Genomic Variants of Cytarabine Sensitivity Associated with Treatment Related Mortality In

Author Manuscript Published OnlineFirst on March 2, 2020; DOI: 10.1158/1078-0432.CCR-19-3117 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Genomic variants of cytarabine sensitivity associated with treatment related mortality in

pediatric AML: A report from the Children’s Oncology Group

Christine L Phillips1,2, Adam Lane3, Robert B Gerbing4, Todd A Alonzo5, Alyss Wilkey2,

Gretchen Radloff2, Beverly Lange6, Eric R Gamazon7,8, M. Eileen Dolan9, Stella M

Davies1,2

1Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH;

2Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital, Cincinnati OH;

3Division of Biostatics and Epidemiology, Cincinnati Children’s Hospital, Cincinnati OH;

4Children’s Oncology Group; 5University of Southern California, Los Angeles CA;

6Children’s Hospital of Philadelphia, Philadelphia PA; 7Vanderbilt Genetics Institute and

the Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN

8Clare Hall, University of Cambridge, Cambridge, United Kingdom

9Section of Hematology/Oncology, The University of Chicago, Chicago IL

Running Title: Cytarabine SNPs predict TRM in pediatric AML

Keywords: cytarabine, pharmacogenetics, pediatrics, AML, treatment related mortality

Financial Support: Research supported by the 2012 AACR-FNAB Career Development

Award for Translational Cancer Research, Grant Number 12-20-14-PHIL, the

Pharmacogenomics of Anticancer Agent Research Grant NIH/NIGMS GM61393 (MED),

Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 2, 2020; DOI: 10.1158/1078-0432.CCR-19-3117 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

a Leukemia Lymphoma SCOR grant (MED), University of Chicago Comprehensive

Cancer Center (MED), NCTN Operations Center Grant U10CA180886, NCTN Statistics

& Data Center Grant U10CA180899. ERG is also supported by an NIH Genomic

Innovator Award (R35HG010718).

Corresponding Author:

Christine Phillips MD

Cincinnati Children’s Hospital Medical Center

3333 Burnet Ave, MLC 7015; Cincinnati OH 45229

Phone: 513-636-4200 Fax 513-636-3534

[email protected]

Potential conflicts of interest: ERG receives an honorarium from Circulation Research of

the AHA, Editorial Board. He performs consulting for the City of Hope / Beckman

Research Institute. All other authors report no conflicts of interest

Abstract: 245

Word count: 2848

References: 22

Tables/Figures: 6

Statement of Translational Relevance:

Genetic polymorphisms influencing sensitivity to cytarabine, identified using genome wide approaches in cell lines, predict outcome of therapy for childhood AML. In this

study, we identify two new SNPs associated with cytarabine toxicity in pediatric AML.

Furthermore, the present study validated a SNP previously identified in a separate

cohort, using large patient numbers and patient outcome data, to identify those at risk of

treatment related mortality. Knowledge of genetic characteristics that predict either

excessive toxicity, or inadequate therapy (relapse) at the time of diagnose will allow for

selection of individualized cancer treatments and will improve survival. These findings

can be validated prospectively in pediatric treatment protocols and ultimately used to

modify treatment selection.

ABSTRACT

Purpose: Cytarabine is an effective treatment for AML with associated toxicities

including treatment related mortality (TRM). The purpose is to determine the clinical relevance of single-nucleotide polymorphisms (SNPs) identified through the use of

HapMap lymphoblastoid cell-based models, in predicting cytarabine response and

toxicity in AML.

Experimental Design: We tested clinical significance of SNPs associated with

cytarabine sensitivity in children with AML treated on Children’s Oncology Group

regimens (CCG 2941/2961). Endpoints included overall survival (OS), event free

survival (EFS) and TRM. Patients who received bone marrow transplant were

excluded. We tested 124 SNPs associated with cytarabine sensitivity in HapMap cell

lines in 348 children to determine if any associated with treatment outcomes. In

addition, we tested five SNPs previously associated with TRM in children with AML in our independent data set of 385 children.

Results: Homozygous variant genotypes of rs2025501 and rs6661575 had increased in vitro cellular sensitivity to cytarabine and were associated with increased TRM. TRM

was particularly increased in children with variant genotype randomized to high dose

cytarabine (rs2025501: p= 0.0024 and rs6661575 p=0.0188). In analysis of previously

reported SNPs, only the variant genotype rs17202778 C/C was significantly associated

with TRM (p<0.0001).

