescein Kit (Bioline Reagents
Ltd.).
Results: The analysis of lncRNA levels showed that DANCR, MEG3
and SCHLAP-1 could distinguish the cells originating from histiocytic
lesions. Moreover, the cells differ in levels for oncogenic miRNAs,
including miR-17-5p, miR-34c-5p, miR-124-1-3p, miR-145-5p and
miR-320a-3p. Non-coding RNAs and their expression patterns deter-
mined in this study may reveal novel transcriptional features of cells
derived from histiocytic tissues.
Conclusions: Analysis of the ncRNA expression profile may give
insights into the molecular mechanisms underlying the develop-
ment of histiocytoses. Obtained results may contribute to a better
understanding the heterogeneity and diversity of cells derived
from histiocytic lesions. We believe that studies on ncRNAs in his-
tiocytoses development may lead to improved classification and
personalized treatment strategies for patients with these rare
disorders.
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ABSTRACTS
CLINICAL CHARACTERISTICS OF MACROPHAGE ACTIVATION
SYNDROME WITH EPSTEIN-BARR VIRUS INFECTION: MORE
RELAPSED OR REFRACTORY: A SINGLE-CENTER
RETROSPECTIVE COHORT STUDY
Deli Song, Jingshi Wang, Lin Wu, Zhao Wang
Department of Hematology, Capital Medical University Affiliated Beijing
Friendship Hospital, 95 Yong An Road, Xicheng District, Beijing 100050,
China
Purpose: Macrophage activation syndrome is a serious and lethal dis-
ease in which Epstein-Barr virus infection is a causative factor. It is
unclear whether EBV infection is associated with the treatment results
and prognosis of MAS. This study explored the clinical features of
patients with MAS in combination with EBV infection.
Methods: In this retrospective study, 128 patients met the inclusion
criteria and were divided into the EBV- negative MAS group (n =
108) and EBV-positive MAS group(n = 20) . We compared the clinical
characteristics, treatment response and prognosis of the two groups.
Propensity score matching (PSM) was used to match patients between
the groups. Kaplan-Meier analysis for elucidating the relationship
between EBV-infected lymphocyte type and prognosis.
Results: Before as well as after the PSM, patients in the group with EBV
infection were more likely to have relapses or be refractory to treat-
ment. However, EBV infection was shown not to affect the prognosis of
MAS after the PSM. KM analysis revealed a significant decrease in sur-
vival in the EBV-infected NK and or T lymphocyte groups compared to
other infected cell types(p<0.01) after further analysis of EBV-infected
cell type.
Conclusion: EBV infection is an independent risk factor for patients
with MAS. In patients diagnosed with MAS, prompt testing for EBV-
infected lymphocyte subsets should be performed once EBV infection
is detected, which is important for treatment and prognostic eval-
uation. This conclusion also holds true for patients with HLH onset
and EBV infection and rheumatic disease identified during etiologic
screening.
MYELODYSPLASTIC SYNDROME AND HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS: A RETROSPECTIVE STUDY OF 15
CASES IN A SINGLE CENTER
Yue Song1,2 , Fei Zhou1,2 , Xiaoli Li3 , Feng Du3 , Ziyan Wang3 , Liyun Bai3 ,
Yifang Yao3 , Limin Liu1,2 , Xiao Ma1,2 , Suning Chen1,2 , Xuefeng He1,2 ,
Depei Wu1,2
1 National Clinical Research Center for Hematologic Diseases, Jiangsu Insti-
tute of Hematology, The First Affiliated Hospital of Soochow University,
Suzhou,215006, China; 2 Institute of Blood and Marrow Transplanta-
tion, Collaborative Innovation Center of Hematology, Soochow Univer-
sity, Suzhou,215031, China; 3 Department of hematology, Soochow Hopes
Hematonosis Hospital, Suzhou,215128, Jiangsu, China
Purpose: Malignancy-associated hemophagocytic lymphohistiocyto-
sis (M-HLH) is a type of secondary HLH commonly triggered by
hematological malignancies such as lymphomas. HLH initiated by

ABSTRACTS
myelodysplastic syndrome (MDS) is exceedingly rare and has not been
extensively studied, leading to limited understanding of its underlying
pathogenesis and optimal treatment strategies.
Methods: A retrospective analysis was conducted on patients diag-
nosed with MDS-HLH between March 1, 2019 and March 1, 2023.
The study primarily evaluated the clinical manifestations, laboratory
indicators, treatment regimens, efficacy and outcome of these patients.
Results: Fifteen patients were included. In addition to typical fea-
tures of aggressive HLH, liver damage was observed in 67% (10/15)
and elevated cytokine levels were present in 93% (13/14) of patients.
Concurrent EBV infection was identified in four patients (27%). Remis-
sion of HLH was achieved in 53.3% (8/15). A comparison between
the lower-risk and higher-risk MDS-HLH groups revealed that all
patients in the lower-risk group developed HLH at the same time as
the diagnosis of MDS, while most patients in the higher-risk group
experienced HLH onset during MDS progression or relapse (p=0.014).
There were eight deaths, with the majority occurring within the first
two months after HLH diagnosis (75%, 6/8). The median overall sur-
vival was 12.3 weeks (95% CI, 1.1-23.5). The remission status of HLH
was significantly associated with a better prognosis (p=0.018, Exp
(B)=0.003).
Conclusion: This is the first comprehensive study focusing specifically
on MDS-HLH, emphasizing the need to consider cytopenia, cytokine
levels, and liver damage in its diagnosis. Pathogenesis differs based on
MDS risk classification, with higher-risk patients driven by malignancy
antigens and lower-risk patients affected by immune dysfunction.
Prognosis is generally poor and the remission status of HLH is cru-
cial for the final outcome. Chemotherapy-free regimens should be
preferred over chemotherapy drugs, and the role of EBV infection in
MDS-HLH development should be recognized.
SUCCESSFUL TREATMENT OF EBV-ASSOCIATED
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS USING
COMBINED PD-1 MONOCLONAL ANTIBODY AND
EMAPALUMAB WITHOUT INTENSIVE CHEMOTHERAPY
Yue Song1,2 , Jianhhong Fu1,2 , Weiyang Li1,2 , Tao You1,2 , Yang Zhang3 ,
Xuefeng He1,2 , Suning Chen1,2 , Depei Wu1,2
1 National Clinical Research Center for Hematologic Diseases, Jiangsu Insti-
tute of Hematology, The First Affiliated Hospital of Soochow University,
Suzhou, China; 2 Institute of Blood and Marrow Transplantation, Collabora-
tive Innovation Center of Hematology, Soochow University, Suzhou, China;
3 Canglang Hospital of Suzhou, Suzhou, Jiangsu, China
Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a rare and
life-threatening syndrome characterized by immune dysregulation and
excessive inflammation. The crucial role of interferon-gamma (IFN-γ)
in the development of HLH has been confirmed, and Emapalumab, an
IFN-γ blocking monoclonal antibody, has shown significant efficacy in
HLH. Epstein-Barr virus associated HLH (EBV-HLH) is a type of sec-
ondary HLH characterized by EBV infection, which progresses rapidly
and lacks effective and safe therapy. Programmed cell death protein
1 (PD-1) is an important immune checkpoint that has demonstrated
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S51 of S64
significant effects on EBV infection-related diseases. The combina-
tion of emapalumab and PD-1 blockade in EBV-HLH has not been
studied.
Methods: We present a 29-year-old male patient diagnosed with
refractory EBV-HLH, with rapid disease progression and multiple
organ failure, resolved successfully by combination of emapalumab and
PD-1 blockade.
Results: This patient exhibited persistent fevers, hepatosplenomegaly,
pancytopenia, hypofibrinogenemia, hypertriglyceridemia, hyperfer-
ritinemia (501,367 ng/mL) and elevated soluble CD25 levels (32,641
pg/mL), which remained unresponsive to corticosteroids, intravenous
immunoglobulins and ruxolitinib. Additionally, his serum interferon-
gamma (IFN-γ) levels were significantly elevated (11,101 pg/mL), and
he rapidly developed multiple organ damage, including liver dys-
function, acute renal dysfunction, and myocardial injury. He showed
a remarkable response to treatment with emapalumab and PD-1
blockade, which resulted in the resolution of his fevers and nor-
malization of laboratory abnormalities without the need for inten-
sive chemotherapy. Notably, the copies of EBV-DNA in his system
decreased rapidly and eventually became undetectable within two
weeks.
Conclusion: This report provides initial evidence supporting the ther-
apeutic efficacy of combining IFN-γ blockade and PD-1 blockade in
refractory EBV-HLH. The combination not only successfully resolved
the disease without the risk of active infections and hematological tox-
icity associated with intensive chemotherapy but also addressed the
issue of variable efficacy observed with PD-1 blockade among different
patients.
NACHO: IF YOU BUILD IT, THEY WILL COME. CLINICAL
RESEARCH OPERATIONS IN A RARE DISEASE CONSORTIUM
James Sparks, Heidi Clough
St. Jude Children’s Research Hospital, Memphis, TN USA
Purpose: Histiocytosis is a rare disease affecting children and adults
that can lead to devastating outcomes if left untreated. Access to clin-
ical trials may be a patients’ only option for treatment. The mission of
NACHO (North American Consortium for Histiocytosis) is to cure all
patients with histiocytic diseases and clinical trial access can help fulfill
this mission.
Methods: By implementing a robust research infrastructure, NACHO
assists in the development and implementation of clinical trials as well
as providing operational support of those trials for our increasing num-
ber of member institutions, thereby making them available to more
patients with histiocytosis.
Results: NACHO has developed several committees that oversee
research operations within our consortium: Executive Committee, Sci-
entific Committee, Clinical Studies Committee, and a Data and Safety
Monitoring Committee. Additionally, NACHO has the following oper-
ational team members in place to manage key clinical trial tasks:
Principal Investigator, Program Manager, Clinical Research Coordina-
tor, Study Manager(s), and Clinical Research Monitor(s). We support

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several multi-site histiocyte studies, four of which are currently open
to enrollment. Additionally, we have completed two studies. With this
infrastructure in place, NACHO has increased membership from an ini-
tial 12 institutions in 2014 to over 60 institutions to date. As such,
we have been able to establish a community of experts that can dis-
seminate treatment guidance for those treating histiocytosis patients
and provide access to clinical trials that may be otherwise unavail-
able to smaller institutions in North America. Additionally, we have
enhanced consortium wide collaborations to promote ideas within the
histiocytosis community.
Conclusion: With a solid base of operations, NACHO is strategically
positioned to sustain clinical trials and provide the best treatment
knowledge to those caring for patients with histiocytosis.
USING PROTEIN MODELING TO EVALUATE THE FUNCTIONAL
CONSEQUENCES OF PATIENT-DERIVED MISSENSE VARIANTS
IN FAMILIAL HLH
Erica Steen1 , Lauren Meyer2 , Darcie Miller3 , Adam Olshen4 , Kim
Nichols3
1 University of California, San Diego, CA USA; 2 University of Washington,
Seattle, WA USA; 3 St. Jude Children’s Research Hospital, Memphis, TN USA;
4 University of California, San Francisco, CA USA
Purpose: Perforin (PRF1) is a pore-forming protein expressed in cyto-
toxic lymphocytes that facilitates the delivery of granzymes into target
cells, resulting in apoptosis. Bi-allelic loss-of-function mutations in
PRF1 are the most common mutations underlying familial hemophago-
cytic lymphohistiocytosis (fHLH). However, many variants identi-
fied in patients have unknown molecular consequences. We utilized
computational modeling tools to better understand how missense
variants impact perforin structure and function.
