Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant

Background Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. Patients and Methods We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. Results CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among non-responders (95% CI, 1.8-4.4 months; log-rank, P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. Conclusion These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity. MicroAbstract The combination of hypomethylating agents and venetoclax have revolutionized frontline management of acute myeloid leukemia, but its efficacy and safety following allogeneic hematopoietic cell transplant relapse are not well understood. We conducted a retrospective review of 72 such patients treated with this combination in our center comprising the largest single-institution cohort reported. Responses occurred in nearly half the patients (48% complete response rate with or without hematologic recovery) comparing favorably with historical estimates observed with chemotherapy and could be deep (10 of 12 tested patients achieved minimal residual disease-negative status) and durable lasting on median 18 months. Although better tolerated than intensive cytotoxic chemotherapy and having the advantage of outpatient administration, we observed prolonged cytopenias in nearly a third of patients and modification of the Venetoclax schedule was commonly required.