VOLUME 33 䡠 NUMBER 27 䡠 SEPTEMBER 20 2015
JOURNAL OF CLINICAL ONCOLOGY
Author affiliations appear at the end of
this article.
Published online ahead of print at
www.jco.org on August 24, 2015.
Supported in part by Grants No.
CA21765, CA36401, U01 GM92666,
U10 CA98543 (to the Children’s Oncol-
ogy Group [COG] Chair), and U10
CA98413 (to the COG Statistical
Center) from the National Institutes of
Health; by the United Kingdom Medical
Research Council, Leukaemia and
Lymphoma Research and National
Cancer Research Institute (United King-
dom Childhood Acute Lymphoblastic
Leukemia trials); by a Stand Up to
Cancer Innovative Research Grant
(C.G.M.); by the Singapore VIVA Foun-
dation; and by the American Lebanese
Syrian Associated Charities. S.P.H. is
the Ergen Family Chair in Pediatric
Cancer, C.G.M. is a St Baldrick’s
Scholar and Pew Scholar in the
Biomedical Sciences, and C.-H.P. is an
American Cancer Society professor.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Ching-Hon Pui,
MD, St Jude Children’s Research
Hospital, 262 Danny Thomas Place,
Memphis, TN 38105; e-mail: ching-hon
.pui@stjude.org.
© 2015 by American Society of Clinical
Oncology
0732-183X/15/3327w-2938w/$20.00
DOI: 10.1200/JCO.2014.59.1636
2938 © 2015 by American Society of Clinical Oncology
R E V I E W A R T I C L E
Childhood Acute Lymphoblastic Leukemia: Progress
Through Collaboration
Ching-Hon Pui, Jun J. Yang, Stephen P. Hunger, Rob Pieters, Martin Schrappe, Andrea Biondi, Ajay Vora,
André Baruchel, Lewis B. Silverman, Kjeld Schmiegelow, Gabriele Escherich, Keizo Horibe, Yves C.M. Benoit,
Shai Izraeli, Allen Eng Juh Yeoh, Der-Cherng Liang, James R. Downing, William E. Evans, Mary V. Relling,
and Charles G. Mullighan
A B S T R A C T
Purpose
To review the impact of collaborative studies on advances in the biology and treatment of acute
lymphoblastic leukemia (ALL) in children and adolescents.
Methods
A review of English literature on childhood ALL focusing on collaborative studies was
performed. The resulting article was reviewed and revised by the committee chairs of the
major ALL study groups.
Results
With long-term survival rates for ALL approaching 90% and the advent of high-resolution
genome-wide analyses, several international study groups or consortia were established to
conduct collaborative research to further improve outcome. As a result, treatment strategies have
been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia
chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormal-
ities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug
resistance and toxicities have been identified to help develop targeted therapy. Several genetic
polymorphisms have been recognized that show susceptibility to developing ALL and that help
explain the racial/ethnic differences in the incidence of ALL.
Conclusion
The information gained from collaborative studies has helped decipher the heterogeneity of ALL
to help improve personalized treatment, which will further advance the current high cure rate and
the quality of life for children and adolescents with ALL.
J Clin Oncol 33:2938-2948. © 2015 by American Society of Clinical Oncology
resistant leukemia, and they require concerted
INTRODUCTION
efforts by multiple study groups to identify effec-
Remarkable progress has been made in the treat- tive treatment strategies. Parallel to the therapeu-
ment of childhood acute lymphoblastic leukemia tic gain have been the major advances in our
(ALL) in the past two decades, with the propor- knowledge of leukemic cell biology, especially
tion of patients surviving for 5 years approaching with the recent advent of genome-wide analysis.15
and even exceeding 90% in many developed Genome-wide studies to identify inherited and
countries (Table 1).1-14 Improved outcome can be somatically acquired genomic variations that in-
attributed to the optimal risk-directed therapy fluence disease incidence, treatment response, or
that incorporates delayed intensification with toxicities also require a large number of patients
vincristine, asparaginase, and dexamethasone; for discovery and validation studies and to adjust
high dose or escalating dose of methotrexate; and for the ancestral composition of study cohorts.
early use of intrathecal therapy. These treatment Indeed, many recent advances in genomics have
components were primarily established by the also been the results of national and, in many
randomized clinical trials performed by major co- instances, international collaborations. We high-
operative study groups. With the improved cure light here some of the major accomplishments
rates, current research efforts have focused in- resulting from these collaborations and point to
creasingly on small subsets of patients with drug- ongoing efforts for further advances.
 Childhood ALL: Progress Through Collaboration

Table 1. Patient Characteristics and Treatment Results From Selected Clinical Trials

5-Year Cumulative Rate

No. of Age Range T-Cell of Isolated CNS 5-Year EFS 5-Year Overall
Study Group Years of Study Patients (years) ALL (%) Relapse (% ⫾ SE) (% ⫾ SE) Survival (% ⫾ SE) Reference
AIEOP-95 1995-2000 1,743 0-18 11 1.2 ⫾ 0.3 75.9 ⫾ 1.0 85.5 ⫾ 0.8 Conter et al1
BFM-95 1995-1999 2,169 0-18 13 1.8 ⫾ 0.3 79.6 ⫾ 0.9 87.0 ⫾ 0.7 Möricke et al2
CoALL-97 1997-2003 667 1-18 14 4.0 ⫾ 0.8 76.7 ⫾ 1.7 85.4 ⫾ 1.4 Escherich et al3
COG 2000-2005 7,153 0-21 7 NA NA 90.4 ⫾ 0.5 Hunger et al4
DCOG-9 1997-2004 859 1-18 11 2.6 ⫾ 0.6 80.6 ⫾ 1.4 86.4 ⫾ 1.2 Veerman et al5
DFCI 00-01 2000-2004 492 1-18 11 NA 80.0 ⫾ 2 91 ⫾ 1 Vrooman et al6
EORTC-CLG 1998-2008 1,947 1-18 15.2 1.7 ⫾ 0.3 82.7 ⫾ 0.9 89.7 ⫾ 0.7 Domenech et al7
IC-BFM 2002 2002-2007 5,060 1-18 13.3 1.9 ⫾ 0.1 74 ⫾ 1 82 ⫾ 1 Stary et al8
JCCLSG ALL 2000 2000-2004 305 1-15 9.8 0.9 ⫾ 0.1 79.7 ⫾ 2.4 89.2 ⫾ 1.8 Yamaji et al9
Ma-Spore ALL 2003 2002-2011 556 0-18 8.8 1.4 80.6 ⫾ 3.5 89.2 ⫾ 2.7 Yeoh et al10
MRC UKALL 2003 2003-2011 3,126 1-25 12 1.9 ⫾ 0.6 87.3 ⫾ 1.4 91.6 ⫾ 1.2 Vora et al11
NOPHO-2000 2002-2007 1,023 1-15 11 2.7 ⫾ 0.6 79.4 ⫾ 1.5 89.1 ⫾ 1.1 Schmiegelow et al12
SJCRH XV 2000-2007 498 1-18 15 2.7 ⫾ 0.8 87.3 ⫾ 2.9 93.5 ⫾ 1.9 Pui et al13
TPOG 1999-2010 152 0-18 7.2 1.4 ⫾ 1.0 84.2 ⫾ 3.0 90.2 ⫾ 2.4 Liu et al14

