Advancing the standard: venetoclax combined with intensive induction and consolidation therapy for acute myeloid leukemia

Abstract

The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with lower-intensity therapy is an efficacious treatment for acute myeloid leukemia (AML). VEN in combination with the hypomethylating agent azacitidine improved rates of response and measurable residual disease (MRD)-negative remissions in addition to overall survival in the pivotal phase 3 VIALE-A trial compared with azacitidine monotherapy and has since emerged as the current standard of care in older or unfit patients with AML. In younger, fit patients with AML, intensive induction and consolidation chemotherapy (IC) is commonly employed as frontline therapy; however, relapse remains the principal cause of treatment failure in approximately 30-40% of patients. Improved IC regimens that increase MRD-negative response rates, result in durable remissions, and enable transition to curative allogeneic hematopoietic stem cell transplantation in appropriate patients remain an area of active inquiry. Preliminary results from trials investigating the combination of VEN with IC have reported promising findings to date, with composite complete remission and MRD-negative remission rates of approximately 89-94% and 82-93%, respectively, correlating with improved 12-month event-free and overall survival compared to historical outcomes with IC. Herein, we discuss ongoing trials investigating VEN in combination with IC in addition to outcomes within specific molecularly defined subgroups; review the molecular mechanisms of sensitivity and resistance to VEN, and highlight future combinations of VEN with novel targeted therapies for the treatment of AML.

Keywords: acute myeloid leukemia; intensive induction; venetoclax.

Figure 1.

Intrinsic apoptotic pathway and BCL-2 family biology.

Figure 2.

Intensive chemotherapy-based induction and consolidation regimens incorporating venetoclax for the treatment of AML. *peg-filgrastim permitted to replace filgrastim on D5 (induction) or D3 (consolidation). ψ venetoclax administered at varying dosage by cohort (A: 50 mg, B: 100 mg, C: 200 mg, D: 400 mg, E: 600 mg).