Real-World Analysis of Adverse Event Rates after Initiation of Ibrutinib Among Medicare Beneficiaries with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia By Ibrutinib Discontinuation Status

Background: Ibrutinib is a standard of care in the treatment of frontline and relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). RCTs and prior multi-institutional real-world evidence (RWE) studies have shown several side effects to be associated with its use, often resulting in discontinuation of treatment earlier in the disease course. However, studies to date have not been drawn from large representative samples. The objective of this study was to describe the incidence rate of adverse events observed after ibrutinib treatment initiation in a real-world national sample of U.S. Medicare beneficiaries with CLL/SLL, stratified by ibrutinib discontinuation status (none vs. early vs. late).

Methods: This real-world cohort study used 2013-2019 100% Medicare claims data for elderly fee-for-service Medicare beneficiaries who newly initiated ibrutinib between 01/01/2014 to 12/31/2018 (index date = first ibrutinib prescription claim date). Patients were required to meet the following criteria: continuous Medicare Part A, B, and D coverage in the 12 months before and at least 4-months after the index date, presence of a diagnosis of CLL/SLL in the 12 months pre-index period and at any time over the follow-up period, ≥66 years on index date, absence of ≥2 diagnoses for another FDA-approved indication of ibrutinib, and absence of ibrutinib prescription in the 12 months pre-index period. Patients were classified as discontinuers (defined as the presence of a consecutive 60-day gap in treatment) or non-discontinuers; discontinuers were further stratified by whether they discontinued within 12 months of ibrutinib initiation or not (i.e., early vs. late). The primary outcome was the adverse event (AE) incidence rate per 1000 patient-months ([# of new AE cases / total person-months] * 1000). AEs were identified by the presence of an ICD-9/ICD-10 code in the medical claims and were measured over the duration of ibrutinib exposure (i.e., from ibrutinib initiation date to date of ibrutinib discontinuation or in the case of non-discontinuers until the end of the observation period). Only new cases of each of the AEs were coded and reported; hence, patients with evidence of a specific AE in the 12 months pre-index period (i.e., prior to ibrutinib initiation) were not coded as having an AE.

Results: The final sample contained 11,870 Medicare patients who newly initiated ibrutinib treatment (mean age 77.2, 35.3% age >80 years, 58.5% male, 90.1% White). Over a mean follow-up of 2.3 years, approximately two-thirds (65.2%) of patients discontinued ibrutinib. Among discontinuers, 69.2% discontinued within 12 months of starting treatment.

The most common AEs observed in both groups of discontinuers and non-discontinuers were hematologic AEs of anemia and thrombocytopenia and non-hematologic AEs of infections, arthralgia/myalgia, and cardiovascular comorbidities such as atrial fibrillation, heart failure, and ventricular arrhythmia. However, discontinuers had a higher incidence rate of AEs compared to non-discontinuers for each of the AEs examined (Table/Figure). Notably, the incidence rate of atrial fibrillation per 1000 patient months was 7.0 in non-discontinuers, 15.1 among all discontinuers, and 30.2 among discontinuers ≤12 months. The overall incidence rate including all examined AEs was nearly double for all discontinuers relative to non-discontinuers (62.5 vs. 32.9 per 1000 patient months) and over four times higher for the subgroup of discontinuers ≤12 months relative to both non-discontinuers (140.2 vs. 32.9 AEs per 1000 patient months) and discontinuers >12 months (140.2 vs. 34.5 AEs per 1000 patient months).

Conclusions: In this real-world study using 100% Medicare claims data, we observed higher AE incidence rates among patients who discontinued ibrutinib vs. non-discontinuers, particularly among patients who discontinued within 12 months of ibrutinib initiation. This study highlights a clear unmet need for improved management of treatment-related AEs and/or new treatments to improve real-world outcomes in patients with CLL.

De Nigris:Merck Sharp & Dohme: Current Employment. Huntington:Janssen: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; FlatonIron Health: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Merck: Consultancy; Seattle Genetics: Consultancy, Honoraria; Tyme: Consultancy; Pharmacyclics: Honoraria; AstraZeneca: Consultancy; Arvinas, Novartis, Servier, Bayer, SeaGen: Consultancy; Agios: Research Funding; Debiopharm Group: Research Funding; TG Therapeutics: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Celgene: Research Funding. Puckett:COVIA Health Solutions: Current Employment. Kamal-Bahl:COVIA Health Solutions: Current Employment; AbbVie, Inc.: Consultancy; Janssen, Inc.: Consultancy; Novartis, Inc.: Consultancy; Merck & Co., Inc.: Consultancy; 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:AbbVie, Inc.: Consultancy; Acadia: Consultancy; Allergan: Consultancy; Janssen: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Otsuka: Consultancy; Takeda: Consultancy; National Institutes of Health: Research Funding; PAN Foundation: Research Funding; Regeneron: Research Funding.