Methods: Residues known to be critical for murine perforin func-
tion, including calcium-binding sites, glycosylation sites, transmem-
brane regions, and residues critical for lytic function and oligomer-
ization were collected from the literature. By sequence conser-
vation, these residues were overlaid onto the AlphaFold gener-
ated structure of human perforin. Protein-protein interaction sites
were predicted using a consensus neural network method (cons-
PPISP). Known pathogenic (n=31) and benign (n=8) missense vari-
ants spanning the membrane attack complex/perforin superfamily
(MACPF), calcium-binding (C2), and epidermal growth factor (EGF)-
like domains within perforin were collected from the ClinVar database.
Perforin structures containing these variants were modeled using
RoseTTAfold and were compared to the wild-type structure by cal-
culating a root-mean-square deviation (RMSD) between all atom
pairs.
Results: Within both the C2 and EGF-like domains, pathogenic vari-
ants tend to cluster with predicted protein-protein interaction sites.
Within the MACPF domain, pathogenic variants tend to cluster with
transmembrane regions and sites critical for oligomerization and lytic
function. One pathogenic variant overlapped a residue critical for dis-
ruption of the target cell membrane. The greatest RMSD was observed
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ABSTRACTS
for a pathogenic variant that appears to cluster with a transmembrane
region and sites critical for oligomerization.
Conclusion: Computational modeling and annotation of the three-
dimensional perforin structure provides insight into the localization
and molecular consequences of pathogenic missense variants. This
approach may have utility in predicting the pathogenicity of novel vari-
ants or variants of unknown significance in patients with suspected
fHLH.
DEP REGIMEN IN COMBINATION WITH PD-1 MONOCLONAL
ANTIBODY FOR REFRACTORY RELAPSED EBV-ASSOCIATED
PHAGOCYTIC LYMPHOID HYPERPLASIA
Suolitiken Dina, Dina Suolitiken, Yahong You, Jingshi Wang, Yini Wang,
Zhao Wang
Department of Hematology, Beijing Friendship Hospital, Capital Medical
University, Beijing, People’s Republic of China
Purpose: Epstein-Barr virus-associated hemophagocytic lymphohisti-
ocytosis (EBV-HLH) is the most common subtype of secondary HLH
caused by infection, with high prevalence and mortality in Asian pop-
ulations. This study investigated the efficacy and safety of the DEP
regimen combined with a PD-1 monoclonal antibody as a remedial
therapy for relapsed/refractory EBV-HLH.
Methods: This study included an analysis of 21 patients with refrac-
tory/relapsed EBV-HLH treated with the DEP regimen combined with
PD-1 monoclonal antibody at Beijing Friendship Hospital, Capital Med-
ical University, from June 2021 to May 2023. Treatment outcomes
and adverse events after treatment with DEP combined with PD1
monoclonal antibody.
Results: The mean plasma EBV-DNA before and after PD-1 mono-
clonal antibody combination therapy with DEP was 84,275 copies/mL
and 8711, which decreased significantly after treatment (P = 0.0345).
21 patients with refractory/relapsed EBV-HLH had an overall
remission rate of 61.9% (CR+PR). 6 patients underwent allogeneic
hematopoietic stem cell transplantation (allo-HSCT), 12 of the 21
patients survived until June 1, 2023.The main adverse effects of the
DEP regimen of PD-1 monoclonal antibody combination therapy were
infection and bone marrow suppression.
Conclusion: This study demonstrates that the DEP regimen PD-1 mon-
oclonal antibody is a safe and effective salvage therapy for refractory
EBV-HLH prior to allo-HSCT and increases the likelihood that such
patients will receive allo-HSCT. A prospective multicenter, large-scale
clinical trial to validate the DEP regimen PD-1 monoclonal anti-
body regimen for EBV-HLH is currently underway (ClinicalTrails.gov
identifier: NCT05315336).
REDUCED QUALITY OF LIFE AFTER CHILDHOOD LANGERHANS
CELL HISTIOCYTOSIS
Malin Sveijer1,2,3 , Désirée Gavhed1,4 ; Helena Hertzberg4 ; Eric
Zander5 ; Jan-Inge Henter1,4 , Tatiana von Bahr Greenwood1,4

ABSTRACTS
1 Childhood Cancer Research Unit, Department of Women’s and Children’s
Health, Karolinska Institutet, Stockholm, Sweden; 2 Department of Pedi-
atrics, Eskilstuna Hospital, Eskilstuna, Sweden; 3 Centre for Clinical Research
Sörmland, Uppsala University, Eskilstuna, Sweden; 4 Astrid Lindgren Chil-
dren’s Hospital, Karolinska University Hospital, Stockholm, Sweden; 5 Center
of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research;
Department of Women’s and Children’s Health, Karolinska Institutet &
Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
Purpose: Langerhans cell histiocytosis (LCH) is an inflammatory
myeloid neoplastic disorder with variable clinical presentation, ranging
from self-healing single lesions to multisystemic potentially fatal dis-
ease. Years after assumed remission there is risk of reactivation, and
long-term consequences are common, including progressive neurode-
generation. How LCH affects long-term everyday life is not well known,
which this study aimed to investigate.
Methods: Currently, 28/51 eligible individuals ≥10 years old, treated
for LCH in childhood (<18 years) at Karolinska University Hospi-
tal during 1990-2014, completed ≥5 years later questionnaires to
report quality-of-life, fatigue, pain, depression and attention deficit.
Additional data is pending.
Results: 11/28 (39%) had had multisystem disease, including 3/28
(11%) with risk organ involvement (RO+). A third (7/22) of the patients
now ≥15 years reported symptoms of depression. 25% (5/20) of
the now adult (≥18 years) patients’ Adult ADHD Self-Report Scales
(ASRS) scores indicated symptoms of inattention, and 15% (3/20)
reported a neuropsychiatric diagnosis. 45% (10/22) of the patients
now ≥15 years reported chronic pain. RO+ patients rated their pain
(0-10) during the last year markedly higher than patients without
risk organ involvement (RO-) (mean 7.3 and 3.2 out of 10, respec-
tively). The mean total health-related quality-of-life (HRQOL) score
of all patients was 77.7). RO+ patients reported a markedly lower
total HRQOL score (mean 53.2) and PedsQL fatigue score (mean 39.8)
than RO- patients (mean 80.7, and mean 70.0, respectively). Higher
scores (0-100) indicate better HRQOL and less fatigue. Poorer HRQOL
was correlated to more fatigue (R2 : 0.78, Pearson’s Correlation
p<0.001).
Conclusions: At follow-up, patients with LCH in childhood reported
high frequencies of depressive symptoms and pain, and their scores
indicate a suboptimal quality of life including problems with attention
deficit and fatigue. Moreover, RO+ patients described more pain and
fatigue and poorer quality of life than other LCH patients.
A CASE REPORT OF AN INFANT WITH ISOLATED THYMIC
LANGERHANS CELL HISTIOCYTOSIS
Wee Nee Tan, Boon Siew Ai, Kok Hoi Teh
Hospital Tunku Azizah, Kuala Lumpur, Malaysia
Background: Thymic involvement encounter about 4.4% overall of
Paediatric Langerhans Cell Histiocytosis. All reported pediatric LCH-
thymic cases presented with multisystem disease. Rare cases of iso-
lated LCH involving thymus in adult associated with myasthenia gravis.
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OBJECTIVE: We report 1 case of isolated Paediatric LCH from our
centre.
Case Report: 9 months old boy, presented with cough for 3 weeks and
low-grade temperature for 2 weeks. Clincal examination revealed mild
respiratory distress, mildly tachypnea with subcostal recession. No skin
rashes and no hepatosplenomegaly. He was treated as chest infection
at regional hospital. Due to persistent symptoms, CXR and CT thorax
was performed which showed anterior mediastinal mass. Alpha feto-
protein and Beta HCG was within normal range. Bone marrow exam-
ination shows no excess blasts, no abnormal lymphoid population, no
infiltration of non-hematopoietic malignancy cells. Biopsy was done on
which shows tumour cells positive immunohistochemical staining for
CD1a and S100; Negative for CD3, CD20, TDT and CD34. CD99 shows
non-specific patchy cytoplasmic staining, Ki-67 proliferation index:
40%. Suggestive of Langerhans Cell Histiocytosis. While waiting for
histopathological report, child developed superior vena cava obstruc-
tion symptoms and was intubated for 6 days.He was started on oral
prednisolone 40mg/m2/day for 4 weeks and weekly IV vinblastine for 6
weeks. He was extubated successfully after 1 week of prednisolone and
1 dose of vinblastine. Repeated X ray or CT after initial course therapy
shows resolution of mediastinal widening/mass. His treatment contin-
ued with continuation therapy of 3 weekly IV Vinblastine 6mg/m2/dose
and 3 weekly pulsatile oral prednisolone 40mg/m2/day for a total ther-
apy of 52 weeks. His end of treatment assessment on shows total
remission.
Conclusion: LCH should be considered as a differential in isolated
thymic lesion especially in infants. My patient achieved remission with
chemotherapy alone, this is similar outcome with recent published
study.
CARDIOVASCULAR CO-MORBIDITIES IN CARDIAC-INVOLVED
ERDHEIM-CHESTER DISEASE (ECD)
Reema Tawfiq1 , Jason Young1 , Madeline Mahowald2 , Saurabh
Zanwar3 , Gordon Ruan3 , Karen Rech3 , Matthew Koster3 , Lucinda
Gruber3 , Aishwarya Ravindran4 , Mithun Shah3 , Nora Bennani3 ,
Robert Vassallo3 , Jay Ryu3 , Caroline J. Davidge-Pitts3 , Gaurav Goyal4 ,
Ronald S. Go3 , Jithma P. Abeykoon3
1 Mayo Clinic, Jacksonville, FL USA; 2 University of Florida, Jacksonville, FL
USA; 3 Mayo Clinic, Rochester, FL USA; 4 University of Alabama, Birmingham,
AL USA
Purpose: Our understanding of the characteristics of cardiac-involved
ECD (ECD-CV) and how this affects outcomes and pre-existing dis-
eases remains limited. We aimed to determine the association of pre-
existing cardiovascular (CV) co-morbidities with ECD-CV compared to
patients without cardiac-involved ECD (ECD-noCV).
Methods: Records of patients with ECD diagnosed from Jan-1990 to
Dec-2021, consecutively seen at Mayo Clinic, were reviewed. Car-
diac involvement was diagnosed by imaging. CV co-morbidities were
captured before and after ECD diagnosis. CTCAE v3.0 based grading
system was used to assess CV co-morbidities.