Conclusions: We report clinical importance of two SNPs not previously associated

with cytarabine toxicity. Moreover, we confirm that SNP rs17202778 significantly

impacts TRM in pediatric AML. Cytarabine sensitivity genotypes may predict TRM and

could be used to stratify to standard vs. high dose cytarabine regimens, warranting further study in prospective AML trials.

INTRODUCTION:

Pediatric acute myeloid leukemia (AML) accounts for 15%-20% of childhood leukemia, but is responsible for the majority of pediatric deaths caused by leukemia. (1)

Intensification of chemotherapy over the past several decades has resulted in

improvements in survival; however, the five year survival remains only about 50-60%.

(2, 3) Intensification of dose and aggressive timing of induction therapy, as well as

appropriate use of transplant, have been employed to cure a higher percentage of

patients with AML. While increasing the success of therapy for some, this approach has

resulted in increased toxicity in contemporary regimens. Other children still do not achieve cure due to failure to achieve remission or early relapse of the disease. The 5- year event-free survival (EFS) and overall survival (OS) were 42% ± 3% and 52% ± 4%, respectively, on Children’s Cancer Group study, CCG 2961, the study from which the

patient samples discussed further in this manuscript were obtained.(2) Importantly, the

overall treatment related mortality (TRM) was significant, ranging from 9 ± 4% to 17 ±

5% depending on treatment arm, largely due to infection secondary to neutropenia and

mucosal barrier injury.

The backbone of contemporary AML therapy is cytarabine plus an anthracycline.

(4-6) Cytarabine is currently the single most effective agent in the treatment of acute

myeloid leukemia and failure to respond to cytarabine is associated with poor survival.

(7-11) In one study, patient leukemia samples at diagnosis which demonstrated in vitro resistance to cytarabine predicted a four-fold increased risk of relapse. (12)

The dose of cytarabine that is used is based on a population average, however a

subset of patients will experience adverse reactions while another subset will have an

inadequate therapeutic effect from the drug. The potential benefit of implementing

pharmacogenetics to identify patients at greatest risk of nonresponse or serious toxicity

would have enormous benefit in pediatric AML. Cure is dependent on the ability to

achieve remission of the leukemia. Only 30-50% of children with relapsed disease will

achieve a second remission and have a chance at cure. (6) The development of a

genetic model that can be used to predict inter-individual variability to chemotherapy

response will allow upfront tailoring of therapy to reduce acute and chronic toxicities and

cure a larger number of patients.

MATERIALS AND METHODS

Identification of SNPs to be tested

We used two different approaches to identify SNPs that would be tested for association

with outcome in pediatric AML patients (Figure 1). Our first approach used a set of

SNPs first identified in a genome-wide association study (GWAS) of cellular sensitivity to cytarabine in 85 European (CEU) lymphoblastoid cell lines (LCLs). (13) SNPs (n=

124) were selected from the GWAS based on their strong association with cytarabine sensitivity phenotype (p

>5%. Appendix A lists the SNPs that were included in the first approach.

In our second approach we focused on a small number of SNPs identified using multiple

HapMap LCL populations followed by genotyping in a single institution study and found to be significant. (14) We selected five SNPs described as modifying risk of TRM in

children with AML, to determine whether they replicated in this entirely new dataset.

Clinical Samples

The study cohort consists of 455 patients with de novo AML treated on Children’s

Cancer Group (CCG) protocols 2941 and 2961 between 1995 and 2002. Clinical data,

including age, sex, white blood cell count (WBC) at diagnosis, race, presence of

chloromas, CNS status, immunophenotyping and cytogenetic analysis were collected

prospectively. Cases were reviewed by central pathology and were classified by the

French-American-British (FAB) Cooperative Study Group criteria. All AML subtypes, except APL, were eligible and treated on the same chemotherapy regimens.(2)

Patients or legal guardians provided written consent to enrollment on the therapeutic studies after approval of the study by the IRB of each participating institution, and to submission of samples for biologic studies. Studies were conducted in accordance with recognized ethical guidelines according to Declaration of Helsinki. Patients who received bone marrow transplant (BMT) were omitted from the current analysis of

EFS/OS/TRM as the transplantation confounds the outcome being studied. Stored blood samples from study patients, who gave permission for storage and future use at time of initial consent, were used for genotyping. After exclusion of patients who received BMT, SNPs derived from CEU cell lines in the first approach using OpenArray were genotyped in 348 patients. In our second approach, 385 non-BMT patient

samples were genotyped for the five SNPs previously linked to TRM (Figure 1). (14)

Some patient samples did not have sufficient amount of concentrated DNA to be analyzed via OpenArray platform leading to the variation in sample numbers between the two approaches.

