Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer?

ABSTRACT

Introduction

Acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis and high rates of relapse, especially in elderly patients who are ineligible to receive intensive chemotherapy. Venetoclax, an oral BCL-2 inhibitor, is approved by the Food and Drug Administration in combination with hypomethylating agents or low-dose cytarabine in newly-diagnosed AML patients who are ineligible to receive intensive chemotherapy. Confirmatory phase III VIALE-A and VIALE-C trials showed a composite complete remission rate of 66.4% and 48%, respectively. Thus, further validating venetoclax as an attractive therapeutic option in the AML treatment landscape.

Areas covered

A review of venetoclax in AML, focusing on preclinical and clinical data, toxicity profile, and mechanisms of resistance; and its strengths and weaknesses in regards to its current and future role in AML treatment is discussed. To find relevant studies, authors searched PubMed/Medline and ClinicalTrials.gov.

Expert opinion

The introduction of venetoclax-based combination therapies has greatly expanded the therapeutic options for elderly and chemotherapy-ineligible AML patients. Additional studies with extended follow-up are necessary to address remaining open questions such as (I) durability of responses, (II) head-to-head comparisons with intensive chemotherapy in selected patients (e.g. TP53 mutations), and (III) novel triplet combinations using an HMA-venetoclax backbone.

KEYWORDS:

• Venetoclax
• acute myeloid leukemia
• venetoclax with azacitidine/decitabine
• venetoclax mechanism of resistance
• aml in elderly patients
• treatment for intensive chemotherapy ineligible aml patients

Article highlights

• While treatment options for elderly patients or the patients who are unfit to receive intensive chemotherapy regimens are hypomethylating agents or low-dose cytarabine; almost 60% of patients do not receive specific antileukemic treatment which is associated with poor survival.

• Venetoclax (ABT-199) is a BH3 mimetic that confers high selectivity for the BCL-2 protein, which plays a major role in the intrinsic (mitochondrial) apoptotic pathway.

• Two recently published pivotal phase II trials VIALE-A and VIALE-C established the role of using venetoclax in combination with HMAs and LDAC, respectively, for AML patients unfit for intensive chemotherapy regimen.

• Considerable number of patients either do not respond to the treatment with venetoclax or experience early relapse due to various resistance mechanisms including but not limited to overexpression of other antiapoptotic protein -myeloid cell leukemia-1 and BCL-XL; decreased proapoptotic protein expression – p53, NOXA; or increased levels of nicotinamide. Better understanding of mechanism is needed to optimize venetoclax effect and reduce resistance.

• Various clinical trials are ongoing that evaluate the use of venetoclax or venetoclax with HMA/LDAC in combination with novel agents including myeloid cell leukemia-1 (MCL-1) inhibitors, cyclin-dependent kinase 9 (CDK9) inhibitors, murine double minute homolog 2 (MDM2) inhibitor, neural cell developmentally downregulated 8 (NEDD8) inhibitor, FLT3 inhibitors, and IDH1/2 inhibitors.

Declaration of interest

A. Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA); received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics; participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Trovagene, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, and Tyme; served on steering and independent data review committees for clinical trials for Novartis, Abbvie, Geron, and Janssen and has received travel support for meetings from Pfizer, Novartis, and Trovagene. 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Research reported in this publication was supported by the NCI of the National Institutes of Health under Award Number P30 CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.