S54 of S64
Results: Among 106 ECD patients, 38% (n=40) had cardiac involve-
ment. The median age at diagnosis was 57 years (range:49-67); 61%
were males. The median follow-up was 5 years (95% CI:3.5-6.1) and 4.1
years (95% CI:3.2-6.5) for ECD-CV and ECD-noCV patients, respec-
tively, p=0.92. BRAFV600E mutation was present in 65% (n=26) of
ECD-CV vs. 42% (n=28) of ECD-noCV, p=0.024. During follow-up, 8
patients with ECD-CV died (one from sudden cardiac death) compared
to 9 ECD-noCV patients, p=0.387. Smoking was present in 43% (n=18)
of ECD-CV patients compared to 24% with ECD-noCV (n=16), p=0.05.
In comparison to ECD-noCV patients, pre-existing hypertension [59%
(n=23) vs. 35% (n=23), p=0.016] and myocardial infarction [10% (n=4)
vs. 2% (n=1), p=0.046] were more often seen in ECD-CV. There was
no difference in hyperlipidemia, diabetes mellitus, coronary artery dis-
ease, congestive heart failure (CHF), valvular disease, atrial fibrillation,
and conduction disorder among the two cohorts. After ECD diagno-
sis, de novo diagnosis of hyperlipidemia [67% (n=26) vs. 38% (n=25);
p=0.004] and CHF [35% (n=14) vs. 7% (n=5); p=<0.001] was seen
more frequently in ECD-CV patients compared to ECD-nonCV. There
was no change in severity of pre-existing conditions in patients with or
without ECD-CV.
Conclusion: Cardiac involvement by ECD did not prognosticate
patients and did not worsen the pre-existing CV conditions compared
to patients with ECD-noCV.
CLUSTER ANALYSIS UNVEILS THE CLINICAL SPECTRUM OF
ERDHEIM-CHESTER DISEASE
Michelangelo Tesi1 , Francesco Pegoraro2 , Francesco Peyronel1 , Elena
Gelain1 , Martina Mazzariol3 , Matthew Koster4 , Ronald Go4 , Gaurav
Goyal4 , Matthew Collin5 , Paul Milne5 , Sarah Pagan5 , Fleur Cohen-
Aubart6 , Matthias Papo6 , Juvianee Estrada-Veras7 , Roei Mazor8 ,
Lorenzo Dagna9 , Eli Diamond10 , Augusto Vaglio1,11 , Julien Haroche6
1 Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Firenze,
Italy; 2 Department of Health Sciences, University of Firenze, Firenze, Italy;
3 Medical Sciences, University of Torino, Torino, Italy; 4 Rheumatology,
Mayo Clinic, Rochester, MN USA; 5 Haematology, Newcastle Upon
Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK;
6 Internal Medicine, Hôpital Pitié Salpêtrière, Paris, France; 7 Pediatrics
and Medical Genetics, NIH, Bethesda, MD USA; 8 Clinic of Histiocytic
Neoplasms, Institute of Hematology, Assuta Medical Centre, Tel Aviv,
Israel; 9 Clinical Immunology and Rheumatology, San Raffaele Hospi-
tal, Milano, Italy; 10 Neuro-oncology, Memorial Sloan Kettering Cancer
Center, New York, NY USA; 11 Department of Biomedical, Experimen-
tal and Clinical Sciences “Mario Serio”, University of Firenze, Firenze,
Italy
Purpose: Erdheim-Chester Disease (ECD) is a rare non-Langerhans
cell histiocytosis characterized by tissue infiltration by foamy his-
tiocytes. The disease is driven by mutations in proto-oncogenes
such as BRAF while immune-mediated mechanisms contribute
to disease development and progression. Clinical manifestations
are extremely heterogeneous and virtually every organ system
can be affected. In the present cohort study, we aimed at clas-
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ABSTRACTS
sifying patients with ECD based on clinical presentation and
mutational status using an unsupervised data-driven clustering
approach.
Methods: Clinical features at presentation along with mutational sta-
tus (BRAF and other relevant genes) from a dataset of 356 patients
with ECD were included as twenty input variables in the clustering
model. The dimensionality of the dataset was reduced through a prin-
cipal component method, and then a hierarchical clustering approach
was used. Each generated cluster was characterized by analyzing its
summary features.
Results: The clustering algorithm produced two models, one with
four clusters and one with five. The generated clusters were labeled
with their prominent features or given a representative name. The
clusters named “Digestive/Hematologic/Myelodysplastic Syndrome”
(around 3% of subjects), “Testis/Lymph Nodes/MAP2K1 mutation”
(8%), and “Limited Disease” (30%) were similar across the two mod-
els. The remaining patients showed a high rate of BRAF muta-
tion (around 90%) and were aggregated in a single large clus-
ter named “Widespread Disease” (59%) in the four-cluster model,
whereas they were split into two different clusters - the “Hypotha-
lamic/Pituitary/Associated” Langerhans Cell Histiocytosis” (25%) and
the “Cardiovascular/Perirenal"(34%) - in the five-cluster model.
Conclusions: Hierarchical clustering on principal components
subdivided the ECD patient sample into clusters which reflect
what has often already been observed in the clinical practice,
with regard to the widespread disease phenotype as opposed
to the limited one, and with regard to the phenotypes of ECD
associated with other types of histiocytosis or myelodysplastic
syndrome.
HEMATOLOGICAL INVOLVEMENT IN CHILDHOOD
LANGERHANS CELL HISTIOCYTOSIS. A COHORT STUDY OF 303
PATIENTS
Julian Thalhammer1 , Perrine Marec-Bérard1 , Mohamed Barkaoui2 ,
Eric Jeziorski3 , Angelique Rome4 , Anne Pagnier5 , Pierre-Simon
Rohrlich6 , Nathalie Aladjidi7 , Charlotte Rigaud8 , Amaury Lerustre9 ,
Saba Azarnoush10 , Thomas Lauvray11 , Solenne Le Louet12 , Vir-
ginie Gandemer13 , Pauline Treguier14 , Ludovic Mansuy15 , Marlene
Pasquet16 , Florentina-Claudia Isfan17 , Cécile Renard18 , Alexan-
dra Salmon19 , Laurence Blanc20 , Wadih Abou Chahla21 , Anne
Lambilliotte21 , Coralie Mallebranche22 , Caroline Thomas23 , Despina
Moshous24 , Geneviève de Saint-Basile25,26 , Jean-François Emile27 ,
Sébastien Héritier2 , Jean Donadieu2
1 Institut d’Hématologie et d’Oncologie Pédiatrique, Centre Leon Berard,
Lyon France; 2 French Reference Center for Langerhans Cell Histio-
cytosis, Trousseau Hospital, Paris, France; 3 Department of Pediatric
Hematology and Oncology, Centre Hospitalo-Universitaire de Montpel-
lier, France; 4 Department of Pediatric Hematology and Oncology, Centre
Hospitalo-Universitaire de Marseille, France; 5 Department of Pediatric
Hematology and Oncology, Centre Hospitalo-Universitaire de Grenoble,
France; 6 Department of Pediatric Hematology and Oncology, Centre

ABSTRACTS
Hospitalo-Universitaire de Nice, France; 7 Department of Pediatric Hema-
tology and Oncology, Centre Hospitalo-Universitaire de Bordeaux, France;
8 Department of Pediatric Hematology and Oncology, Institut Gustave-
Roussy, Villejuif, France; 9 Pediatric Immuno-Oncology, Institut Curie, Paris,
France; 10 Pediatric Immuno-Oncology, Hôpital Robert-Debré, Paris, France;
11 Department of Pediatric Hematology and Oncology, Centre Hospitalo-
Universitaire de Limoges, France; 12 Pediatric Immuno-Oncology, Hôpital
Armand Trousseau, Paris, France; 13 Department of Pediatric Hematol-
ogy and Oncology, Centre Hospitalo-Universitaire de Rennes, France;
14 Department of Pediatric Hematology and Oncology, Centre Hospitalo-
Universitaire de Rouen, France; 15 Department of Pediatric Hematol-
ogy and Oncology, Centre Hospitalo-Universitaire de Nancy, France;
16 Department of Pediatric Hematology and Oncology, Centre Hospitalo-
Universitaire de Toulouse, France; 17 Department of Pediatric Hematology
and Oncology, Centre Hospitalo-Universitaire de Clermont-Ferrand, France;
18 Institut d’Hématologie et d’Oncologie Pédiatrique, Hospice Civils de
Lyon, Lyon France; 19 Department of Pediatric Hematology and Oncol-
ogy, Centre Hospitalo-Universitaire de Strasbourg, France; 20 Department
of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de
Poitiers, France; 21 Department of Pediatric Hematology and Oncology,
Centre Hospitalo-Universitaire de Lille, France; 22 Department of Pediatric
Hematology and Oncology, Centre Hospitalo-Universitaire, Angers, France;
23 Department of Pediatric Hematology and Oncology, Centre Hospitalo-
Universitaire de Nantes, France; 24 Pediatric Immuno-Oncology, Hôpital
Necker-Enfants Malades, Paris, France; 25 Laboratory of Normal and Patho-
logical Homeostasis of the Immune System, INSERM U1163, Institut
Imagine, and Université Paris Descartes-Sorbonne Paris Cité, Paris, France;
26 Centre d’Etudes des Déficits Immunitaires, Centre Hospitalier Univer-
sitaire Paris, Hôpital Necker-Enfants Malades, Paris, France; 27 EA4340
BECCOH, Université de Versailles SQY, Service de Pathologie, Hôpital
Ambroise Paré, AP-HP, Boulogne, France
Purpose: Hematological involvement (HI) is a life-threatening involve-
ment of Langerhans cell histiocytosis (LCH). Since 1975, its definition is
based on the Lahey criteria.
Methods: Among 2,234 patients < 18 years enrolled in the French
histiocytosis registry (cutoff date May 2023), 303 patients pre-
sented HI. We differentiated mild HI (MHI) (Hb > 7g/l and Platelets
> 20,000/mm3) from severe HI (SHI) (Hb < =7 g/l and Platelets
<=20000/mm3).
Results: Median age (male 49%) at diagnosis was one year. The median
follow-up in the 258 survivors was 10.9 years, while death occurred
after a median of 0.9 years in the 45 patients who died. The HI
was mild in 150 cases and severe in 153 cases. Three deaths were
observed among the MHI and 42 among the SHI. 20 patients did not
receive any therapy, including one with SHI and 19 with MHI. An
intensive approach with hematologic stem cell transplantation (HSCT)
(n=11) and 2-chlorodeoxyadenosine-Cytarabine (2-Cda-Arac) (n=44)
was proposed almost only for SHI. MAPK-inhibition was used in 40
patients. Neuro degenerative (ND) complications were observed in
35 patients. BRAFv600E was found in 90 among the 103 patients
for which mutation analysis was documented. Lastly, 44 macrophage
activation syndromes were observed exclusively in SHI. For 11 of
those patients panel analyses of hemophagocytic lymphohistiocyto-
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S55 of S64
sis genes did not show any pathogenic variants. Since 2014, patients
received only MAPK-inhibition as second line treatment and not HSCT
or 2-Cda-AraC, which resulted in a survival > 98%.
