Clinical Pediatric Hematology-Oncology Volume 29ㆍNumber 2ㆍOctober 2022 CASE REPORT

Improvement of Neurodegenerative Disease after Use of Vemurafenib in Refractory

BRAF V600E-Mutated Langerhans Cell Histiocytosis: A Case Report

Young Kwon Koh1, Su Hyun Yoon1, Sung Han Kang1, Hyery Kim1, Ho Joon Im1,
Pyeong Hwa Kim2, Ah Young Jung2 and Kyung-Nam Koh1
1
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan
College of Medicine, 2Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder characterized by het- pISSN 2233-5250 / eISSN 2233-4580
https://doi.org/10.15264/cpho.2022.29.2.97
erogenous lesions infiltrated with CD1a+/CD207+ cells. Although LCH has a relatively
Clin Pediatr Hematol Oncol
good prognosis, the prognosis for patients with LCH refractory to standard chemo- 2022;29:97∼101
therapy is poor. Neurodegenerative LCH (ND-LCH) is a central nervous system com-
plication of LCH that is characterized by progressive radiological and clinical Received on September 14, 2022
abnormalities. Symptomatic ND-LCH is difficult to treat and therefore has a poor Revised on October 13, 2022
Accepted on October 21, 2022
prognosis. A two-year-old boy presented with a scalp mass. Biopsy confirmed LCH.
Whole-body imaging revealed LCH involvement in multiple bones of the skull, facial
bones, and lungs. Prednisolone and vinblastine chemotherapy was initiated.
One-year post-treatment, most of the lesions in the bones and lung nodules dis-
appeared, and chemotherapy was discontinued. New neurodegenerative lesions ap-
peared 4 months after chemotherapy was discontinued. Second-line chemotherapy
using cytarabine, vincristine, and prednisolone was initiated. However, neurological
manifestations of ND-LCH worsened post second-line treatment, and the treatment Corresponding Author: Kyung-Nam Koh
Division of Pediatric
was switched to cytarabine and cladribine. Despite third-line chemotherapy, the le-
Hematology/Oncology, Department
sions progressed, and neurological deficits worsened. After identifying BRAF V600E
of Pediatrics, Asan Medical Center
mutation in the tumor tissue using next-generation sequencing, cytotoxic chemo- Children’s Hospital, University of
therapy was discontinued and vemurafenib treatment was initiated. One-year Ulsan College of Medicine, 88
post-vemurafenib therapy, ND-LCH manifestations regressed, and the patient experi- Olympic-ro 43-gil, Songpa-gu,
Seoul 05505, Korea
enced neurological improvement.
Tel: +82-2-3010-5994
Fax: +82-2-473-3725
E-mail: pedkkn@amc.seoul.kr
Key Words: LCH, Langerhans cell histiocytosis, Vemurafenib ORCID ID: orcid.org/0000-0002-6376-672X

with single-system LCH require local treatment; however,

Introduction
Langerhans cell histiocytosis (LCH) is a rare histiocytic
disorder characterized by heterogenous lesions infiltrated
with CD1a+/CD207+ cells arising from myeloid cell pre-
cursors [1]. LCH was recently categorized as a neoplastic
disease, owing to the fact that LCH is a clonal disorder
caused by mutations in genes associated with the mi-
togen-activated protein kinase (MAPK) pathway [2]. Patients
patients with multisystem LCH or LCH involving organs
at risk require systemic therapy, including chemotherapy
[2]. Although LCH has a relatively good prognosis, the
prognosis for patients with LCH refractory to standard
chemotherapy is poor [3]. In particular, neurodegenerative
LCH (ND-LCH) has a poor prognosis and is accompanied
by progressive deterioration of neurologic symptoms.
Furthermore, standard treatment for ND-LCH has not
been established. Vemurafenib, a BRAF inhibitor, was

