Germline exome variation in children with acute lymphoblastic leukemia (ALL): Preliminary Findings

Pennsylvania; Department of Dermatology, University of Pennsylvania; Clinical Trial Service Unit; Rambam Medical Center; North London Cancer Network, University College London Hospital; Hematology, University College London; University Hospitals NHS foundation trust; Mayo Clinic; Montefiore Medical Center; Case Western Reserve University; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Department of Hematology/Oncology, University of Pennsylvania; Department of Hematology/Oncology, University of Pennsylvania Context: ALL has a high relapse rate in adults. While different biology may partly account for poorer survival in comparison to children, adherence to complex chemotherapy regimens may also play a role. Objective: To identify risk factors and outcomes associated with delays during chemotherapy for adults with ALL. Design: We conducted an observational study using data from ECOG 2993/ MRC_UKALLXII. We analyzed Phpatients who started intensification after documented complete remission (CR). Long delay (LD) was defined as > 98 days from induction start to intensification start (IS), corresponding with >2 weeks delay per protocol. Very Long Delay (VLD) was defined as a >4 weeks delay. Results: 1247 patients met inclusion criteria. Female sex (p<0.001), Black race (p1⁄40.01), and older age (p<0.001) were associated with increased LD. During induction, infection (p1⁄40.01), dose reductions (p1⁄40.001), neutropenia duration (p1⁄40.007), thrombocytopenia (p<0.001), and hospitalization (p<0.001) were associated with LD. Table 1 shows multivariate analysis risk factors. 687/1247 (55%) patients died, with median time to death from IS of 13.3 months (0.8-231). Myeloablative allogeneic HCT (allo HCT) patients had poorer overall survival from start of intensification (OS-IS) and event free survival (EFSIS) after VLD (p1⁄40.02, p1⁄40.03). Survival was not worse for non-transplant patients after VLD (p1⁄40.24, p1⁄40.10). In a multivariate Cox regression, allo HCT patients with a VLD had significantly worse OS-IS (HR 1.4, p1⁄40.02) and EFS-IS (HR 1.4, p1⁄40.02). There was no difference in OS or EFS in patients who received non-transplant post-remission therapy based on delay. Conclusion: In a comprehensive analysis of the largest adult ALL study reported, we identified risk factors predictive of LD and VLD. Our findings highlighted that delays were associated with chemotherapy toxicity and healthcare disparities. Further studies will prospectively identify patient barriers to on-schedule treatment with a goal of improved adherence and long-term survival. Table 1 Multivariate Regression for LD and VLD Risk Factors Variable Odds Ratio 95% CI p-value Hospital Days, Phase I Induction 1.01 1.00-1.02 0.04 Duration of Thrombocytopenia, Phase I 1.02 1.01-1.03 0.001 Age (Decade) 1.2 1.08-1.31 <0.001 Reduced Dose in Induction 1.54 1.08-2.22 0.019 Female Sex 1.56 1.22-2.0 <0.001 Black Race 3.4 1.41-7.96 0.006 114 Germline exome variation in children with acute lymphoblastic leukemia (ALL): Preliminary Findings Seth E. Karol, MD, Wenjian Yang, Steven W. Paugh, Jinghui Zhang, Geoffe Neale, Charles G. Mullighan, Ching-Hon Pui, Jun J. Yang, William E. Evans, Mary V. Relling Oncology, St. Jude Children’s Research Hospital; Pharmaceutical Sciences, St. Jude Children’s Research Hospital; Pharmaceutical Sciences, St. Jude Children’s Research Hospital; Computational Biology, St. Jude Children’s Research Hospital; Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital; Pathology, St. Jude Children’s Research Hospital; Oncology, St. Jude Children’s Research Hospital; Pharmaceutical Sciences, St. Jude Children’s Research Hospital; Pharmaceutical Sciences, St. Jude Children’s Research Hospital; Pharmaceutical Sciences, St. Jude Children’s Research Hospital Context: Next generation sequencing of matched tumor and nontumor DNA samples from patients with acute lymphoblastic leukemia (ALL) offers the opportunity to identify rare and/or novel variants associated with the efficacy and/or toxicity of treatment. Here, we describe the germline exome sequencing results of 719pediatricpatients with ALL treated on the St. Jude institutional protocols. Design: Leukemia samples were obtained from diagnostic bone marrow aspirates. GermlineDNAwas obtained fromperipheral blood after patients achieved complete remission. Most samples were sequenced using the IlluminaTruSeq platform. Sequencing results were aligned using BWA to hg19 and variants were called with GATK version 3.1. Results: A total of 223,069 distinct non-synonymous single nucleotide variants in 24,056 genes were detected in the germline of at least 1 patient within the cohort. There was a mean of 8,664 germline non-synonymous variants and a mean of 57 nonsense variants per patient. Using a clustering approach based on the principal component analysis, patients were assigned to 1 of 5 genetic ancestry groups: European, African, Asian, Native American/ Hispanic, or other. A subset of patients with previously identified ancestry using STRUCTURE was used to identify these populations, with excellent concordance between the two methods. Patients with African ancestry had higher numbers of germline variants compared to those of other ancestries, consistent with prior findings. Germline genotyping was also performed on the Illumina Human Exome Beadchip array in 684 of these patients, and whole exome sequencing was performed on diagnostic leukemia samples in 414 patients. There was a high rate of concordance between the 98,285 overlapping SNPs in the germline samples assayedby exome array and exome sequencing,with amean concordance of 99%.Therewas also a high rate of concordance between somatic and germline sequencing results, with 98.8% of variants identified in germline samples also identified in the corresponding somatic samples. Patients with large chromosomal duplications or deletions had lower rates of concordance than those with a normal ALL karyotypes (97% vs. 99.4%). Conclusion: This project demonstrates the feasibility of whole exome sequencing on a large population of patients with pediatric ALL and is expected to provide novel insights into inter-individual variation in response to therapy. Clinical Lymphoma, Myeloma & Leukemia June 2015 S177