Conclusion: The classic definition of HI could be reconsidered. HI may
be limited to severe HI that included most of the medical complications.
Even if progress has been achieved in the short term of HI patients, long
term ND remains a challenge in this group of patients, which should be
considered at risk of ND.
NEURODEGENERATIVE CONSEQUENCE IN LANGERHANS CELL
HISTIOCYTOSIS - REPORT FROM THE ITALIAN LCH REGISTRY
Irene Trambusti1 , Stefania Gaspari2 , Stefano Chiaravalli3 , Fabiola
Dell’acqua4 , Carmen De Fusco5 , Antonino Trizzino6 , Antonio Verrico7 ,
Veronica Barat8 , Maria Luisa Coniglio1 , Marzia Mortilla9 , Francesco
Pegoraro1 , Annalisa Tondo1 , Carmen Barba10 , Elena Sieni1
1 Pediatric Hematology-Oncology Department, IRCCS Meyer Children’s Uni-
versity Hospital, Florence, Italy; 2 Pediatric Hematology/Oncology Depart-
ment, Cell and Gene Therapy, Scientific Institute for Research, IRCCS
Bambino Gesù Children’s Hospital, Rome, Italy; 3 Pediatric Oncology Unit,
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 4 Pediatric
Hematology-Oncology Department, Fondazione IRCCS San Gerardo dei
Tintori, Monza, Italy; 5 Department of Haematology, AORN “Santobono-
Pausilipon”, Naples, Italy; 6 Department of Pediatric Hemato-Oncology,
ARNAS Ospedali Civico, G. Di Cristina, Palermo, Italy; 7 Neuro-Oncology
Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy; 8 Pediatric Hematology-
Oncology Department, AOU Cittí della Salute e della Scienza, Torino, Italy;
9 Pediatric Radiology Department, IRCCS Meyer Children’s University Hos-
pital, Florence, Italy; 10 Neuroscience Department, IRCCS Meyer Children’s
University Hospital, Florence, Italy
Neurodegenerative Langerhans cell histiocytosis (ND-LCH) is a poten-
tially devastating progressive consequence of Langerhans cell histi-
ocytosis (LCH). Follow-up studies are limited, diagnostic approach is
not standardized and effective treatment is lacking. Out of the 625
patients enrolled in the Italian LCH Registry, 54 were referred for
ND-LCH (8.6%) from 8 italian centres. 33 were male. Median age at
LCH diagnosis was 21 months. ND-LCH developed at a median of
59 months, with a delay of 2.6 years from the LCH diagnosis. Out
of the 54 patients, 35 (65%)had multisystem disease, 10/35 with risk
organ involvement. Diabetes insipidus and/or craniofacial bone lesions
were reported in 44/54 (81%) patients; the remaining 10 patients
were BRAF V600E mutated in 9/10 cases. Overall, 37% (20/54)
patients were completely asymptomatic, 39% (21/54) had mild clini-
cal manifestations including abnormal neurological examination and/or
evoked potentials but without overt clinical picture, 13/54 developed
overt symptoms. The patients were followed-up for a median of 8.5
years (1- 18 years) from ND-LCH diagnosis with a multidisciplinary
protocol including: brain MRI, evoked potential and neurological exam-
ination. Brain MRI worsened in 10/54 (19%) patients over a median
of 5 years (1-12 years). Clinical ND-LCH developed after a median
time of 2.6 years (range, 0-7 years) from ND-LCH diagnosis. Twenty-
eight of the54 patients (19 asymptomatic, 4 pauci-symptomatic,

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5 symptomatic) were not treatedand remained stable in 89% of
cases (25/28). The remaining 26 patients (18 pauci-symptomatic, 8
symptomatic) received high dose immunoglobulin (n=23), mitogen-
activated protein kinase inhibitors (n=6) or both (n=2). Overall, 13/18
patients (72%) were stable or improved, all symptomatic patients wors-
ened. In conclusion, 9% of patients with LCH develops ND-LCH in
the Italian cohort. This is the longest follow-up study reported so far.
The use of a standardized monitoring protocol is helpful to evaluate
treatment response.
VEMURAFENIB DID NOT PREVENT NEURODEGENERATION IN
PATIENTS WITH MULTISYSTEM LANGERHANS CELL
HISTIOCYTOSIS
Irene Trambusti1 , Stefania Gaspari2 , Fabiola Dell’acqua3 , Monica
Cellini4 , Antonino Trizzino5 , Francesco Pegoraro1 , Annalisa Tondo1 ,
Marzia Mortilla6 , Carmen Barba7 , Elena Sieni1
1 Pediatric Hematology-Oncology Department, IRCCS Meyer Children’s Uni-
versity Hospital, Florence, Italy; 2 Pediatric Hematology/Oncology Depart-
ment, Cell and Gene Therapy, Scientific Institute for Research, IRCCS
Bambino Gesù Children’s Hospital, Rome, Italy; 3 Pediatric Hematology-
Oncology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza,
Italy; 4 Pediatric Hematology Oncology Department, Azienda Ospedaliero
Universitaria Policlinico di Modena, Modena, Italy; 5 Pediatric Hemato-
Oncology Department, ARNAS Ospedali Civico, G. Di Cristina, Palermo,
Italy; 6 Pediatric Radiology Department, IRCCS Meyer Children’s Univer-
sity Hospital, Florence, Italy; 7 Neuroscience Department, IRCCS Meyer
Children’s University Hospital, Florence, Italy
Vemurafenib radically improved the outcome of patients with multi-
system Langerhans cell histiocytosis (LCH) and its use for neurodegen-
erative LCH (ND-LCH) has been suggested. We report five patients,
3 males, referred from 4 italian centres with BRAF V600E mutated
multisystem LCH (MS-LCH) diagnosed at a median age of 5 months.
All patients were treated with Vemurafenib for MS-LCH refractory
to at least one line of conventional treatment. Brain MRI was nor-
mal before Vemurafenib administration in 5/5 patients. Known risk
factors for ND-LCH were present in 2/5 patients (diabetes insipidus,
n=1; craniofacial bone lesions, n=1). Risk organs were involved in 4/5
patients. Skin involvement and reactivating disease were present in
4/5 each. ND-LCH was diagnosed at a median of 2 years from Vemu-
rafenib start. Median age at ND-LCH diagnosis was 3.3 years, with
a delay of 2.9 years from LCH diagnosis. MRI abnormalities were
severe in 3/5 cases, mild in 2/5. Out of the 5 patients, 1 showed
overt clinical manifestations, 2 had neurophysiological abnormalities
and 3 were asymptomatic. At ND-LCH diagnosis Vemurafenib was
discontinued in 2/5 patients. All patients were monitored every 6
months with a standardized protocol including brain MRI, neurolog-
ical evaluation and evoked potentials. At a median of 18 months,
4/5 patients were stable, the only symptomatic patient worsened.
Pre-clinical studies support the use of BRAF inhibitors for ND-LCH.
However, in our cohort Vemurafenib did not prevent the development
of this complication in patients who were treated for MS-LCH. Further
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ABSTRACTS
studies with larger cohorts and alternative BRAF-inhibitors appear
warranted.
OUTCOME OF PEDIATRIC PATIENTS WITH LANGERHANS CELL
HISTIOCYTOSIS: A GREEK SINGLE CENTER EXPERIENCE
Haroula Tsipou1 , Natalia Tourkantoni1 , Efthimia Rigatou1 ,Kalliopi
Stefanaki2 , Antonis Kattamis1
1 Department of Pediatric Hematology/Oncology, 1st Department of Pedi-
atrics, University of Athens, Agia Sophia Children’s Hospital, Athens,
Greece; 2 Pathology Department, Agia Sophia Children’s Hospital, Athens,
Greece
Purpose: Langerhans cell histiocytosis (LCH) is characterized by vari-
ability in clinical presentation, course, and outcome, ranging from a
single isolated, spontaneously remitting bony lesions to multisystemic
disease with life threatening organ dysfunction. Our aim was to study
the characteristics and outcome of children with LCH treated at a
single center.
Methods: A retrospective analysis of children with LCH treated at
our institution between September/2012-June /2023 was performed.
Based on site and extent of disease at diagnosis, patients were either
treated with chemotherapy per LCH II/III/IV protocol or local therapy
(biopsy, curettage, and/or intralesional steroids).
Results: During the study period, 44 children and adolescents were
diagnosed; the median age at diagnosis was 6,39 years (range, 0.0-15.9)
and 24/44 were males. Among these patients, 40 (91%) had single sys-
tem LCH (SS-LCH), 2 (4,5%) had multisystemic LCH without risk organ
involvement (MS-RO-) and 2 (4,5 %) had multisystemic LCH with risk
organ involvement (MS-RO+). Bone was the most frequently affected
organ (N = 32, 73%) followed by skin (N = 8, 18%) and mediastinum (N
= 2, 5%). Of the 32 patients with SS bony disease, 26 (81%) had unifo-
cal disease and 6 (19%) had multifocal disease. CNS-risk lesions were
found in 8 patients (18%) at diagnosis. Diabetes insipidus occurred in
2/44 patients (5 %). BRAFV600E mutation status was performed in
29 patients and detected in 15/29 (52%). Chemotherapy treatment
was decided in 27/44 (61%) patients with minor toxicities and relapse
occurred in 4/44 (9%) with BRAFV600E mutation found in 2/3 patients
with relapse. One patient with relapse had unknown status. All children
are alive and in good condition.
Conclusions: LCH in children has a wide range of clinical onset and
progress of disease but with excellent outcome and quality of life.
RARE HISTIOCYTOSES - EXPERIENCE IN A GREEK PEDIATRIC
HEMATOLOGY-ONCOLOGY UNIT
Haroula Tsipou1 , Natalia Tourkantoni1 , Efthimia Rigatou1 ,Kalliopi
Stefanaki2 ,Antonis Kattamis1
1 Department of Pediatric Hematology/Oncology, 1st Department of Pedi-
atrics, University of Athens, Agia Sophia Children’s Hospital, Athens,
Greece; 2 Pathology Department, Agia Sophia Children’s Hospital, Athens,
Greece

ABSTRACTS
Purpose: Rare histiocytoses, also called non-Langerhans cell histiocy-
toses, include all proliferative disorders of histiocytes, macrophages
and dendritic cells that are not classified as Langerhans cell histiocyto-
sis (LCH) and do not belong to the hemophagocytic lymphohistiocytosis
(HLH) group of diseases. In pediatrics, the most frequent are Rosai-
Dorfman disease (RDD) and Juvenile xanthogranulomatosis (JXG),
followed by Erdheim-Chester disease (ECD), and malignant histiocy-
toses. Our aim is to study the rare histiocytoses diagnosed at our
unit.
Methods: This is a retrospective analysis of children with rare
histiocytoses diagnosed and treated at our institution between
September/2012-June/2023.
