Real‐World Survival Outcomes of Venetoclax Combination Therapies in Acute Myeloid Leukemia: Impact of Minimal Residual Disease Status and Antifungal Prophylaxis

In recent years the addition of the oral BCL2 inhibitor venetoclax to hypomethylating agents (HMAs) has emerged as the standard-of-care for patients with acute myeloid leukemia (AML) who are not fit for intensive chemotherapy, significantly improving survival and quality-of-life. Venetoclax is metabolized mainly by cytochrome P450 3A4 enzymes and serves as a P-glycoprotein substrate, which make it largely affected by interactions with drugs. Dose reductions are needed to allow mold active antifungal prophylaxis, but there is no consensus on the exact venetoclax target dose concomitantly with posaconazole. We report on efficacy and safety of venetoclax combinations in 38 first-line (FL) and 51 relapsed-refractory (R/R) AML patients. Although complete remission (CR) rate was lower in R/R than in FL (49% vs. 68%; p = 0.08), achievement of this status was associated with comparable median overall survival (OS) in R/R and FL (13.67 vs. 13.72 months). Eighteen (20%) patients underwent allogenic hematopoietic stem cell transplantation (HSCT) with a 2-year OS probability of 66.7%. Although antifungal prophylaxis was associated with a lower rate of grade 3-4 fungal infections (6% vs. 24%, p 0.044), patients treated with venetoclax daily dose of 50 mg with posaconazole had significantly shorter mOS in multivariate analysis (16.5 vs. 4.5 months; p 0.011). We conclude that AML patients in remission with venetoclax combinations may still be consolidated, and potentially cured, by HSCT, even after failure of intensive chemotherapy. Posaconazole prophylaxis effectively reduces risk of severe fungal infections, but a concomitant venetoclax dose of 50 mg may be sub-optimal.