How I Treat

How I treat ALL in Downs syndrome: pathobiology and management

Shai Izraeli,
1
Ajay Vora,
2
C. Michel Zwaan,
3
and James Whitlock
4
1
Department of Pediatric Hemato-Oncology, Edmond and Lily Safra Childrens Hospital, Sheba Medical Centre, Tel-Hashomer, Ramat Gan, and Tel Aviv
University Medical School, Tel Aviv, Israel;
2
Department of Haematology, Sheffield Childrens Hospital, Sheffield, United Kingdom;
3
Pediatric Oncology/
Hematology, Erasmus MCSophia Childrens Hospital, Rotterdam, The Netherlands; and
4
Division of Haematology/Oncology, The Hospital for Sick
Children and University of Toronto, Toronto, ON, Canada
Children with Down syndrome are at
high risk for developing B-cell precur-
sor acute lymphoblastic leukemia (DS-
ALL) associated with poor outcome due
to both a high relapse rate and increased
treatment-related mortality (TRM) from
infections. Biologically, these hetero-
geneous leukemias are characterized
by under-representation of the common
cytogenetic subgroups of childhood ALL
and overrepresentation of CRLF2-IL7R-
JAK-STAT activating genetic aberrations.
Although relapse is the major determinant
of poor outcomes in this population, de-
escalation of chemotherapy intensity might
be feasible in the 10% to 15% DS-ALL
patients with ETV6-RUNX1 or high hyper-
dipoidy in whom TRM is the major limiting
event. As infection-associated TRM occurs
during all treatment phases, including the
maintenance period, increased surveil-
lance and supportive care is required
throughout therapy. Improvement in out-
come will require better understanding of
the causes of treatment failure and TRM,
incorporation of new therapies targeting
the unique biological properties of DS-ALL,
and enhanced supportive care measures
to reduce the risk of infection-related TRM.
To facilitate these goals, an international
collaboration plans to establish a prospec-
tive DS-ALL registry and develop specific
supportive care recommendations for this
at-risk population. (Blood. 2014;123(1):
35-40)
Introduction
Children with Down syndrome (DS) are at an increased risk for
development of both acute myeloid and lymphoid leukemias (DS-
ML and DS-ALL, respectively).
1,2
Although DS-ML is highly
curable, the prognosis of DS-ALL is relatively poor compared
with the excellent outcomes for ALL in children without DS.
3
The following cases highlight several aspects of the diagnosis
and management of DS-ALL.
Case 1
A 4-year-old boy was diagnosed with common B-cell precursor,
National Cancer Institute (NCI) standard risk, central nervous
systemneg, normal karyotype ALL. He had previously been
treated for acute myeloid leukemia (AML; normal karyotype,
positive for GATA-1 mutation) at the age of 23 months with 4 courses
of intensive chemotherapy without exceptional problems and re-
mained in remission of AML at diagnosis of ALL.
He was treated according to the standard risk arm of United
Kingdom Acute Lymphoblastic Leukemia (UKALL) 2003
4
and
obtained a rapid morphological marrow response at day 15 of a 3-
drug induction comprising vincristine, pegylated asparaginase, and
dexamethasone but was high risk by the level of minimal residual
disease (MRD . 10
24
) at day 29. He received the most intensive
protocol consisting of augmented consolidation and 2 delayed
intensications (DIs) interspersed with escalating dose intravenous
Capizzi methotrexate (MTX) without folinic acid rescue. Although he
tolerated the intensive consolidation and DI courses, including 12
pegylated asparaginase doses (1000 U/m
2
subcutaneously), without
excess toxicity, he had prolonged pancytopenia and moderately severe
mucositis after the second Capizzi MTX dose (100 mg/m
2
) and
thereafter received standard interim maintenance instead.
The rst year of maintenance therapy was complicated by leg
pains and limp, which improved on withholding vincristine and
dexamethasone pulses, and an episode of Escherichia coli sep-
ticemia. In view of the latter, and frequent episodes of prolonged
neutropenia despite reduced doses of mercaptopurine and metho-
trexate, his maintenance was shortened from 3 to 2 years. He
remains in complete remission 7 years from diagnosis.
