Pediatrics International (2015) 57, 811819 doi: 10.1111/ped.

12758

Review Article

Recent progress in the treatment of infant acute lymphoblastic leukemia

Daisuke Tomizawa
Division of Leukemia and Lymphoma, Childrens Cancer Center, National Center for Child Health and Development, Tokyo, Japan

Abstract Treatment of infants with acute lymphoblastic leukemia (ALL), especially those with mixed lineage leukemia (MLL)
rearrangement (MLL-r), which account for approximately 80% of cases, is still a major challenge for pediatric
hematologists and oncologists worldwide. Continuing efforts by collaborative clinical study groups in Europe, North
America, and Japan have rescued approximately half of the MLL-r ALL patients with intensive chemotherapy with or with-
out allogeneic hematopoietic stem cell transplantation. Recent progress has claried the unique mechanism of MLL-r ALL:
the aberrant methylation and histone modications via DOT1L and other related molecules by MLL fusion proteins lead to
leukemogenetic gene expression, thus to overt leukemia. In order to overcome this dismal subtype of ALL, novel targeted
therapy based on leukemia biology is urgently needed. Due to the extreme rarity of the disease, collaboration between the
study groups in Europe (Interfant), North America (Childrens Oncology Group), and Japan (Japanese Pediatric
Leukemia/Lymphoma Study Group) is under way.

Key words acute lymphoblastic leukemia, epigenetics, hematopoietic stem cell transplantation, infant, mixed lineage leukemia.

Acute lymphoblastic leukemia (ALL), a malignant disorder of lym-
phoid progenitor cells, is the most common type of malignant neo-
plasms in children and adolescents, with approximately 444532
cases diagnosed annually in Japan.1 Optimal use of old drugs, de-
veloped between the 1950s and 1970s under successive collabora-
tive clinical trials, has improved the outcome of childhood ALL to
achieve an event-free survival (EFS) rate of 80.487.2% and an
overall survival (OS) rate of 91.893.5% in recently completed
clinical trials.25 The progress in the treatment of infant ALL (diag-
nosed at age <12 months), however, is lagging behind compared
with the treatment of children 1 year: EFS and OS remain at
41.750.9% and 44.860.5%, respectively (Table 1).9,1113 In this
review, advances in the pathobiology and clinical management of
ALL in infants is described.
Epidemiology and characteristics
Infant ALL accounts for <5% of childhood ALL, with 2025 new
cases diagnosed annually in Japan. In children 1 year, ALL com-
prises 7580% of all childhood leukemia because of the high peak
incidence of B-lineage ALL between the age of 2 and 5 years, with
a predominance in boys. In contrast, the incidence of ALL in in-
fants is the same as that of acute myeloid leukemia (AML), with
a slight predominance in girls.1,11
Biologically and clinically, infant ALL consists of two dis-
tinct subtypes: one involves rearrangements of mixed lineage
leukemia (MLL also called KMT2A), which accounts for
Correspondence: Daisuke Tomizawa, MD PhD, Division of Leuke-
mia and Lymphoma, Childrens Cancer Center, National Center
for Child Health and Development, 2-10-1 Okura, Setagaya-ku,
Tokyo 157-8535, Japan. Email: tomizawa-d@ncchd.go.jp
Received 31 May 2015; revised 25 June 2015; accepted 10
July 2015.
approximately 80% of infant ALL; and the other with germline
MLL. Infant ALL with rearranged MLL (MLL-r) is a highly ag-
gressive leukemia with high white blood cell (WBC) count and
frequent involvement of extramedullary sites including the cen-
tral nervous system (CNS) at diagnosis.9,11 In addition, MLL-r
ALL has a very immature CD10-negative B-cell precursor phe-
notype in approximately two-thirds of cases and is frequently
associated with co-expression of myeloid-specic antigens,
while mature B-cell or T-cell phenotype is extremely rare. This
suggests that infant MLL-r ALL arises from an immature pre-
cursor hematopoietic cell that is not fully committed to lym-
phoid lineage. In fact, several cases of lineage switch from
B-cell lineage to monocytic lineage leukemia have been
reported.14 In contrast, infant ALL involving germline MLL
(MLL-g) generally occurs in late infancy, has a more mature
CD10-positive B-cell precursor phenotype, shares similar cyto-
genetic abnormalities with ALL in older children, and is associ-
ated with better outcome.8,15
Pathobiology
Pathogenesis of MLL rearrangement
The MLL rearrangement, a hallmark of most infant ALL, occurs as
a result of balanced chromosomal translocations that fuse the
N-terminus of MLL on chromosome 11q23 to the C-terminus of
one of more than 70 known partner genes.16 The most common
in infant ALL is t(4;11)(q21;q23) or MLL-AF4 (MLL-AFF1),
which accounts for approximately half of the cases, followed
by t(11:19)(q23;p13.3) or MLL-ENL (MLL-MLLT1), and t(9;11)
(p22;q23) or MLL-AF9 (MLL-MLLT3). t(9;11)/MLL-AF9 occurs
in relatively older infants and is associated with more mature
phenotypes compared with other subtypes of infant MLL-r ALL.

