Integrated and Long-Term Safety Analysis of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Ibrutinib (ibr), a first-in-class, oral once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Unlike chemotherapy that is given for a finite number of cycles, ibr is continued until progressive disease (PD) or unacceptable toxicity, leading to extended ibr treatment duration in many patients. Coutre and colleagues presented the results of a study designed to examine the long-term safety and tolerability of single-agent ibr therapy in patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL using an integrated safety analysis approach.

The analysis included patients from the RESONATE study, in which patients with R/R CLL/SLL received ibr 420 mg orally once daily versus ofatumumab1; and RESONATE-2, in which patients age ≥65 years with TN CLL/SLL received ibr 420 mg orally once daily versus chlorambucil.2 Data from patients treated with ibr 420 mg daily from these randomized controlled studies were pooled for an integrated safety analysis.

The integrated analysis included 330 patients: 51% Rai III/IV, 54% with bulky disease ≥5 cm, 28% with del11q, 37% with creatinine clearance <60 mL/min, and 59% with baseline cytopenias. Patients received ibr for a median of 29.0 months (max 42.9); 280 (85%) treated for >1 year, 193 (58%) for >2 to 3 years, and 53 (16%) for >3 years. A total of 124 patients (38%) discontinued treatment, whether for progressive disease (16%), adverse events (AEs; 11%), or other reasons. The most common AEs were diarrhea (53%) and fatigue (36%). Other AEs experienced by ≥25% of patients were upper respiratory tract infection (30%), nausea (29%), pyrexia (28%), and anemia (27%). Grade ≥3 AEs reported in ≥5% of patients were neutropenia (18%), pneumonia (12%), anemia (7%), and hypertension (6%). AEs of any grade that led to dose reductions and discontinuation were reported in 13% and 19% of patients, respectively. AEs leading to discontinuation in >1 patient included pneumonia (n = 4), anemia (n = 3), atrial fibrillation (n = 3), diarrhea (n = 2), subdural hematoma (n = 2), and thrombocytopenia (n = 2). Twenty-nine (9%) patients died, the most common causes of death were PD (n = 8) and pneumonia/lung infection (n = 7). Overall survival for R/R patients was 74% at 36 months in RESONATE, and 62% at 60 months in a long-term extension study of RESONATE/RESONATE-2. Survival of TN patients was 95% at 24 months in RESONATE-2, and 91% at 60 months in the long-term extension studies. The authors conclude that in these analyses, of 424 patients, which included up to 5.6 years of follow-up in TN and R/R CLL treated with single-agent ibr, AEs were primarily grade 1/2 and were manageable, allowing the majority of these older patients to have prolonged treatment.

Coutre S, et al. ASH 2016. Abstract 4383.

1. Byrd JC, et al. N Engl J Med. 2013;369:32-42.
2. Burger JA, et al. N Engl J Med. 2015;373:2425-2437.

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