Utilization of Pharmacogenomics in Assessment of Tolerability and Efficacy of BTK Inhibitors

Background: Oral inhibitors of Bruton's tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). Despite excellent hematologic responses often seen with this class of medications, discontinuation may occur due to progression or intolerable side effects. It is not fully understood why some patients develop adverse events and discontinue BTKi therapy. A previous study suggested and association between intolerance to BTKi or phosphoinositide 3-kinase (PI3K) inhibitors in CLL patients with genetic polymorphisms in cytochrome P450 enzymes. Polymorphisms in CYP3A and CYP2D6 affect the metabolism of these agents and may lead to higher-than-expected plasma levels, leading to more adverse events. We therefore evaluated the results of pharmacogenomic testing in Veterans treated with BTKi to determine the extent to which pharmacogenomics polymorphisms are associated with response and intolerance to BTKi therapy.

Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and had undergone pharmacogenetic testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered to veterans at 22 sites across the United States. We retrospectively analyzed clinical factors including time on BTKi, reasons for temporary or permanent discontinuation or dose changes, medical comorbidities, and grade of pertinent side effects associated with BTKi (arrhythmia, hypertension, bleeding, fatigue, arthralgias, rash, diarrhea) as well as use of concomitant medications known to interact with CYP3A or CYP2D6.

Results:

A total of 61 Veterans were identified, of which 97% (59) were male and 72% (44) were diagnosed with CLL. Of the remaining patients, three were diagnosed with MCL, three with WM/LPL, two with refractory diffuse large B cell lymphoma (DLBCL), one with MZL, and one with monoclonal gammopathy and cold agglutinin disease. Forty-three patients (70.5%) were prescribed ibrutinib, while eight were prescribed acalabrutinib and two zanubrutinib. Twelve patients (20%) permanently discontinued therapy due to intolerance and eight patients (13%) progressed. Another 10 patients temporarily discontinued therapy due to side effects or infection. Median time treated with BTKi was 6.7 months for patients discontinuing for intolerance, 30.1 months for those discontinuing for progression, and 32.9 months for those not requiring discontinuation. The majority of patients who either temporarily or permanently discontinued therapy did so due to new arrhythmia (10 patients), while other complications included infection, pancytopenia, arthralgias, and fatigue. Nearly half of patients were concurrently taking another medication also metabolized through the CYP3A or CYP2D6. Of the 20 patients who progressed or were intolerant of BTKi, 14 (70%) were identified as CYP3A5 poor metabolizers, while 6 (30%) exhibited CYP2D6 intermediate metabolizing function. In comparison, of patients who did not discontinue BTKi, 31 patients (76%) were CYP3A5 poor metabolizers and 11 patients (27%) were CYP2D6 intermediate metabolizers.

Conclusions: In our cohort of patients with B cell malignancies who were prescribed BTKi, we identified those who discontinued either due to intolerable side effects or progression at a rate lower than previously reported in the Veteran population. We identified patient with pharmacogenomics polymorphisms that can affect plasma drug levels and are evaluating concurrent use of medication with can affect BTKi metabolism, as well as their effect on time to therapy discontinuation and adverse events. These results will inform the personalized selection of BTKi therapy for patients with B cell malignancies.

No relevant conflicts of interest to declare.