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812 D Tomizawa

Table 1 Outcome of infant ALL in recent clinical trials

No. patients treated

Study Study acronym and No. patients with HSCT in
group inclusion time (MLL-r/MLL-g) rst CR CR (%) EFS (%) OS (%) Source
JILSG MLL96/98 102 (80/22) 49 94.1 4 years 50.9 4.9 4 years 60.5 4.8 Kosaka et al.6
(19952001) Isoyama et al.7
Nagayama et al.8
Tomizawa et al.9
JPLSG MLL03 62 (62/) 44 80.6 4 years 43.2 6.3 4 years 67.2 6.0 Koh et al.10
(20042009)
Interfant Interfant-99 482 (314/82) 37 94 4 years 47.0 2.6 4 years 55.3 2.7 Pieters et al.11
(19992005)
CCG CCG1953 115 (79/36) 37 82.5 5 years 41.7 9.2 5 years 44.8 5.6 Hilden et al.12
(19962000)
COG COG P9407 147 (100/35) 0 91.8 5 years 42.3 6.0 5 years 52.9 6.5 Dreyer et al.13
(20012006)
ALL, acute lymphoblastic leukemia; CCG, Childrens Cancer Group; COG, Childrens Oncology Group; CR, complete remission; EFS, event-
free survival; HSCT, hematopoietic stem cell transplantation; JILSG, Japan Infant Leukemia Study Group; JPLSG, Japanese Pediatric Leukemia/
Lymphoma Study Group; MLL, mixed lineage leukemia; MLL-g, germline MLL; MLL-r, rearranged MLL; OS, overall survival.

It is well recognized that the genetic event involving MLL takes
place in utero. This is supported by evidence of the very early onset
of infant ALL, the high rate of concordance of leukemia in mono-
zygotic twins when one twin developed leukemia in the rst year of
life, and the prenatal origin of infant ALL conrmed directly by the
detection of unique MLL-AF4 fusion in neonatal blood spots on
Guthrie cards from infants with MLL-AF4-positive ALL.17,18
MLL rearrangements are often recognized in patients with
treatment-related AML arising after exposure to topoisomerase II
inhibitors. As for infant ALL, epidemiologic studies indicated that
exposure to topoisomerase II-like materials (such as bioavonoids)
via the maternal diet might be involved in leukemogenesis.19
Genetics of infant ALL and MLL rearrangement
The mechanism of leukemogenesis in infants after the initial
genetic event in MLL has been a mystery for decades. On early
gene expression proling, that of infant MLL-r ALL was highly
distinct, consistent with an early hematopoietic progenitor express-
ing select multilineage markers and individual HOX genes, com-
pared with those of ALL diagnosed in older children and AML.
Notably, overexpression of wild-type fms-related tyrosine kinase
3 (FLT3) distinguished infant MLL-r ALL from ALL in older
children and AML.20
It is known that multiple stepwise mutations are necessary for
leukemogenesis in general. In mouse models of MLL-r leukemia,
expression of MLL chimeric gene alone is insufcient for full
transformation to leukemia.21 The St Jude Childrens Research
Hospital and Washington Universitys Pediatric Cancer Genome
Project, however, showed that for the genome, exome, RNA
and targeted DNA sequencing on MLL-r ALL, the majority of
copy number alterations (CNA) and structural variations found
in infant MLL-r ALL was a direct consequence of MLL rear-
rangement, and only a mean of 1.3 non-silent mutations per case
was detected in the dominant leukemic clone, which is one of the
lowest frequencies of somatic mutations of any sequenced cancer
ever.22 These data clearly imply that the MLL fusion protein is a
potent driver and plays a dominant role in leukemogenesis of in-
fant MLL-r ALL without cooperating mutations.
Disorder of epigenetic regulation in MLL fusions
The MLL gene is a human homologue of Drosophila melanogaster
trithorax, which encodes a DNA-binding protein that methylates
histone H3 lysine 4 (H3K4) and positively regulates gene expres-
sion including multiple Hox genes. As a result of inter-
chromosomal translocations, disrupted MLL in a breakpoint cluster
region that spans exons 812 loses the H3K4 methyltransferase
(SET) domain, and is replaced by one of the translocation partner
genes. MLL fusion proteins, MLL-AF10, MLL-ENL, and MLL-
AF9, however, recruit and directly interact with histone H3 lysine
79 (H3K79) methyltransferase DOT1L (Fig. 1).23 Other major
MLL fusion proteins, MLL-AF4, MLL-AF5q31, and MLL-ELL1
recruit and interact directly with positive transcription elongation
factor b (pTEFb) that phosphorylates RNA polymerase II, and
Fig. 1 Molecular actions induced by mixed lineage leukemia (MLL)
fusion. Direct or indirect recruitment of aberrant DOT1L by MLL fu-
sion proteins induces site-specic hyper-methylation and inappropriate
transcription of several leukemogenic genes, which leads to leukemia
subsequently. BRD4, bromodomain-containing protein 4; H3K79,
H3 lysine 79; H4K16, H4 lysine 16; LEDGF, lens epithelium-derived
growth factor; PAFc, polymerase-associated factor c; pTEFb, positive
transcription elongation factor b; SEC, superelongation complex.

