Dr Islam on Novel Explorations of BTK Inhibitors in MCL and CLL

Prioty Islam, MD, MSc, attending physician, medical oncologist, Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the exploration of novel roles for BTK inhibitors in the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (MCL).

Due to recent successes derived from treatment with BTK inhibitors in CLL and MCL, there continues to be interest in furthering their utility by harnessing novel combination regimens, targeting mechanisms, and prognostic features, Islam begins.

Many clinical trials are evaluating the addition of BTK inhibitors with BCL2 inhibitors, such as an investigation of frontline acalabrutinib (Calquence) and venetoclax (Venclexta), Islam states. This could provide patients with an all-oral, time-limited treatment alternative to either standard continuous BTK inhibitor therapy or the combination of a BCL2 inhibitor and a monoclonal antibody infusion, Islam explains. The goal of further developing novel combination regimens is to improve upon the convenience, tolerability, and efficacy of currently available strategies, she adds.

Moreover, there is additional interest in if minimal residual disease (MRD) may inform the duration of BTK inhibitor treatment, Islam continues. Any BTK inhibitors that are currently approved for use are approved with continuous administration until disease progression or intolerance, she says. Some patient subsets may benefit more from a truncated or attenuated treatment course, but this population has not yet been identified, Islam notes. To utilize a time-limited treatment strategy with BTK inhibitors, co-administration of an additional novel therapy may be necessary. This could induce deeper remissions, as complete responses with BTK inhibitor monotherapy are typically uncommon, Islam details.

Lastly, an emerging area of research in both MCL and CLL is focused on discovering alternative methods of targeting the BTK protein, Islam says. Current BTK inhibitors are either covalent, in which the agent irreversibly binds to the BTK protein, or noncovalent, in which this bond is reversible.

However, there may be other ways to inhibit BTK mutations. For example, several agents currently in development have been designed to degrade the BTK protein, Islam introduces. Because this approach would blockthe BTK signaling pathway in its entirety, this method could also overcome or prevent the development of BTK inhibitor resistance through its varied mechanisms, Islam concludes.

Disclosures: Dr Islam reports consulting roles with AbbVie, AstraZeneca, BeiGene, DAVA Oncology, and LOXO Oncology; as well as speaking roles with Targeted Oncology and The Video Journal of Hematologic Oncology (VJHemOnc).

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