Nursing Experience in Patients with Chronic Lymphocytic Leukemia Receiving First-Line Ibrutinib: Up to 7 Years of Follow-Up from the Phase 3 RESONATE-2 Study

December 2021 Vol 12, No 12
Cara McGowan, NP
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
Jillian Settlemire, RN
Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA
Anita Szoke, MD
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA
Gabriel Krigsfeld, PhD
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA
Steven Coutre, MD
Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA
Paul Barr, MD
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY

Background: Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, is the only targeted therapy to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits in multiple randomized phase 3 studies in previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Single-agent ibrutinib is used as a continuous therapy, making oncology nurses critically important in supporting patients for maximum benefit with ibrutinib.

Objectives: To report up to 7 years of follow-up data for the RESONATE-2 study and provide experience-based nursing recommendations for educating patients on adverse event (AE) management and benefits of long-term adherence, aiming to optimize outcomes in patients with CLL/SLL receiving first-line ibrutinib.

Methods: The phase 3, open-label RESONATE-2 study compared efficacy and safety of first-line ibrutinib versus chlorambucil in older patients with CLL/SLL. Patients ≥65 years with previously untreated CLL/SLL and without del(17p) (N = 269) were randomized 1:1 to receive oral ibrutinib 420 mg once daily until disease progression (PD) or unacceptable toxicity (n = 136), or chlorambucil 0.5-0.8 mg/kg on days 1 and 15 of up to twelve 28-day cycles (n = 133). Outcomes included PFS, OS, overall response rate (ORR), and safety.

Results: After up to 7 years of follow-up (median 74.9 months; range, 0.1-86.8), ibrutinib resulted in significantly longer PFS (median not reached vs 15.0 months with chlorambucil), with 84% reduction in risk of PD or death versus chlorambucil. In patients with the high-risk genomic features del(11q) and unmutated IGHV, ibrutinib resulted in reductions of 97% and 89%, respectively, in risk of PD or death versus chlorambucil. After up to 6.5 years of ibrutinib, OS was 78%, and ORR was 92%. The complete response (CR/CRi) rate continued to deepen, with a rate of 34% at this follow-up. Rates of grade ≥3 AEs of clinical interest remained low: hypertension (5-6 year interval: 5%, n = 4; 6-7 years: 4%, n = 3), atrial fibrillation (5-6 years: 1%, n = 1; 6-7 years: 1%, n = 1), and no grade ≥3 major hemorrhage from 5-7 years. Dose reductions due to AEs decreased over time, occurring in 4% (n = 3) of patients from 5-6 years and 4% (n = 3) from 6-7 years. Ibrutinib discontinuations due to AEs also decreased, with 3% (n = 2) from 5-6 years and none from 6-7 years. The primary reason for ibrutinib discontinuation from 5-7 years was PD (5-6 years: 5%, n = 4; 6-7 years: 6%, n = 4). After up to 7 years, 47% of patients remained on ibrutinib. Nurses can educate patients on potential AEs and how active dose management can be used effectively throughout treatment. Nurses can encourage ibrutinib adherence by discussing long-term benefits of continuous therapy and/or providing medication diaries for tracking doses.

Conclusion: With up to 7 years of follow-up, first-line ibrutinib therapy demonstrated sustained PFS and OS benefits in patients with CLL, including those with high-risk genomic features. Rates of grade ≥3 hypertension, atrial fibrillation, and major hemorrhage remained low with long-term ibrutinib treatment, and discontinuations or dose reductions due to AEs were rare. Based on the long-term data available with ibrutinib, nurses can have an important role in discussing AE management and the risks and benefits of long-term ibrutinib treatment with their patients.

Sponsor: Pharmacyclics LLC, an AbbVie Company.


Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34:787-798.

Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133:2031-2042.

Fraser GAM, Chanan-Khan A, Demirkan F, et al. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020;61:3188-3197.

Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:43-56.

Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94:1353-1363.

Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381: 432-443.

Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528.

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