Abbreviations: AIEOP, Associazione Italiana di Ematologia Pediatrica; ALL, acute lymphoblastic leukemia; BFM, Berlin-Frankfurt-Münster; CoALL, Cooperative ALL (study group);
COG, Children’s Oncology Group; DCOG, Dutch Children’s Oncology Group; DFCI, Dana-Farber Cancer Institute (consortium); EFS, event-free survival; EORTC-CLG, European
Organisation for Research and Treatment of Cancer-Children’s Leukemia Group; IC-BFM, Intercontinental BFM; JCCLSG, Japanese Children’s Cancer and Leukemia Study Group;
Ma-Spore, Malaysia-Singapore; MRC UKALL, Medical Research Council United Kingdom Acute Lymphoblastic Leukemia; NA, not available; NOPHO, Nordic Society of Pediatric
Hematology and Oncology; SJCRH, St Jude Children’s Research Hospital; TPOG, Taiwan Pediatric Oncology Group.

tional Study and Multicentre, Randomised Trial in Infants Younger

INTERNATIONAL COLLABORATIVE STUDY GROUPS
The Ponte di Legno group, named after the site of the first major
meeting, was formed in 1995,16 has since been joined by 15 major
study groups or institutions, and has held 14 working group meet-
ings.17 The participants agreed to use the same or similar criteria to
present the treatment outcome so that results could be compared
among various clinical trials to identify effective treatment strategies
for specific subsets of ALL. The first series of 12 articles on long-term
results of clinical trials was published in Leukemia in 2000, and the
second series of 15 articles was published in Leukemia in 2010.18 The
group also studied challenging subsets of ALL, the key findings of
which are described in this review.
Under the leadership of Haig Riehm and Giuseppe Masera, the
Berlin-Frankfurt-Münster (BFM) and the Associazione Italiana di
Ematologia Pediatrica (AIEOP) study groups set an early example of
fruitful international collaboration. Among their many collaborative
studies, the two groups recently confirmed that minimal residual
disease (MRD) assessment is the most prognostic indicator in both B-
and T-cell ALL.19,20 They were also instrumental in developing the
Intercontinental BFM (IC-BFM) Study Group comprising study
groups from more than 30 countries worldwide to address therapeutic
questions tailored to their resources and technology. The IC-BFM
2002 (A Randomized Trial of the I-BFM-SG for Management of
Childhood Non-B Acute Lymphoblastic Leukemia) study, which en-
rolled 5,060 patients between 2002 and 2007 showed no significant
improvement in outcome with intensive or prolonged delayed-
intensification therapy, and it achieved a 5-year event-free survival of
74% and 5-year overall survival of 82%.8 Although the overall results
were inferior to those of contemporaneous BFM studies because of the
high rate of treatment-related mortality, the national results have
generally improved and, importantly, this network demonstrated
their ability to perform randomized clinical trials across continents.
Because of the rarity and distinct characteristics of infant ALL, 17
study groups collaborated on a clinical trial, Interfant-99 (Observa-
Than 1 Year With Acute Lymphoblastic Leukaemia), which enrolled
482 infants age 0 to 12 months between 1999 and 2005 to investigate
the efficacy of a hybrid treatment regimen with elements for treating
both ALL and acute myeloid leukemia.21 The study achieved a 4-year
event-free survival of 47.0% and overall survival of 55.3%, outcomes
better than those achieved with most previous protocols but showing
no benefit from delayed-intensification therapy with high-dose cytar-
abine and methotrexate. The current study, Interfant-06 (NCT00550992:
International Collaborative Treatment Protocol for Infants Under One
Year With Acute Lymphoblastic or Biphenotypic Leukemia), assesses
early intensification with two blocks of acute myeloid leukemia induction
therapy to improve outcome and examines the role of hematopoietic
stem-celltransplantationininfantsathighriskofrelapse(age⬍6months,
MLL rearrangement, and initial leukocyte count ⱖ 300 ⫻ 109/L).22
To identify treatment components responsible for improved
treatment outcome, the Childhood ALL Collaborative Group was
formed in 1994 to systematically review and analyze results from
relevant randomized trials. Analysis of data from four clinical trials
that enrolled patients between 1972 and 1984 showed that anthracy-
clines reduced hematologic relapse but failed to improve event-free
survival, partly because of the increased induction failures and deaths
in remission.23 Meta-analysis of trials started between 1965 and 1998
showed that the addition of vincristine plus prednisone or pred-
nisolone pulses during postremission therapy improved event-free
survival; the lack of improvement with vincristine and dexamethasone
pulses in the more recent trials was attributed to the greater intensity of
the early therapy.24 Meta-analysis of three trials that enrolled patients
between 1992 and 2002 suggested that thioguanine improved event-
free survival compared with mercaptopurine for males younger than
age 10 years, but its lack of effect on survival and association with a
high risk of veno-occlusive disease of the liver made mercaptopurine
the standard thiopurine of choice.25 Meta-analysis of 47 trials of CNS-
directed therapy conducted between 1970 and 1999 showed that
CNS radiotherapy can generally be replaced by intrathecal therapy,

