Frequency and Impact of Somatic Co-occurring Mutations on Post-Transplant Outcomes in Acute Myeloid Leukemia: A Multicenter Registry Analysis on Behalf of the EBMT ALWP

Acute myeloid leukemia (AML) includes genetically defined subsets. In allogeneic hematopoietic cell transplantation (allo-HCT) setting, the frequency and prognosis of gene-gene interactions may differ from those of patients treated with chemotherapy alone. In this study, adult patients (N = 952) with AML allografted between 2015–2023, with available next generation sequencing (NGS) at diagnosis were included. The most frequent mutations were DNMT3A (24%), FLT3- ITD (21%), NPM1 (21%), RUNX1 (16%), NRAS (16%), TET2 (14%) , and IDH2 (12%). Multiple correspondence analysis identified distinct groups of co-occurring mutations. Outcome analysis was performed on 646 AML patients allografted in first complete remission (CR1). Six non-overlapping groups were constructed according to found groups and well-known clinical impact of NPM1 and TP53 mutations: 1) TP53 mutation; 2) NPM1 mutation; 3) FLT3 -ITD and/or DNMT3A mutation; 4) SRSF2 and/or ASXL1 and/or RUNX1 mutation (SAR group); 5) IDH1 and/or IDH2 and/or TET2 mutation; and 6) all ten genes unmutated. In multivariable analysis, TP53 mutation, adverse karyotype, and age negatively affected leukemia-free survival (LFS) and overall survival (OS). OS was additionally negatively affected when the ten genes were unmutated. Notably, outcomes were excellent for SAR mutations (2-year LFS 76%, OS 84%), indicating allo-HCT in CR1 can overcome their adverse risk at diagnosis.