Distinct Co-Occurring Mutational Profiles in Acute Myeloid Leukemia Confers Prognostic Significance in Children and Young Adults with FLT3/ITD Mutations

FLT3/ITD mutations occur in approximately 15%-25% of AML in children and young adults and can be amenable to targeting with FLT3 inhibitors. We have demonstrated that those with high ITD allelic ratio (AR) have an adverse prognosis, which can be ameliorated in part by hematopoietic stem cell transplant (HSCT) in CR1. However, even with aggressive therapy only a subset FLT3/ITD (ITD+) patients are cured, suggesting that within this cohort there exists heterogeneity among responses to therapy and overall outcomes. As next generation sequencing has illuminated the distinct and complex genomic profiles of pediatric AML, we hypothesized that presence of cooperating mutations may provide further prognostic information in this group of patients.In an international collaborative effort, children and young adults (n=1786; age < 1 month - 29 years, non-APL or Down syndrome) treated on the CCG/COG trials (2961, AAML03P1, AAML0531; n=1472) as well as those treated on the DCOG/BFM/MRC trials (ANLL87, ANLL97, BFM98, BFM04, MRC12, MRC15; n=314) were included in this study. All patients were tested for FLT3/ITD, NPM1, CEBPA, WT1, and NUP98-NSD1 mutations. COG patients underwent either targeted exome or clinical sequencing, while patients in DCOG/BFM/MRC analysis underwent targeted clinical sequencing of hotspot regions in 9 genes. As expected given the heterogeneity of AML, we detected a variety of co-occurring mutations among the ITD+ patients (n=255), ranging from 1-13 (median 2) additi...
Source: Blood - Category: Hematology Authors: Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis III Source Type: research