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interact indirectly with DOT1L.24 Most of the major fusion part-
ners with MLL directly interact with superelongation complex
(SEC). Together with polymerase-associated factor c (PAFc),
SEC binds bromodomain and extra-terminal (BET) family member
BRD4, which is able to bind acetylated histone through its
bromodomains.25 Direct or indirect interactions of DOT1L,
pTEFb, SEC, PAFc, and/or BRD4 with MLL fusion proteins, en-
hance expression of leukemogenic genes, including HOXA9 and
MEIS1.26
Although the exact mechanism of MLL-r leukemogenesis in in-
fants is not fully understood, it is estimated that aberrant epigenetic
regulation induced by MLL fusions brings about a unique prole of
gene expression, thus leading to leukemia without additional gene
mutations.
Leukemia-initiating cells in infant MLL-r ALL
There is increasing evidence suggesting that some leukemia, such
as AML, is maintained by self-renewing leukemia-initiating cells
(LIC), a leukemia cell of origin, which exists at the apex of a hier-
archy and is capable of differentiating into leukemic blasts.27 This
model suggests that therapy failure results from residual LIC after
eradication of differentiated leukemic blasts with current treatment
modalities; therefore, identication and characterization of LIC in
infant MLL-r ALL may lead to the development of effective thera-
peutic strategies. Using a xenotransplantation model, Aoki et al.
found that LIC in infant MLL-r ALL have distinct surface expres-
sion patterns of CD34, CD38, CD19, and CD33 according to the
fusion subtypes: CD34+CD38+CD19+ and CD34 CD19+ cells ini-
tiated leukemia in MLL-AF4 patients, CD34 CD19+ in MLL-AF9
patients, and either CD34+ or CD34 depending on the pattern of
CD34 expression in MLL-ENL patients.28 In addition, CD9,
CD32, and CD24 were differentially overexpressed in MLL-r
LIC compared with normal hematopoietic stem cells. By targeting
these surface molecules that are selectively expressed in MLL-r
LIC with recently developed immunotherapeutic modalities such
as bi-specic T-cell engager (BiTE) antibodies or chimeric antigen
receptor (CAR) T cells, it may be possible to treat MLL-r ALL
more effectively while minimizing treatment-related hematopoietic
adverse events.
Clinical management
Prognostic factors
Among all the known prognostic factors, presence of MLL rear-
rangement is the strongest.29 Recently completed clinical trials
show similar outcomes among the subtypes of translocation or fu-
sion partners of rearranged MLL.11 Other factors such as high
WBC, CNS involvement, and absence of CD10 expression on leu-
kemic cells are also prognostic but are highly correlated with MLL
rearrangement. The second most prognostic is young age at onset
of ALL: outcome of infants younger than 3 or 6 months is ex-
tremely poor compared with older infants.9,11,12 Finally, treatment
response evaluated in the early phase of the treatment has evolved
as a powerful prognostic factor. Classically, peripheral blood blast
count after 8 days of prednisolone therapy (prednisolone response)
has been used for risk stratication in the therapy of ALL in older
Treatment progress in infant ALL 813
children, and has also been proven to be prognostic in infants.11,30
Recently, detection of minimal residual disease (MRD) measured
by polymerase chain reaction (PCR) or ow cytometry has been
shown to be a strong and independent prognostic factor in several
clinical studies, and is currently considered to be the standard of
care in ALL children aged >1 year.31,32 The Interfant-99 study,
an international collaborative infant ALL study that consisted
mainly of European countries, reported that MRD targeting the
rearranged MLL breakpoint is a powerful tool for better risk strati-
cation of MLL-r ALL infants.33 The study also indicated that
MLL rearrangement was the preferred PCR MRD target over im-
munoglobulin (Ig) or T-cell receptor (TCR) rearrangement, be-
cause of the oligoclonality of leukemia clones, which is
frequently seen in infant MLL-r ALL. Although MLL rearrange-
ments are assumed to be present in the total leukemic clone, there
is a risk of detecting subclone only when targeting Ig/TCR rear-
rangements, resulting in underestimation of actual MRD load.
Chemotherapy
Leukemic cells from infants with MLL-r ALL are more resistant
