Real-world safety and discontinuation patterns of ibrutinib in B-cell malignancies: A 9-year experience from Qatar

Abstract

Abstract Background: Ibrutinib, the first approved Bruton's tyrosine kinase inhibitor, is used in the management of first-line and relapsed/refractory (R/R) of B-cell malignancies, either as monotherapy or in combination with other agents.While effective, ibrutinib is associated with adverse drug events (AEs) that can lead to treatment discontinuation. This study aimed to evaluate the incidence of AEs, time to and reasons for discontinuation, and explore treatment patterns for patients who received ibrutinib in Qatar. Methods: This retrospective observational cohort study was conducted at the National Center for Cancer Care and Research (the only cancer center in Qatar) to evaluate the use and safety profile of ibrutinib in patients who initiated treatment between Jan 2016 and Dec 2024. Patients aged 18 years or older were identified through local electronic health records. Follow-up continued until the last visit, treatment discontinuation, death, or loss to follow-up. The data collected included patient demographics, ECOG performance status, comorbidities, and treatment details (dose, indication, drug interactions). AEs were reviewed from physician documentation and AEs reporting forms. Comorbidity burden was assessed using a simplified Cumulative Illness Rating Scale (CIRS). Statistical analyses included descriptive statistics, Kaplan–Meier estimates for 12-month AE incidence, and Cox proportional hazards modeling to identify factors associated with significant AEs. All analyses were performed using R version 4.3. Results: A total of 65 patients were included, 76.9% of whom were male with a median age of 62 years (IQR: 51–68). ECOG performance status was ≥2 in 25.7% of patients. Comorbidities included Hypertension (HTN; 48%), type 2 diabetes mellitus (32%), dyslipidemia (25%), and chronic kidney disease (11%). Cardiac history was documented in 25% of patients. Concomitant antiplatelet or anticoagulant use was reported in 20%, with drug interactions identified in 28%. Most patients were prescribed ibrutinib monotherapy (58.5%) in the R/R setting (64.6%), at the initial dose approved per indication (83.1%). The most common indication for ibrutinib was chronic lymphocytic leukemia (72%), followed by marginal zone lymphoma (9.2%) and mantle cell lymphoma (6.2%). Overall, most patients (45%) experienced ≥ 2 toxicities, with the most frequent AEs being cardiac (40.6%), and worsening HTN in 29% of patients with baseline HTN (n=31). Other common AEs were dermatologic (25%), hematologic (21.9%), and infections (20%). Bleeding occurred in nine patients, with two being on antiplatelet or anticoagulant therapy. Dose reduction was performed in 12 patients, with the reasons including physician assessment of patient tolerance (n = 5), skin toxicity (n = 2), uncontrolled HTN (n = 1), palpitations (n = 1), neutropenia (n = 1), epigastric pain (n = 1), and an unspecified reason (n = 1). Logistic regression analysis showed no significant association between toxicity and either age (p = 0.36) or type of therapy (monotherapy vs. combination; p = 0.61). The median duration of treatment was 748 days (range, 14–2,949 days). The 1-year cumulative incidence of toxicity was 76%, with a median time to first toxicity of 114 days (95% CI: 63–194). The median time to ibrutinib discontinuation was 265 days (95% CI: 190–576), which was significantly shorter among patients with an ECOG score of 3 (p = 0.01). Although not statistically significant, patients with CIRS ≥ 4 tended to have higher rates of AEs and earlier discontinuation. Overall, ibrutinib was discontinued due to toxicity (n = 8), disease progression (n = 7), and repatriation (n = 8). At the time of analysis, 63% of patients were alive, 15% lost follow-up, and all-cause mortality was 20%. Documented causes of death included disease progression (15.4%), COVID-19 complications (23.1%), sepsis (30.8%), and other events such as malignancy-related death. Conclusion: In this real-world analysis, ibrutinib was associated with a high incidence of AEs, particularly cardiac, dermatologic, and hematologic toxicities, resulting in a median treatment duration of less than nine months. The rate of treatment discontinuation due to toxicity was comparable to that in other real-world studies and was significantly influenced by performance status. This highlights the need for close monitoring and proactive management of adverse events, particularly in patients with comorbidities or poor functional status.