www.jco.org © 2015 by American Society of Clinical Oncology 2939

 Pui et al

and triple intrathecal therapy should be used with effective sys-
temic therapy such as intravenous high-dose methotrexate to real-
ize its full benefit of CNS control without the hazard of increased
systemic relapse.26
Several working groups investigated the optimal use of asparagi-
nase. In one review, intensive use of asparaginase during the intensifi-
cation phase of therapy was credited for improved outcome.27 Two
studies showed improved outcome with therapeutic drug monitoring
during Escherichia coli asparaginase treatment; detection of silent in-
activation of the drug as a result of asparaginase antibody allowed for
early replacement with Erwinia asparaginase.6,28
CLINICAL ADVANCES IN SPECIFIC SUBTYPES OF ALL
Table 2 summarizes the findings of a few selected collaborative studies
that have had a major impact on clinical management.
ALL With 11q23 Rearrangement
There is apparent clinical heterogeneity within each of the subtypes
of rearrangement of MLL at 11q23. In a study of 497 patients with 11q23
rearrangements diagnosed between 1983 and 1995, infants younger than
1 year fared significantly worse than older patients, and any category of
11q23 abnormality conferred a dismal prognosis among infants,29 a find-
ing confirmed by the Interfant-99 study.21 In the largest subgroup of
infants and children with t(4;11)(q21;q23), any type of transplantation,
evenwithamatched-relateddonor,failedtoimproveoutcomecompared
with chemotherapy alone.29 A separate analysis of the same cohort
showed that among patients with t(4;11)(q21;q23), infants fared signifi-
cantly worse than older patients.30 The Interfant-99 study showed that
young age and MLL rearrangement independently predicted poor
outcome in infant ALL.21 Importantly, hematopoietic stem-cell
transplantation failed to improve the outcome of infants with MLL
rearrangement in the Interfant-99 study, with the exception of a
small subset of infants younger than age 6 months with either poor
response to steroids or presenting leukocyte count ⱖ 300 ⫻ 109/L
who seemed to benefit from transplantation.22
Hypodiploid ALL
The clinical and biologic characteristics of hypodiploid ALL have
been poorly defined. In a study of 139 hypodiploid patients diagnosed
between 1986 and 1996, even after excluding nine patients with Phil-
adelphia chromosome (Ph), the remaining 130 patients still had a
poor outcome with an event-free survival of 38.3% at 8 years; inter-
estingly, there were no induction failures, but information on the level

Table 2. Clinical Research Findings From Selected Collaborative Studies

No. of
Subgroup of Years Study No. of
ALL of Study Groups Patients Major Findings Reference
11q23 1983-1995 11 497 Prognosis was particularly dismal in infants; allogeneic transplantation did not Pui et al29,30
rearranged improve outcome in patients with t(4;11) ALL. Poor early response to
prednisone or age younger than 3 months conferred a particularly dismal
prognosis among infants with t(4;11).
Hypodiploid 1986-1996 11 139 Prognosis was very poor, especially among patients with fewer than 44 Nachman et al31
chromosomes.
Hypodiploid 2008-2013 2 126 Genome profiling and sequencing identifies distinct genetic alterations in Holmfeldt et al41
subtypes of hypodiploid ALL. Near-haploid patients have Ras pathway
mutations and IKZF3 mutations; low-hypodiploid patients have IKZF2
alterations and TP53 mutations, many of which are inherited.
Ph positive 1986-1996 10 326 Presenting age, leukocyte counts, and response to initial treatment with Aricò et al32
glucocorticoids and intrathecal methotrexate affected treatment outcome;
matched-related transplantation improved outcome.
Ph positive 1995-2005 10 610 Both matched-related and matched-unrelated transplantation improved Aricò et al33
treatment outcome.
Ph positive 2004-2009 10 178 Imatinib combined with intensive chemotherapy was well tolerated and might Biondi et al34
improve outcome.
Ph-like 2008-2009 2 221 Genetic alteration of IKZF1 was associated with high levels of minimal residual Mullighan et al35
disease and a very poor outcome.
Ph-like 2008-2009 2 297 These cases were associated with a high frequency of deletions in genes Den Boer et al36
involved in B-cell development, resistance to asparaginase and daunorubicin,
and unfavorable outcome.
Ph-like 2014 5 264 More than 90% of the patients had kinase-activating alterations, some of Roberts et al37
which were amenable to inhibition with tyrosine kinase inhibitors such as
imatinib or dasatinib.
Early T-cell 1992-2006 2 30 These patients had distinctive immunophenotype (CD1a⫺, CD8⫺, or CD5weak Coustan-Smith et al38
precursor with stem-cell or myeloid markers) and high risk of remission induction
failure or hematologic relapse.
Down syndrome 1995-2004 16 653 Compared with other patients, these patients have lower event-free survival as Buitenkamp et al39
a result of increased relapse hazard and treatment-related mortality. Younger
age and leukocyte count ⬍ 10 ⫻ 109/L at diagnosis and the presence of
high hyperdiploidy and ETV6-RUNX1 are favorable prognostic factors.
Induction failure 1985-2000 14 1,041 Patients with induction failure are highly heterogeneous. Although allogeneic Schrappe et al40
transplantation improved outcome for T-cell ALL, chemotherapy should be
the treatment of choice for B-ALL without other adverse features.

Abbreviations: ALL, acute lymphoblastic leukemia; Ph, Philadelphia chromosome.