in vitro to prednisolone and L-asparaginase, which are the key
drugs for treating ALL, than cells from older children with ALL.
In contrast, infant ALL cells are more sensitive to cytarabine
(Ara-C) irrespective of MLL status.34 The greater Ara-C sensitivity
is explained by the high expression of human equilibrative nucleo-
side transporter 1 (hENT1) on infant ALL cells, which Ara-C
mainly depends on to permeate the cell membrane.35 From these
observations, a hybrid chemotherapy combining ALL-oriented
drugs (e.g. corticosteroids, vincristine, L-asparaginase, and metho-
trexate [MTX]) and AML-oriented drugs (e.g. anthracyclines,
etoposide, and especially Ara-C) is considered effective and is of-
ten used for treating infants with ALL. Remission induction che-
motherapy results in a high complete remission (CR) rate 90%
in general, but a high incidence of relapse occurs 45 months after
achieving CR. Attempt to improve outcome of infants with ALL by
intensifying delayed intensication with high-dose Ara-C and
high-dose MTX failed in the Interfant-99 study.11 Therefore, the
current ongoing Interfant-06 is investigating whether early
intensication with AML-oriented chemotherapy with Ara-C,
daunorubicin or mitoxantrone, and etoposide will be superior to
ALL-oriented chemotherapy with cyclophosphamide, Ara-C, and
6-mercaputopurine in MLL-r infants. Regardless, it is likely that
medium-risk MLL-r infants can be effectively treated with chemo-
therapy only. The Interfant-99 study noted a disease-free survival
(DFS) rate of 53.8% with chemotherapy for MLL-r infants without
additional poor prognostic factors (age <6 months at onset with ei-
ther WBC 300 109/L or poor prednisolone response).36 The
Childrens Oncology Group (COG) in North America also showed
in the COG P9407 study that an EFS of 43.8% was achieved for in-
fants >90 days old at onset of MLL-r ALL with only chemother-
apy.13 Given the experience in Europe and North America, a
strategy omitting the indication of allogeneic hematopoietic stem
cell transplantation (HSCT) but with the introduction of the
Interfant induction followed by COG post-remission chemotherapy
for MLL-r infants 6 months old without CNS involvement, is
currently being evaluated in the Japanese nationwide MLL-10
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trial (UMIN000004801) conducted by the Japanese Pediatric
Leukemia/Lymphoma Study Group (JPLSG).
Infants with MLL-g ALL may be cured with a chemotherapy
regimen relatively similar to the treatment regimen for older chil-
dren with ALL. Four year EFS and OS of 67% and 77%, respec-
tively, were achieved in the combined results of the Interfant-99
study and the COG-P9407 study.15 Moreover, in Japan, 5 year
EFS and OS rates of 95.5% were achieved in the combined results
of the MLL96 and MLL98 trials.8
Irrespective of MLL status, special attention needs to be paid
when prescribing chemotherapeutic drugs for infants because of
the following factors: higher percentage of total and extracellular
body water content than older children or adults, higher unbound
active fraction of drugs because of lower afnity of drugs to serum
protein, lower P450 enzyme activity, lower tubular and glomerular
function, lower bodyweight to body surface area ratio and so on.
Dose adjustments (e.g. 2/3 of the calculated dose for infants
<6 months old, 3/4 dose for 6<12 months old, and full dose for
12 months old, used in Interfant-99) are generally recommended
but these are somewhat arbitrary due to a lack of pharmacokinetic
(PK) data for infants for many of the drugs. PK analysis of high-
dose MTX (5 g/m2/dose) in the Interfant-99, applying the afore-
mentioned dose reduction rule, indicated a slightly lower MTX
clearance in younger infants, but the toxicity prole was similar
to that for older infants.37
HSCT
Clinical trials in Japan
The dismal outcome of 24 infants with ALL noted in a retrospec-
tive survey conducted by Ishii et al. in the 1980s led to the rst in-
fant ALL-specic clinical trial in Japan conducted by the
Aggressive Treatment (AT) Research Group and the Childhood
Leukemia Study Group of the Ministry of Health and Welfare.38
Between 1989 and 1995, 37 infants were registered and treated
with intensive chemotherapy. As a result, the 3 year EFS rate was
33%, but an EFS rate of 75% was observed for infants with
CD10-positive phenotype without 11q23/MLL involvement.39
