Ibrutinib in Elderly Patients with Chronic Lymphocytic Leukemia: Adverse Event Incidence, Management, and Outcome in a Canadian Real-World Setting

Introduction: The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib was first authorized by Health Canada in 2014 due to transformational efficacy in the treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and subsequently in patients with previously untreated CLL. Long-term clinical trial and real-world experiences have informed a comprehensive risk-benefit profile, enabling adverse event (AE) management strategies that optimize patient safety and efficacy outcomes. However, reports of serious AEs and recent head-to-head trials comparing next-generation BTKis to ibrutinib have led to concerns about its toxicity and continued use in clinical practice. To investigate and clarify this further, we assessed the incidence of AEs of special interest, and AE management strategies and their outcomes, in clinical practices that encompass all patients treated with ibrutinib for CLL in Saskatchewan since 2014. Methods: This is a retrospective cohort study utilizing medical chart reviewsof patients treated with ibrutinib for CLL in Saskatchewan from 2014-2023 with ≥12 months of follow-up from treatment start. Incidence of AEs of interest (anemia, arthralgia, atrial fibrillation, diarrhea, hypertension, infection, major bleeding, neutropenia, rash, thrombocytopenia) experienced while on active ibrutinib are reported. Management strategies for cases of first-onset AEs (foAEs; defined as initial occurrences of all AE types experienced by a patient) are characterized and include ibrutinib dose management (hold, reduction, discontinuation), symptomatic therapy (concomitant medication), and supportive (IV fluids, blood products) and vigorous supportive (surgery, intubation) interventions. Successful management of foAE is defined as resolution or control allowing continued active ibrutinib treatment. Results: Overall, 187 patients were treated with ibrutinib, with median time from treatment initiation to data cutoff of 3.1 years. Most patients received ibrutinib for relapsed CLL (33.7% 2L; 32.6% 3L+), with 33.7% receiving it 1L. Median [IQR] age was 75.7 [66.7-82.4] years, 63% male, with the highest prevalence of coexisting conditions at ibrutinib initiation being diabetes (15.5%), renal disease (10.2%), and chronic obstructive pulmonary disease (8.6%). All patients initiated ibrutinib as monotherapy at 420 mg. Median [IQR] duration of ibrutinib treatment was 2.9 [0.8-5.6] years. ≥1 AE of interest was observed in 81.3% of patients; 42.8% experienced two or more. AE incidence included infections (42.8%), diarrhea (29.4%), rash (17.6%), neutropenia (12.8%), arthralgia (10.2%), thrombocytopenia (10.2%), anemia (9.6%), atrial fibrillation (8.6%), hypertension (7.0%), and major bleeding (3.7%). No grade 5 AEs were observed. Overall AEs led to ibrutinib hold, dose reduction, and discontinuation in 29.9%, 11.8%, and 16.6% of patients, respectively. Of 284 foAE cases (72.2% gr1/2, 27.8% gr3/4) in 152 patients with ≥1 AE, 90.8% were successfully managed allowing continued active ibrutinib treatment [anemia (100%), rash (97%), arthralgia (94.7%), infection (93.7%), hypertension (92.3%), diarrhea (90.9%), thrombocytopenia (89.5%), neutropenia (87.5%), atrial fibrillation (75%), and major bleeding (42.9%)]. Management strategies included ≤1-month dose hold (12.3% cases) or 1-2 month hold (1.8% cases) followed by ibrutinib reinitiation at same or lower dose; symptomatic therapy (45%); and supportive (17.6%) and/or vigorous supportive (1.7%) interventions. Median time to successful management ranged from 27.0 days [range: 12.5-73.0] for infections to 84.0 days [range: 55.0-141] for hypertension. Overall, in patients with ≥1 AE, 82.2% had all, 7.9% had some, and 7.9% had no foAEs successfully managed (n=3 data missing). Conclusion: Overall AE and discontinuation rates were comparable or favourable to previous reports, with no AE-related deaths observed. Management strategies were effective for the majority of foAEs, enabling continued active ibrutinib treatment for most patients with ≥1 AE. This real-world analysis suggests that ibrutinib may be safely used and managed in a majority of CLL patients encountered in routine practice, including elderly patients. Future analyses should provide additional insight into any impacts of line of therapy, age, and comorbidities on AE incidence, management, and outcomes.

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