2940 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Childhood ALL: Progress Through Collaboration
of MRD was not available.31 There were no significant differences in
outcome among patients with near haploidy (24 to 29 chromosomes),
low hypodiploidy (33 to 39 chromosomes), or high hypodiploidy (40
to 43 chromosomes).31 Patients with fewer than 44 chromosomes
fared significantly worse than patients with 44 chromosomes, among
whom those with monosomy 7, a dicentric chromosome, or both had
a significantly worse event-free survival. There was no difference in
outcome between patients with or without doubling of their hypodip-
loid clone. The efficacy of hematopoietic stem-cell transplantation
could not be adequately evaluated because only nine patients under-
went this procedure.
Ph-Positive ALL
Before the development of ABL tyrosine kinase inhibitors, there
was no consensus on the optimal treatment of Ph-positive ALL. A
combined study of 326 children and young adults diagnosed between
1985 and 1996 disclosed a 5-year event-free survival (⫾ SE) of only
28% ⫾ 3% and that older age, high initial leukocyte count, and poor
response to initial treatment with glucocorticoids and intrathecal
methotrexate adversely affected treatment outcome.32 Compared
with chemotherapy alone, matched-related transplantation improved
outcome.32 A follow-up study of 610 patients diagnosed between 1995
and 2005 and treated without tyrosine kinase inhibitor showed that
the event-free survival had improved to 32% ⫾ 2% at 7 years, and both
matched-related and matched-unrelated transplantation improved
outcome compared with chemotherapy alone.33 The results of this
study served as a historical reference to the subsequent Children’s
Oncology Group (COG) and European intergroup studies, showing
that postinduction imatinib mesylate plus intensive chemotherapy
improved disease-free survival to 70% ⫾ 12% at 5 years and could
spare patients with good initial response to remission induction from
transplantation.34,42 Whether dasatinib, a potent ABL tyrosine kinase
inhibitor,43 given in conjunction with a BFM high-risk chemotherapy
backbone can result in noninferior or improved outcome while reduc-
ing the need for transplantation is being evaluated in a multicenter
study (NCT01460160: A Phase 2 Multi-Center, Historically Con-
trolled Study of Dasatinib Added to Standard Chemotherapy in Pedi-
atric Patients With Newly Diagnosed Philadelphia Chromosome
Positive Acute Lymphoblastic Leukemia).
Ph-Like (BCR-ABL1–like) ALL
By using single nucleotide polymorphism microarrays, tran-
scriptional profiling, and gene resequencing, two group studies inde-
pendently identified a novel high-risk subtype of B-ALL that exhibits a
gene expression profile similar to that of Ph-positive ALL with a high
frequency of alterations of the IKZF1 gene but lacks the BCR-ABL1
fusion protein.35,36 These patients were characterized by resistance
to asparaginase and daunorubicin, a high level of MRD at the end
of induction, and overall poor outcome.35,36 The BCR-ABL1–like
expression profile and IKZF1 deletions had independent poor
prognostic impact in a European collaborative study.44 Although
risk-directed therapy, including intensive chemotherapy and allo-
geneic transplantation, could abolish the adverse prognostic signif-
icance of this genotype,45 a recent large collaborative study showed
that a substantial proportion of patients have genomic alterations
that are amenable to inhibition with ABL tyrosine kinase inhibitors
and potentially JAK inhibitors, which may spare some patients
from transplantation.37
www.jco.org
Early T-Cell Precursor ALL
On the basis of gene expression profiling and flow cytometry, a
collaborative study identified a distinct group of patients who repre-
sent approximately 12% of T-cell ALL with leukemia originating from
a subset of thymocytes that retain a stem-cell–like feature.38 Although
the initial report showed that these patients had a high risk of remis-
sion induction failure or hematologic relapse,38 a recent study showed
that they have intermediate-risk outcome (5-year event-free survival
of 76.7%) when treated with intensive chemotherapy, including dexa-
methasone and pegylated asparaginase.46
Down Syndrome ALL
Patients with Down syndrome who have ALL have inferior sur-
vival because of increased risk of relapse and treatment-related mor-
tality. The specific treatment phase responsible for increased death
related to toxicity and the prognostic factors among these patients
were not well characterized in previous small studies. In a large collab-
orative study, these patients were found to have increased risk of
relapse, which tended to occur late, and to have increased treatment-
related mortality throughout treatment, which resulted in lower
event-free survival and overall survival but lower incidence of second-
ary malignancies compared with other children with ALL.39 Indepen-
dent favorable prognostic factors included age younger than 6 years,
leukocyte count less than 10 ⫻ 109/L, high hyperdiploidy, and ETV6-
RUNX1 fusion. The lower rates of high hyperdiploidy (9% v 33%) and
ETV6-RUNX1 fusion (8% v 26%) than that found in other children
may contribute partly to the increased risk of relapse in patients with
Down syndrome. The low rates of relapse among patients with Down
syndrome with ETV6-RUNX1 fusion (3%) and especially those with
high hyperdiploidy and trisomies 4 and 10 (0%) suggested that treat-
ment reduction may be warranted for these subgroups of patients.39
However, one study suggested that insufficient treatment intensity
during maintenance therapy (based on median WBC count) could
contribute to poor prognosis of patients with Down syndrome.47 A
Dutch Children’s Oncology Group (DCOG) study showed that the
IKZF1 deletion, which occurred in one third of patients with Down
syndrome, was a strong adverse prognostic factor.48 Because up to
60% of patients with Down syndrome are Ph-like and are character-
ized by CRLF2 overexpression and JAK-STAT activation, they may
potentially benefit from future therapy targeting kinase pathways.49,50
ALL With Induction Failure
Because induction failure occurs in only 2% to 3% of all patients,
little was known about the heterogeneity among this group of patients
who were generally offered allogeneic transplantation as the treatment
of choice. In a large collaborative study, these patients, as expected,
were associated with older age, high leukocyte count, T-cell pheno-
type, Ph-positive ALL, and 11q23 chromosomal rearrangement.40
Interestingly, although patients with T-cell ALL had improved out-
come with matched-related transplantation, children younger than 6
years with B-ALL and no other adverse genetic features had an excel-
lent 10-year survival of 72% ⫾ 5% when treated with chemotherapy
alone. The relatively favorable outcome of these patients with B-ALL
may be the result of increased sensitivity of the blast cells to metho-
trexate and mercaptopurine, which are generally not used during
remission induction. Thus, this rare subset of patients with B-ALL
who readily achieve remission with subsequent consolidation therapy
© 2015 by American Society of Clinical Oncology 2941

