The Growing Role of the BH3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Abstract

Despite recent progress, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in the therapy of Venetoclax (VEN), a potent BH3 mimetic targeting the antiapoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed, and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacitidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2, and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes, and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients, the responses have only a limited duration, and the development of resistance is frequently observed. Therefore, understanding the resistance mechanisms is crucial for developing new strategies and identifying rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy), and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.