Background: Ibrutinib is a first-in-class, once-daily inhibitor of BTK approved in the United States for treatment of CLL/SLL. RESONATE-2 is a phase 3 study comparing first-line ibrutinib versus chlorambucil in patients with CLL/SLL. Primary results (median follow-up, 18.4 months) demonstrated ibrutinib reduced risk of progressive disease (PD) or death by 84% (Burger, 2015).
Objectives: Educate on the benefits of continuous ibrutinib in the context of adverse event (AE) management and concomitant medications.
Methods: RESONATE-2 is an open-label, randomized study in first-line patients with CLL/SLL (N = 269) aged ≥65 years. Patients were randomized 1:1 to continuous once-daily 420-mg ibrutinib or ≤12 cycles of chlorambucil. In extended follow-up, progression-free survival (PFS) was investigator assessed. Safety data in extended follow-up focused on ibrutinib (n = 135).
Results: Median patient age was 73 years, 35% had lymph nodes ≥5 cm, 39% had anemia, and 65% had β2-microglobulin >3.5 mg/L. With a maximum follow-up of 55 months (median 48 months), ibrutinib resulted in significantly longer PFS (median not reached vs 15 months with chlorambucil), with 86% reduction in risk of PD or death versus chlorambucil. At 48 months, PFS rates were 74% and 16%, and overall survival rates were 86% and 76% for patients treated with ibrutinib and chlorambucil, respectively. With ibrutinib, overall response rate was 91%; investigator-assessed complete response with or without complete bone marrow recovery (CR/CRi) rates increased from 11% at primary analysis (3.7% CR rate by independent review) to 27% (16.2% CR rate sponsor confirmed) at median 48 months follow-up. CLL-related symptoms (weight loss, fatigue, fever, night sweats, abdominal pain, anorexia) improved more frequently with ibrutinib versus chlorambucil. Sixty-five percent of patients continue ibrutinib (median time on ibrutinib = 47 months; ≥3 years, 73%; ≥4 years, 41%). Reasons for ibrutinib discontinuation were AEs (19%), PD, or death (5% each), and patient or investigator decision (4%). AEs in ≥2 patients leading to ibrutinib discontinuation included atrial fibrillation (n = 4), palpitations (n = 2), and pneumonia (n = 2). Common AEs (≥25% of patients) occurring in follow-up included diarrhea (49%), fatigue (34%), cough (33%), peripheral edema (27%), anemia (25%), and nausea (25%). Major hemorrhage occurred in 10%, and atrial fibrillation occurred in 13% of ibrutinib-treated patients. Grade ≥3 AEs decreased from 58% in year 1 to 35% in year 4. AEs leading to ibrutinib dose reduction in >1 patient were anemia, thrombocytopenia, and arthralgia (n = 2 each). Ibrutinib was successfully re-escalated in 8 patients (range 75-1059 days) after dose reductions for AEs lasting 8-868 days. Discontinuations (7% in 0-1 year to 4% in 3-4 years) and dose reductions (8% to 3%) due to AEs decreased over time. Based on nurse experience with ibrutinib and RESONATE-2, education on AE management is important; nurses can educate patients, helping to optimize risk/benefit of ibrutinib. Nurse knowledge of potential concomitant medications (eg, azoles, CYP3A inhibitors, anticoagulants, amiodarone) that interact with ibrutinib is also critical.
Conclusions: With 4-year median follow-up, single-agent ibrutinib demonstrates continued efficacy with 86% reduction in risk of PD or death versus chlorambucil. The CR/CRi rate increased with ongoing ibrutinib. Discontinuation or dose reductions due to AEs decreased over time, with 65% of patients continuing first-line ibrutinib. Discussing AE management and drug-drug interactions with patients is important; nurses can help educate on the risk/benefit of continuous ibrutinib.
Funding source: Pharmacyclics LLC, an AbbVie company.