Chemotherapy Treatment Regimen

The study design of CCG 2961 is shown in Figure 2. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, cytarabine, thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER

(dexamethasone, cytarabine, thioguanine, etoposide and daunomycin) given on days 10 to 13 for total dose of cytarabine 1600mg/m2. On recovery of white blood cell and platelet counts, patients were randomly assigned to receive consolidation therapy with

Regimen A i.e. DCTER (1600 mg/m2 cytarabine) or Regimen B i.e. IDA-FLAG

(idarubicin, fludarabine, cytarabine and G-CSF) with total dose of cytarabine at 7590

mg/m2. Intrathecal (IT) cytarabine was used for central nervous system (CNS)

prophylaxis. Following consolidation, patients with a matched related donor proceeded to

allogeneic marrow transplant (BMT) with ablative conditioning (busulfan and cytoxan).

Those without a related donor received intensification with high-dose cytarabine (24,000

mg/m2), L-asparaginase (Capizzi II) and additional IT cytarabine. Patients on the Capizzi

II arm were further randomized to receive Interleukin-2 or standard follow-up. BMT

recipients were excluded from this randomization. (2) This study was suspended due to

unacceptably high TRM from September 1999 to May 2000, and reopened after

amendments to incorporate multiple changes including mandatory hospitalization for

neutropenia, use of broad-spectrum antibiotics including vancomycin with fever, empiric

anti-fungal therapy. (2) CCG 2941 was a pilot study of intensively timed IDA-

DCTER/DCTER and patients were non-randomly assigned to treatment as shown for regimen A. (15) Results comparing treatment arms of IDA-DCTER and IDA-FLAG are therefore limited to patients on 2961.

Genotyping

We used Applied Biosystems Taqman OpenArray technology to genotype the samples.

A small number of SNPs were unsuitable for OpenArray analysis and were genotyped

using the fluorogenic PCR-based allelic discrimination (single TaqMan) assay using the

PE Applied Biosystems 7200 Sequence Detection System.

Statistical Analyses

Clinical data were collected prospectively, audited and error checked and provided for

analysis by the statistical staff of the Children’s Oncology Group. Collection of follow-up

data were completed for pilot study CCG-2941 on 9/1/05 and 1/1/11 for CCG-2961.

The median follow-up time was 3609 days (9.9 years), [range 0-4717 days (0-12.9

years)]. Differences in induction outcome, dichotomized into complete remission or no

remission by genotype, were tested with Pearson’s chi square statistic or Fisher’s exact

test when data were sparse. OS was defined as the time from study entry until death.

EFS was defined as a time from study entry until induction failure, relapse or death.

Survival estimates of OS and EFS were reported using the Kaplan and Meier

method.(16) Differences in OS and EFS were evaluated using the log-rank statistic.

TRM and relapse rate (RR) were determined using methods that account for competing

events (17). TRM was defined as time from study entry to death from non-progressive

disease where relapses were treated as competing events. RR was defined as time

from study entry to relapse where deaths from non-progressive disease were treated as

competing events. Gray’s test was used to test differences between groups for RR and

TRM. All estimates at 1 year were reported with their corresponding standard error. A

multivariate competing risks regression was performed to assess the impact on TRM of

the significant SNPs. Analyses comparing patients randomized to IDA-DCTER or IDA-

FLAG were limited to the CCG-2961 study.

Evaluation of genomic location and potential functional significance of SNPs.

Statistically significant SNPs were evaluated for functional significance through

expression quantitative trait loci (eQTLs) and transcription factor binding analysis using

48 tissues in GTEx v7 (18) and RegulomeDB (19), respectively. The overall

deleteriousness of identified SNPs was evaluated through Combined Annotation

Dependent Depletion (CADD), a tool that evaluates the deleteriousness of single

nucleotide, insertion and deletion variants in the human genome through the integration

of annotations from more than 60 different databases into one metric. (20, 21)

RESULTS

Approach 1: Association of Candidate Genes Selected from GWAS with Clinical

Outcome in Pediatric AML Cohort

Previous work identified single nucleotide polymorphisms (SNPs) that are associated with in vitro cytarabine sensitivity in a GWAS conducted in HapMap LCLs. (13) A panel of relevant SNPs from the European (CEU) population of LCLs was selected for testing,

as most children enrolled on the study were of European ancestry. SNPs included in

this panel were initially selected based on association with cytarabine sensitivity with a

p-value less than 0.0001. We further refined the list by eliminating any SNPs with a

minor allele frequency of less than 0.05 in the CEU population. An additional three

SNPs were excluded due to failure to genotype on OpenArray chip, resulting in 124

SNPs successfully genotyped in 348 patients.