with high-dose methotrexate and oral mercaptopurine could be
spared from transplantation.
BIOLOGIC ADVANCES
Next-Generation Sequencing Studies
Genome-wide studies have revolutionized our understanding
of the genetic basis of ALL.51 These studies, using microarray
profiling of DNA copy number alterations and gene expression,
candidate gene sequencing and, more recently, second-generation
sequencing (exome, transcriptome, and/or whole-genome se-
quencing), have resulted in three major advances: (1) revision of
the genetic subclassification of ALL by identifying new subtypes,
notably Ph-like, CRLF2-rearranged, ERG-deregulated, intrachro-
mosomal amplification of chromosome 21 (iAMP21), and early
T-cell precursor ALL (Fig 1); (2) definition of the constellations of
gross and submicroscopic structural genetic alterations and se-
quence mutations that characterize each ALL subtype; and (3)
identification of genomic aberrations or profiles with diagnostic or
prognostic implication (eg, IKZF1 alterations)35 or as targets for
therapy (eg, kinase-activating alterations).37,45,52-54 Importantly,
these studies have enabled comprehensive genomic characteriza-
tion of the three high-risk subtypes as described in this section.
IKZF1 alterations in high-risk B-ALL and Ph-like ALL. In 2009,
two groups of investigators using a different gene expression profiling
approach identified a subtype of high-risk B ALL that lacked a known
chromosomal rearrangement but exhibited a gene expression profile
similar to that of Ph-positive ALL with deletions and, less commonly,
sequence mutations of IKZF1.35,36 A recent study of this entity of
Ph-like or BCR-ABL1–like ALL showed that the prevalence increases
from 10% of standard-risk childhood ALL to more than one quarter
of young adult (age 21 to 39 years) ALL.37 The genetic basis of Ph-like
ALL is complex, including more than 30 rearrangements involving 13
kinase, cytokine, or cytokine-receptor genes,37 but several key sub-
groups with therapeutic implications have been identified: (1) ABL-
class rearrangements targeting ABL1, ABL2, CSF1R, and PDGFRB,
which are sensitive to imatinib and dasatinib; (2) EPOR and JAK2
rearrangements sensitive to JAK inhibitors; (3) CRLF2 rearrange-
ments, frequently with concomitant activating JAK point mutations
that may also be sensitive to JAK inhibition; (4) other JAK-STAT-
A T-ALL ETP
1.2%
12.6%
Hyperdiploid
28.2%
B-other
16.0%
CRLF2 (not Ph-like)
1.7%
MLL
1.4%
BCR-ABL1
1.7% Hypodiploid
2.6% ERG
3.1% TCF3-PBX1 Ph-like
8.8%
4.1%
Fig 1. Estimated frequency of specific genotypes of childhood acute lymphoblastic leukemia (ALL) among patients treated in the St Jude Total Therapy Study XV.13
Genetic abnormalities among (A) all but black patients and (B) black patients who are more likely to have TCF3-PBX1 fusion and T-cell ALL (including early T-cell
precursor [ETP] ALL) but less likely to have hyperdiploidy. Ph, Philadelphia chromosome.
2942 © 2015 by American Society of Clinical Oncology
Pui et al
activating mutations and deletions, including those involving IL7R,
FLT3, SH2B3, and others; and (5) infrequent targets of rearrangement
including NTRK3 and others. Patients with Ph-like ALL commonly
exhibit high-risk features and have a suboptimal response to ther-
apy,36,37,45 and anecdotal reports are emerging of profound and lasting
response to the addition of tyrosine kinase inhibitors to patients with
Ph-like ALL with ABL1-class rearrangements.55,56 These findings have
led to prospective studies to identify Ph-like ALL (by low-density gene
expression arrays and/or sequencing) and the underlying rearrange-
ments and to direct patients to logical kinase inhibitor therapy.
Early T-cell precursor ALL. By St Jude criteria, early T-cell pre-
cursor (ETP) ALL is defined as a T-cell (cytoplasmic CD3⫹) leukemia
that lacks expression of markers otherwise observed in T-cell ALL
(CD1a, CD8, and weak and/or absent CD5) and has aberrant expres-
sion of myeloid or stem-cell markers.38 ETP ALL lacks a unifying
chromosomal alteration,38 has a low frequency of genetic alterations
otherwise common in T-ALL (eg, NOTCH1 mutations), and is
associated with MEF2C abnormalities in one European study.57
One collaborative study of ETP ALL with whole-genome se-
quencing identified frequent mutations in three pathways: hemato-
poietic development (eg, GATA3, IKZF1, RUNX1), cytokine receptor
and Ras signaling (eg, IL7R, NRAS, KRAS), and chromatin modifica-
tion (eg, the polycomb repressor complex 2 and SETD2).58 Moreover,
human ETP ALL cells58 and a mouse model of Il7r-mutant ETP ALL59
exhibit JAK-STAT activation that is inhibited by the JAK inhibitor
ruxolitinib. These findings raise the prospect of targeted or pathway-
directed therapies, such as JAK inhibitors or epigenetic modifiers, to
improve the outcome of ETP ALL.
Hypodiploid ALL. Until recently, the genetic basis for this high-
risk hypodiploid ALL subtype has been poorly understood. A collab-
orative study of 126 patients with hypodiploid ALL identified distinct
submicroscopic alterations in each subtype.41 Patients with the near-
haploid subtype had a high frequency of activating Ras pathway mu-
tations (particularly novel deletions in NF1) and IKZF3 (Aiolos)
alterations, and patients with low-hypodiploid IKZF2 (Helios) muta-
tions. A remarkable finding was the near universal presence of TP53
mutations in low-hypodiploid ALL, which were in nontumor cells in
more than half of patients and were shown to be inherited in a kindred
with other non-ALL tumors. Both near-haploid and low-hypodiploid
leukemic cells had activation of the PI3K and Ras-Raf-MEK-ERK
B ETP Hyperdiploid
T-ALL 6.3% 11.4%
12.7%
ETV6-RUNX1
21.5%
B-other
20.3% Ph-like
ETV6-RUNX1 3.8%
18.6%
CRLF2 (non-Ph-like)
1.3% MLL TCF3-PBX1
3.8% BCR-ABL1 ERG
13.9%
3.8% 1.3%
JOURNAL OF CLINICAL ONCOLOGY
 Childhood ALL: Progress Through Collaboration

