Four Years of Follow-Up for Ibrutinib as First-Line Treatment of Older Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Long-Term Data and Oncology Nurses’ Experience with Adverse Event Management

November 2018 Vol 9, NO 11
Edythe M. Greenberg, PhD, RN, FNP-BC
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Jillian Settlemire, RN
Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA
Sandra Dai, PhD, MS
The University of Texas MD Anderson Cancer Center
James P. Dean, MD, PhD
The University of Texas MD Anderson Cancer Center
Tony Lin, PharmD
The University of Texas MD Anderson Cancer Center
Steven Coutre, MD
Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA
Jan Berger, MD, PhD
The University of Texas MD Anderson Cancer Center

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.

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