A concise review of BCL-2 inhibition in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal proliferation of myeloid precursors with impaired ability to differentiate to mature cells causing accumulation of leukemic blasts in bone marrow, peripheral blood, and extramedullary tissue. Our understanding of the genomic landscape of AML has improved prognostic accuracy and lead to the development of targeted therapies. In 2017 the Food and Drug Administration (FDA) approved midostaurin, gemtuzumab ozogamicin, CPX-351 and enasidenib for the treatment of AML. There are many novel agents under investigation for treatment of AML, but those that inhibit the anti-apoptotic molecule BCL-2 are of particular interest due to strong pre-clinical data and early promising clinical results. Areas covered: This article provides an overview of the pathophysiology of BCL-2 inhibition in AML, biomarkers and resistance mechanisms to BCL-2 inhibition and an update of results of the preclinical and clinical trials. Expert commentary: Venetoclax-based combination treatment for newly diagnosed elderly patients for whom intense chemotherapy is not an option may be the first setting in which this agent may be employed in AML. Based on pre-clinical evidence, BCL-2 inhibition may be useful in relapsed/refractory disease in conjunction with cytotoxic therapy, but has modest single agent activity.

Keywords: ABT 199; AML; BCL-2 inhibitors; novel agents in AML; venetoclax.