To address this poor prognosis, the Japanese Infant Leuke-
mia Study Group was established in cooperation with the
existing childhood leukemia study groups in Japan at that time,
and two consecutive clinical trials, designated MLL96
(19951998) and MLL98 (19982002), were performed with
102 ALL infants (80 MLL-r and 22 MLL-g).69 These were
the rst studies to stratify ALL infants according to MLL status
conrmed on either Southern blot or split-signal uorescence in
situ hybridization (FISH). Use of these molecular methods for
the detection of MLL rearrangements is critical because 13/80
MLL-r ALL patients (16.2%) had no 11q23 abnormalities on
cytogenetic analysis with the G-banding technique, which would
have been missed otherwise. Given the poor outcome by che-
motherapy for MLL-r patients as historically observed, all the
infants with MLL-r ALL were assigned to receive allogeneic
HSCT in rst CR. Due to the frequent treatment failure (27/49
events) before HSCT, 5 year EFS and OS of the 80 infants with
MLL-r ALL remained at 38.6% and 50.8%, respectively.9 The
2015 Japan Pediatric Society
outcome of 22 infants with MLL-g ALL was excellent with
chemotherapy only, as previously described.8
In 2003, a new Japanese nationwide clinical study group for
childhood hematological malignancies, the JPLSG, was esta-
blished, as a result of the merging of the four existing study groups
in Japan (Tokyo Childrens Cancer Study Group [TCCSG], Japan
Association of Childhood Leukemia Study [JACLS], Kyushu
Yamaguchi Childrens Cancer Study Group [KYCCSG], and
Japanese Childhood Cancer and Leukemia Study Group
[CCLSG]). An encouraging result in the previous MLL98 study
for 3 year post-transplantation EFS (64.4%) in 29 infants with
MLL-r ALL transplanted at the rst CR prompted us to speculate
whether an intervention with more effective chemotherapy and
HSCT in an earlier phase could prevent early relapse and produce
a better outcome.6 Thus, the MLL03 study was conducted, which
recruited 62 eligible infants with MLL-r ALL between 2004 and
2009.10 In that study, pre-transplant chemotherapy was intensied
with high-dose Ara-C and all the patients at their rst CR were
assigned to receive HSCT within 4 months of initial induction. Be-
cause there are no differences in the outcome of HSCT for ALL in-
fants according to either donor source (cord blood vs unrelated
bone marrow [BM] vs related BM) or conditioning regimen
(myeloablative busulfan [BU] based vs myeloablative total body ir-
radiation [TBI] based), the donors were restricted to either human
leukocyte antigen 4/6 serologically matched unrelated cord blood
or human leukocyte antigen 5/6 matched related donor; condition-
ing was a non-TBI myeloablative regimen with BU (dose adjusted
according to individual PK test), etoposide and cyclophospha-
mide.9,40 The prophylaxis for graft-versus-host disease (GVHD)
was either cyclosporine or tacrolimus combined with short-term
MTX. As a result, 4 year EFS and OS were 43.2% and 67.2%,
respectively. The strategy of early HSCT effectively prevented
early relapse and was feasible for infants with MLL-r ALL,
given that 44/50 (88%) of those who achieved CR were able
to receive HSCT in rst CR. Modest improvement in the out-
come has been observed through the MLL96, MLL98, and
MLL03 studies (Fig. 2), but the fact that 18/44 (40%) of pa-
tients in MLL03 still relapsed despite receiving transplantation
in their rst CR indicates the limited anti-leukemic efcacy of
allogeneic HSCT for infants with MLL-r ALL.
Clinical trials in North America and Europe
Sanders et al. reported the outcome of allogeneic HSCT with TBI
conditioning for 40 infants with ALL (17 at rst CR, seven at sec-
ond or third CR, and 16 at relapse) at the Fred Hutchinson Cancer
Research Center between 1982 and 2003.41 Eleven of the 14 in-
fants with MLL-r ALL transplanted at rst CR survived. This re-
sult, however, should be interpreted with caution because many
of the patients were >6 months of age at diagnosis, and, if it were
present day, they would have been successfully treated with che-
motherapy without HSCT. In addition, analysis of HSCT outcome
should take into account the waiting time from diagnosis to trans-
plantation, especially for analyzing infants with MLL-r ALL be-
cause they tend to relapse at a very early stage. In fact, most of
the study reports that adjusted waiting time to HSCT found that