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97
Young Kwon Koh, et al
found to be effective in the treatment of BRAF V600E-
mutated LCH [2,4,5]. In this case report, we described a
case of refractory BRAF V600E-mutated LCH involving
neurodegenerative manifestations, that was successfully
treated using vemurafenib. The Institutional Review Board
of Asan Medical Center approved this case report (IRB
approval no: 2022-1271).
Case Report
A two-year-old boy presented with a scalp mass in the
left parietal region that had persisted for 6 months.
Physical examination revealed a non-tender soft scalp
98
mass (3 cm in diameter) in the left parietal region, diffuse
erythema with discharge in the external auditory canals
of both ears, and mild hepatomegaly (3 cm below the
costal margin). Laboratory tests revealed no signs of cy-
topenia or liver function abnormalities. Additionally, no
evidence of bone marrow involvement was shown. Chest
computed tomography revealed the presence of multiple
irregular nodules with and without cavities in both lungs
(Fig. 1A). Whole-body magnetic resonance imaging (MRI)
revealed enlarged masses on the left frontal and occipital
bones of the skull, skull base, left zygomatic bone, and
maxillae (Fig. 2A-C). Brain MRI confirmed the absence
of pathological lesions in the brain parenchyma (Fig. 3A).
Fig. 1. Contrast-enhanced chest CT
scans at the time of diagnosis (A)
and one year post first-line chemo-
therapy (B). (A) Centrilobular no-
dules with and without cavities in
both the lungs (arrows). (B) A follow-
up CT scan one year post first-line
chemotherapy revealed that most
of the lesions in the lung nodules
disappeared.
Fig. 2. Contrast-enhanced T1-
weighted MRI scans at the time of
diagnosis (A-C) and one year post
first-line chemotherapy (D-F). Co-
ronal images revealed enlarged
masses on (A) the maxillae (arrows)
and (B) the left frontal bone (arrow-
head) and left zygomatic bone
(arrow). (C) The sagittal image
revealed enlarged masses on the
skull base (arrow). (D-F) A follow-
up CT scan one year post first-line
chemotherapy revealed that most
of the lesions in the bones dis-
appeared.
Vol. 29, No. 2, October 2022