SNPs and increased TRM

Two SNPs (rs6661575 (T/T) and rs2025501 (A/A) were significantly associated with

both increased in vitro sensitivity to cytarabine in LCL (13) and increased TRM in

children (Figure 3). Children with a T/T genotype at rs6661575 (n=7) had a one year cumulative incidence of TRM of 57 ± 22% versus those who were wild type, 15 ± 3%

(p=0.0077). Those carrying the homozygous variant genotype A/A at rs2025501 (n=68) had a one year cumulative incidence of TRM of 29 ±7% vs 11 ± 3%, 20 ± 4% for genotypes A/G and G/G respectively (p=0.0228). (Table 1). Of note, the heterozygous

genotype had unexpectedly lower TRM than either of homozygous variants. The impact

of genotype on TRM was more notable in children randomized to consolidation with

IDA-FLAG which contains higher dosing of cytarabine (7590 mg/m2) than IDA-DCTER

(1600 mg/m2). Patients with the recessive genotype A/A rs2025501 who were

randomized to IDA-FLAG had increased TRM compared to A/G and G/G (34 ± 9% vs 5

± 3% and 19 ± 8%; p-=0.0024). A similar change was not observed with rs6661575.

However, the homozygous variant genotype is rare and the number of affected children

was small, limiting power. A trend towards decreased relapse rate for the homozygous

variant of both SNPs was noted (Table 1). In terms of functional significance, rs6661575

is intronic to FMOD on chromosome 1 and is an eQTL for the gene with a CADD score

= 13.26. In contrast, rs2025501 is in a gene desert on chromosome 9, with no known

functional annotation and a very low CADD score of 0.005.

We assessed whether treatment selection may mitigate adverse outcomes for children with the variant (A/A) genotype of rs2025501 by examining OS according to

randomization to IDA-FLAG versus IDA-DCTER. Those carrying the variant genotype demonstrated a trend toward improved overall survival when randomized to IDA

DCTER arm with less cumulative cytarabine exposure (p=0.19) (Figure 4A). The small

number of patients with variant genotype limited this analysis for SNP rs6661575 as

only three patients with the variant genotype were randomized to IDA-DCTER, shown in

Figure 4B

Approach 2: Replication of Previously Published SNPs associated with TRM

We sought to replicate previous findings of SNPs that impact response to cytarabine

based chemotherapy in the St Jude’s AML02 study in our Children’s Cancer Group

CCG2941/2961 AML cohort. (14) We genotyped five SNPs (rs17202778, rs1533140,

rs6550826, rs9883101, rs1203633) that had a significant impact on TRM in the St

Jude’s study in our cohort of 385 patients. In agreement with the report from St Jude’s

Children’s Hospital, the variant genotype, rs17202778 C/C was significantly associated

with TRM in our independent dataset (p<0.0001) (Figure 5). One year cumulative

incidences of TRM were 72.9% for C/C vs 17.0% and 13.8% for C/T and T/T genotypes,

respectively. The variant genotype C/C had lower three year relapse rate of 11% than

the other genotypes, 23% C/T and 49% T/T (p=0.0013). We examined the impact of treatment randomization on survival for patients carrying the variant genotype (C/C) and noted a non-significant trend towards improved survival for patients treated with lower dosing of cytarabine (p=0.2) (Figure 4C). We performed a multivariate analysis for

rs17202278 and the two SNPs identified in our first approach (rs6661575 and rs2025501). Both rs17202278 and rs6661575 remained significant (p = <0.0001 and p=0.0008, respectively). Although rs17202778 is in a gene desert on chromosome 2 with no known biological significance, this SNP has a very high CADD score = 19.50

(among the 10% most deleterious variants in the genome).

