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Ex vivo venetoclax sensitivity predicts clinical response in acute myeloid leukemia in the prospective VenEx trial
Abstract 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.
VenEx precisely predicts ven-aza response
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Introduction to a How I Treat series on iron overload in hematologic disorders
It has long been recognized that iron overload is toxic and that diagnosis and management of iron overload in patients with hematological disorders are complex and can be disease-specific. Associate Editor Thomas D. Coates presents a series that aims to deconvolute iron overload and provide advice on management. An overarching theme is that the magnitude and duration of exposure to reactive non–transferrin-bound iron, increased by ineffective erythropoiesis, transfusion, or upregulated iron absorption, determine tissue damage. Understanding this biology in a specific disease setting guides management. Coates reviews iron overload in transfusion-dependent hemoglobinopathies; Angelucci contributes insights on treating iron overload before, during, and after stem cell transplantation through discussion of 5 cases; and Leitch and Buckstein share their wisdom on treating iron overload in patients with myelodysplastic syndromes, outlining their approach in several common clinical scenarios.