Prognostic Impact of Variant Allelic Frequency of Molecular Mutations in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) on Allogeneic Hematopoietic Cell Transplant (HCT) Outcomes

Allogeneic HCT is the only therapy for high risk AML and MDS with curative potential. However, subsequent relapse-free survival remains poor. Next generation sequencing (NGS) is an important tool in understanding the genetic complexity of myeloid malignancies, and informs disease risk and treatment decisions. We performed multi-amplicon targeted pre-HCT NGS using a panel of the 60 most commonly mutated somatic genes in myeloid neoplasia on 112 patients with AML, and 80 with MDS, who then underwent HCT. Mutations were analyzed individually, and by molecular pathway. Variant allelic frequencies (VAF) of individual mutated genes were also studied. AML and MDS cohorts were analyzed separately. Baseline characteristics within the AML and MDS cohorts are shown in Table 1. Median follow up was 47 months (range 17-125) for AML patients, and 33 months (range 14-111) for MDS. The most recurrent mutations in the AML cohort were TET2 (14.7%), DNMT3A (12.1%), RUNX1 (7.8%), IDH1, NRAS, and STAG2 (6.9% each). FLT3 (1.7%) and NPM1 (2.8%) were underrepresented. Complex cytogenetics (HR 2.82, 95% CI 1.21-6.6, P = .017) and disease status (33% were associated with worse RFS (HR 3.57, 95% CI 1.25-10.2, P = .017; and HR 6.57, 95% CI 1.93-22.3, P = .003; respectively). With adjustment for complex karyotype, TP53 and EZH2 mutations were not prognostic for RFS (P = .16 and .34 respectively). Molecular profiling is increasingly important in the care of patients with AML and MDS. Further large-scale studies are needed to enhance our understanding of the molecular complexities, including the importance of allelic frequency, to better inform care decisions and identify ways to improve post-HCT outcomes.