signaling pathways, with sensitivity to PI3K/mTOR inhibitors, but not
MEK inhibitors. These findings have important clinical implications:
patients with low-hypodiploid ALL should be tested for TP53 status to
enable appropriate surveillance and counseling, and preclinical stud-
ies are evaluating the potential for PI3K and MEK inhibitors alone and
in combination for hypodiploid ALL.
Inherited Genetic Determinants of Leukemogenesis
Children with certain constitutional genetic abnormalities (eg,
trisomy 21) are at increased risk of developing ALL, and inherited
mutations in TP53 and PAX5 have also been described recently in
familial (as well as sporadic) ALL.41,60 However, the vast majority of
childhood ALL occurences are not explained by these predisposing
genetic abnormalities; instead, disease susceptibility is mainly influ-
enced by common genetic variants. Recent advances in genome-wide
association studies (GWASs) substantially improved our understand-
ing of genetic susceptibility to the development of childhood ALL.
Because GWASs compare single nucleotide polymorphism genotypes
across the whole genome between patients with ALL and non-ALL
controls, hundreds or thousands of participants are required to obtain
robust results and to identify associations with ALL subtypes. Because
of the relatively rarity of childhood ALL, collaborative efforts are
almost always needed for these studies. In 2009, two independent
studies described ARID5B and IKZF1 as loci having the strongest
association with the risk of developing ALL.61,62 A subsequent collab-
orative study using meta-analysis identified yet another susceptibility
locus at the CDKN2A/CDKN2B locus.63 A recent GWAS by St Jude

Table 3. Genome-Wide Association of Studies of Susceptibility of Childhood ALL

Study Group and Location Study Population Sample Size Susceptibility Loci OR 95% CI Comment Reference
COG, SJCRH Europeans 441 ARID5B (rs10821936) 1.91 1.6 to 2.2 ARID5B SNP discriminated Treviño et al61
IKZF1 (rs11978267) 1.69 1.4 to 1.9 hyperdiploid ALL from
other subtypes of ALL
and was associated with
accumulation of
methotrexate
polyglutamates.
UKCCS, MRC Europeans 907 ARID5B (rs7089424) 1.65 1.5 to 1.7 ARID5B variant was over- Papaemmanuil
IKZF1 (rs4132601) 1.69 1.5 to 1.8 represented in et al62
hyperdiploid ALL.
CEBPE (rs2239633) 1.34 1.2 to 1.4
UK, BFM, Spain, Hungary, Europeans and European 3,293 ARID5B CDKN2A encoded both p16 Sherborne
Canada Canadians IKZF1 and p14 and was et al63
associated with the
CEBPE
development of both B-
CDKN2A (rs3731217) 0.71 0.6 to 07 and T-ALL.
COG, SJCRH European Americans, African 2,450 ARID5B (rs10821936) 1.86 1.7 to 2.0 ARID5B, BMI1-PIP4K2A, Xu et al64
Americans, Hispanic IKZF1 (rs11978267) 1.59 1.4 to 1.7 and IKZF1 associations
Americans were consistent across
CEBPE (rs4982731) 1.36 1.2 to 1.4
ethnicity, and the
CDKN2A 1.36 1.1 to 1.5 frequencies of the
(rs17756311) ARID5B and BMI1-
PIP4K2A (rs7088318) 1.40 1.2 to 1.5 PIP4K2A variants differed
BMI1 (rs4748793) 1.40 1.2 to 1.5 in parallel with the ethnic
differences in ALL
incidence. These variants
independently and
cumulatively contribute
to ALL risk.
AIEOP, BFM, CoALL Europeans 1,370 TP63 (rs17505102) 0.63 0.5 to 0.7 In addition to IKZF1, DDC, Ellinghaus et
PTPRJ (rs3942852) 0.77 0.6 to 0.8 ARID5B, and CEBPE, al66
variants in TP63 (a
member of the TP53
gene family) and PTPRJ
(a receptor type protein
tyrosine phosphatase)
were associated with
ETV6-RUNX1 ALL.
COG, SJCRH Americans of different 682 GATA3 (rs3824662) 3.85 2.7 to 5.4 GATA3 was associated with Perez-Andreu
ancestry Ph-like ALL and risk of et al67
ALL relapse.
UKCCS, MRC UKALL, Europeans 3,107 ARID5B GATA3 influenced ALL risk Migliorini et
BFM IKZF1 and was associated with al65
worse prognosis.
CEBPE
CDKN2A
PIP4K2A (rs10828317) 1.23 1.1 to 1.3
GATA3 (rs3824662) 1.31 1.2 to 1.4

Abbreviations: AIEOP, Associazione Italiana di Ematologia Pediatrica; ALL, acute lymphoblastic leukemia; BFM, Berlin-Frankfurt-Münster; CoALL, Cooperative ALL
(study group); COG, Children’s Oncology Group; MRC, Medical Research Council; OR, odds ratio; Ph, Philadelphia chromosome; SJCRH, St Jude Children’s
Research Hospital; SNP, single nucleotide polymorphism; UK, United Kingdom; UKALL, United Kingdom Acute Lymphoblastic Leukemia (study group); UKCCS,
United Kingdom Childhood Cancer Study.