Case 2
A girl was diagnosed with common ALL at the age of 4.5 years,
with normal karyotype. She was treated according to a modied
version of the Berlin Frankfurt Munster (BFM)-based Dutch
Childhood Oncology Group (DCOG) ALL-10 protocol for children
with DS, ie, only 2 daunorubicin doses in induction instead of 4
dosages and a lower dose of MTX. As a child with DS-ALL, she
also received anti-infectious prophylactic therapy with ciprooxacine
and itraconazole during intensive chemotherapy phases in addition to
the customary cotrimoxazole.
The rst induction cycle was complicated by mucositis and an
oral herpes simplex infection, for which she was admitted and
treated with intravenous acyclovir. Six weeks after diagnosis, she
was admitted with bilateral pneumonia, which required mechanical
ventilations for 8 days. She did not receive chemotherapy for
approximately 4 weeks, after which protocol 1B was continued.
Cyclophosphamide at the end of protocol 1B was not given.
Despite these delays in therapy, polymerase chain reactionMRD
evaluation was negative, and the patient was stratied in the standard
risk armof the protocol, consisting of oral 6-mercaptopurine and MTX.
She frequently needed dose adaptations for low leucocyte counts
and continued to receive ciprooxacin prophylaxis during $1
Submitted July 17, 2013; accepted October 1, 2013. Prepublished online as
Blood First Edition paper, November 14, 2013; DOI 10.1182/blood-2013-07-
453480.
2014 by The American Society of Hematology
BLOOD, 2 JANUARY 2014 x VOLUME 123, NUMBER 1 35
year during maintenance, as she suffered from frequent viral upper
airway infections, and we wanted to prevent bacterial superinfection.
No other severe complications arose. She is in remission ;1.5 years
after stopping chemotherapy.
Case 3
An 8-year-old girl with DS was found to have a white blood cell of
234 000/cmm. The blasts marked as early pre-B-cell ALL; cytogenetic
abnormalities included t(X;14)(p22.3;q32), likely corresponding to an
IGH-CRLF2 gene rearrangement leading to overexpression of CRLF2.
5
CRLF2 overexpression was conrmed by ow cytometry, and a JAK2
mutation was identied by sequence analysis. She was treated accor-
ding to AALL0232, a childrens oncology group (COG) high-risk ALL
protocol using a 4-drug induction. A bone marrow evaluation at end
induction showed morphologic remission but a high level (2.3%) of
minimal residual disease by ow cytometry. She received extended
induction chemotherapy, followed by an augmented BFM consolida-
tion, a modied interim maintenance with escalating doses of metho-
trexate beginning at 0.5 g/m
2
, delayed intensication, and maintenance
chemotherapy. Her course was complicated by several episodes of
febrile neutropenia, each with negative blood cultures.
While receiving maintenance chemotherapy, she was found to
have circulating blasts signifying recurrence of her ALL. She received
reinduction chemotherapy according to the UK ALLR3 chemotherapy
regimen; despite antimicrobial prophylaxis, she developed sepsis due
to Stenotrophomonas bacteremia and died.
Although the occurrence of both AML and ALL in the same DS
patient is quite rare and reects the increased risk of both types of
leukemias in DS, the rest of the course of the rst child reects many
of the typical issues encountered in children with DS-ALL. The
leukemia is a typical B-cell precursor but usually has a normal
karyotype lacking any of the usual genetic aberrations of childhood
ALL. It often responds poorly to therapy and thus is classied as
high risk. This child generally tolerated intensive therapy quite well;
however, he had excess toxicity during maintenance that necessi-
tated therapy modication. The girl in the second case depicts the
rarer child with standard risk ALL, based on excellent MRD
response. She suffered life-endangering toxicity during the initial
intensive phase of therapy. The third case illustrates the association of
DS-ALL with specic cytogenetic abnormalities and highlights the
challenges in managing treatment-related mortality (TRM) in relapsed
DS-ALL despite aggressive supportive care.
Notwithstanding the poorer prognosis of DS-ALL compared
with ALL in children without DS (NDS-ALL), it is important to
stress that like the rst 2 patients, the majority of children with DS-
ALL are cured. Together these 3 cases depict the challenges in
treatment of ALL in children with DS. It is a delicate balancing act
between the need for intensive chemotherapy and the markedly
increased toxicity of such therapy. Questions about the risks and
benets of intensive chemotherapy, despite the anticipated toxicity,
and the role of reductions in therapy are constantly raised.