DISCUSSION

Chemotherapeutic regimens for acute myeloid leukemia are intensive and carry a risk of

TRM, thus a significant number of children will die of toxicity from the therapy. (2) We

hypothesized that genetic susceptibility to the deleterious effects of chemotherapy is in

part responsible for the inter-individual variability in outcomes seen in clinical trials. In

the two parts of this study, we have found three SNPs associated with TRM. The

variant genotypes with increased in vitro sensitivity to cytarabine in the cell-based

models were also associated with increased TRM in the children treated on the CCG

clinical trial. Two of the SNPs are newly identified, while one of the SNPs, also

identified in cell based models, was previously reported to be associated with increased

mortality on the St. Jude’s AML trial. (14)

Recessive variants of rs6661575 (T/T) and rs2025501 (A/A) had significantly increased in vitro sensitivity to cytarabine in the LCL in the prior GWAS and were

associated with increased treatment related deaths in children suggesting a direct effect

of cytarabine chemotherapy, as the deaths were largely due to infections that result

from mucosal barrier breakdown and profound neutropenia. Children with A/A genotype

at rs2025501 randomized to the IDA-FLAG arm with higher doses of cytarabine had the

more notable increase in TRM. We have previously reported a similar finding of

increased toxicity in the risk genotype with higher doses of cytarabine in a previous

pharmacogenetic study of cytidine deaminase (CDA), an enzyme responsible for

irreversibly deaminating cytarabine. (22) Genotyping of children on the same CCG

2941/CCG 2961 study revealed increased TRM for those children carrying the

homozygous variant gene of CDA associated with reduced enzyme activity. This effect

was more pronounced for those children who were randomized to receive higher doses

of cytarabine. (22)

The expected directionality of cellular sensitivity in vitro was observed via

increased chemotherapy sensitivity and subsequent toxicity in children with these SNPs

identified in this approach, suggesting a plausible genotype effect that warrants

validation in an independent dataset. The functional implications of these SNPs is

unclear at this time as they are both intergenic. The SNP rs6661575 is located on

chromosome 1q32.1 close to gene FMOD, which encodes fibromodulin. Fibromodulin

is an extracellular matrix proteoglycan which has an important role in matrix

organization and is necessary for tissue repair in many organs. Recent studies have

shown that it may play a role in various cancers, including leukemias, through

angiogenesis and suppressing apoptosis.(23) It is also possible that these SNPs are in

close linkage with other functionally important genes. Neither of our newly identified

SNPs were included in the data set which was genotyped on the St Jude cohort as they

did not meet significance parameters after meta-analysis of the six pooled GWAS

studies used to identify candidate genes in that study.(14)

The second aim of our study was to replicate and validate the findings of the St

Jude‘s AML clinical trial which evaluated relevant SNPs derived from the meta-analysis of six different population based GWAS studies. Five SNPs that were associated with variable cytarabine sensitivity in vitro were also associated with treatment related

mortality in their pediatric cohort. In our cohort, we found only one of the 5 SNPs to be

associated with clinical outcomes. SNP rs17202778 (C/C) was found to be significantly associated with markedly increased treatment related mortality in children carrying the variant alleles in our independent data set. The very high burden of mortality in these children carrying the variant genotype in our study, which represents an independent validation of a previously identified signal for mortality in children with AML and is complementary to the studies of in vitro sensitivity, underscores the potential importance of this SNP in cytarabine-based chemotherapy. This SNP should be

studied in upcoming prospective clinical trials in AML to ascertain whether this genotype

can be used to stratify to standard versus high dose cytarabine based chemotherapy or

a less intensive chemotherapy regimen if the excessive toxicity is again noted.

Pharmacogenetic studies for AML have several limitations which must be

addressed in the context of these results. Chemotherapeutic regimens for AML

incorporate multiple drugs, limiting our ability to decipher whether the outcomes we

observe are the direct effect of cytarabine. The congruence of the in vitro sensitivity

with expected treatment outcome allows us to infer an effect of cytarabine.

Additionally, multiple previous studies have linked cytarabine sensitivity to outcome

which supports the importance of this drug in both clearance of leukemia and excess

toxicity.(6, 12) For two of the SNPs, we demonstrated an increase in toxicity signal

when patients were randomized to increasing doses of cytarabine, again suggesting a

dosage effect of this drug. The large number of SNPs analyzed allows for the risk of

false discovery. Our risk of false discovery was minimized by our priori hypothesis of

biologic plausibility of the data that increased in vitro sensitivity to cytarabine would

predict toxicity, and maintaining a strict p-value for significance (p<0.01). These

findings resulted from a multicenter national study with audited data and large number

of patients, but we recognize that these limitations are not insignificant. The two newly

discovered SNPs should be validated in an independent dataset to validate the clinical

significance of our findings. In our second aim, we were able to provide supportive data

that the previously identified SNP rs17202278 impacts TRM in children with AML. The

reproducibility of the clinical importance of rs17202278 C/C predicting TRM,

demonstrated in two large independent clinical trials, overcomes many of the expected

limitations described above.

