Ibrutinib Interactions Raise Infection Risk 30%

There was a strong association between drug interactions and hospitalizations among patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib (Imbruvica; Pharmacyclics and Johnson & Johnson) in a recent study, underscoring the need for careful monitoring for these patients in real-world practice.1

The population-based study, recently published in the British Journal of Haematology, found that while survival outcomes were not impacted, risk of infection was notable.

The first-generation Bruton tyrosine kinase inhibitor is metabolized by cytochrome P450 3A (CYP3A), making it highly susceptible to drug-drug interactions. Concomitant use of CYP3A inhibitors can raise ibrutinib levels and toxicity risk, while inducers can lower its effectiveness. Data have shown that co-administration of ibrutinib and a strong CYP3A inhibitor increases the serum concentration of ibrutinib by nearly 30-fold and that a strong CYP3A inducer decreases serum concentrations by more than 13-fold.2

Despite clinical trial protocols excluding patients on strong CYP3A modulators, real-world use is complicated by polypharmacy, particularly in older patients with multiple comorbidities. In this new study, researchers analyzed data from 642 patients in Ontario, Canada, aged 66 years or older who started ibrutinib between 2007 and 2019. Over half received ibrutinib as first-line therapy, and most were treated at its full dose.1

Nearly 3 in 4 (71.8%) patients received at least one potentially interacting drug throughout treatment. CYP3A inhibitors were most frequent, prescribed in 62.9% of cases, while 10.9% received CYP3A inducers. Common inhibitors included ciprofloxacin, fluconazole, and diltiazem, while inducers were most often phenytoin and carbamazepine.

Despite the frequent potential for drug-drug interaction, exposure to CYP3A inducers or inhibitors was not linked to worse overall survival (OS) after adjusting for age, comorbidity, and dosing. Across the cohort, 25% of patients died during follow-up, most commonly due to disease progression.

“Reassuringly, there was no association with OS, which may suggest that providers are appropriately monitoring these interactions and making dose adjustments when required.” Wrote the researchers. “The role of oncology pharmacists in assessing drug–drug interactions has been deemed important by patients and providers, which is of particular importance as several new drugs for front-line and relapse refractory CLL, including acalabrutinib, zanubrutinib, and venetoclax, are metabolized by CYP3A isozyme and will also need careful drug–drug interaction assessment.”

A secondary analysis done by the researchers showed that 13.4% of patients were admitted to the hospital for bleeding, and concomitant CYP3A inhibitor use showed a trend toward increased bleeding risk, though it did not reach statistical significance.

Hospitalizations due to infection were more common, with 44.7% of patients being hospitalized due to the complication, most commonly (70.6%) for bacterial infection. Viral infections accounted for 24% of infection-related hospitalizations. Patients receiving a CYP3A inhibitor were nearly 3 times more likely to be hospitalized for infection (odds ratio, 2.88; 95% CI, 1.29-6.43). This association remained significant at 60- and 90-day windows.

Notably, anticoagulant and antiplatelet use was also common (27% and 6%, respectively). Given ibrutinib’s inherent bleeding risk and potential CYP3A competition with anticoagulants, the study reinforces guideline recommendations to avoid or minimize dual therapy when possible.

“In general, concurrent use of ibrutinib and anticoagulants is not recommended,” wrote the researchers. “If anticoagulation is required and no alternate therapies for CLL are available, careful discussion with the patient regarding the risks versus benefits is suggested. For patients at high cardiovascular risk, ibrutinib and low-dose aspirin can be considered for secondary prevention.”

With a median follow-up of only 1.7 years, longer studies will be needed to assess whether interactions impact long-term outcomes.