Dose-adjusted treatment with venetoclax for 7 days and 5-azacitidine or decitabine in patients with Acute Myeloid Leukemia or higher risk myelodysplastic neoplasms

Abstract

Abstract Introduction In patients unfit for intensive treatment, the combination of hypomethylating agents such as 5-azacitidine (AZA) or decitabine (DEC) with the oral BCL2-inhibitor venetoclax (VEN) has been the gold standard in treatment of acute myeloid leukemia (AML) in recent years. Initially, 7 days of AZA application in combination with VEN treatment for 28 days in 28-day cycles led to the approval of this treatment strategy in AML. Nonetheless, complications such as infections and thrombocytopenia frequently pose clinical challenges. We here report on n=61 patients with primary or secondary AML and n=5 higher-risk myelodysplastic neoplasm (MDS) of which n=14 were treated in a dosage reduced treatment regimen with AZA 75mg/m² for 7 days (5+2) or DEC 20mg/m² for 5 days and VEN for only 7 days. In this retrospective study, we sought to evaluate the feasibility of a reduced VEN duration of 7 days combined with standard doses of AZA or DEC in a cohort of AML and MDS patients who were either ineligible for intensive therapy or at high risk for treatment-related complications. Our goal was to assess whether a shorter VEN treatment period would maintain efficacy while reducing toxicity. Methods/Results We investigated AML/MDS cases with different durations of VEN application for either 7 days (7d), 14 days (14d) or >14 days (>14d), who were treated in our institution since 2018. Remission status was assessed according to EuropeanLeukemiaNet (ELN) 2022 AML response criteria. Overall response rate (ORR) was defined as best response (complete remission (CR), CR with incomplete hematologic recovery, CR with partial hematologic recovery, morphologic leukemia-free state) at any time after start with DEC/AZA and VEN. Complications of these therapies, namely infections, bleeding events and other events such as tumor lysis syndrome or cardiac failure were annotated for all groups. The cohort consisted of n=32 (n=3 MDS) patients with VEN treatment >14d, n=20 (n=2 MDS) with 14d and n=14 (no MDS) with 7d with similar clinical characteristics. There were no significant differences in age, ECOG status and ELN risk category between the treatment groups. ORR across all evaluable patients was 74% (37/50). No ORR differences were found with 64% (16/25) vs 79% (11/14) vs 91% (10/11) in evaluable cases (p=0.23) treated with >14, 14d and 7d, respectively. Compared to 7d VEN application (400mg daily or equivalent), complications, such as infections or bleeding were significantly higher in the >14d group (p=0.007) during the first 28 days of therapy. Evaluation of neutropenia was performed in 321, 244 and 289 28d-cycles of therapy in patients with >14d, 14d and 7d therapy regimens, respectively. Regarding thrombocytopenia, 402, 292 and 342 cycles were analyzed in the respective groups. At any time during the 28d-cycles, the rate of grade 4 neutropenia (p<0.001) or thrombocytopenia (p<0.001) was significantly lower in the 7d group compared to the >14d group. Of note, overall survival (OS) was not significantly different (p=0.4) between the three groups with median OS of 14, 22 and 29 months, respectively. Conclusion Our data suggest that a 7-day VEN regimen combined with AZA or DEC in standard doses yields response rates comparable to longer VEN application, with no differences in ORR when comparing similar cohorts. Shorter VEN exposure was associated with significantly fewer complications and less grade 4 neutropenia and thrombocytopenia, which are relevant concerns in these frequently elderly and frail patients.Importantly, OS did not differ significantly between treatment groups. These findings support that reducing VEN duration could be an effective yet less toxic treatment option, warranting further prospective evaluation.