Fig. 2 Event-free survival (EFS) in infants with acute lymphoblastic
leukemia and mixed lineage leukemia (MLL) rearrangements registered
in the ( ) MLL96 (n = 42, 19951998), ( ) MLL98
(n = 38, 19982002), and ( ) MLL03 (n = 62, 20042009)
in Japan.
allogeneic HSCT had a negative impact on clinical benet in in-
fants with ALL. Pui et al. conducted a retrospective analysis of
497 ALL children (including 214 infants) and various 11q23 ab-
normalities from 11 study groups and single institutions between
1983 and 1995, and concluded that any type of HSCT was associ-
ated with signicantly worse DFS and OS compared with chemo-
therapy only in 256 patients with t(4;11) ALL.42 As for
prospective studies, combined results from North American stud-
ies, Childrens Cancer Group (CCG) 1953 and Pediatric Oncology
Group (POG) 9407, showed a 5 year EFS rate of 48.8% in infants
who received HSCT (n = 53) and 48.7% in infants who received
chemotherapy (n = 47; P = 0.60).43 In the following COG trials
for infant ALL, amended COG P9407 (20042006) and
AALL0631 (20082014, NCT00557193) trials eliminated the in-
dication of HSCT in rst CR. Finally, a report from the Interfant-
99 study compared 37 infants with MLL-r ALL who received
HSCT and 240 who received chemotherapy only, and noted bet-
ter DFS (60.1% vs 46.8%, P = 0.03) and OS (65.6% vs 48.6%,
P = 0.02) for the HSCT group. The advantage of HSCT, however,
was restricted to only the high-risk group, dened as MLL-r ALL
infants aged <6 months, and either WBC 300 109/L or poor
prednisolone response.36 In the current ongoing Interfant-06 study
(EudraCT No. 2005-004 599-19), HSCT is indicated only for high-
risk patients and medium-risk patients (other MLL-r ALL infants)
with MRD 10 4 after consolidation chemotherapy.
Problematic issues of HSCT
Recent progress in supportive therapy has resulted in substantial re-
duction of the non-relapse mortality (NRM) rate related to alloge-
neic HSCT for infants with ALL. According to the nationwide
registry of the Japan Society for Hematopoietic Cell Transplanta-
tion, overall NRM rate was 12.0% among 132 infants with
Treatment progress in infant ALL 815
MLL-r ALL who received allogeneic HSCT from 1996 to 2011;
the NRM rate of 5.6% for the recent period (20042011) was lower
than the 20.8% for the previous period (19962003).40 The causes
of overall non-relapse deaths in 15 cases were pulmonary compli-
cations (n = 6), infection (n = 5), GVHD (n = 3), and veno-
occlusive disease/sinusoidal obstruction syndrome (VOD/SOS;
n = 1). Given that BU-based myeloablative conditioning is widely
used as standard conditioning for transplantation in ALL infants,
one should be aware of pulmonary complications as well as hepatic
VOD/SOS. Kawashima et al. reported that infants with
BU-conditioning might be at risk of pulmonary VOD or pulmonary
hypertension, and the latter could be treated with sildenal and
beraprost.44 Although there was only one death due to VOD/SOS
in the Japanese HSCT registry data, the incidence of VOD/SOS
was 14% (6/44) in the JPLSG MLL03 trial.10 Therefore, in order,
at least, to reduce the risk of VOD/SOS, treosulphan, an alkylating
agent similar to BU but with lower risk of seizures, severe mucosi-
tis, and hepatotoxicity, might be an alternative to BU.45
In addition, late effects need to be borne in mind when treating
infants with HSCT, although little is known about them. The
Japanese MLL96 and MLL98 studies noted no severe late effects
for MLL-g patients who received chemotherapy only, but various
late complications such as chronic GVHD, hypothyroidism, skin
abnormalities, ophthalmologic complications, pulmonary compli-
cations, dental abnormalities, and neurocognitive problems were
observed in MLL-r patients who did receive allogeneic HSCT.9
The most frequently observed late effect was short stature, espe-
cially for those who received TBI conditioning, but ve of the 14
patients who received BU conditioning also had height SD score
