Enhancing venetoclax activity in hematological malignancies

ABSTRACT

Introduction

Targeting anti-apoptotic pathways involving the BCL2 family proteins represents a novel treatment strategy in hematologic malignancies. Venetoclax, a selective BCL2 inhibitor, represents the first approved agent of this class, and is currently used in CLL and AML. However, monotherapy is rarely sufficient for sustained responses due to the development of drug resistance and loss of dependence upon the targeted protein. Numerous pre-clinical studies have shown that combining venetoclax with other agents may represent a more effective therapeutic strategy by circumventing resistance mechanisms. In this review, we summarize pre-clinical data providing a foundation for rational combination strategies involving venetoclax.

Areas covered

Novel combination strategies in hematologic malignancies involving venetoclax, primarily at the pre-clinical level, will be reviewed. We emphasize novel agents that interrupt complementary or compensatory pro-survival pathways, and particularly mechanistic insights underlying synergism. PubMed, Cochrane, EMBASE, and Google scholar were searched from 2000.

Expert opinion

Although venetoclax has proven to be an effective therapeutic in hematologic malignancies, monotherapy may be insufficient for maximal effectiveness due to the development of resistance and/or loss of BCL2 addiction. Further pre-clinical and clinical development of combination therapies may be necessary for optimal outcomes in patients with diverse blood cancers.

KEYWORDS:

• Antiapoptotic pathway
• BCL2
• leukemia
• lymphoma
• MCL1
• myeloma
• venetoclax

Article highlights

• BCL2 is one of the anti-apoptotic proteins and an important determinant of cell survival in various hematological malignancies.

• Venetoclax is an oral, highly selective BCL2 inhibitor that was developed to overcome on-target-related adverse effects of navitoclax.

• While venetoclax showed promising efficacy in vitro and in vivo, in early phase clinical trials, resistance to single-agent treatment occurred either de novo or was acquired during treatment.

• MCL1 upregulation is one of the major mechanisms of venetoclax resistance.

• Rational combination approaches with other novel agents to overcome resistance based on mechanistic considerations will be important to improve clinical outcomes.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One of the peer reviewers on this manuscript is subject to a share of royalty payments in relation to venetoclax. Additional reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Research funded by Leukemia and Lymphoma Society (R6508-18) and National Cancer Institute (P30CA016059,R01CA205607-03).