Abstract
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western adult population; it is also prevalent worldwide. The B cell lymphoma-2 (BCL-2) family proteins play a key role in regulating intrinsic apoptosis and, in many cancers, are the main culprits behind tumor survival and therapy resistance. Hence, the role of BCL-2 inhibitors is very beneficial in the treatment of CLL. Venetoclax is the first selective, orally bioavailable BCL-2 inhibitor.This review article discusses factors such as the pharmacokinetics, pharmacodynamics, acquired resistance to venetoclax, responders vs. non-responders in venetoclax monotherapy, and the synergistic role of venetoclax with other drugs in detail. Venetoclax is the first BH3 mimetic drug and selective BCL-2 inhibitor that has received FDA approval. This drug has proved to provide good therapeutic responses in CLL patients irrespective of the presence of adverse clinical or genetic features, including in patients with relapsed or refractory forms of CLL. We anticipate that novel combination therapies, including venetoclax and immunotherapy, will further alter the treatment landscape for patients with relapsed CLL, particularly for those with deletion 17p (del 17p) CLL, which carries a very poor prognosis.
Highlights
BackgroundChronic lymphocytic leukemiaChronic lymphocytic leukemia (CLL) is a hematological monoclonal neoplastic disorder
The main advantage of venetoclax over other agents is that it has a high binding affinity for B cell lymphoma-2 (BCL-2) receptors and it very selectively inhibits BCL-2, maintaining anti-apoptotic activity in cancer cells (Figure 1)[22]
Increased awareness and knowledge of CLL biology has enabled the synthesis of novel therapies that target specific steps of molecular pathways that facilitate tumor cell survival
Summary
Chronic lymphocytic leukemia (CLL) is a hematological monoclonal neoplastic disorder. The main advantage of venetoclax over other agents is that it has a high binding affinity for BCL-2 receptors and it very selectively inhibits BCL-2, maintaining anti-apoptotic activity in cancer cells (Figure 1)[22] Monotherapy with this agent facilitates a rapid reduction in the disease burden with a high overall response of about 80% and a complete response of 6-20% in patients with relapsed or refractory CCL, including those with chromosome 17p deletions [18,20]. Stimulation with CD40 and interleukin-4 (IL-4) causes overexpression of BCL-XL in CLL patients This can lead to resistance to much higher doses of venetoclax [42]. The overall survival estimate during the two-year duration for all the patients was 84% [18] Another multicenter, monotherapy, phase 2, single-arm clinical trial with venetoclax in patients with relapsed or refractory del(17p) CLL, was carried out by Stilgenbauer et al (2016).
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