Outcomes of elderly (≥ 70) Acute Myeloid Leukemia (AML) patients receiving continued hypomethylating agent/venetoclax (HMA/VEN) versus allogeneic hematopoietic cell transplantation (HCT)

Abstract

Abstract Introduction: HMA/VEN has transformed therapy for elderly patients with AML by improving complete remission (CR) rates, survival, and enabling more patients to proceed with curative allogeneic HCT. At the same time, implementation of safer conditioning and effective GVHD prevention regimens made HCT increasingly feasible for older patients by reducing non-relapse mortality (NRM). In this study, we evaluate whether elderly AML patients achieve superior outcomes with continuous HMA/VEN vs. undergoing HCT in CR. Methods: This single center, retrospective study included elderly (≥70 years) AML patients treated with either HMA/VEN or HCT (10/2008 – 4/2023). HMA/VEN group was restricted to patients who received at least 3 cycles of HMA/VEN and never had HCT. HCT group included all patients who received HCT in CR regardless of prior treatment type. Comorbidity score (CS) was assessed in HMA/VEN group by AML Composite Model (AML-CM) and in HCT group by HCT Comorbidity Index (HCT-CI). Kaplan-Meier analysis with log-rank test was used to estimate relapse free survival (RFS) and overall survival (OS) from the time of AML diagnosis. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were performed using Gray's test. Results: A total of 284 patients were identified: 139 in HMA/VEN group and 145 in HCT group. Median age at diagnosis was 77 years (range, 70-89) in HMA/VEN group and 72 years (range, 70-78) in HCT. Median follow up for the entire cohort was 54 months. Most patients were male (69.1% in HMA/VEN vs. 69.7% in HCT) and had ECOG 0-1 performance score (95% in HMA/VEN vs. 100% in HCT). The HMA/VEN and HCT groups were also balanced by CS: 37.4% vs. 40.0% for CS 0-2, 37.4% vs. 30.3% for CS 3-4, and 25.2% vs. 29.7% for CS ³5, p=0.483. AML genetic risk by ELN 2022 was 7.9% vs. 6.2% favorable, 16.6% vs. 30.3% intermediate, and 70% vs. 57.2% adverse risk in HMA/VEN and HCT groups, respectively (p=0.05). Mutations defining myelodysplasia-related AML according to the WHO 2022 were present in 51% of HMA/VEN and 43.4% of HCT treated patients (p=0.194). Key mutations occurring in >10% of the entire cohort included RUNX1 (19.3%), ASXL1 (19%), TP53 (16.2%), and SRSF2 (16.2%). Secondary/therapy-related AML was more frequent in HCT group (54.2%) vs HMA/VEN group (36.7%, p=0.003). In HMA/VEN group, 69.8% of patients achieved CR or CR with incomplete count recovery (CRi) following HMA/VEN therapy, which was the initial treatment for 81.3% of patients. HCT group received various frontline regimens prior to HCT including intensive induction (58.3%) and lower intensity regimen (41.7%) of which 22.8% was HMA/VEN. OS at 3 years was 20% in HMA/VEN and 62% in HCT groups (p<0.001). In multivariable analysis, HCT resulted in significantly better OS compared to HMA/VEN (HR=0.37, 95% CI 0.27-0.51; p<0.001). OS was significantly worse in patients with CS ³5 (HR=1.49, 95% CI 1.01-2.19; p=0.043) and with ELN adverse risk AML (HR=1.53, 95% CI 1.08-2.15; p=0.016). Among key mutations with sufficient sample size for evaluation, HCT was associated with significantly better 3-year OS compared to HMA/VEN in patients harboring mutations in ASXL1 (77% vs 24%, p=0.0001), RUNX1 (65% vs. 18%, p=0.006), TP53 (47% vs. 11%, p=0.022), SRSF2 (62% vs. 28%, p=0.032), NPM1 (72% vs. 38%, p=0.030), or FLT3-ITD (48% vs. 0%, p=0.003). No statistically significant differences in survival were observed between patients with mutated and wild-type IDH2, NRAS, STAG2, and U2AF1. Analysis restricted to patients achieving CR/CRi in the HMA/VEN group, HCT group continued to show significant benefit not only in 3-year OS (62% vs. 29%, p<0.0001) but also in RFS (56% vs. 22%, p<0.0001). This was because of lower 3-year relapse rate in the HCT group compared to the HMA/VEN group in CR/CRi (26% vs. 56%, p<0.0001). NRM was not significantly different between the treatment groups at 3 years (18% vs. 22%, p=0.488). Furthermore, we examined patients age ≥75 years and confirmed improved 3-year OS with HCT vs. HMA/VEN (58% vs. 19%, p=0.0006). Conclusions: HCT provides OS benefit with HCT compared to HMA/VEN in patients ≥70 years, in subset ≥75 years and in patients achieving CR/CRi. These outcomes were primarily driven by an increased risk of relapse in patients treated with HMA/VEN. Although HMA/VEN is highly effective therapy for AML patients aged 70 an older, our study findings support treatment with HCT instead of continued HMA/VEN when clinically appropriate.