Here we will provide some guidelines to assist clinicians in
dealing with these questions by reviewing recent data on the biology
of this disease and the clinical course of children with DS-ALL
treated with contemporary protocols.
Epidemiology and genetics
The risk of ALL in children with DS is ;20-fold higher compared
with children without DS,
2
and children with DS comprise 2% to
3% of all children enrolled on prospective treatment protocols of
ALL (Table 1).
6
The epidemiology of DS-ALL is very different
from DS-ML. Although transient myeloid neoplasms are present at
birth in ;5% of all DS infants, and full-blown DS-ML usually
develops before the age of 4 years,
3
infant ALL is extremely rare in
DS.
7,8
In fact, the peak age of ALL is slightly higher than in
children without DS, and age of diagnosis extends into adolescents
and young adulthood.
Another striking feature of DS-ALL is the almost complete
absence of T-cell ALL (T-ALL). In the recent study conducted by
the Ponte Di Legno working group on childhood ALL
7
(herein PdL
study), only 5 patients among 708 DS-ALL patients had T-ALL
compared with the 10% to 15% expected rate. Thus, the increased
risk of ALL in DS is limited to the B-cell precursor phenotype.
Interestingly, acquired polysomy of chromosome 21 is also mainly
found in B-cell precursor ALL in children without DS (NDS-ALL),
for example, in the hyperdiploid phenotype.
9
The myeloid leukemia of DS is a unique syndrome characterized
by an acquired mutation in the GATA1 transcription factor, which is
encoded by a gene on chromosome X in virtually all cases.
3
In
contrast, DS-ALL is not a single biologic entity. This heterogeneity
is conrmed by both gene expression and cytogenetic analyses.
10,11
The common cytogenetic subgroups of childhood NDS-ALL are less
common in DS.
7,10
Approximately 15% of DS-ALLs are positive for
the ETV6-RUNX1 translocation or are high hyperdiploid compared
with ;40% of NDS-ALLs. Similarly, the unfavorable translocations
BCR-ABL and MLL-AF4 are also less common in DS-ALL. Con-
sequently, similar to the rst 2 cases presented, 40% of DS-ALLs
have a normal karyotype compared with only 7% of NDS-ALLs.
As detailed below, these genetic differences between DS and NDS
ALLs have implications for therapy outcome.
Recently abnormal expression of the cytokine receptor CRLF2 has
been identied in ;60%of DS-ALLs.
5,11-13
CRLF2, together with the
a chain of the receptor to interleukin 7 (IL7R), forms a receptor for the
cytokine thymic stromal lymphopoietin (TSLP). The TSLP receptor is
normally present on dendritic cells, CD4
1
T lymphocytes and
basophils and mediates allergic and inammatory responses to TSLP,
which is secreted by epithelial cells in the bronchial tree or the gut and
by keratinocytes.
14
Thus, as illustrated in the third case, in 60%of DS-
ALLs, this pathway is hijacked by the leukemic cells, enabling them
to respond to TSLP with increased survival and proliferation.
Interestingly, in at least half of these CRLF2-positive DS-ALLs,
there are additional activating mutations either in the CRLF2 or
IL7R proteins or in the signaling components downstream that
include the enzymes JAK2 and JAK1.
11,15-18
These mutations lead
to constitutive activation of this pathway. The CRLF2 abnormalities
Table 1. Clinical and biological features of DS-ALL
Biological features Almost exclusively B cell precursor immunophenotype
Heterogeneity - no DS ALL typical genetic abnormality
as in DS myeloid leukemias
Decreased prevalence of favorable chromosomal
aberrations of childhood ALL (ETV6-RUNX1, high
hyperdiploid)
Decreased prevalence of unfavorable chromosomal
aberrations of childhood ALL (BCR-ABL, AF4-MLL)
Aberrant expression of CRLF2 in 60% of DS-ALLs
Large proportion of cytogenetically normal ALL
Clinical features No Infant leukemia
High risk of relapse
High infectious associated therapy related mortality
throughout treatment period
36 IZRAELI et al BLOOD, 2 JANUARY 2014 x VOLUME 123, NUMBER 1
are probably not associated with worse prognosis in DS-ALL except
when associated with deletions in the IKZF1 gene.
