Ex vivo venetoclax sensitivity predicts clinical response in acute myeloid leukemia in the prospective VenEx trial

The B-cell lymphoma 2 inhibitor venetoclax has shown promise for treating acute myeloid leukemia (AML). However, identifying patients likely to respond remains a challenge, especially for those with relapsed/refractory (R/R) disease. We evaluated the utility of ex vivo venetoclax sensitivity testing to predict treatment responses to venetoclax-azacitidine in a prospective, multicenter, phase 2 trial. The trial recruited 104 participants with previously untreated (n = 48), R/R (n = 39), or previously treated secondary AML (sAML) (n = 17). The primary end point was complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate in ex vivo sensitive trial participants during the first 3 therapy cycles. The key secondary end points included the correlations between ex vivo drug sensitivity, responses, and survival. Venetoclax sensitivity was successfully assessed in 102 of 104 participants, with results available within a median of 3 days from sampling. In previously untreated AML, ex vivo sensitivity corresponded to an 85% (34/40) CR/CRi rate, with a median overall survival (OS) of 28.7 months, compared with 5.5 months for ex vivo resistant patients (P = .002). For R/R/sAML, ex vivo sensitivity resulted in a 62% CR/CRi rate (21/34) and median OS of 9.7 vs 3.3 months for ex vivo resistant patients (P < .001). In univariate and multivariate analysis, ex vivo venetoclax sensitivity was the strongest predictor for a favorable treatment response and survival. This trial demonstrates the feasibility of integrating ex vivo drug testing into clinical practice to identify patients with AML, particularly in the R/R setting, who benefit from venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04267081.