Impact of induction response and co-mutations on transplant outcomes in AML with myelodysplasia-related gene mutations: A multicenter retrospective study

Abstract

Abstract Background: Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Risk stratification in AML is primarily determined by genomic classification and cytogenetic alterations. The International Consensus Classification (ICC)-2022 classifies AML with mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2, or RUNX1 as AML with myelodysplasia-related gene mutations (AML-MR). According to the European Leukaemia Net-2022 guidelines (ELN-2022), MR-associated mutations are categorized as adverse-risk. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important curative approach for AML, however, its survival benefit in patients harboring AML-MR mutations with additional co-mutations remains controversial. Methods This is a multicenter, retrospective designed study, based on the transplant database of the TROPHY group. AML patients receiving allo-HSCT from February 2016 to December 2023 were screened. Eligibility criteria included: (1) diagnosis of AML, (2) ELN-2022 adverse-risk classification, (3) presence of ≥1 AML-MR mutation. Induction therapy was administered following the recommendations outlined in the National Comprehensive Cancer Network (NCCN) guidelines. Complete remission (CR) was defined as <5% blasts in bone marrow, absence of circulating blasts or extramedullary leukemia and peripheral blood recovery (absolute neutrophil count ≥1,000/μL and platelet count ≥100,000/μL). If CR was not achieved after the first cycle, a second induction using the same or an intensified cytarabine-based regimen was administered. Selection of consolidation treatment was based on measurable residual disease (MRD) status, donor availability, and the patients' fitness. Key outcomes included relapse-free survival (RFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). The study was approved by the institutional review board of each participated hospital and was conducted in accordance with the Declaration of Helsinki. Results A total of 341 acute myeloid leukemia patients were enrolled. Among the AML-MR defining genes, the most frequently mutated were ASXL1 (32%), RUNX1 (29%), and BCOR (22%). Common co-mutated genes included TP53 (7%) and epigenetic regulator genes such as IDH1/2 (6%), DNMT3A (6%), and TET2 (6%). Overall, 193 patients (56.6%) achieved CR after the first induction. Regimens incorporating hypomethylating agents or venetoclax yielded significantly higher CR rates than conventional idarubicin-cytarabine (IA) regimens (64.4% vs. 43.3%; HR = 1.979, 95% CI: 1.197–3.272, p = 0.008). A total of 322 patients (94.4%) had achieved CR prior to allo-HSCT, the entire cohort demonstrated a 2-year OS of 77.4% and RFS of 70%. Patients achieved CR prior to transplantation had significantly improved RFS (2y-RFS: 71.1% vs. 49.3%, P=0.026) and a trend toward lower CIR (2y-CIR: 13.7% vs. 33.7%, P=0.052), although OS was not significantly different. Achieving CR after first induction was associated with superior RFS (2y-RFS: 81.8% vs. 55,5%, P＜0.001), OS (2y-OS: 85.6% vs. 66.3%, P＜0.001), lower CIR (2y-CIR: 9.5% vs. 18.8%, P=0.025), and reduced NRM (2y-NRM: 8.7% vs. 25.5%, P＜0.001). Multivariate analysis identified post-remission consolidation therapy as an independent predictor of improved OS (HR = 0.56, 95% CI: 0.32–0.97, p = 0.015). Conversely, Grade III-IV aGvHD and TET2 co-mutation were associated with inferior OS (HR= 2.32, 95% CI: 1.35–3.98, p = 0.002; HR= 4.15, 95% CI: 1.90–9.05, p< 0.001, respectively). Additionally, both Grade III-IV aGvHD and pre-transplant MRD positivity predicted inferior RFS (HR= 1.86, 95% CI: 1.14–3.05, p = 0.014; HR= 1.73, 95% CI: 1.10–2.74, p = 0.019, respectively). NPM1 co-mutation (n=9) and TP53 co-mutation (n=25) showed no significant impact on RFS or OS. However, patients harboring epigenetic regulator mutations had significantly reduced OS (2y-OS: 73.0% vs. 83.1%, P=0.044), without affecting other endpoints. Conclusion In patients with AML-MR, induction regimens incorporating hypomethylating agents or venetoclax are recommended due to their efficacy in improving CR rates. Achieving CR after first induction significantly improves post-transplant RFS and OS along with reduced CIR and NRM. Co-mutations in TP53 and NPM1 did not significantly impact survival. Notably, epigenetic regulator mutations were linked to reduced OS, highlighting the prognostic relevance of specific co-mutations in AML-MR.