Abstract
Background: Over the past decade, the chronic lymphocytic leukemia (CLL) treatment landscape has evolved with the approval of novel therapies such as covalent Bruton's tyrosine kinase inhibitors (cBTKis) and the BCL-2 inhibitor (BCL-2i) venetoclax. These agents have largely replaced traditional chemotherapy in clinical guidelines, yet real-world evidence comparing these therapies on key outcomes remains limited. This study sought to address this gap in the evidence by examining overall survival (OS) and time to next treatment (TTNT) in a national sample of fee-for-service U.S. Medicare beneficiaries initiating CLL treatment in the frontline setting.
Methods: This retrospective cohort study used 2016-2023 100% Medicare fee-for-service claims, identifying elderly patients initiating frontline CLL treatment between 6/1/2019 and 12/31/2022 (index date = date of first prescription fill or infusion). Type of CLL treatment initiated was categorized into BCL-2i venetoclax-based regimens (VEN), cBTKi ibrutinib-, acalabrutinib-, or zanubrutinib-based regimens (cBTKis), or other CLL treatments such as anti-CD20 monotherapy and traditional chemotherapy (Other). Kaplan-Meier (KM) curves for OS and TTNT were generated in the overall sample by type of CLL treatment received. Cox regressions including a series of covariates for type of CLL treatment received, sociodemographic factors, and clinical characteristics were used to examine the outcomes of OS and TTNT. A sensitivity analysis was also performed, restricting the VEN group to those receiving venetoclax plus obinutuzumab (V+O).
Results: The final sample contained 10,949 patients treated for frontline CLL; 13.7% of patients received VEN (n=1,503), 54.5% received cBTKis (n=5,956), and the remaining patients (31.8%) received other CLL therapies. The sample had a mean age of 76.2-78.3 years and was primarily White (91.7-92.4%), male (55.3-64.1%), and urban (79.6-81.1%). The median length of available follow-up after CLL treatment initiation ranged from 1.8 years (other CLL treatments) to 2.2 years (VEN and cBTKi groups). The mean (SD) number of first-line prescription claims observed over follow-up was 15.3 (12.6) for cBTKis and 11.2 (7.8) for VEN.
Overall Survival. KM curves showed longer OS for VEN relative to both cBTKis and other CLL treatments; specifically, the 1-year and 3-year survival rates, respectively, were highest for patients receiving VEN (90% and 77%), followed by cBTKis (85% and 67%) and other therapies (81% and 62%). Cox regressions confirmed that relative to VEN use, cBTKi (hazard ratio [HR]: 1.49, 95% CI 1.32-1.68, p<0.001) and other CLL therapy (HR: 1.65, 95% CI 1.46-1.87, p<0.001) use were associated with poorer OS. In the overall sample, relative to patients aged 65-69 years, OS was worse in patients aged 75-79 years (HR: 1.55, 95% CI 1.30-1.84, p<0.001) and aged 80+ years (HR: 2.66, 95% CI 2.25-3.15, p<0.001). No statistically significant differences in OS by race/ethnicity were observed.
Time To Next Treatment. KM curves also showed superior TTNT for VEN relative to cBTKis and other CLL treatments. With a median follow-up of 2 years for each treatment class cohort, the percentage of patients with no evidence of second-line treatment at 1-year and 3-year was significantly higher for VEN patients (93% and 86%) compared to cBTKis (80% and 69%) and other CLL treatments (62% and 52%). Cox regressions confirmed that relative to VEN use, cBTKi (HR: 2.69, 95% CI 2.23-3.26, p<0.001) and other CLL therapy (HR: 6.47, 95% CI 5.32-7.86, p<0.001) use were associated with shorter TTNT. No statistically significant differences in TTNT by age or race/ethnicity were observed.
Sensitivity Analysis. Limiting the VEN group to patients receiving V+O (n=910, 60%) showed similar findings to those in the main VEN group, with superior OS and TTNT for V+O relative to cBTKis and other CLL treatments.
Conclusions: In a national sample of elderly Medicare beneficiaries initiating frontline CLL treatment, venetoclax-based therapy was associated with significantly longer OS and TTNT compared to cBTKis and other CLL therapies. These findings suggest that VEN may offer greater treatment durability and real-world effectiveness among older adults. Given the growing number of treatment options for CLL, these early results may inform treatment selection in the Medicare population, where optimizing outcomes and minimizing the need for subsequent treatment are especially beneficial.