< -2.0. A likely reason why little attention has been paid to late
effects in ALL infants is that their survival is poor. That said, as
the survival rate grows, issues such as pubertal problems should
be claried in order to improve quality of life.
Treatment for refractory or relapsed disease
Although we have encountered refractory or relapsed disease in
approximately 50% of MLL-r ALL infants, few reports have
focused on clinical course and outcome. A Japanese report on
39 refractory or relapsed patients from the MLL96 and MLL98
studies showed a 40.5% CR rate with various chemotherapy
regimens (ALL-oriented, AML-oriented, or ALL/AML hybrid)
and a 25.6% nal OS rate.46 Notably, OS was 21.4% even in
patients with a history of prior HSCT. Achievement of CR after
second-line treatment was the most signicant prognostic factor,
with a >50% chance of survival once CR was obtained.
Supportive care
Sufcient supportive care is an essential part of treating infants with
ALL, because infants are particularly vulnerable to intensive cyto-
toxic therapy. In particular, during the remission induction phase,
infants are at high risk of tumor lysis syndrome and intracranial
hemorrhage because of the very high tumor burden in MLL-r, to-
gether with a risk of mucositis, severe infection, and pulmonary
complications. In the Japanese MLL03 study, tumor lysis syn-
drome was observed in 40% of cases presumably because
rasburicase, a recombinant urate oxidase, was not available in
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Japan during the study period; the situation improved after authoriza-
tion of rasburicase in Japan in December 2009.10,47 In the COG
P9407 study, an unacceptably high rate of early death from bacterial,
fungal, and viral infections prompted the investigators to amend the
protocol by substituting dexamethasone with prednisolone, changing
the delivery of daunorubicin from 48 h continuous infusion to 30 min
infusion, and introducing an enhanced supportive care guideline.48
These amendments led to a signicant reduction in early mortality
rate from 13.7% to 3.5% (P = 0.036). Respiratory syncytial virus
(RSV) infection can cause serious lower respiratory complications
in infants, which may result in death. Palivizumab, a humanized
monoclonal antibody that targets RSV epitope, was approved for
use in Japan in August 2013 in young children (<2 years old) with
malignant disease who receive cytotoxic chemotherapy.49 Together
with universal vaccination for RSV, which is currently in develop-
ment, it is expected that RSV-induced pulmonary complications
could be effectively prevented in infants with ALL.
Novel therapies
Intensication of conventional cytotoxic chemotherapeutic drugs
with or without HSCT has enabled cure in approximately 50% of
the infants with ALL, but this is far from satisfactory and further
improvement in the outcome of this dismal disease is unlikely to
be achieved with this approach. Novel therapies are urgently re-
quired, especially for those with MLL rearrangements. New agents
with potential efcacy for infant ALL are listed in Table 2.
Clofarabine
Given that infant leukemia cells are sensitive to purine nucleoside
analogues such as Ara-C, a newly developed nucleoside analogue,
clofarabine, might be a good candidate for use in treating infants
with ALL.
FLT3 inhibitors
High expression of wild-type FLT3 is observed in 80% of the in-
fants with MLL-r ALL. In in vitro studies, high-level FLT3 expres-
sion in primary infant MLL-r ALL samples was associated with
activated FLT3 and cytotoxic responsiveness to FLT3 inhibi-
tors.5052 The role of several small-molecule FLT3 inhibitors has
been investigated in North America and Europe.
Epigenetic modiers
Currently, the most attractive class of agents for infant MLL-r ALL
is epigenetic modiers. Genome-wide methylation studies have
shown that MLL-r infant ALL cells are characterized by aberrant