www.jco.org © 2015 by American Society of Clinical Oncology 2943

 Pui et al

and the COG discovered novel ALL risk variants at the PIP4K2A-
BMI1 locus and, for the first time, focused on multiethnic popula-
tions.64 The inclusion of non-European patients in this study not only
improved the statistical power of detecting association signals at the
PIP4K2A variants but also revealed striking differences in the preva-
lence of these genetic risk variants among groups with different ances-
tries and their contribution to racial and ethnic differences in the
incidence of ALL. Notably, several germline susceptibility loci are
targeted by somatic genomic alterations in ALL blasts (IKZF1,
CDKN2A/CDKN2B),68 suggesting that inherited and acquired genetic
variations should be regarded as a continuum in the development of
childhood ALL.
GWASs of susceptibility to specific ALL subtypes have received
increasing attention. In 2012, a collaborative study reported that vari-
ants in the TP63 and PTPRJ genes were associated with the acquisition
of the ETV6-RUNX1 fusion.66 More recently, inherited variants in the
GATA3 gene were associated with the development of Ph-like ALL
and also the increased risk of relapse in two separate studies,65,67
illustrating interactions between genetic variations in the host and
those in the cancer cells and their unique contributions to pathogen-
esis and treatment outcomes of ALL.
GWASs have been successful in unequivocally establishing an
inherited genetic basis for ALL susceptibility with seven risk loci
discovered thus far (Table 3). Future studies will require even more
extensive intergroup collaborations to characterize the role of
germline genetic variations in uncommon ALL phenotypes and to
characterize the combined effects of multiple variants acting
within the same pathway.69
Genomic Determinants of Drug Resistance
Pharmacokinetic, pharmacodynamic, and pharmacogenomic
studies have shown important determinants of interpatient differ-
ences in treatment response that can affect clinical outcome. Recent
technologies for interrogating inherited and acquired genome varia-
tion have accelerated the discovery of genomic determinants of de
novo drug resistance. Initially, by using genome-wide gene expression
arrays, the expression (mRNA) of a relatively small number of genes in
leukemia cells was linked to de novo sensitivity of glucocorticoids,
vincristine, daunorubicin, and L-asparaginase,70 multidrug cross-
resistance,71 in vivo response to initial treatment with high-dose meth-
otrexate,72 and inherited genome variants related to response to
remission induction therapy.73 Indeed, both germline and somatic
genome variation can influence the effects of ALL chemotherapy,74-78
which emphasizes the importance of assessing both inherited and
somatic genome variation in cancer pharmacogenomics. Further-
more, genome-wide mRNA expression analyses have identified ge-
nome variation that influences the accumulation of the active
polyglutamylated metabolites of methotrexate in ALL cells after in
vivo methotrexate treatment.79,80 These studies and others have pro-
vided mechanistic insights into the need for different dosages of meth-
otrexate in certain ALL subtypes (eg, higher dosage in T-ALL) and
have revealed drug-specific differences in genomic determinants of de
novo drug resistance in childhood ALL. These findings also hold
promise for developing strategies to mitigate drug resistance by target-
ing proteins whose overexpression or enhanced function leads to
resistance to conventional antileukemic agents. Ongoing genome-
wide interrogation of germline and somatic DNA variation (genetic
and epigenetic) should lead to greater insights into the mechanism of
drug resistance and yield new treatment strategies to further enhance
the effectiveness of ALL treatment.
Genomic Determinants of Drug Toxicities
Many serious toxicities of ALL therapy are relatively uncommon,
and they vary substantially in prevalence by treatment regimen. Al-
though genome-wide approaches have shown tremendous potential
for uncovering novel mechanisms and new risk factors of drug toxic-
ities, large sample sizes from collaborations are necessary to have
adequate power to uncover underlying genomic determinants with
hazard ratios on the order of 1.5-fold to three-fold. Indeed, collabora-
tions have already identified inherited genomic variation associated with
asparaginase allergy81 and with high-dose methotrexate clearance and
toxicity (Table 4).75,82 Other examples of inherited genomic variation that
contribute to ALL toxicity phenotypes include the association of TPMT
variants83-87 and an NUDT15 variant88 with thiopurine-induced myelo-
suppression; CEP72 polymorphism with vincristine-related peripheral
neuropathy89; CRHR1 polymorphisms and steroid-induced low bone
density, which was replicated in a pediatric asthma population90;
several genes associated with osteonecrosis91,92; and methotrexate-
induced leukoencephalopathy.93

Table 4. Selected Examples of Genomic Determinants of Drug Toxicities Involving Multiple Collaborative Study Groups

Drug Gene Name Comments Reference

Asparaginase HLA-DRB1ⴱ07:01 HLA-DRB1ⴱ07:01-encoded protein is associated with the development of anti- Fernandez et al81
asparaginase antibody and a high frequency of asparaginase hypersensitivity,
probably through its high binding affinity for asparaginase epitopes.
Methotrexate SLCO1B1 Methotrexate clearance is associated with polymorphisms of SLCO1B1 which Treviño et al,75 Ramsey et al,77 Ramsey
encode a hepatic solute carrier organic anion transporter that mediates et al82
disposition of many medications, including methotrexate.
Mercaptopurine, TPMT Genetic polymorphisms in TPMT (thiopurine S-methyltransferase) are known to Ramsey et al,82 Lennard et al,83 Stanulla
thioguanine have a marked effect on mercaptopurine metabolism and myelosuppressive et al,84 Schmiegelow et al,85 Relling
toxicity. et al,86 Evans et al87
NUDT15 A polymorphism of NUDT15 is associated with mercaptopurine intolerance and Yang et al88
is most common in East Asians and Hispanics.
Vincristine CEP72 A polymorphism of CEP72 reduces expression of its encoded centrosomal Diouf et al89
protein 72 kD, which functions as the major microtubule-organizing center,
regulates proper bipolar spindle formation, and is associated with an
increased risk of vincristine-induced neuropathy.

2944 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Childhood ALL: Progress Through Collaboration