Results: Nine children with Rare histiocytoses were diagnosed. Seven
children had JXG, one RDD and one histiocytic sarcoma with median
age at diagnosis 1,24 years old (range 0.1-3.1). Among 7 JXG patients
(median age 0,73 years old, 4/7 males), 5 had only localized skin
disease, 1 liver involvement and 1 had skin and hematopoietic involve-
ment and received chemotherapy according to protocol LCH-II. The
patient that was diagnosed with histiocytic sarcoma at calf without
metastases was a 3-year-old girl that received chemotherapy accord-
ing to protocol LCH-IV and achieved complete response. The patient
with RDD was a 2,5-year-old girl with a brain tumor at left ventricle
compatible with RDD histologically diagnosed by MRI brain which per-
formed due to muscle weakness. The patient didn’t receive any therapy
and is under follow up. BRAF V600E mutation status was performed
was performed in 3 patients; (2 JXG, 1 histiocytic sarcoma) and was
negative. All patients are under regular follow up and remain alive with
a good medical status.
Conclusion: Rare histiocytoses represent a very heterogeneous dis-
ease spectrum. Since they are so rare, systematic collection and
analysis of cases are extremely important, to learn more about possible
new treatment strategies.
CLINICAL CHARACTERISTICS AND OUTCOME OF PEDIATRIC
PATIENTS WITH JUVENILE XANTHOGRANULOMA: THE
25-YEAR EXPERIENCE OF THE DEPARTMENT OF PEDIATRIC
HEMATOLOGY-ONCOLOGY (TAO), GREECE
Vasiliki Tzotzola, Vassilios Papadakis, Kondylia Antoniadi, Sophia Poly-
chronopoulou
Department of Pediatric Hematology Oncology (TAO), Aghia Sophia Chil-
dren’s Hospital, Athens, Greece
Purpose: Juvenile xanthogranuloma is the commonest non-LCH histio-
cytosis and mainly affects infants and toddlers. It ranges from benign,
self-limiting skin disease to rarely systemic and life-threatening. The
aim is to analyze our cohort of children with JXG.
Methods: Pediatric patients with a histological diagnosis of a JXG-
disorder were diagnosed and managed in our Department during
1998-2022.
Results: Twenty-three patients were included (male:female ratio
2.6:1). Seven cases were congenital. One patient was clinically sus-
picious for neurofibromatosis type I but was lost-to-follow-up. No
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S57 of S64
hematological or other malignancy occurred. Ten patients (43.4%)
presented with solitary skin lesion at a median age of 2.5(0-
4.1)months. Lesions localized in the head(3/10), axis(3/10) and extrem-
ities(4/10). All the lesions were surgically removed. At a median
follow-up time of 3.8(0.5-10.7) years, seven patients remained in remis-
sion and one was lost-to-follow-up. Two patients, 9 and 22months
old, relapsed locally and were surgically managed. Multiple skin
lesions were present in 12/23 (52.2%) patients with a median age
of presentation of 6.0(0-21) months. The JXG distribution was in
the head(n=2), axis(n=1), head/axis(n=5), head/extremities(n=1) and
head/axis/extremities(n=3). At a median follow-up period of 6.4(0.8-
16.5)years, one patient was lost-to-follow-up, and two patients aged
8.2 and 9.9 years old, had skin disease reactivation, 7.5 and 2.4 years
after initial diagnosis, respectively. Overall, lesions fully regressed
in 9/12 patients until the age of 5, and persisted in three patients
aged 12, 12 and 25 years old. No specific treatment was adminis-
tered. Systemic JXG occurred in one patient, who presented at birth
with organomegaly, ascites, pancytopenia, failure-to-thrive and multi-
ple skin lesions(doi:10.1097/MPH.0b013e3182203086). Therapy was
based on LCH-II protocol, sustaining remission for 17 years.
Conclusions: Our study confirmed the excellent prognosis of patients
with solitary or multiple skin lesion. The systemic type of JXG could
present at birth and be life-threatening. Treatment based on LCH
protocols may achieve remission.
COMBINING BRAFV600E MUTATION IN PLASMA AND PBMC
COULD HELP PREDICT PROGRESSION/RECURRENCE IN
CHILDREN WITH LCH
Chanjuan Wang1 , Lei Cui2 , Zhigang Li2 , TIanyou Wang1 , Rui Zhang1
Hematology Center, Beijing Children’s Hospital, Capital Medical University,
National Center for Children’s Health, Beijing 100045, China; 2 Laboratory
of Hematologic Diseases, hematology Center, Beijing Pediatric Research
Institute, Beijing Children’s Hospital, Capital Medical University, National
Center for Children’s Health, Beijing 100045, China
The aim of this study was to investigate the prognostic significance
of BRAFV600E in cell-free (cf) DNA (cfBRAFV600E) and Peripheral
blood mononuclear cell (PBMCs BRAFV600E) in pediatric LCH. This
study included a total of 103 patients with BRAFV600E mutation
in the biopsy. And we got cfDNA from plasma and genomic DNA
from PBMC at diagnosis. We used ddPCR to detect BRAFV600E in
cfDNA, and qRT-PCR to detect the mutation in PBMCs. As a result,
the patients with positive PBMCs BRAFV600E had a much lower
5-year progression-free survival (PFS) rate and a higher progres-
sion/reactivation rate than those with negative PBMCs BRAFV600E
(50.0% ± 11.2% vs. 74.5% ± 5.5%, P=0.02; 44.8% vs. 21.6%, P=0.028,
respectively). We observed similar results in cfBRAFV600E (P <0.001
and 0.001, respectively). In addition, we combined the BRAFV600E
mutation in plasma and PBMC. The PFS of cf-/ PBMC- group was sig-
nificantly higher than that of the other three groups (Log-Rank test,
χ2=14.017, P=0.001). The PFS of cf-/ PBMC-group was 91.2±4.9%,
and that of cf+/PBMC+ group was the worst (47.1±12.1%). At the

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same time, we monitored the mutation in plasma and PBMC in six
children with LCH during targeted therapy. In general, the level of
cfBRAFV600E was reduced by targeted therapy, but BRAFV600E was
consistently detectable in PBMC. Therefore, the BRAFV600E muta-
tion load in cfDNA and PBMC can be used as a marker of LCH
recurrence, and the two are complementary and should be monitored
at follow-up.
POLYMORPHISM OR RISK ALLELE? PRF1 A91V IN TRANS
WITH A “SEVERE” PRF1 MUTATION
Oliver Wegehaupt1,2 , Oleg Borisov3 , Florian Oyen4 , Jasmin Mann1 , Kai
Lehmberg4 , Despina Moshous5 , Geneviève de Saint Basile5 , Kimberly
Gilmour6 , Wenying Zhang7 , Rebecca Marsh7 , Eberhard Gunsilius8 ,
Sharon Choo9 , Gillian Griffiths10 , Anna Köttgen3 , Stephan Ehl1
1 Institute for Immunodeficiency, Center for Chronic Immunodeficiency,
Medical Center, Freiburg, Germany; Faculty of Medicine, University of
Freiburg, Freiburg, Germany; 2 Department of Pediatrics and Adolescent
Medicine, Division of Pediatric Hematology and Oncology, Medical Center,
Faculty of Medicine, University of Freiburg, Freiburg, Germany; 3 Institute
of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of
Medicine and Medical Center-University of Freiburg, Freiburg, Germany;
4 Division of Pediatric Stem Cell Transplantation and Immunology, Univer-
sity Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5 Imagine
Institute, Université de Paris, INSERM U1163, Paris, France; 6 Department
of Immunology, Great Ormond Street Hospital, London, UK; 7 Division of
Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH USA; 8 Department of Hematology
& Oncology, Medical University Innsbruck, Innsbruck, Austria; 9 Department
of Allergy and Immunology, The Royal Children’s Hospital, Melbourne,
VIC, Australia; 10 Cambridge Institute for Medical Research, University of
Cambridge, Cambridge Biomedical Campus, UK
Background: Familial hemophagocytic lymphohistiocytosis type 2
(FHL2) is caused by mutations in the perforin gene (PRF1). Null
mutations lead to absent cytotoxicity and predispose to hemophago-
cytic lymphohistiocytosis (HLH). Hypomorphic variants allow resid-
ual cytotoxicity and can cause later onset of HLH, neuroinflamma-
tion or lymphoma. PRF1 A91V, carried by 4% of the population
leads to reduced perforin expression and cytolytic activity, but does
not affect health or longevity even in homocygocity. Uncertainty
remains whether this is also true if A91V pairs with a loss-of-
function PRF1 allele ("X"). Since FHL2 is an attractive target for
newborn screening, we study the clinical significance of the A91V/X
constellation.
Methods: (1) We recruit A91V/X individuals through our networks and
literature; (2) We gather epidemiological data on A91V/X carriers using
the UK Biobank; (3) We investigate the functional consequences of
A91V/X for cytotoxicity.
Results: Perforin expression in A91V/X lymphocytes is reduced vari-
ably depending on the “X”. Consequences for cytotoxicity remain to
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ABSTRACTS
be evaluated. Of 31 PRF1 A91V/X individuals reported by the HLH
network, 22 were identified because of FHL-2 related symptoms
(12 HLH, 6 neuroinflammation, 4 lymphoma) with variable disease
onset (mean 22.9y; range: neonatal-52y). Surprisingly, all 9 individu-
als identified by family screening of early-onset FHL2 patients were
asymptomatic (mean 36.3y; range: 4-81y). In the UK Biobank, the
prevalence of A91V/X is around 0.04%. We identified 8/9691 A91V/X
carriers among individuals with splenomegaly/cytopenia, neuroinflam-
mation or lymphoma versus 165/460106 among control individuals
(OR 2.3; p=0.028).
Conclusions: Our preliminary data indicate that PRF1 A91V/X does not
significantly predispose to FHL2-related disease manifestations. Com-
pletion of this study will help guide clinical decision-making in A91V/X
individuals.
ASYMPOTOMATIC A SINGLE ALLELE MUTATION CARRIER
ALSO AN OPTIONAL DONOR FOR PATIENTS WITH PRIMARY
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
Na Wei, Jingshi Wang, Lin Wu, Yini Wang, Zhao Wang
Beijing Friendship Hospital, Capital Medical University, Beijing, China
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the
only curative approach for most primary HLH (pHLH). Both HLA-
identical related and unrelated donors without HLH gene defects are
recommended donors for pHLH. When the patient does not have the
above donor, asymptomatic siblings who carry a single allele muta-
tion maybe also acceptable. Between January 2015 and June 2022, 18
pHLH lacking donors without HLH gene defects underwent allo-HSCT
using asymptomatic related donors who carry a single allele mutation
at Beijing Friendship Hospital, Capital Medical University. The median
age at allo-HSCT was 17 years (range, 7 to 52). 9 had PRF1 gene
mutations, 6 had MUNC13D mutations, 3 had others. Sibling matched
donor for 2 and haploidentical related donor for 16 patients. 7 patients
treated with TBI-based and 11 patients treated with busulfan-based
conditioning regimens. 18 patients achieved neutrophil engraftment at
13 days (range, 11 to 22). 17 patients achieved platelet engraftment at
14 days (range, 11 to 35) after HCT. 14 had complete donor chimerism
at 1 month after HCT and sustained until last follow-up. 3 with mixed
chimerism got complete chimerism after multiple donor stem cell and
lymphocyte infusions. 1 (5.6%) got graft rejected. 7 patients developed
aGVHD grades 2 to 4. cGVHD was seen in 7 patients. Infectious com-
plications were encountered in all patients. Two died of severe pneu-
monia and multiple organ failure. Followed up to January 2023, 13 sur-
vived without HLH recurrence and 5 died. Of the 5 deaths, 2 for severe
pneumonia, 1 for TMA, 1 for hemorrhage, 1 for graft rejected and HLH
relapse. All deaths occurred within 1 year after HCT. The 5-year over-
all survival was 72.2%. No HLH recurrence in survival patients. This
series demonstrates that, asymptomatic a single allele mutation car-
rier also an optional donor for patients with primary hemophagocytic
lymphohistiocytosis.