7,19
However, they
provide a pathway relevant to a substantial proportion of DS-ALLs that
may be targeted by inhibitors of the JAK-STAT or mammalian target
of rapamycin (mTOR) pathways.
Thus, although no unique genetic aberrations have been iden-
tied in DS-ALL to date, the distribution of the cytogenetic sub-
groups is markedly different from NDS-ALL. Host factors are
also altered, as all the normal blood and body cells of DS patients
contain a trisomy of chromosome 21. These differences in the
biology of the disease and the host impact the clinical course.
Clinical course
Relapse risk
In sharp contrast to the excellent prognosis of the myeloid leukemias
of DS, the prognosis of children with DS-ALL is signicantly worse
than children without DS.
7,20-27
The 10-year survival of 653 DS-
ALL patients enrolled in 16 international prospective therapeutic
studies between 1995 and 2005 analyzed in the PdL study was 70%
compared with 88% in children without DS.
7
This poor outcome is
related to increased relapse risk coupled with increased TRM.
That intrinsic resistance of DS-ALL to therapy
28
is the major
cause of treatment failure was also suggested by 2 smaller studies.
Whitlock et al,
23
analyzing the outcome of DS-ALL in childrens
cancer group treatment protocols, reported the surprising observation
that the poorer outcome of DS-ALL was limited to the NCI standard-
risk group, suggesting that the NCI criteria do not accurately predict
outcome in DS-ALL due to the unique biology of DS-ALL. Indeed,
intensied chemotherapy may be associated with improved prog-
nosis of these patients as DS patients stratied to NCI high-risk
treatment groups fared similarly to non-DS patients. These ob-
servations were conrmed by Maloney et al,
29
who demonstrated
that DS-ALL patients fared worse because of the paucity of
favorable risk chromosomal aberrations, namely ETV6-RUNX1
and hyperdiploidy.
One confounding factor that could affect the high incidence of
relapse in DS-ALL is poor adherence of physicians to protocol
guidelines. A recent study from the NOrdic society of Pediatric
Hematology and Oncology (NOPHO) collaborative group
30
indicated
that physicians were less willing to increase MTX/6-mercaptopurine
maintenance doses for DS patients with white blood cell counts above
the target level. Consequently, the median doses of these medications
were 25% lower for children with DS compared with NDS patients.
Other studies
7,8
reported that ;40% of DS patients underwent dose
reductions during specic protocol courses, especially during high-dose
MTXblocks. Thus, it is possible that reduction of therapy caused by the
concerns of increased toxicity contributed to relapses in some DS-ALL
patients. However, the notion that the biological properties of the
leukemias also play a major role in determining resistance to therapy is
supported by cellular in vitro cytotoxicity assays demonstrating relative
resistance of DS-ALL blasts to a variety of chemotherapeutic agents.
28
Taken together, these observations suggest that some children with
DS-ALL may benet from intensied chemotherapy and that
physicians need to be careful in reducing treatment intensity.
Treatment-related mortality
A recommendation for intensied treatment in some children with
DS-ALL is offset by the well-recognized increased chemotherapy-
associated toxicity in children with DS-ALL. Fatal infections, most
commonly bacterial and viral, are the major causes of TRM in
children with DS-ALL.
7,8,21,26,31
The causes of infectious toxicities
are multifactorial. Increased tendency for cellular apoptosis
coupled with altered intracellular metabolism of certain drugs,
such as methotrexate, lead to breakdown in cellular barriers and
increased mucositis. Immunodeciency, narrowed and hyperac-
tive respiratory tract, and congenital cardiac defects increase the
risk for respiratory and other infections.
The toxicity associated with the administration of MTX is the
best-studied specic toxicity of a chemotherapeutic drug in DS.
8
It is
mainly related to a pharmacodynamic effect.
32
Gene dosage effect
of extra copies of the reduced folate carrier SLC19A1, located on
chromosome 21, appears to cause increased intracellular accumu-
lation of MTX in trisomy 21 cells.