The underlying genomic risk factors for some adverse effects are
likely to differ by treatment regimen. For example, asparaginase may
potentiate the osteonecrosis risk of glucocorticoids, partly via effects
on lipid homeostasis94 and partly by affecting glucocorticoid disposi-
tion.95 Dosage may also play a critical role: for example, anthracycline-
induced cardiomyopathy is related to inherited variants in HAS3, but
only in patients who received higher cumulative doses of anthracy-
cline.96 By contrast, genetic risk factors for vincristine neuropathy are
apparent only at lower doses of the drug, because at higher doses,
almost all patients are at risk for the adverse effect.89
CONCLUSIONS AND FUTURE DIRECTIONS
Collaborative group studies have refined the molecular classification
of ALL and have substantially improved strategies for personalized
treatment by identifying new targets for therapeutic intervention.
These collaborative studies should continue to address many unre-
solved issues and questions. Next-generation sequencing studies to
analyze the genome, transcriptome, and epigenome of patients will
comprehensively identify all genetic variations contributing to leuke-
mogenesis and treatment outcome; interpreting the complex protein-
protein and pathway interactions will be the challenge. Detailed
analysis of germline genetic variations will unravel the role of inherited
polymorphisms in leukemia susceptibility and the acquisition of so-
matic genetic abnormalities. Experimental models will be developed
to faithfully recapitulate the human leukemias, and novel, rationally
targeted therapeutic approaches to reverse or mitigate the driver mu-
tations with small molecules will become available for most patients.
Effective immunotherapy and cellular therapy will be developed, es-
pecially for patients with no known genetic lesions that are responsive
to available molecular-targeted therapy. Collaborative clinical trials
will be initiated for patients with challenging or drug-resistant leuke-
mia. These efforts will be extended beyond the current study groups
and consortia that investigate patients residing mainly in the United
States (eg, Therapeutic Advances in Childhood Leukemia & Lym-
phoma Consortium) and Europe (eg, International Study for Treat-
ment of Childhood Relapsed ALL Consortium). The VIVA-Asia
Acute Leukemia group has recently been formed to collaborate on and
address the topics relevant to patients in Asia, which not only has the
largest patient population but also has different leukemia subtypes,
environmental characteristics, population genetics, and resources.97
Historically, older adolescents and young adults had poorer treatment
outcomes than young children and received little research attention.
Because pediatric-based regimens improved outcome for this age
group,98-100 pediatric and adult oncologists have started to form con-
sortia to focus on the unique clinical, biologic, psychosocial, and
survivorship of this age group.101 There is a great hope and expectation
that their treatment outcomes will dramatically improve in the com-
ing years.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Ching-Hon Pui, Allen Eng Juh Yeoh
Financial support: Ching-Hon Pui
Administrative support: Ching-Hon Pui, Stephen P. Hunger
Provision of study materials or patients: All authors
Collection and assembly of data: Ching-Hon Pui, Jun J. Yang, Lewis B.
Silverman, Kjeld Schmiegelow, Yves C.M. Benoit, Shai Izraeli
Data analysis and interpretation: Ching-Hon Pui, Jun J. Yang, Stephen
P. Hunger, Martin Schrappe, Andrea Biondi, Ajay Vora, André Baruchel,
Kjeld Schmiegelow, Shai Izraeli, Mary V. Relling
Manuscript writing: All authors
Final approval of manuscript: All authors

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Affiliations
Ching-Hon Pui, Jun J. Yang, James R. Downing, Williams E. Evans, Mary V. Relling, and Charles G. Mullighan, St Jude Children’s
Research Hospital and the University of Tennessee Health Science Center, Memphis, TN; Stephen P. Hunger, University of Colorado School
of Medicine and the University of Colorado Cancer Center and Children’s Hospital Colorado, Aurora, CO; Rob Pieters, Princess Máxima
Center for Pediatric Oncology, Utrecht, the Netherlands; Martin Schrappe, University Medical Center Schleswig-Holstein, Christian-
Albrechts-University, Kiel; Gabriele Escherich, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg
Eppendorf, Hamburg, Germany; Andrea Biondi, Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Monza,
Italy; Ajay Vora, Children’s Cancer Group, School of Cancer, Manchester Academic Health Sciences Centre, University of Manchester,
Manchester, United Kingdom; André Baruchel, Hôpital Robert Debré and University of Paris Diderot, Paris, France; Lewis B. Silverman,
Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, MA; Kjeld Schmiegelow, Institute of Clinical Medicine, University of
Copenhagen and Juliane Marie Centre, the University Hospital Rigshospitalet, Copenhagen, Denmark; Keizo Horibe, Nagoya Medical
Center, Clinical Research Center, Nagoya, Japan; Yves C.M. Benoit, Universiteit Gent, Gent, Belgium; Shai Izraeli, Chaim Sheba Medical

www.jco.org © 2015 by American Society of Clinical Oncology 2947

 Pui et al

Center and Sackler Medical School, Tel Aviv University, Tel Aviv, Israel; Allen Eng Juh Yeoh, Yong Loo Lin School of Medicine and Cancer
Science Institute, National University of Singapore, and Viva-University Children’s Cancer Centre, National University Hospital, Singapore;
and Der-Cherng Liang, Mackay Memorial Hospital, Taipei, Taiwan.
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 Childhood ALL: Progress Through Collaboration

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Ching-Hon Pui Lewis B. Silverman
No relationship to disclose Consulting or Advisory Role: Epizyme, Seattle Genetics
Research Funding: Sigma Tau Pharmaceuticals
Jun J. Yang
No relationship to disclose Kjeld Schmiegelow
No relationship to disclose
Stephen P. Hunger
Stock or Other Ownership: Express Scripts, Amgen, Merck (I), Amgen Gabriele Escherich
(I), Pfizer (I) No relationship to disclose
Honoraria: Jazz Pharmaceuticals, Sigma Tau Pharmaceuticals Keizo Horibe
Patents, Royalties, Other Intellectual Property: I am a co-inventor on a No relationship to disclose
US patent #8,568,974 B2: Identification of novel subgroups of high-risk
pediatric precursor-B acute lymphoblastic leukemia, outcome Yves C.M. Benoit
correlations and diagnostic and therapeutic methods related to same. It No relationship to disclose
has not been licensed and there is no income Shai Izraeli
Travel, Accommodations, Expenses: Amgen Consulting or Advisory Role: Novartis
Research Funding: Pfizer
Rob Pieters
Patents, Royalties, Other Intellectual Property: US patent 8,841,266.
No relationship to disclose
Pharmacological composition and method for regulating abnormal
Martin Schrappe cellular proliferation
Consulting or Advisory Role: Novartis Allen Eng Juh Yeoh
Research Funding: SigmaTau Pharmaceuticals (Inst), Jazz Speakers’ Bureau: Sanofi
Pharmaceuticals (Inst)
Travel, Accommodations, Expenses: Medac Pharma Der-Cherng Liang
No relationship to disclose
Andrea Biondi
No relationship to disclose James R. Downing
No relationship to disclose
Ajay Vora
Consulting or Advisory Role: Jazz Pharmaceuticals, Novartis William E. Evans
No relationship to disclose
André Baruchel
Honoraria: Sigma Tau Pharmaceuticals Mary V. Relling
Patents, Royalties, Other Intellectual Property: Prometheus
Consulting or Advisory Role: Jazz Pharmaceuticals, Novartis, Seattle
Laboratories, royalties from licensing TPMT genotyping
Genetics, Pfizer, Servier
Travel, Accommodations, Expenses: ARIAD Pharmaceuticals, Jazz Charles G. Mullighan
Pharmaceuticals No relationship to disclose

www.jco.org © 2015 by American Society of Clinical Oncology