ABSTRACTS
THE BASELINE METABOLISM PARAMETERS OF 18F-FDG
PET/CT AS PROMISING PROGNOSTIC BIOMARKERS IN
PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS
Ang Wei, Honghao Ma, Liping Zhang, Wenxin Ou, Dong Wang, Rui
Zhang, Tianyou Wang
Beijing Children’s Hospital, Beijing, China
Purpose: The purpose was to evaluate the prognostic value of
the pre-treatment metabolism parameters of baseline 18F-
FDG PET/CT in children with Langerhans cell histiocytosis
(LCH).
Methods: Pre-treatment 18F-FDG-PET/CT of 37 children (24
males and 13 females; median age, 5.1 years; range, 2.4-7.8
years) with biopsy proven LCH were retrospectively analyzed.
Five metabolism parameters were analyzed, including maximum
standardized uptake (SUVmax), tumor-to-normal liver standard
uptake value ratio (SUVRliver), tumor-to-normal bone marrow
standard uptake value ratio (SUVRBM), sum of metabolic tumor
volume (tMTV) and sum of total lesion glycolysis (tTLG) of all lesions.
All patients were followed up for more than 1 year. Univariate
and multivariate analysis of progression-free survival (PFS) was
performed.
Results: During follow-up, 11 (29.7%) patients got disease progres-
sion or relapse. Univariate analysis revealed that Univariate analysis
revealed that the age, RO involvement, the treatment response at
the 5th or 11th week, tTLG, and tMTV were significantly associ-
ated with PFS (P = 0.041, 0.024, 0.018, 0.006, 0.030, and 0.015,
respectively). Multivariate COX analysis revealed that tMTV > 32.55
g/cm3 (HR (95%CI) 2.261-56.208, P = 0.003) and tTLG > 98.86 g (HR
(95%CI) 1.240-42.140, P = 0.028) were both independent risk factors
of PFS.
Conclusion: The baseline metabolism parameters of 18F-FDG PET/CT
could be promising imaging biomarkers for predicting prognosis in
children with LCH.
THE ROLE OF 18F-FDG PET IN CFBRAF MUTATION AND
PROGNOSIS OF CHILDREN WITH LANGERHANS CELL
HISTIOCYTOSIS
Ang Wei, Honghao Ma, Liping Zhang, Wenxin Ou, Dong Wang,
Hongyun Lian, Rui Zhang, Tianyou Wang
Beijing Children’s Hospital, Beijing, China
Purpose: To evaluate the relationship between the metabolism param-
eter of 18F-fluorodeoxyglucose positron emission tomography (18F-
FDG PET) and cell-free BRAF (cfBRAF) mutation, and the value of
metabolic parameters of 18F-FDG PET in predicting prognosis in
children with langerhans cell histiocytosis (LCH).
Methods: We retrospectively collected the children who were newly
diagnosed with LCH from September 2020 to September 2022, and
underwent 18F-FDG PET /CT within 1 week. The 18F-FDG PET/CT
scans and clincal data were acquired. The metabolic PET parameters
of primary lesion and metastatic lesions were measured, including
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S59 of S64
maximum standardized uptake values (SUVmax), SUVRliver (tumor-
to-normal liver standardized uptake value ratio), SUVRBM (tumor-
to-normal bone marrow (BM) standardized uptake value ratio), total
metabolic tumor volume (tMTV), and total total lesion glycolysis (tTLG).
The result of cfBRAF in plasma was collected. Differences in the
progression-free survival (PFS) were examined by the Kaplan-Meier
method.
Results: 16 patients (40%) were considered as cfBRAF mutation and
24 (60%) patients as non-cfBRAF mutation. SUVRliver (6.8±3.5 vs.
4.2±2.7, P=0.014) and SUVRBM (4.3±2.1 vs. 2.9±1.7, P=0.026) were
significantly higher in the cfBRAF mutation than those in non-cfBRAF
mutation. According to the results of the receiver operating charac-
teristic curve analysis, SUVRliver showed a best predictive value for
cfBRAF mutation (area under curve=0.714, with the optimal diagnos-
tic threshold of 5.1). When using MTV of 44.3 as a threshold, patients
with high MTV had superior PFS (log-rank test, P<0.001) compared
with those with low MTV.
Conclusion: The metabolic parameters of 18F-FDG PET can predict
cfBRAF mutation in children with LCH. In addition, the metabolic
parameters of 18F-FDG PET have certain value in predicting the
prognosis of children with LCH.
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
IN PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
WITH CENTRAL NERVOUS SYSTEM INVOLVEMENT FOR
CHILDREN
Juan Xiao, Shifen Fan, Zhouyang Liu, Fan Jiang, Jiao Chen, Yuan Sun
Department of Hematology, Beijing Jingdu Children’s Hospital, Beijing,
China
Purpose: To investigate the efficacy of allogeneic HSCT(allo-HSCT)
in primary hemophagocytic lymphohistiocytosis(PHLH) with central
nervous system (CNS) involvement.
Methods: A retrospective analysis was performed on 56 pediatric
patients with PHLH undergoing allo-HSCT at Beijing JingDu Children’s
Hospital between January 2016 and June 2022. Of these, 14 were
CNS-HLH.
Results: Of the 14 patients, 9 were male and 5 were female, median
age was 3.4(1.2-10.4) years. 6 were FHL-2 (PRF1), 4 were FHL-3
(UNC13D), 2 were XLP1 (SH2D1A )<1 was FHL-4 (STX11) and 1 was
CHS (LYST). 4 patients had CNS symptoms as the first manifestation,
and 10 showed central involvement during the course of disease pro-
gression. 7 were haplo-HSCT, 5 were unrelated matched HSCT and 2
were sibling compatible HSCT. All patients received induce chemother-
apy with HLH-94, HLH-2004 or DEP regimen and intrathecal injection
treatment before transplantation, 4 patients achieved complete remis-
sion (CR) and 6 patients achieved partial remission (PR), but 4 patients
still in active disease (AD).The Conditioning regimen was VP-16 / Bu
/ Flud / ATG ± CTX. The GVHD prophylaxis was either CSA or FK-
506+MMF±Basiliximab. All patients achieved Stable hematopoietic
reconstruction. With a median follow-up of 28.6 (12 - 72) months, 8
patients are alive and 6 were dead. The main causes of death were

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severe infection and TMA. The 8 patients who survived, 2 developed
epilepsy requiring drug control, and the remaining 6 had no neurolog-
ical symptoms with normal intelligence and development of the same
age. The expected 5-year OS rate of patients with CR and PR before
transplantation obviously better than the patients with AD.
Conclusion: Allo-HSCT is an effective treatment for primary HLH with
CNS involvement. Disease remission before transplantation achieves
better survival. Once FHLH diagnosed, allo-HSCT as soon as possible.
STUDY ON THE MECHANISM OF MACROPHAGE COLONY
STIMULATING FACTOR RECEPTOR AND
REGULATORY-ASSOCIATED PROTEIN OF MTOR IN CHILDREN
WITH LANGERHANS CELL HISTIOCYTOSIS
Ying Yang, Chanjuan Wang, Lei Cui, Na Li, Hongyun Lian, Honghao
Ma, Dong Wang, Yunze Zhao, Liping Zhang, Qing Zhang, Xiaoxi Zhao,
Tianyou Wang, Rui Zhang, Zhigang Li
1 Hematology Center, Beijing Children’s Hospital, Capital Medical University,
National Center for Children’s Health, Beijing 100045, China; 2 Laboratory
of Hematologic Diseases, hematology Center, Beijing Pediatric Research
Institute, Beijing Children’s Hospital, Capital Medical University, National
Center for Children’s Health, Beijing 100045, China
Purpose: To explore the mechanism of macrophage colony stimulating
factor (CSF1) and its receptor (CSF1R) in Langerhans cell histiocytosis
(LCH).
Methods: The CSF1 concentration of the serum was measured by Elisa.
The expression of proteins in LCH lesions with BRAF mutation were
detected by multiple immunohisto-chemical assay. In THP1 cell line,
the variations of total expression, membrane / cytoplasm and nucleus
of proteins under different stimulation and inhibitors were measured
by western blot.
Results: The average fluorescence intensity of CSF1R in MS-RO+
group was higher than that in MS-RO- group and SS group. The serum
CSF1 in patients with active LCH was significantly higher than that
in healthy controls (P=0.033) and non-active LCH patients (P<0.001).
After the stimulation of 100ng/mL human recombinant CSF1, the
expression of Raptor and CSF1R in THP1 cell line changed in the same
direction. The inhibition of 10nM Rapamycin, a inhibitor of mTOR,
decreased the expression of Raptor and up-regulated the expression
of CSF1R, while 5 μM GW2580, a potent inhibitor of CSF1R, increased
the expression of CSF1R and Raptor in THP1 cell line (P<0.05). CSF1R
could enter into nucleus and might positively regulate the expression of
Raptor, and there was an interaction between CSF1R and Raptor, but
not with mTOR. After the stimulation of CSF1, the activity of mTOR
decreased temporarily, then increased and reached the highest at the
6th hour after stimulation, and finally decreased to the normal level
after 12-hour stimulation, while the activity of mTOR decreased after
6-hour inhibition of GW2580.
Conclusion: The expression of CSF1R in LCH cells is related to the
severity, and the increase of serum CSF1 may be related to the dis-
ease activity. In THP1 cell line, Raptor, as a downstream protein, may be
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ABSTRACTS
positively regulated by upstream CSF1R. There is interaction between
Raptor and CSF1R.
LONG-TERM ADMINISTRATION OF BRAF INHIBITOR FOR
REFRACTORY INFANT LANGERHANS CELL HISTIOCYTOSIS
Shiho Yasue1 , Kenichi Sakamoto1,2 , Yoshihiro Gocho1 , Yoko Shioda1 ,
Kimikazu Matsumoto1
1 Children’s Cancer Center, National Center for Child health and Develop-
ment, Tokyo, Japan; 2 Department of Pediatrics, Shiga University of Medical
Science, Otsu, Japan
Background: Despite a significant improvement of the overall survival
in pediatric Langerhans cell histiocytosis (LCH) patients, refractory
LCH who do not respond conventional chemotherapy still has a poor
prognosis. Although the BRAF inhibitor shows “dramatic” response
for these high-risk patients, almost of all patients relapse quickly
if BRAF inhibitor is discontinued. Thus, long-term administration of
BRAF inhibitor is often needed but efficacy and safety profile are
still scarce. Here, we describe a refractory LCH patients controlled
by BRAF inhibitor and long-term remission for two years from start
of BRAF inhibitor. CASE: A 6 months boy admitted our hospital due
to prolonged fever, diarrhea, hepatosplenomegaly, pancytopenia and
skin rash. We performed skin biopsy and pathologically diagnosed him
multi-system risk organ positive LCH. Immediately, we started cytara-
bine, vincristine, and prednisolone for 6 weeks. But, his symptoms did
not improved, and he developed hemophagocytic lymphoproliferation
(HLH) at week 5. We decided to administrate cladribine and cytarabine.
