Outcomes of Hypomethylating Agents/Venetoclax (HMA/VEN) Treatment for Relapse of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) after Allogeneic Hematopoietic Cell Transplant (alloHCT)
Authors: Samuels Diana T , Ball Brian J. , Tsai NI-Chun , Blackmon Amanda , Agrawal Vaibhav , Pourhassan Hoda , Amanam Idoroenyi , Koller Paul B. , Arslan Shukaib , Otoukesh Salman , Sandhu Karamjeet S , Aldoss Ibrahim , Ali Haris , Salhotra Amandeep , Al Malki MHD Monzr M. , Artz Andrew , Becker Pamela S. , Aribi Ahmed , Smith Eileen Patricia , Forman Stephen J. , Stein Anthony S. , Marcucci Guido , Nakamura Ryotaro , Pullarkat Vinod 
Published: December 2024

The outcomes for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that have relapsed after allogeneic hematopoietic stem cell transplant (alloHCT) are poor. The regimens that have been used range from single agent hypomethylating agents to intensive regimens. There are limited data reporting on the efficacy of a hypomethylating agent with venetoclax (HMA/VEN) in this setting. In this study, we perform a retrospective review of HMA/VEN as salvage for relapse after alloHCT.
We retrospectively identified patients with relapsed AML or MDS after alloHCT between March 2017 and December 2023. The primary study endpoints were the rates of complete response (CR) and complete response with incomplete hematological recovery (CRi), and CR with minimal residual disease (MRD) negativity. CR and CRi were defined by the European Leukemia Net (ELN) 2022 classifications. MRD negativity was assessed using multiparametric flow cytometry with sensitivity of 0.01%. The secondary endpoint was overall survival (OS) starting from post-alloHCT HMV/VEN treatment. Fisher's exact test was used to assess contingency tables. OS was estimated using the Kaplan and Meier method, and differences were examined by the log-rank test. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). All tests were 2-sided at a significance level of p≤0.05.
A total of 84 patients with relapsed AML (n = 71) or MDS (n = 13) after allo-HCT were included. The median age was 64 (range 21-80), and median cycles of HMA/VEN received was 2 (range 1-21). Of these 84 patients, 46 (54.7%) had prior exposure to HMA/VEN. CR/CRi was achieved by 41.6% (n = 35) patients and of those patients 57.1% (n = 20) patients had MRD negative CR. Prior HMA/VEN exposure was not associated with response (35/64 vs 11/20, p=1.0).
At 6 and 9 months, OS for all patients was 53% (95% CI: 41.5-63.3) and 43% (95% CI: 31.7-53.7) respectively. OS for AML and MDS patients were not significantly different (P = 0.25). 6-month OS for AML and MDS patients were 49.6% (95% CI: 37.3-60.7) and 73.3% (95% CI: 37.9-90.6), and 9-month OS for AML and MDS patients were 39.7% (95% CI: 28-51.3) and 62.9% (95% CI: 28.2-84.3). Median OS for AML and MDS patients are 5.6 months (95% CI: 3.0 - 9.2) and 9.6 months (95% CI: 5.4 - 22.8), respectively. Additionally, OS at 6 and 9 months for both HMA/VEN naïve and HMA/VEN experienced patients was 57.2% (95% CI: 39.9-71.2) and 42.9% (95% CI: 26.7 - 58.1) versus 49.3% (95% CI: 33.7-63.2) and 43.2% (95% CI: 27.7 - 57.7) respectively (p = 0.53). Of note, HMA/VEN was combined with donor lymphocyte infusion (DLI) for 10.7% (n = 9) patients, and 23.8% (n = 20) patients had a second alloHCT after HMA/VEN. The most common adverse event was neutropenia, which occurred in 98.8% (n = 83) of patients and 97.6% (n = 82) had grade 3-4 neutropenia due to HMA/VEN. Within 30 days of the start of the last treatment cycle, the death rate due to adverse treatment effects was 4.76% (n = 4) and the cause of death for these patients were bacterial infections.
In summary, HMA/Ven is an effective and well tolerated salvage therapy for relapsed AML and MDS after alloHCT even for patients with prior HMA/VEN exposure. The optimal consolidation strategy after HMA/Ven treatment is unknown. Molecular and clinical determinants will be analyzed further to determine which patients may have the most benefit.