Table 2 New agents under investigation for infant ALL

Class
Nucleoside analogues
Clofarabine
FLT3 inhibitors
Lestaurtinib (CEP-701)
Midostaurin (PKC412)
Quizartinib (AC220)
Epigenetic modiers
Demethylating agents
(Azacitidine, decitabine)
Histone deacetylase inhibitors
(Vorinostat, panobinostat)
DOT1L inhibitor (EPZ-5676)
BET protein inhibitors
(OTX-015)
Immunotherapy
CD19 BiTE (Blinatumomab)
CD19 CAR T-cells
(CART19 etc.)
Comments
Investigated within Total XVI study ongoing at SJCRH, a phase III study for pediatric ALL (NCT00549848).
Evaluating its role in early and delayed intensication in combination with cyclophosphamide
and etoposide for infant MLL-r ALL.
Phase III study, COG ALLL0631, for infant ALL (NCT00557193). Randomizing to receive or not to receive
lestaurtinib combined with conventional chemotherapy. Closed to accrual.
ITCC phase I/II study for children with R/R MLL-r ALL or FLT3 mutated AML (NCT00866281, EudraCT
No. 2008006 93111). Completed.
TACL phase I study in combination with Ara-C and etoposide for children with R/R MLL-r ALL or FLT3
mutated AML (NCT01411267, T2009-004). Completed.
TACL phase I study testing azacitidine followed by udarabine/Ara-C for children with R/R ALL or AML
(NCT01861002). Infants were not included. Completed.
Ongoing TACL pilot study testing decitabine and vorinostat with chemotherapy (vincristine, dexamethasone,
mitoxantrone, pegasparaginase, methotrexate) for relapsed ALL (NCT01483690). Infants not included.
Ongoing SJCRH phase II study, RELMLL, testing combination of vorinostat and bortezomib (proteasome
inhibitor) for R/R MLL-r hematologic malignancies (NCT02419755).
Ongoing TACL phase I study testing panobinostat in combination with Ara-C for children with refractory
hematological malignancies (NCT01321346, T2009-012). Infants not included.
Inhibition of the DOT1L histone methyltransferase for R/R MLL-r leukemia including AML with MLL-PTD.
Ongoing pediatric phase I study in North America (NCT02141828).
Inhibition of BET-proteins (e.g. BRD4) with BRD2/3/4 inhibitor (OTX015) may provide a new treatment
strategy in infant ALL. Evaluated in adult phase I trial for hematological malignancies (NCT01713582).
Phase I/II study testing BiTE antibodies targeting CD19 for children and adolescents with R/R B-precursor
ALL in North America and Europe (NCT01471782). Closed to accrual.
Infusion of autologous T cells transduced with CD19-directed chimeric antigen receptor lentiviral vector
for children and adolescents with R/R CD19 + ALL or lymphoma (NCT01626495). Infants not included.

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BET, bromodomain and extra-terminal; BiTE, bi-specic T-cell engager;
Ara-C, cytarabine; CAR, chimeric antigen receptor; FLT3, fms-related tyrosine kinase 3; ITCC, Innovative Therapy for Childhood Cancer;
MLL, mixed lineage leukemia; MLL-PTD, partial tandem duplication of MLL; MLL-r, rearranged MLL; R/R, relapsed or refractory; SJCRH,
St Jude Childrens Research Hospital; TACL, Therapeutic Advances in Childhood Leukemia Consortium.

2015 Japan Pediatric Society


methylated genomic state and respond well to demethylating agents,
leading to apoptosis in these cells.53,54 In addition, leukemia-
specic histone modications such as H3K79 dimethylation in-
duced via DOT1L recruitment by MLL fusion proteins can be effec-
tively modulated by histone deacetylase (HDAC) inhibitors.55
These ndings support the use of demethylating agents and/or
HDAC inhibitors that might reverse the inherent resistance to che-
motherapy for infant MLL-r ALL. A possible international collabo-
rative trial for infant ALL involving this strategy is in development
by the Interfant, COG, and JPLSG. Direct inhibition of DOT1L is
also currently being investigated in an early clinical trial.56,57
Immunotherapy
Another attractive approach, especially for relapsed/refractory
cases, is immunotherapy targeting CD19, a B-lymphocyte antigen
universally expressed in infant MLL-r ALL cells. Recently, a phase
I/II study evaluating CD19-targeting BiTE antibodies for children
and adolescents with relapsed/refractory ALL was closed to patient
accrual.58 Another CD19-targeting immunotherapy using CAR-
modied autologous T-cell therapy is also in development for
children and adolescents with relapsed/refractory CD19 + ALL or
lymphoma, and early reports have been encouraging.59
Conclusions and future directions
Infant ALL, especially that involving MLL rearrangements, is one
of the most difcult to cure among all the subtypes of childhood
acute leukemia. Efforts by clinical trial groups in Europe, North
America, and Japan to overcome this difcult disease with inten-
sive chemotherapy with or without HSCT has improved EFS to
40-50%. Further improvement will not be achieved without the de-
velopment of novel targeted therapies based on the unique biology
of the type of leukemia. Unfortunately, the extreme rarity of the dis-
ease is a major obstacle to drug development. Close, proactive col-
laboration between Interfant, COG, and JPLSG would be a key
solution to this issue.
Acknowledgments
The author acknowledges all the individuals who were involved in
infant ALL studies in Japan, especially Drs Eiichi Ishii (Department
of Pediatrics, Ehime University Graduate School of Medicine) and
Katsuyoshi Koh (Department of Hematology/Oncology, Saitama
Childrens Medical Center) for their strong leadership. Infant
ALL studies in Japan are supported by Grants for Clinical Cancer
Research and Grants-in-Aid for Cancer Research from the Ministry
of Health, Labour, and Welfare of Japan. The author also acknowl-
edges Dr Julian Tang of the Department of Education for Clinical
Research, National Center for Child Health and Development, for
critical comments and assistance with the manuscript. The author
declares that he has no conicts of interest.
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