Although this combination therapy was partially responded, his HLH
and LCH lesions remained refractory. Conventional chemotherapy
could not control his LCH symptoms, thus we started BRAF inhibitor at
week 9. Soon after the start of BRAF inhibitor, his LCH symptoms dis-
appeared and his hepatosplenomegaly was gradually improved. After
2 years from start of BRAF inhibitors, he remained no active disease
and no severe adverse effect of BRAF inhibitor. On the other hand, the
BRAFV600E mutation in cell free DNA and bone marrow was still high.
We could not stop BRAF inhibitor until now.
Conclusions: In this case, the therapeutic response of BRAF inhibitor
is “dramatic”, efficacy and safety profile. New treatment strategy was
needed for the cure of refractory LCH after the achievement of NAD
using BRAF inhibitor.
RETROSPECTIVE ANALYSIS OF 45 UNSELECTED PATIENTS
WITH HISTIOCYTOSIS CONFIRMS PROGNOSTIC RELEVANCE
OF ORGAN INVOLVEMENT: SINGLE CENTER EXPERIENCE
Hulya Yilmaz1 , Guldane Cengiz Seval2 , Selami Kocak Toprak2 , Meltem
Kurt Yuksel2 , Pervin Topcuoglu2 , Onder Arslan2 ,Taner Demirer2 , Meral
Beksac2 , Isinsu Kuzu2 , Muhit Ozcan2
1 Mardin Training and Research Hospital, Mardin, Turkey; 2 Ankara Univer-
sity School of Medicine, Ankara, Turkey

ABSTRACTS
The histiocytosis is rare disorder characterized by the accumulation
of macrophage, dendritic cell, or monocyte-derived cells in various tis-
sues and organs of children and adults. Their clinical behavior ranges
from mild to disseminated and, sometimes, life-threatening forms. We
aimed to review our clinical findings and treatment outcomes in a
retrospective series of adult of L(Langerhans) and R(Rosai Dorfman)
group histiocytosis patients. We retrospectively evaluated clinical find-
ings and outcomes of treatment in a retrospective series of 45 adult
patients, treated at our center between 2007-2022. 86% (n=39) of
the patients were diagnosed with Langerhans cell histiocytosis (LCH),
11% (n=5) with Erdheim-Chester Disease (ECD) and 2% (n=1) with
Rosai Dorfman (RD). The median age of diagnosis was 32 (18-62), and
the F/M ratio was 20/25. Clinical characteristics of the LCH cohort
showed in table 1. In 2 patients with risky organ involvement; bone
marrow (n=1), spleen (n=2) and liver (n=1) lesions were found. In
26% (n=12) cases with central nervous system involvement; pituitary
involvement (n=3), diabetes insipidus (n=8), hypogonadism (n=1) and
cranial mass (n=3) were found. Treatment approaches and outcomes
by disease category showed in table 2. Molecular tests were performed
in 35% (n=16) of patients, and mutation was detected in 14 of them.
We used targeted drug therapies BRAF (n=5) and MEK (n=2) inhibitors
in these patients. Two LCH patients were treated with allogeneic stem
cell transplantation, one of them because of concomitant diagnosis of
MDS/MPN and the other one because of refractory disease.Both are
in remission at follow-up. Median overall survival for the cohort as
a whole was 92.1 % at 5 years and median PFS was 171.7 months
not reached yet (Figure-1). In conclusion pulmonary involvement may
cause very serious respiratory failure resulting in death. The response
was obtained with targeted drugs and the side-effect profile was well
tolerated.
CLINICAL STUDY OF LANGERHANS CELL HISTIOCYTOSIS WITH
NEURODEGENERATIVE DISEASE IN CHILDREN
Liping Zhang, Hongyun Lian, Honghao Ma, Li Li, Ang Wei, Zhigang Li,
Tianyou Wang, Rui Zhang
Beijing Children’s Hospital,Beijing, China
We aim to summarize the clinical characteristics, risk factors and treat-
ment of Langerhans cell histiocytosis with neurodegenerative disease
(LCH-ND) in children. We collected the clinical data of children with
LCH-ND from January 2013 to December 2022, retrospectively. A
total of 738 patients with LCH were included in this study, and 12
patients(1.76%) were diagnosed with LCH-ND. The ratio of male to
female was 2:1. Among all the patients, there were 7 patients with
clinical ND and 5 patients with radiological ND. The median onset
ages of RND and CND were 2.58 years and 4.2 years, respectively.
Two patients were single system affected, 6 patients were multisys-
tem RO -, and 4 patients were multisystem RO+. In CND, there were
4 cases happened to mood change, with 3 cases with attention and
learning disabilities, 2 cases with cerebellar ataxia and 2 cases of poor
fine movements such as needle threading, building blocks, and but-
ton shaking. In imaging studies, it was found that there were 8 cases
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of cerebellar hemisphere involvement, including 6 cases in dentate
nucleus. The involvement of basal ganglia were involved in 7 cases, and
only 1 case of cerebellar atrophy. We found that the shortest time for
RND to progress to CND is only 6 months. All patitents with LCH-ND
survived. Only 1 patient (8.3%)had relieved with first-line treatment.
Four patients alleviated in imaging and clinical manifestation after
second-line chemotherapy. But no disappearance of imaging signals in
all patients, only 4 (33.3%) patients showed improvement in MRI signal.
LCH-ND was rare and its clinical manifestations and radiological abnor-
malities are a slow progression process. MRI is a sensitive technique
for detecting and monitoring LCH-ND, with the cerebellum being the
most commonly affected site. Chemotherapy and targeted therapy can
effectively alleviate LCH-ND, but its therapeutic effect still needs to be
tracked.
THE CLINICAL FEATURES AND OUTCOMES OF CHILDREN
WITH DRUG INDUCED HYPERSENSITIVITY SYNDROME
RELATED-HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
Yunze Zhao, Honghao Ma, Hongyun Lian, Dong Wang, Tianyou Wang,
Rui Zhang
Hematology Center, Beijing Children’s Hospital, Capital Med-
ical University, National Center for Children’s Health, Beijing,
China
Objective: To analyze the clinical features, laboratory results, treat-
ment and outcomes of drug induced hypersensitivity syndrome
related-hemophagocytic lymphohistiocytosis (DIHS-HLH) in 16pedi-
atric patients.
Methods: A total of 16 children diagnosed with DIHS-HLH in Beijing
Children’s Hospital Affiliated to Capital Medical University between
January 1st 2019 and December 31st 2022 were enrolled. The clin-
ical and laboratory features, therapy and prognosis were analyzed
retrospectively.
Results: Among the 16 children, all patients had fever, rash, hep-
atomegaly and multiple lymph node enlargement. Other manifes-
tations included splenomegaly (44.4%), pulmonary imaging changes
(66.7%), central nervous system symptoms (33.3%), and so on. Most
patients (77.8%) showed hepatic dysfunction and ferrinemia, other
laboratory examination abnormality included hemophagia in bone
marrow (55.6%), hypofibrinogen (33.3%) and hypertriglyceridaemia
(22.2%). Ascending levels of interkeukin-5 (IL-5), IL-8 and interferon-
γ (IFN-γ) were detected in more than 6 patients. Treatments included
immunoglobulin, glucocorticoid and ruxolitinib, and the over-all sur-
vival rate was 77.8%. There were two children who had no response
to immunoglobulin, methylprednisolone with the dose of 2mg/kg and
ruxolitinib and died later. After analyzing these clinical and laboratory
index, we found that patients with watery diarrhea, increased levels
of C respond protein, IL-5 and IL-8 and decreased IgM showed a poor
prognosis.
Conclusions: The clinical manifestations of chilldren with DIHS-HLH
are complex, leading to a high mortality when rapid progression. For
patients with fever and rash, if complicating with hepatomegaly, lymph

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node enlargement, ferrinemia, high levels of IL-5 and IL-8, pulmonary
imaging changes, DIHS-HLH should be considered. For DIHS-HLH
patients, doctors should stop the usage of suspicious drugs imme-
diately, and give immunoglobulin, glucocorticoid and ruxolitinib to
control disease.
CLINICAL VALUES OF ABNORMAL T-CELL PHENOTYPES IN
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
Xiao-xi zhao, Hong-yun Lian, Hong-hao Ma, Dong Wang, Yun-ze Zhao,
Rui Zhang, Zhi-gang Li
Beijing Children’s Hospital, Beijing, China
Purpose: Goal of this study is to investigate T lymphocytes
presenting 3 types of abnormal Immunophenotypes, focusing
on their possible relations to underlying diseases, and their
connections with nearby and long term conditions of HLH
patients.
Methods: Bone marrow phenotyping results of patients at
diagnose were collected. From which, abnormal T-cell pheno-
types were selected and then analyzed on their distributions
among different groups of HLH, and their possible relations
with first-line treatment reactions as well as further outcomes of
HLH.
Results: Samples from 197 HLH patients were included. 41 of the
cohort(20.8%) carried T cells with abnormal phenotypes, and this
phenomenon was mostly seen in EBV-HLH, comparisons to the
rest HLH groups(P<0.001). T-cell abnormal phenotypes were cate-
gorized in 3 types: CD38+/HLA-DR+(N=11, 26.8%), TCRVβ clonal
expansion(N=18, 43.9%), and CD5 down-regulation(N=29, 70.7%).
It was shown by Chi-square test that the presence of T cell with
abnormal phenotypes in bone marrow linked to weaker response
to first-line treatment(P=0.006). However, none of these pheno-
types was fond to be related to death or HLH relapse. None of the
patients with abnormal T-cell markers developed malignancies, except
for 1.
Conclusion: CD3+ T cells with atypical surface markers are sometimes
seen in HLH. It could be told from our study on 3 types that early
treatment response could be effected by T cells with these phenotypes.
CLINICAL SIGNIFICANCE OF SOLUBLE CD25 LEVELS IN
CHILDREN WITH LANGERHANS HISTIOCYTOSIS
Zijing Zhao2 , Dong Wang1 , Honghao Ma1 , Hongyun Lian1 , Tianyou
Wang1 , Rui Zhang2 , Zhigang Li2 , Lei Cui2
1 Hematology Center, Beijing Key Laboratory of Pediatric HematologyOncol-
ogy, National Key Discipline of Pediatrics (Capital Medical University), Key
Laboratory of Major Disease in Children, Ministry of Education, Beijing Chil-
dren’s Hospital, Capital Medical University, National Center for Children’s
Health, Beijing, China; 2 Hematologic Disease Laboratory, Beijing Pediatric
Research Institute, Hematology Center, Beijing Key Laboratory of Pediatric
Hematology Oncology, National Key Discipline of Pediatrics (Capital Med-
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ABSTRACTS
ical University), Key Laboratory of Major Disease in Children, Ministry of
Education, Beijing Children’s Hospital, Capital Medical University, National
Center for Children’s Health, Beijing, China
Purpose: Langerhans cell histiocytosis (LCH) is a rare myeloid
neoplasm with inflammatory characteristics, characterized by
proliferation of CD1a+/CD207+ histiocytes and inflamma-
tory cell infiltration. Elevated levels of soluble CD25 (sCD25)
can be used to monitor several immune-mediated diseases and
are associated with diagnosis and prognosis. The aim of this
study was to investigate the correlation between serum sCD25
levels and clinical characteristics and prognosis of pediatric
LCH.