Fig. 3. Axial FLAIR MRI scans of the cerebellum. (A) No lesions
were observed in the brain parenchyma at the time of diagnosis.
(B) T2-FLAIR hyperintensities were observed in the bilateral
cerebellar white matter four months after first-line chemotherapy
was discontinued (arrows). (C) Lesion progression three months
after the initiation of second-line therapy (arrows). (D) Neuro-
degenerative lesion regression three months post-vemurafenib
treatment (arrows).
LCH diagnosis was confirmed by histopathological and
immunohistochemical examination of the scalp mass.
First-line chemotherapy was initiated using prednisolone
2
(40 mg/m /day for 4 weeks, followed by a tapered dose
2
for another 2 weeks) and vinblastine (6 mg/m /week) for
2
6 weeks, followed by vinblastine (6 mg/m ) and pre-
2
dnisolone (40 mg/m /day for 5 days) every 3 weeks for
the next 46 weeks (LCH-III protocol). One-year post-
treatment, most of the lesions in the bones and lung nod-
ules disappeared (Fig. 1B, 2D-F), and chemotherapy was
discontinued. Four months after chemotherapy was dis-
continued, no significant neurological abnormalities
were identified and a follow-up brain MRI revealed that
all lesions in the bones of the skull disappeared; how-
ever, new T2-fluid-attenuated inversion recovery (FLAIR)
hyperintensities were observed in the bilateral cerebellar
white matter and dorsal brainstem (Fig. 3B). Based on the
development of neurodegenerative manifestations, sec-
2
ond-line chemotherapy using cytarabine (100 mg/m /day
Clin Pediatr Hematol Oncol
Vemurafenib in Langerhans Cell Histiocytosis
for 4 days), vincristine (1.5 mg/m2) every 3 weeks, and
prednisolone was initiated. A follow-up brain MRI per-
formed 3 months after the initiation of second-line ther-
apy revealed that ND-LCH had worsened (Fig. 3C).
Therefore, the treatment was switched to cytarabine (a
2
dose of 100 mg/m twice a day for 3 days) and cladribine
2
(5 mg/m /day for 5 days) every 3 weeks (third-line che-
motherapy).
Mild dysarthria and gait disturbances were reported
after two cycles of third-line chemotherapy. Brain MRI
revealed increased T2-FLAIR hyperintensities in the bi-
lateral cerebellar white matter, dorsal brainstem, and bi-
lateral basal ganglia. The gross motor function measure
(GMFM) after third-line chemotherapy was 57.7%. Next-
generation sequencing of the biopsy specimen (specimen
used initially for LCH diagnosis) revealed presence of the
BRAF V600E mutation. Cytotoxic chemotherapy was dis-
continued and vemurafenib treatment (15 mg/kg body
weight, twice daily) was initiated. Three months post-ve-
murafenib treatment, brain MRI revealed that hyper-
intensities captured by T2-FLAIR images had signifi-
cantly regressed (Fig. 3D). Additionally, 4 months post-
vemurafenib treatment, dysarthria and gait disturbances
improved. The GMFM calculated post-vemurafenib treat-
ment was 73.3%.
The patient continued to receive vemurafenib for a
year. Brain MRI performed 1-year post-initiation of ve-
murafenib treatment indicated that ND-LCH was stabi-
lized in the patient. Dysarthria and gait disturbances
continued to improve. The GMFM after a year of vemur-
afenib treatment was 95%. The patient did not experi-
ence any adverse effects (CTCAE grade 3 or higher) dur-
ing the course of treatment with vemurafenib. Skeletal
survey and physical examination confirmed that there
was neither reappearance of older lesions nor appear-
ance of new ones. If there are no unfavorable adverse
effects, the patient plans to use vemurafenib for two
years.
Discussion
LCH is a clonal disorder characterized by lesions in-
99
Young Kwon Koh, et al
filtrated with CD1a+/CD207+ cells arising from myeloid
cell precursors [2]. It is mainly caused by mutations in
genes associated with the MAPK pathway, particularly
the BRAF V600E mutation observed in 57% of LCH cases
[2,6]. Although LCH can affect any organ system, it main-
ly affects the bones, skin, lungs, and brain. The clinical
manifestations of LCH range from isolated indolent lesions
to explosive multisystem diseases [3]. Chemotherapy based
on a risk-adapted approach is the treatment of choice
for multisystem LCH or LCH involving organs at risk [1].
Recently, a growing understanding of MAPK pathway
gene mutations and their role in the development of LCH
has further substantiated the use of BRAF and MEK in-
hibitors for the treatment of LCH [1,4,5].
Central nervous system Langerhans cell histiocytosis
(CNS-LCH) develops due to active LCH infiltration and
leads to long-term sequelae [7]. The prevalence of CNS-
LCH is not well-established and ranges from 3.7-57.0%
[8]. CNS-LCH manifests as mass lesions and a neuro-
degenerative disease [2]. Mass lesions are histologically
similar to extracranial lesions and arise from the pineal
gland, hypothalamus, ependyma, meninges, choroid plexus,
and brain parenchyma [9]. Since the hypothalamic-pitui-
tary region is considered to be the control center of the
endocrine system, it is closely associated with the devel-
opment of conditions such as diabetes insipidus, growth
hormone deficiency, and thyroid dysfunction [2]. ND-LCH
is characterized by progressive radiological and clinical
abnormalities [8]. ND-LCH manifestations include pro-
gressive cerebellar ataxia associated with spastic quad-
riplegia, pseudobulbar paralysis, and cognitive decline,
sometimes leading to severe disability and complete de-
pendence [10]. Although neurological symptoms may be
an early manifestation of the disease, they typically de-
velop several years after the initial diagnosis is made
[11]. ND-LCH is radiologically confirmed using T2-FLAIR
images of MRI hyperintensities in the cerebellar pe-
duncles, dentate nuclei, basal ganglia, and brainstem
[7,11]. Lesions are usually symmetrical [11]. The preva-
lence of ND-LCH ranges from 1.9-11% and was found to
be higher in patients with multi-system disease, diabetes
insipidus, history of involvement of skull-base or orbit,
100
and BRAF V600E-mutated LCH [1,12]. It is unclear whether
ND-LCH represents an active disease or a radiologic
scar. A recent study suggested that ND-LCH is neither an
autoimmune disease nor a paraneoplastic syndrome, but
rather it is a neurodegenerative disease regulated by
BRAF V600E-positive myeloid progenitor cells that also
give rise to systemic CD207+ lesion cells in LCH [7].
Standard treatment guidelines for patients with ND-
LCH have not been established. Treatment of ND-LCH
using prednisolone, vinblastine, and cytarabine was in-
vestigated in earlier studies [1,13]. Some studies reported
treatment of ND-LCH using intravenous immunoglobulin
or rituximab [14,15]. In a recent study, twelve out of thir-
teen patients with ND-LCH responded to treatment with
BRAF inhibitors [5]. In the present case report, the pa-
tient diagnosed with ND-LCH was initially treated with
cytarabine, vincristine, and cladribine. However, neuro-
degenerative lesions progressed, and neurological dys-
function worsened. Vemurafenib, a BRAF inhibitor, ex-
hibited excellent therapeutic effects in the patient with
significant improvement in neurological impairments.
Although vemurafenib caused adverse effects such as ar-
thralgia and skin rashes in patients from earlier studies
[5], the patient in this report did not experience any ad-
verse effects.
In conclusion, vemurafenib is an effective alternative
that can be used in BRAF V600E-mutated LCH refractory
to standard chemotherapy. Vemurafenib may also be ef-
fective in the treatment of patients with ND-LCH.
However, the effective duration of treatment with vemur-
afenib is still not known [5]. Further investigation is es-
sential to determine the optimum duration of vemur-
afenib therapy, treatment initiation parameters, and
combination treatment with other classes of drugs (e.g.,
nucleoside analogs or MEK inhibitors).
Acknowledgments
This study was supported by a grant from the Korea
Disease Control and Prevention Agency (2019ER690301,
2022ER050200).
Vol. 29, No. 2, October 2022

Conflict of Interest Statement
The authors have no conflict of interest to declare.
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