Improved outcomes with low-dose hypomethylating agent plus venetoclax as post-transplant maintenance in patients undergoing reduced intensity conditioning allogeneic hematopoietic stem cell transplantation for myeloid malignancies Free

Introduction: Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in patients receiving reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), is a major cause of treatment failure. The use of low dose hypomethylating agents (HMAs) such as azacitidine (AZA) or decitabine (DEC) in combination with venetoclax (VEN) has been shown to be a feasible post-HSCT maintenance strategy in myeloid malignancies. However, whether low dose HMA+VEN maintenance improves outcomes compared to no maintenance in patients undergoing RIC allo-HSCT is unclear.

Methods: We compared outcomes of adult patients with AML and MDS undergoing RIC allo-HSCT and receiving post-HSCT low dose HMA+VEN maintenance to a matched cohort of RIC allo-HSCT recipients that did not receive maintenance at our site from March 2020 to April 2025. Patients treated with post-HSCT HMA+VEN maintenance were matched in a 1:1 ratio to patients not receiving maintenance following a hierarchal algorithm based on age at transplant, disease type (AML vs. MDS), risk stratification (ELN for AML and IPSS-M for MDS), disease status at transplant, donor type, Fludarabine/Melphalan (Flu/Mel) conditioning and year of diagnosis. DEC was administered at 10mg/m² on days 1-3 per cycle, AZA was administered at 32.5mg/m² on days 1-5 per cycle and VEN was given at a target dose of 200mg per cycle. The dose of VEN was reduced to 20mg when administered with voriconazole or posaconazole or 100mg when administered with fluconazole or isavuconazium. The cycle length was 4-6 weeks.

Results: We identified 37 patients who received HMA+VEN maintenance following RIC allo-HSCT and matched them to 37 patients who did not receive maintenance therapy. The median follow-up for the maintenance and no maintenance group was 18m (range 4-54m) and 16m (range 1-62m), respectively. The maintenance and no maintenance groups were well balanced in terms of age (64y (range 34-75y) vs. 64y (range 19-73y)), gender (males: 60% vs. 60%), race and ethnicity (non-Hispanic whites: 70% vs. 80%), disease classification (AML: 62% vs 62%, MDS 38% vs. 38%), disease risk (AML ELN 2022 adverse risk 74% vs. 66%, MDS high/very high risk per IPSS-M 65% vs. 63%), disease status at transplant (AML CR 87% vs. 89% (MRD negative 65% vs. 67%) , MDS stable disease 64% vs. 71%), donor type (fully matched related or unrelated donors: 77% vs 84%) and Flu/Mel conditioning (59% vs 54%). More patients in the maintenance group received post-transplant cyclophosphamide-based graft versus host disease (GVHD) prophylaxis, compared to the no maintenance group (49% vs. 31%, p=0.03).

Maintenance was initiated after a median of 58d (range 45-207d) post-HSCT. Most patients received DEC (84%) and the median duration of VEN was 14d per cycle (range 7-28d). The median number of cycles administered was 5 (range 1-31). Grade III-IV neutropenia, anemia and thrombocytopenia occurred in 28%, 31% and 24% patients, respectively. Dose reduction or interruption of VEN was required in 37% patients due to adverse events with >90% of those patients being on 21 or 28d of VEN per cycle. The cumulative incidence (CI) of day 100 grade II-IV and III-IV acute GVHD was 24% and 3% in the maintenance group and 34% and 9% in the no maintenance group, respectively. The 1y CI of moderate-severe chronic GVHD was 28% and 35% in the maintenance and no maintenance groups, respectively. The median RFS and OS for the maintenance group vs. no maintenance group was NR vs. 21.9m (p=0.01) and NR vs. 31.3m (p=0.01), respectively. In multivariable analysis, maintenance (HR=0.61, 95% CI 0.41-0.78, p=0.01) improved OS whereas adverse-risk AML/high/very high risk MDS (HR=1.24, 95% CI 1.11-1.89, p=0.03) was associated with worse OS.

Conclusion: We report that the use of low-dose HMA+VEN as post-HSCT maintenance in patients undergoing RIC allo-HSCT for AML and MDS is a safe strategy with manageable hematological toxicities and no increased risk of GVHD. In this matched cohort, the use of maintenance was associated with improved survival compared to no maintenance. Further studies are needed to better understand the optimal dose and schedule of HMA+VEN post-HSCT maintenance and to validate the difference observed in our study.