33
This gene dosage effect may
also explain the increased sensitivity of hyperdiploid ALL blasts,
which uniformly carry 3 or 4 copies of chromosome 21. However in
DS, the presence of trisomy 21 in constitutional cells also increases
susceptibility to the systemic toxicity of MTX. Therefore, in protocols
using high-dose MTX, it is generally recommended to reduce
higher dosages of MTX in children with DS. For example, the
BFMAssociazione Italiana Ematologia Oncologia Pediatrica (AEIOP)
protocol recommends reduction from 5000 to 500 mg/m
2
of MTX in
the rst block of high-dose MTX, with a gradual increase in subsequent
courses as tolerated.
Despite these concerns about the toxicity of MTX in DS-
ALL, the recent international PdL study has shown that TRM in
DS-ALL is not linked to MTX blocks or to any other treatment
element.
5
Similarly, escalating dose MTX was associated with
increased toxicity but not increased TRM in DS-ALL patients in
the childrens cancer group1991 study, and DS-ALL patients
who received the intensied MTX therapy had better survival
than those who did not.
34
TRM is not limited to the intensive
phases of the treatment protocol, as 40% of TRM occurs during
maintenance.
7
The immunodeciency of DS is complex and incompletely
understood.
35,36
Several immune regulatory and developmental
genes such as those encoding the interferon a and g receptors,
AIRE, the suppressors of the nuclear factor of activated T cells
(NFAT) pathway (RCAN and DYRK1A), RUNX1, mir125b, and
more are located on chromosome 21. Recent analysis of fetal and
perinatal hematopoiesis in DS revealed severe defects in early B-
cell development.
37,38
This B-cell deciency is only partially
corrected later in childhood; B lymphocytes, especially nave
B cells, remain below the 10th percentile.
39-41
Defects in B-cell
function are reected in mild dysgammaglobulinemia, de-
creased salivary IgA levels, and reduced antibody responses to
immunization.
42-48
Mild to moderate T-cell dysfunction was also reported in
children with DS. The NFAT-calcineurin pathway is a major
regulator of T-cell development and function and is inhibited in
DS due to the increased dosage of regulator of calcineurin 1 and
dual-specicity tyrosine-(Y)-phosphorylation regulated Kinase
1A1.
49,50
This is the same pathway that is targeted by the immu-
nosuppressants cyclosporine and tacrolimus. It is also tempting to
speculate that the rarity of T-ALL in DS is also possibly due to the
block in the NFAT pathway. The major T-cell defect has been
recently shown to be in decreased thymic output of new T cells, as
reected by reduced T-cell receptor excision circles.
51
These im-
munodeciencies are reected in increased susceptibility to severe
respiratory infections and bacteremias in nonleukemic children
with DS.
35
BLOOD, 2 JANUARY 2014 x VOLUME 123, NUMBER 1 HOW DO I TREAT DS-ALL 37
Current treatment approaches
In an attempt to reduce excess treatment-associated morbidity and
mortality, a majority of cooperative groups presently modify the
treatment of DS-ALL patients as revealed in a survey of 20 national
study groups (A.V., personal communication, May 2013). To date,
treatment is stratied by MRDresponse by all groups surveyed. All
groups limit exposure to high doses of intravenous MTX by
adopting a dose capping (500-1000 mg/m
2
with folinic acid re-
scue) or a cautious dose escalation strategy (starting dose, 500-2000
mg/m
2
). None of the groups give cranial radiotherapy to patients
with DS-ALL. NOPHO(Nordic), UKALL, and COGlimit the use of
anthracycline in induction to patients with a slow morphological
marrow response (.25% blasts) at day 15 of a 3-drug regimen
(steroid, vincristine, and pegylated asparaginase). DCOG (Dutch)
and FRance Acute Lymphoblastic LEukemia (FRALLE) (French)
groups avoid exposure to induction anthracyclines in all DS patients,
whereas AIOEP-BFM (Italian-German consortium) gives 2 to 4
doses depending on karyotype and early MRD response, similar to
patients with NDS-ALL. Whereas dexamethasone is given in
induction to all DS patients in the United Kingdom, the COGgives it
only to patients ,10 years old and AIEOP-BFM (Italian-German
consortium) gives it to patients with T-cell phenotype and a good re-
sponse to prephase prednisolone. There are no planned alterations
in maintenance therapy except in the United Kingdom and in DS-
ALL patients in COG protocols, where the duration of maintenance
has been shortened from 3 to 2 years for boys with DS-ALL and with
a reduction in monthly vincristine/steroid pulses in COG protocols.