GWAS studies are helpful in finding novel determinants of drug sensitivity if

validated in clinical samples.(24-27) The toxicity profile of cytarabine is well-established

and notably dose dependent, with increased toxicity with high dose cytarabine

(>1g/m2).(2) Pharmogenomic studies can be complementary to molecular and

cytogenetic exploration of leukemia, offering further prognostication and chemotherapy

selection in children with leukemia. The number of children with these genotypes is not

insignificant, as even the rare recessive genotype (rs6661575) is present in 2% of our

cohort. While the two newly discovered variants warrant additional validation in an

independent clinical dataset, SNP rs17202278 has a toxicity signal in two independent

datasets, and should be evaluated in prospective studies as it may impact dose-specific

treatment strata or the need for additional supportive care in the future to reduce the significant mortality seen in those children harboring the recessive alleles.

Acknowledgements.

ERG is grateful to the President and Fellows of Clare Hall, University of Cambridge for providing a stimulating intellectual home and for the generous support. The authors would also like to thank Matthew Trendowski from the University of Chicago who

provided thoughtful insight for the genetic analyses.

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FIGURE LEGENDS

Figure 1: Study Design. Shaded areas represent previously published data used to identify SNPs for testing, unshaded boxes represent data presented in this paper. The

CEU1/2 population consisted of 85 lymphoblastoid cell lines as described in Hartford et al., (13) and the meta-analysis SNPs associated with cytarabine were obtained from

523 lymphoblastoid cell lines as described in Gamazon et al., (14).

CEU: refers to HapMap population samples of Northern and Western European

descents; YRI: Yoruba, refers to HapMap population samples from Ibadan, Nigeria;

ASW: refers to population African American of Southwestern United States; ASN: refers

to HapMap population samples of Asian descent

Figure 2: Clinical trial CCG 2961 design. Design schema of chemotherapy backbone

CCG 2961 with cumulative doses of cytarabine in bold.

Figure 3: (A) Homozygous variant genotypes of rs2025501 and rs6661575 associated

with increased cytarabine sensitivity in 85 LCLs of European ancestry from Hartford et

al (previously unpublished figures) (13) (B) Patients carrying these homozygous

variants randomized to regimen B (IDA-FLAG) with higher dose cytarabine have

significantly increased TRM.

Figure 4: Survival probability for children carrying each homozygous variant genotype

according to treatment randomization to either IDA-FLAG or IDA-DCTER

4A. rs2025501 (p=0.19) 4B. rs6661575 (p=0.38) 4C. rs17202778 (p=0.2)

Figure 5. TRM for rs17202778. Cumulative incidence of TRM in patients treated on

CCG2941/2961 by genotype. BMT patients excluded

1 year cumulative TRM randomized to TRM randomized to 3 year relapse rs6661575 incidence TRM IDA‐FLAG arm IDA‐DCTER arm rate (RR) Genotype (n) n = 343 n = 130 n = 131 n = 279 C/C (263) 15 ± 3 % 16 ± 5 % 9 ± 3 % 44 ± 3 % C/T (73) 21 ± 5 % 14 ± 6 % 10 ± 7 % 40 ± 7 % T/T (7) 57 ± 22 % 60 ± 26 % 50 ± 50 % 14 ± 15 % p‐value 0.0077 0.0188 0.1086 0.5441

1 year cumulative TRM randomized to TRM randomized to 3 year relapse rs2025501 incidence TRM IDA‐FLAG arm IDA‐DCTER arm rate (RR) Genotype (n) n = 342 n = 130 n = 130 n = 278 G/G (106) 20 ± 4 % 19 ± 8 % 12 ± 5 % 46 ± 5 % A/G (169) 11 ± 3 % 5 ± 3 % 6 ± 3 % 45 ± 4 % A/A (67) 29 ± 7 % 34 ± 9 % 12 ± 8 % 31 ± 6 % p‐value 0.0228 0.0024 0.7697 0.2549

Genomic variants of cytarabine sensitivity associated with treatment related mortality in pediatric AML: A report from the Children's Oncology Group

Christine L Phillips, Adam Lane, Robert B Gerbing, et al.

Clin Cancer Res Published OnlineFirst March 2, 2020.

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