In a study presented at the 2023 ASCO Annual Meeting in Chicago, Illinois, researchers used pharmacogenomic (PGx) testing to determine whether cytochrome P450 (CYP) polymorphisms contribute to Bruton’s tyrosine kinase inhibitor (BTKi) discontinuation. BTKis are commonly used to treat a variety of B-cell lymphomas, including chronic lymphocytic leukemia, mantle cell lymphoma, and marginal zone lymphoma, and treatment is typically stopped due to drug intolerance. The researchers sought to determine what potential factors, such as CYP polymorphisms, contribute to that intolerance.

Fahmin Basher, MD, Duke Cancer Institute, Durham, North Carolina, and colleagues evaluated patients treated through the Veterans Administration and included in their study those that had been prescribed a BTKi and had taken part in the Pharmacogenomic Testing for Veterans program. They included factors such as the time on BTKi therapy, discontinuation reasons, and use of concomitant medications in their analyses. The time from BTKi start to discontinuation was established as the event-free survival (EFS) period.

Basher and colleagues were able to identify 89 veterans who were treated with a BTKi and had undergone PGx testing. About 97% of these patients were male, and 85% had a CLL diagnosis. Of these 89 patients, 77 were given ibrutinib, 9 acalabrutinib, and 3 zanubrutinib. In addition, 25 patients received strong CYP2C19 inhibitors and 3 were classified as having the poor metabolizer genotype (PMG) for CYP2C19. Within the median follow-up period of 38.9 months, 25 patients had discontinued their BTKi treatment temporarily, 25 had permanently discontinued because of intolerance, and 10 experienced disease progression. In the study, the median treatment duration was 38.5 months for patients who continued BTKi therapy, 23.2 months for those who discontinued because of disease progression, and 11.0 months for those who discontinued because of treatment intolerance. Patients cited arrhythmia, bleeding, and infections as some of the reasons for the intolerance.

When they calculated EFS, the researchers found that there was statistical significance in EFS from intolerance in patients categorized as CYP2C19 PMG or patients who received strong CYP2C19 inhibitors vs other patient groups (P = .014, median 49.4 months vs not reported). However, EFS from disease progression (P = .76, median 79.6 vs not reported) and overall EFS were not statistically significant.

Finally, Basher and colleagues found that participants who were given a BTKi as a part of their treatment and either also took strong CYP2C19 inhibitors or were identified as CYP2C19 PMG were more likely to experience side effects during BTKi treatment that led to discontinuation. “Our results suggest that evaluating polypharmacy and PGx factors should be considered when prescribing BTKi,” the authors stated in their study. These side effects often lead to discontinuation of BTKi therapy and should be considered when giving patient care.

Source:

Basher F, Scobie M, Kelley M, et al. Utility of pharmacogenomic testing in predicting intolerance to BTK inhibitors; June 2-6, 2023; Chicago, IL, and virtual; Abstract 7541.