Interestingly, despitea these variabilities in treatments, no sig-
nicant differences in outcome were detected between the major
therapeutic protocols of DS-ALL.
7
Additional supportivea care measures are recommended for
DS-ALL patients by all groups ranging from antibiotic and anti-
fungal prophylaxis during periods of neutropenia to intravenous
immunoglobulin infusions to maintain IgG level above a dened
threshold. However, there is no evidence of the efcacy of these
measures in this setting and, for that reason, no consensus on the
matter.
Facing the challenge: how best to treat
children with newly diagnosed ALL
c We strongly recommend that, like every other child with ALL,
DS children should be treated on prospective treatment protocols
(Table 2). More than 70% of children with DS-ALL treated with
such protocols will be cured.
c As DS-ALL is a high-risk disease, we recommend avoidance of
any dose reduction that is not specied in the protocol. Children
with high-risk criteria, eg, high MRD, should be treated ac-
cording to high-risk protocols.
c As poor adherence to dosing in maintenance has been shown to
be associated with increased relapse in DS-ALL, we recommend
that fear of infection should not deter clinicians from timely
protocol-specic dose escalations in patients with stable counts.
c The child with DS-ALL with ETV6-RUNX1 or hyperdiploidy has
excellent prognosis similar to NDS-ALL, with most deaths due to
toxicity.
7
For these children and probably for those with negative
MRD at the end of induction, we recommend consideration of
treatment reduction in the face of moderate to severe toxicity.
c It should be emphasized that the risk of infectious-related TRM
is increased even during maintenance. Hence, children with DS-
ALL should be reviewed more frequently during both intensive
and maintenance periods. Antibiotics should be initiated at the
earliest suspicion of infection even in the absence of neutropenia.
c Sensible approaches for preventing respiratory viral infections by
limiting exposure and vaccinating family members against inu-
enza are warranted.
c The role of prophylactic antibiotics is unclear, and the protocols
we represent (COG, UK, DCOG, and AIEOP-BFM), as well as
our infectious disease specialists, differ in their opinions. Some
experts recommend ciprooxacin prophylaxis during intensive
treatment periods or ampicillin for children with frequent res-
piratory viral infections.
c There is similar debate regarding antifungal prophylaxis, especially
as there is no evidence for increased fungal infections in these
patients.
c Hypogammaglobulinemia should be aggressively investigated
and treated; common recommendations for acquired hypogam-
maglobulinemia are to measure IgG monthly and treat with
intravenous immonoglobulins 0.5 g/kg every 3 to 4 weeks if
levels drop below 4 g/L.
Approach for relapse/role of novel and
emerging technologies
Treatment of relapse
Despite children with relapsed DS-ALL having more favorable
prognostic factors than relapsed NDS-ALL,
52
the prognosis of
relapse of DS-ALL is grim. A recent study analyzing the outcome
of 49 DS-ALL patients treated on the BFM relapse protocol
52
demonstrated only 17%long-termsurvival, with TRMbeing the major
factor determining the worse prognosis compared with NDS-ALL.
Table 2. Therapeutic challenges and possible solutions
Reducing relapse Caution at reducing chemotherapy dosages
in the absence of toxicity
Incorporating clinical trials with novel agents
targeting unique biological features (e.g.
JAK and mTOR inhibitors for CRLF2
expressing DS-ALL)
Reducing therapy related
mortality
Consider chemotherapy dose reduction in
patients with ETV6-RUNX1 or High
hyperdiploidy DS-ALL or MRD negativity at
the end of induction, and excessive toxicity
Careful surveillance throughout therapy
including maintenance period
Intense monitoring/supervision during
periods of prolonged neutropenia
Aggressive treatment of suspected
infections even in absence of neutropenia or
fever
Influenza immunization of family members
and reduced exposure to respiratory
infections
Intravenous immunoglobulin therapy for
children with low/normal or
hypogammaglobulinemia
Antimicrobial prophylaxis for children with
recurrent respiratory infections
38 IZRAELI et al BLOOD, 2 JANUARY 2014 x VOLUME 123, NUMBER 1
There is a general reluctance to use stem cell transplantation (SCT),
because this therapy is considered to be too toxic. Interestingly, how-
ever, of 18 patients transplanted in the PdLcohort, 6 were cured, 2 died
of infections, 1 died from graft-versus-host disease, and 9 died from
relapse.
