Current and emerging investigational venetoclax-based therapies in chronic lymphocytic leukemia

ABSTRACT

Introduction: Venetoclax has emerged as a breakthrough treatment which has revolutionized the therapeutic paradigm of chronic lymphocytic leukemia (CLL). This is primarily attributed to the efficacy of venetoclax as a time-limited, chemo-free, therapy in a field dominated by targeted agents given on a continuous schedule. Furthermore, compelling clinical data support the use of venetoclax in combination with other targeted agents in the hope of preventing drug resistance due to the emergence of acquired mutations.

Areas covered: This paper provides an overview of clinical results of newly approved or investigational venetoclax-based therapies for CLL. In view of current and potential roles in CLL care, the strengths and disadvantages of venetoclax-combinations are discussed. The MEDLINE database, ClinicalTrials.gov and conference proceedings were all reviewed to select the relevant literature.

Expert opinion: While the advent of venetoclax-based combinations has significantly expanded the therapeutic options for patients with CLL, further research with longer follow-up is required to address remaining open questions such as (I) the role of venetoclax as fixed duration therapy(II) timing and threshold of minimal residual disease (MRD) assessment for therapy discontinuation, (III) the efficacy of novel triplet combinations with venetoclax as backbone therapy, (IV) indications for the re-initiation of therapy with venetoclax.

KEYWORDS:

• CLL
• chronic lymphocytic leukemia
• venetoclax
• combination therapy
• venetoclax-based therapies
• minimal residual disease
• MRD

Article highlights

• Targeting the Bcl-2 pathway is a rational therapeutic approach in CLL. Therefore, the addition of venetoclax to the toolkit of CLL therapy represents an important development in the field.

• Double or triple, chemo-free, venetoclax-based combinations have been recently evaluated in CLL. The idea behind these regimens is to administer fixed duration therapy, rather than exposing patients to continuous treatment.

• With the widespread use of venetoclax-based regimens, the treatment of CLL patients who become refractory to novel agents is an area of unmet need.

• Future directions to overcome resistance mechanisms to venetoclax should explore new approaches based on novel BH3 mimetic developed to interact with either MCL-1 protein or transcriptional regulators of Mcl-1 expression.

• Cellular therapies (i.e. CAR-T) are challenging in patients with progressive disease who are double-refractory.

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Declaration of interest

The authors have no 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 reviewer has the following disclosures: Abbott Laboratories: Minority ownership interest.

AbbVie: Consultancy. AstraZeneca: Consultancy. Pfizer: Research funding. Pharmacyclics: Consultancy. Vaniam group: Consultancy. Verastem: Consultancy (uncompensated).

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

Additional information

Funding

This paper was not funded.