Abstract 2870: Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia

Abstract

Abstract Survival for children with acute myeloid leukemia (AML) remains low, with a primary induction remission failure rate of 10-15%. Although some mutations have been identified that are associated with increased relapse risk, the genomic landscape of pediatric AML resistant to primary chemotherapy is not well characterized. As part of the TARGET initiative (Therapeutically Applicable Research To Generate Effective Treatments), we assembled a cohort of 28 pediatric AML patients with primary chemotherapy resistance and failure of induction chemotherapy, uniformly treated as part of the COG AAML0531 study. We analyzed whole-genome DNA, mRNA, and miRNA sequence data obtained at diagnosis and after induction chemotherapy. At least three genetically distinct groups were apparent in this cohort, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of NUP98 variants, and additional recurrent variants including those in KMT2C and MLLT10. Comparisons of mutations before and after chemotherapy revealed both common and distinct gene expression programs. On chemotherapy exposure, these leukemias exhibited diverse forms of clonal evolution. We observed selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination or contraction of FLT3, PTPN11, and NRAS mutant clones. These findings suggest diverse genetic mechanisms for primary chemotherapy resistance in pediatric AML, which should guide new approaches for its diagnosis and therapy. Citation Format: Nicole McNeer, John Philip, Heather Geiger, Rhonda E. Ries, Vincent-Philippe Lavallee, Michael Walsh, Minita Shah, Kanika Arora, Anne-Katrin Emde, Nicolas Robine, Todd A. Alonzo, E. Anders Kolb, Alan S. Gamis, Malcom Smith, Daniela Se Gerhard, Jaime Guidry-Auvil, Soheil Meshinchi, Alex Kentsis. Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2870.