7
Similarly in another smaller cohort,
53
relapse and not TRM
was the major reason for failure after SCT. Hence, SCT can be con-
sidered for DS-ALL patients in good general health, with good
response to relapse induction chemotherapy. As central nervous
system toxicity of total body irradiation is a concern in DS, a
radiation-free approach should be considered as a preparatory
regimen.
Novel therapies
c Antigen-directed immune therapies (eg, Blinatumomabbispecic
anti-CD19 antibody or engineered autologous T cells) are exciting
new technologies for therapy of B-cell precursor ALL.
54-57
Although we currently do not know if their T cells react
similarly to NDS children, participation of eligible children
with DS and either refractory or relapsed ALL in immuno-
therapy trials is recommended. DS-ALL patients may particularly
benet from such therapy due to a reduction in myelosuppression
and concurrent TRM.
c JAK and mTOR inhibitors: Uniquely, 60% of DS-ALLs express
the cytokine receptor CRLF2 that signals through JAK-STAT and
mTOR pathways. Preclinical trials demonstrate activity of either
JAK or mTOR inhibitors.
58
As these drugs are completing phase I
trials in children, we recommend that eligible children with DS
and relapsed or refractory CRLF2-positive ALL be enrolled in
future clinical trials with these drugs. Our unfortunate case 3
represents a child that could have beneted from such therapy.
c As ruxolitinib (a dual JAK1/JAK2 inhibitor) is approved for
adults with myeloproliferative neoplasms, we recommend con-
sidering treatment of adult patients with DS-ALL (provided that
it is CRLF2 positive). These patients are rare, often have re-
fractory disease, and cannot tolerate either the aggressive pedi-
atric ALL regimens nor SCT.
c Liposomal formulations of standard cytotoxic agents used in the
treatment of ALL such as daunomycin and vincristine offer the
promise of improved therapeutic index leading to both improved
outcomes and a reduction in toxicities in all children with ALL.
Similarly, high-dose cytarabine, which is usually tolerated by DS
children treated for AML, may have a role in DS-ALL; however,
to date, no data are available regarding the potential benets of
these agents in DS-ALL.
Improvement in outcomes for DS-ALL will only be realized from
a better understanding of the causes of treatment failure and TRM.
The available evidence indicates that DS-ALL patients have distinct
host and leukemic blast biology, which necessitates the develop-
ment of specic treatment approaches. Given the relatively small
numbers of patients available for study within national groups,
international collaboration is essential to develop and test innovative
treatment strategies. One such collaboration has been established
within the international BFM group with representatives from
European, North and South American, Taiwanese, and Japanese
study groups. In addition to providing a forum for discussion of
existing treatment approaches and outcomes, the collaborative aims
to establish an international prospective registry to collect de-
mographic, biological, and clinical outcome data on a large group of
DS-ALL patients and to agree on uniform immune monitoring and
supportive care recommendations. The longer-term aspiration is to
develop an international DS-ALL protocol that addresses treatment
questions informed by analysis of the registry data.
Acknowledgments
The authors thank Trudy Buitenkamp and the physicians and
investigators from the childhood ALL study protocols around the
world studies that contributed information for this article.
This work was supported by the Israel Science Foundation
Legacy Program, The Waxman Cancer Research Foundation and
the Israel Cancer Association (to S.I.), and Kinderen Kankervrij (to
C.M.Z.). J.W. is supported in part by the Womens Auxiliary
Millennium Chair in Haematology/Oncology, The Hospital for
Sick Children.
Authorship
Contribution: S.I., A.V., C.M.Z., and J.W. wrote the paper.
Conict-of-interest disclosure: The authors declare no compet-
ing nancial interests.
Correspondence: Shai Izraeli, Cancer Research Center, Sheba
Medical Center, Tel Hashomer, Ramat Gan 52621, Israel, and
Department of Human Molecular Genetics and Biochemistry, Tel
Aviv University, Tel Aviv 69978, Israel; e-mail: shai.izraeli@
sheba.health.gov.il.
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