Real-World Treatment Patterns and Outcomes after Ibrutinib Discontinuation Among Elderly Medicare Beneficiaries with Chronic Lymphocytic Leukemia: An Observational Study

Background: Most prior studies of ibrutinib discontinuation in chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) rely on data from clinical trials and/or selected medical centers, which are often limited to younger and/or commercially insured patients and may not be generalizable to routine clinical practice. Also, limited data are available on the next line of treatment initiated after ibrutinib discontinuation in the real-world setting. The objective of this study was to examine ibrutinib discontinuation patterns, overall survival (OS) and factors associated with these patterns among elderly Medicare beneficiaries in the U.S.

Methods: This retrospective cohort study used 2013-2019 100% Medicare claims data to identify beneficiaries who newly initiated ibrutinib from 1/1/2014 to 12/31/2018. Study eligibility criteria included: continuous Medicare Part A, B, and D coverage in 12-months before and at least 4-months after the index date (first ibrutinib prescription claim date), CLL/SLL diagnosis in the 12-month pre-index period and at any time over follow-up, ≥66 years on index date, absence of ≥2 diagnoses for another FDA-approved indication for ibrutinib, and absence of ibrutinib prescription in the 12-month pre-index period. Outcomes included ibrutinib discontinuation (defined as the presence of a consecutive 60-day gap in ibrutinib treatment), time to ibrutinib discontinuation, type of CLL/SLL treatment initiated after ibrutinib discontinuation, and OS. Cox regression models were used to examine factors associated with ibrutinib discontinuation.

Results: Our final sample included a total of 11,870 Medicare patients newly initiating ibrutinib treatment. Nearly two-thirds (65.2%) of our cohort discontinued ibrutinib use over a median follow up of 25.2 months (IQR: 14.4-39.6) from initiation. Among those who discontinued ibrutinib, 51.1% discontinued within 6 months and 69.2% within 12 months. Among discontinuers, approximately 39% initiated another CLL/SLL treatment after ibrutinib discontinuation over a median follow up of 14.4 months (IQR: 4.8-27.6) post-ibrutinib discontinuation. Of the patients who initiated another CLL/SLL treatment after ibrutinib discontinuation, 21.3%, 18.9%, 10.8%, and 10.0% received venetoclax, rituximab, bendamustine and idelalisib, respectively, either as monotherapy or combination therapy. About 25% of patients who discontinued ibrutinib restarted treatment with ibrutinib at some point during follow-up. In multivariable analysis, patients aged ≥80 years (Hazard ratio [HR]: 1.51; 95% CI: 1.41-1.63); lack of low-income subsidy (LIS) to cover all or part of prescription out-of-pocket costs (HR: 1.08; 95% CI: 1.01-1.16); initiation of ibrutinib as part of combination therapy (HR: 1.16, 95% CI: 1.08-1.25); evidence of prior history of CLL treatment (HR: 1.14, 95% CI 1.08-1.20); atrial fibrillation (HR: 1.27, 95% CI 1.19-1.35); conduction disorders (HR: 1.11, 95% CI 1.03-1.20); heart failure (HR:1.09, 95% CI: 1.01-1.17) and; any hospitalization in the 12-month pre-index period were associated with discontinuation (HR:1.10, 95% CI:1.04-1.16). Lastly, median OS in the entire sample was 4.4 years after ibrutinib initiation. The 3-year survival rate was 72.2% for non-discontinuers but only 56.8% for discontinuers. Among patients who discontinued ≤12 months after initiation, less than half (47.4%) were still alive after 3 years.

Conclusions: In this large real-world analysis utilizing 100% Medicare files, the majority (65.2%) of elderly individuals initiating ibrutinib for CLL/SLL discontinued therapy over a median follow up of 25.2 months. Discontinuation was most likely in those with advanced age and baseline comorbidities. Overall, our findings demonstrate a high unmet need with ibrutinib, the widely used first generation Bruton-tyrosine kinase inhibitor (BTKI), in the elderly U.S. population with CLL/SLL. With the development of second and later generations of BTKIs, it will be important to confirm they offer lower discontinuation rates and improved real-world outcomes.

Huntington:Merck: Consultancy; Epizyme: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy; Beigene: Consultancy; FlatonIron Health: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Agios: Research Funding; Debiopharm Group: Research Funding; TG Therapeutics: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Seattle Genetics: Consultancy, Honoraria; Tyme: Consultancy; Pharmacyclics: Honoraria; AstraZeneca: Consultancy; Arvinas, Novartis, Servier, Bayer, SeaGen: Consultancy; Celgene: Research Funding. De Nigris:Merck Sharp & Dohme: Current Employment. Puckett:COVIA Health Solutions: Current Employment. Kamal-Bahl:Merck & Co., Inc.: Consultancy; Novartis, Inc.: Consultancy; Janssen, Inc.: Consultancy; AbbVie, Inc.: Consultancy; COVIA Health Solutions: Current Employment; PhRMA: Consultancy. Farooqui:Merck & Co., Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ryland:Merck & Co., Inc.: Current Employment. Sarpong:Merck & Co., Inc.: Current Employment. Yang:Merck & Co., Inc.: Current Employment. Doshi:PAN Foundation: Research Funding; National Institutes of Health: Research Funding; Takeda: Consultancy; Otsuka: Consultancy; Merck & Co., Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Allergan: Consultancy; Acadia: Consultancy; AbbVie, Inc.: Consultancy; Regeneron: Research Funding.