Early Adoption and Outcomes of Ibrutinib As Treatment for Older Patients with Chronic Lymphocytic Leukemia (CLL): A Population-Based Study
Authors: Olszewski Adam J , Davids Matthew S. , Yakirevich Inna , Egan Pamela C 
Published: February 2020

Background: The availability of ibrutinib, an oral Bruton's tyrosine kinase inhibitor, has transformed the management of CLL. For older patients, first-line ibrutinib (± obinutuzumab) has shown advantage over chlorambucil (± obinutuzumab; Burger, NEJM 2015; Moreno, Lancet Oncol 2018) or bendamustine/rituximab (Woyach, NEJM 2019). However, its high cost raises concerns about potential disparities in access. Other concerns in older patients include the risk of atrial fibrillation (AFib), ventricular arrhythmias (VArr), or central nervous system hemorrhage (CNSh) associated with ibrutinib. We examined treatment patterns and outcomes among Medicare beneficiaries with CLL after the approval of ibrutinib in 2014.
Methods: Using the linked SEER-Medicare registry, which covers ~34% of the US population, we identified Medicare beneficiaries with CLL diagnosed in 2007-2015, who had complete claims (including outpatient prescriptions), and who received systemic treatment in 2007-2016. We identified ibrutinib use as first or subsequent lines of therapy. We classified common first-line regimens as: 1) rituximab alone, 2) bendamustine ± CD20 antibody, 3) obinutuzumab ± chlorambucil, 4) other cytotoxic agents, and 5) ibrutinib (± CD20 antibody). We calculated total spending (observed in SEER-Medicare data) on CLL drugs per year, described duration of ibrutinib therapy, survival after starting ibrutinib, and the cumulative incidence function (CIF) for AFib, VArr, and CNSh during ibrutinib therapy. Using time-split survival analysis, we calculated the incidence rate ratio (IRR) for these events among patients starting ibrutinib compared with those managed without ibrutinib. All estimates report 95% confidence intervals (CI).
Results: Ibrutinib was administered to 594 (18.2%) of 3,271 beneficiaries with CLL (at median age of 77 years [y]), including 196 in first line. The proportion of patients receiving ibrutinib as first-line therapy increased from 7% in 2014 to 36% in 2016 (Fig. A). As a result, Medicare spending on ibrutinib skyrocketed, surpassing all other CLL chemotherapeutics in 2016 (total $29.2M for ibrutinib, $18.5M for other drugs combined; Fig. B).
Median gross cost of the first ibrutinib prescription was $9,301 (interquartile range [IQR], $8,635-10,233). Median patient's out-of-pocket (OOP) responsibility was $2,296 (IQR, $30-2,739), markedly lower for beneficiaries with the low-income subsidy ($4) than those without it ($2,538). Despite this variation, first-line ibrutinib use was not associated with any socio-demographic factor, including the low-income subsidy (P=.67 in χ2 test), age (P=.95), sex (P=.52), race/ethnicity (P=.31), or prevalent poverty (P=.35).
Median duration of ibrutinib therapy was 13.6 months [mo.] (95%CI, 11.7-16.1), similar in first and subsequent line (P=.93, Fig. C). Median overall survival after starting ibrutinib was 30.3 mo. (95%CI, 22.3-not reached) in first line, and 24.6 mo. (95%CI, 21.6-28.7) in subsequent lines (Fig. D; P=.08). Median survival after stopping ibrutinib was 12.4 mo. (95%CI, 7.5-20.6) in first line, and 7.5 mo. (95%CI, 4.6-11.1) in subsequent lines (P=.06).
The CIF of AFib on ibrutinib was 15.7% at 1 y (95%CI, 12.3-19.4), and 23.7% at 2 y (95%CI, 18.9-28.8; Fig. E). The incidence of AFib was significantly higher among patients receiving ibrutinib compared with other treatments (IRR, 1.65; 95%CI, 1.37-2.00). The CIF of VArr at 1 y was 4.4% (95%CI, 2.8-6.5%), also significantly increased (IRR, 1.62; 95%CI, 1.10-2.39). The CIF of CNSh at 1 y was 1.7% (95%CI, 0.8-3.0) (Fig. F), and significantly increased on ibrutinib (IRR, 4.48; 95%CI, 2.31-8.68). Among patients starting ibrutinib, 11.4% were on anticoagulants, 19.2% had prior atrial fibrillation, and 10.8% were on CYP3A4 inhibitors interacting with ibrutinib.
Conclusions: Ibrutinib has been rapidly adopted for treatment of Medicare beneficiaries with CLL, resulting in major shifts in spending on CLL drugs. Despite high OOP costs, the use of first-line ibrutinib is not associated with sociodemographic characteristics, suggesting that therapeutic decisions are determined by clinical factors. The real-world survival of older patients on ibrutinib is poorer than seen in clinical trials, and rates of AFib, VArr and CNSh are higher. The use of ibrutinib in patients with pre-existing Afib or at risk for bleeding because of anticoagulation warrants particular attention.

Disclosures
Olszewski: Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding. Davids:Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees.