Frequency and Impact of Somatic Mutations Alone or in Combination on Post-Transplant Outcomes in Acute Myeloid Leukemia: A Large Study on Behalf of the EBMT Acute Leukemia Working Party

Background: Acute myeloid leukemia (AML) is a very heterogeneous malignancy, which includes numerous genetically defined subsets. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the frequency and prognostic value of different gene-gene interactions has not been studied and may differ from that of patients treated with chemotherapy alone. We aimed at evaluating, through the European Society for Blood and Marrow Transplantation (EBMT) database, the frequency and impact of different recurrent somatic mutations, either alone or in association, on relapse and survival in patients receiving allo-HSCT.

Methods: This is a retrospective, registry-based analysis with the approval of the EBMT Acute Leukemia Working Party. Adult patients with a diagnosis of AML who received an allo-HSCT between 2013-2023, with an available genetic profile determined at diagnosis by next generation sequencing (NGS) were included.

Results: We identified 1403 allografted AML patients who had NGS performed at diagnosis. The most frequent detectable mutations by frequency were DNMT3A (20%), FLT3-ITD (19%), NPM1 (18%), TET2 (14%), RUNX1 (13%), NRAS (11%), IDH2 (10%), ASXL1 (9%), SRSF2 (7%), IDH1 (7%), FLT3-TKD (7%), BCOR (7%), NF1 (7%), WT1 (7%), PTPN11 (6%), KRAS (6%), CEBPA (5%), TP53 (5%) and STAG2 (5%). By multiple correspondence analysis, three independent groups of co-occurring mutations were identified, the first group included DNMT3A, NPM1 and FLT3-ITD, the second group included ASXL1, SRSF2 and RUNX1, the third group included TP53 mutation. Outcome analysis was performed on the subset of 848 patients allografted in CR1 with available data for the aforementioned seven genes (DNMT3A, NPM1, FLT3, ASXL1, SRSF2, RUNX1 and TP53). Most of these patients had de novo AML (74%), with a median age of 55 years (range: 18-75 years). Patients received primarily reduced intensity conditioning (58%) and peripheral blood stem cells (92%) from matched sibling donors (33%), matched unrelated (29%), and haploidentical donors (17%). By ELN 2022, 4% of these patients had favorable-risk cytogenetics, 68% intermediate-risk, and 29% adverse-risk. When outcome analysis was performed according to the presence or absence of single mutations, TP53 mutation significantly increased the 2-year relapse incidence (RI) and decreased leukemia-free survival (LFS) and overall survival (OS) whereas IDH2 mutation significantly decreased the 2-year RI and improved LFS and OS. RI increased with SF3B1 and KMT2A mutation and decreased in the presence of CEBPA or KIT mutation. OS was positively affected by NPM1 mutation and negatively affected by NRAS mutation. According to the 3 groups identified in theMCA analysis and the known impact of NMP1 in the literature, five groups were built: Group 1 comprising TP53 mutation regardless of other co-mutations (N=46; 5%); Group 2 comprising NPM1 mutation and wild type TP53 regardless of other co-mutations (N=140; 17%); Group 3 comprising FLT3-ITD and/or DNMT3A mutation, wild type NPM1 and TP53, regardless of other co-mutations (N= 154; 18%); Group 4 comprising RUNX1 and/or ASXL1 and/or SRSF2 mutation without FLT3-ITD and with wild type NPM1, DNMT3A and TP53 (N=131; 15%); Group 5 with all seven genes unmutated (N=377; 44%). Groups differed for median age (60, 54, 57, 58 and 52 respectively), secondary AML (52%, 15%, 18%, 34% and 26% respectively) and adverse cytogenetics (73%, 8%, 20%, 30%, and 35% respectively). Groups of somatic mutations significantly affected the 2-year RI (45%, 19%, 25%, 15% and 25% for the 5 groups respectively; p<0.01), LFS (29%, 68%, 59%, 76% and 58% respectively; p<0.0001) and OS (41%, 75%, 68%, 84% and 65% respectively; p<0.0001) whereas non relapse mortality was not significantly affected.

Conclusion: NGS at diagnosis can be extremely useful in risk stratification of AML patients undergoing allo-HSCT, potentially allowing adequate post-transplant interventions. Surprisingly, despite their older age and higher frequency of secondary AML and adverse cytogenetics, the best outcomes (2 year LFS 76%, OS 84%) were observed for patients harboring RUNX1 and/or ASXL1 and/or SRSF2 in the absence of FLT3-ITD or NPM1, DNMT3A and TP53 mutation, indicating that allo-HSCT can overcome the adverse risk associated with these somatic mutations at diagnosis.