Methods: A total of 335 newly diagnosed LCH patients were included
in this study. Serum sCD25 levels were measured in patients at the time
of initial diagnosis.
Results: The median serum sCD25 level at initial diagnosis was 3,983
pg/ml (range: 390-44,000). 100 (29.9%) patients had sCD25 levels
higher than the normal range (6,400 pg/ml). Patients with high lev-
els of sCD25 were more likely to have involvements of the liver
(p<0.001), spleen (p<0.001), hematologic system (p<0.001), pituitary
(p=0.005), skin (p<0.001), and lymph nodes (p<0.001). Importantly,
we found that the sCD25 levels at initial diagnosis had significant
predictive value for progression/recurrence in patients receiving first-
line chemotherapy, with an area under the ROC curve of 66.2% (95%
CI: 59.6%-72.8%, p<0.001). Univariate analysis showed that patients
with high levels of sCD25 had a worse prognosis compared to those
with low levels of sCD25, with a 3-year progression-free survival (PFS)
of 27.4%±3.2% and 47.3%±1.7%, respectively (p<0.001). Multivari-
ate analysis showed that high sCD25 at initial diagnosis (p=0.042)
were independent risk factors for the prognosis of LCH after first-line
chemotherapy.
Conclusion: Elevated serum sCD25 levels at initial diagnosis in pedi-
atric LCH patients are associated with high-risk clinical features. The
levels of sCD25 could predict the progression/recurrence of LCH,
and patients with high levels of sCD25 have significantly worse
prognosis compared to those with low levels. Increased sCD25 at
diagnosis is an independent risk factor for the prognosis of pediatric
LCH.
CHARACTERISTICS AND PROGNOSIS OF LANGERHANS CELL
HISTIOCYTOSIS WITH SKIN INVOLVEMENT IN CHILDREN
Ting Zhu1,6 , Lei Cui1,6 , Tian-You Wang1,4 , Zhi-Gang Li1,6 , Rui Zhang1,4*
1 Hematology Center, Beijing Key Laboratory of Pediatric Hematology
Oncology, Beijing, China; 2 National Key Discipline of Pediatrics, Capital
Medical University, Beijing, China; 3 Key Laboratory of Major Disease in
Children, Ministry of Education, Beijing, China; 4 Beijing Children’s Hospital,
Capital Medical University, National Center for Children’s Health, Bei-
jing, China; 5 Hematologic Disease Laboratory, Hematology Center, Beijing
Key Laboratory of Pediatric Hematology Oncology, Beijing, China; 6 Beijing
Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical
University, National Center for Children’s Health, Beijing, China

ABSTRACTS
Purpose: To evaluate the clinical features and prognosis of children
with Langerhans cell histiocytosis (LCH) with skin involvement.
Methods: We retrospectively described the clinical, biological, and
imaging characteristics of a series of 449 patients with LCH with
skin involvement between January 2014 and June 2018 at Beijing
Children’s Hospital.
Results: In a 449-consecutive cohort of children with LCH, 148 (33%)
patients with skin involvement, including 10.1% of SS LCH, 43.9% of MS
RO- LCH, and 45.9% of MS RO+ LCH. Patients with skin involvement
had a younger onset age, with a median age of 1.10 years (0.04-12.14).
The most common rashes morphology is red scaly papules. Compared
to the patients without skin involvement, the positive rates of BRAF-
V600E mutations in tissues (44.6%) and plasma (29.1%) were higher
in patients with skin involvement (P<.05). And LCH patients with skin
involvement showed an increased risk of death, the 5-year OS and 5-
year PFS were lower than those without skin involvement (P =.001).
Moreover, the prognosis of LCH patients with skin involvement was sig-
nificantly correlated with risk organ involvement, and the 5-year OS in
MS RO+ LCH was lower than that in MS RO- LCH (P=.001). Overall,
43.0% (35 of 135) of patients with skin involvement were effective in
the first-line treatment. 32 relapsed/refractory LCH patients with skin
involvement and positive BRAF-V600E mutation received the BRAF
inhibitor dabrafenib. Three months later, 31 patients responded well.
Only one child died of cirrhosis and portal hypertension after 7.4
months of treatment with dabrafenib.
Conclusions: The skin is frequently involved in LCH patients and had
specific clinical characteristics. The LCH patients with skin involve-
ment showed a worse prognosis. Chemotherapy is effective in treating
skin involvement LCH, and targeted therapy may provide a promising
treatment option for children with refractory/relapsed LCH.
Keywords: LCH; Children; Skin; Prognosis; Dabrafenib
TRAMETINIB IN THE TREATMENT OF SYSTEMIC JUVENILE
XANTHOGRANULOMA: A CASE REPORT
Ting Zhu1,6 , Lei Cui1,6 , Tian-You Wang1,4 , Zhi-Gang Li1,6 , Rui Zhang1,4 *
1 Hematology Center, Beijing Key Laboratory of Pediatric Hematology
Oncology, Beijing, China; 2 National Key Discipline of Pediatrics, Capital
Medical University, Beijing, China; 3 Key Laboratory of Major Disease in
Children, Ministry of Education, Beijing, China; 4 Beijing Children’s Hospital,
Capital Medical University, National Center for Children’s Health, Bei-
jing, China; 5 Hematologic Disease Laboratory, Hematology Center, Beijing
Key Laboratory of Pediatric Hematology Oncology, Beijing, China; 6 Beijing
Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical
University, National Center for Children’s Health, Beijing, China
Background: Juvenile xanthogranuloma (JXG) is a common form of
non-Langerhans cell histiocytosis. Rarely, do patients with systemic
juvenile xanthogranuloma (SJXG) involve extracutaneous tissues or
systemic organs, resulting in higher morbidity and mortality. Multidrug
combination chemotherapy is the main method of SJXG treatment, but
the application of targeted therapy is limited. Here, we report a case of
targeted trametinib for SJXG.
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Case Presentation: An 8-year-old girl had intermittent headaches for
4 months. Cranial magnetic resonance imaging (MRI) revealed multiple
intracranial lesions with a maximum diameter of 30 mm in the bilateral
cavernous sinus, sella turcica, tentorial incisure, and choroid plexus.
After evaluation, a craniotomy lesion biopsy was carried out in the
local hospital. The pathological diagnosis indicated Rosai-Dorfman dis-
ease because of the “extension motion” of inflammatory cells. Next, the
child developed the purpura rash of both lower limbs, exophthalmos,
and appendicitis. The PET-CT of our hospital revealed tissue hyperpla-
sia lesions in multiple systems. Skin biopsy revealed giant Touton cells
with positive expression of CD68 and F13 and negative expression of
CD1a and Langerin, indicating JXG. She received first- and second-line
chemotherapy but fail to respond to either. Therefore, we tried trame-
tinib as a targeted therapy based on the genetic test results of MAP2K1
p. E102_I103 mutation. No recurrence was observed after 6 months of
follow-up, which revealed a good reaction.
Conclusions: Most patients with SJXG respond well to chemotherapy
with first-line and second-line treatments. In refractory cases, genetic
testing provides precise targets for treatment. Trametinib is applied for
the SJXG cases with MAP2K1 p. E102_I103 mutation.
Keywords: Systemic juvenile xanthogranuloma, Histiocytosis, MAPK
mutation, Trametinib
RADIOLABELED SOMATOSTATIN ANALOG THERAPY IN
ERDHEIM-CHESTER DISEASE
Timo Zondag1 , Rob Verdijk2,3 , Ellen Stelloo4 , Dion Paridaens5,6 , Astrid
van Halteren1,7 , Martin van Hagen1,8 and Jan van Laar1,8
1 Department of Internal Medicine, Section Clinical Immunology, Erasmus
University Medical Center, Rotterdam, The Netherlands; 2 Department of
Pathology, Erasmus University Medical Center, Rotterdam, The Nether-
lands; 3 Department of Pathology, Leiden University Medical Center, Leiden,
The Netherlands; 4 Cergentis b.v., Utrecht, the Netherlands; 5 Department
of Ophthalmology, Erasmus University Medical Center, Rotterdam, The
Netherlands; 6 Department of Oculoplastic, Orbital and Lacrimal Surgery,
The Rotterdam Eye Hospital, Rotterdam, The Netherlands; 7 Princess Máx-
ima Center for Pediatric Oncology, Utrecht, The Netherlands; 8 Department
of Immunology, Erasmus University Medical Center, Rotterdam, The Nether-
lands
Purpose: Erdheim-Chester disease (ECD) is a disorder charac-
terized by the accumulation of xanthomatous macrophage-like
histiocytes. While targeted therapy seems effective, RAF or MEK
blockade does not completely eradicate the disease. Instead,
it suppresses the production of somatic mutation-expressing
hematopoieitic cells which induce the formation of ECD lesions.
Moreover, severe side effects hamper prolonged use of this type of
medication.
Methods: We explored a novel and potential curative therapy with
limited side effects. We here present an ECD patient with a pos-
itive somatostatin receptor (SSTR) scintigraphy, who was subse-
quently and successfully treated with radiolabeled SSTR analog
therapy.

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Results: A 44-year old male presented with fluctuating vision and
progressive diabetes insipidus. The patient developed exophthalmos
due to a bilateral intra-conal tumor. A biopsy of the ophthalmic
lesion showed a BRAFV600E positive ECD lesion and radiologic
evaluation revealed pathologic lesions in the lung, perirenal and
periaortic region. Immunosuppressive drugs including corticosteroids,
intravenous immunoglobulins, methotrexate, cyclosporine and etan-
ercept could only attain temporary improvement. Targeted therapy
(i.e. BRAF/MEK inhibitors) was not available at the time this patient
was referred to our hospital and the patient refused chemother-
apy. Since the lesions demonstrated somatostatin uptake on indium-
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ABSTRACTS
111-pentetreotide ([111In-DTPA]-octreotide) scintigraphy, a cycle of
3 administrations of radionuclide therapy with a cumulative dose
of 16.5GBq was given. Combined with 7.5mg of prednisone and
100mg azathioprine as maintenance therapy, the ECD lesions sta-
bilized without deterioration for the rest of his life. Moreover,
the vision markedly improved and also stabilized throughout his
life.
Conclusion: We provide data that support a rationale for somatostatin
radionuclide therapy for ECD patients with positive lesions on SSTR
scintigraphy. We stress that more research is needed to substantiate
the efficacy of this unconventional treatment modality.