An update on the efficacy of Venetoclax for chronic lymphocytic leukemia

ABSTRACT

Introduction

The BCL2 inhibitor venetoclax has dramatically changed the treatment of chronic lymphocytic leukemia (CLL) and has introduced the concept of time-limited therapy with targeted agents.

Areas covered

This review discusses the mechanism of action of venetoclax, adverse effects, and the clinical data with this agent as identified by a selective search of clinical trials in the PubMed database. Venetoclax is FDA-approved with anti-CD20 monoclonal antibodies; however, research is ongoing evaluating its efficacy when given in combination with other agents, such as the Bruton’s Tyrosine Kinase (BTK) inhibitors.

Expert opinion

Venetoclax-based therapy is an excellent treatment option for patients interested in time-limited therapy and can be offered in both the front-line and relapsed/refractory settings. Tumor lysis syndrome (TLS) risk evaluation, preventative measures, and strict monitoring should be conducted, while these patients ramp up to target dose. Venetoclax-based therapies produce deep and durable responses with patients often achieving undetectable measurable residual disease (uMRD). This has led to a discussion of MRD-driven, finite-duration treatment approaches, although longer term data is still needed. While many patients eventually lose uMRD status, re-treatment with venetoclax remains an area of interest with promising results. Mechanisms of resistance to venetoclax are being elucidated, and research is ongoing.

KEYWORDS:

• Chronic lymphocytic leukemia
• BCL2 inhibitors
• Venetoclax
• Measurable residual disease
• anti-CD20 monoclonal antibodies
• Bruton‘s tyrosine kinase inhibitors

List of abbreviations

CLL	=	Chronic lymphocytic leukemia
BTK	=	Bruton’s tyrosine kinase
TLS	=	Tumor lysis syndrome
BCL2	=	B-Cell lymphoma 2
PFS	=	Progression free survival
OS	=	Overall survival
DOR	=	Duration of response
MRD	=	Measurable residual disease
uMRD	=	Undetectable measurable residual disease
IGHV	=	Immunoglobulin heavy chain variable
R/R	=	Relapse/refractory
CR	=	Complete response
PR	=	Partial response
CRi	=	Complete response with incomplete count recovery
EFS	=	Event-free survival
EOT	=	End of treatment
ASO-PCR	=	Allele-specific oligonucleotide polymerase-chain-reaction
FC	=	Flow cytometry

Declaration of interest

P Bose reports no disclosures relevant to this manuscript, however, receives research support from Incyte, BMS, CTI, Kartos, Telios, Morphosys, Disc Medicine, Ionis, Blueprint, Geron, Janssen, Cogent and Sumitomo Pharma Oncology, in addition to consulting fees/honoraria from Incyte, BMS, CTI, GSK, Morphosys, Pharma Essentia, Karyopharm, Abbvie, Blueprint, Cogent, Jubilant and Novartis.

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

This paper was funded, in part, by the MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).