Venetoclax: A Game Changer in the Treatment of Younger AML Patients?

Simple Summary In recent studies, the combination of venetoclax with intensive chemotherapy has demonstrated encouraging results in the treatment of fit patients with de novo and relapsed/refractory acute myeloid leukemia (AML). This review focuses on ongoing clinical trials that investigated the addition of venetoclax to frontline regimens in younger AML patients and specific molecularly defined subgroups. Results of these trials indicate the potential benefits of integrating venetoclax into intensive chemotherapy strategies across European Leukemia Net (ELN) risk subcategories, thus offering valuable guidance for developing future clinical trials.Abstract The combination approach based on venetoclax (VEN) with azacytidine (AZA) has significantly improved outcomes for elderly patients with acute myeloid leukemia (AML). This innovative approach has led to higher rates of overall response, measurable residual disease (MRD)-negative remissions, and overall survival compared with AZA monotherapy. As a result, this combination has emerged as the gold-standard treatment for elderly or unfit patients with AML who are not eligible for intensive therapy. In younger, fit patients with AML, intensive induction and consolidation chemotherapy is commonly used as a first-line approach; however, relapse continues to be the main reason for treatment failure in approximately 30-40% of patients. Efforts to improve MRD-negative response rates and to facilitate the transition to allogeneic hematopoietic stem cell transplantation, particularly in high-risk AML, have inspired trials exploring the combination of intensive chemotherapy with targeted agents. VEN, a first-in-class anti-BCL2 agent, combined with intensive chemotherapy regimens has shown deep MRD-negative remissions, producing prolonged event-free survival and enhancing the transition to allogeneic transplant in first-complete-remission patients. These benefits support the incremental advantages of adding VEN to intensive chemotherapy approaches across ELN risk subcategories, and provides a robust benchmark to design future trials. In this review, we will discuss current studies assessing the efficacy of frontline regimens integrating VEN into intensive chemotherapy in younger patients with AML and specific molecularly defined subgroups.