Real-World First-Line Treatment and Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Bruton Tyrosine Kinase Inhibitor (BTKi) or B-Cell Lymphoma 2 (BCL2) Therapy

Introduction: Recent therapeutic advancements in CLL have shifted the treatment landscape, providing expanded options for patients receiving systemic treatment. Notably, targeted therapies have become key therapeutic strategies in the first-line setting. BTK-inhibitors such as ibrutinib or acalabrutinib, and the BCL2-inhibitor venetoclax, have been shown to improve outcomes compared to the prior standard of care. However, with the evolving treatment landscape comes a need to understand the performance of these therapies in the real-world setting. Currently, there are no head-to-head comparisons for these novel therapies in the frontline setting. Real-world data (RWD) is a valuable tool to investigate important clinical questions outside of clinical trials. We sought to use a real-world cohort of patients to characterize the clinical characteristics and outcomes of patients treated with first-line BCL2- or BTK-inhibitor therapies.

Methods: This study was a retrospective, observational cohort study utilizing the COTA real-world database. The COTA database is a de-identified database of curated longitudinal electronic health record (EHR) data pertaining to the diagnosis, clinical management, and outcomes of patients with cancer. Included patients met the following study criteria: age ≥ 18 years, diagnosed CLL/SLL, and initiated 1L treatment of BTKi or BCL2-inhibitor on/after January 1^st, 2016, when the FDA approved ibrutinib for use in treatment-naive patients with CLL. Patients were excluded if they had missing or imprecise dates on critical study events including date of diagnosis, date of last visit, or date of death. Descriptive analyses were conducted to summarize patient demographic and clinical characteristics. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier (KM) method. The index date for time-to-event analyses was the initiation of first-line treatment.

Results: A total of N=909 patients were identified in the COTA database to meet the study criteria and received venetoclax (N=94) or BTKi (N=815) as first-line treatment. Within the BTKi cohort, most patients received ibrutinib (84.7%), followed by acalabrutinib (14.5%). A small proportion of patients received both ibrutinib and acalabrutinib, or zanubrutinib (0.8%). Nearly all patients treated with venetoclax also received concomitant anti-CD20 therapy (97.9%), as compared to only 9.9% of patients treated with BTKi therapy. Patient characteristics by treatment are shown in Table 1. The overall study population had a median age of 66 years and were predominantly white (79.8%), male (60.5%), and treated in the community setting (88.3%). Patients receiving venetoclax were more likely to be younger with a median age of 63 compared to 67 in the BTKi cohort. Venetoclax treated patients were also more recently diagnosed (2019-2021). High-risk molecular abnormalities were similar between the cohorts, although most patients did not undergo risk factor testing prior to treatment. Patients treated with BTKi had a slightly higher proportion of Trisomy 12 positivity (20.9%) as compared to patients treated with venetoclax (11.7%). Patients receiving venetoclax had a shorter median (IQR) follow up time from 1L as compared to the BTKi cohort, 15.9 months (10.7, 22.7) vs. 24.4 (13.4, 39.7), respectively. The 3-year PFS (95% CI) was greater for patients receiving venetoclax (87.8% (79.6, 96.8)) as compared to BTKi therapy (61.4% (57.3, 65.6)). The KM curve of PFS by treatment is shown in Figure 1. Similarly, the 3-year OS (95% CI) was greater for patients receiving venetoclax (86.7% (78.1, 96.4)) as compared to BTKi therapy (77.7% (74.1, 81.5)).

Conclusions: In our real-world cohort of patients treated with venetoclax or BTKi therapy in the first-line setting, patients receiving venetoclax tended to be younger and diagnosed more recently compared to those receiving BTKi treatment. We found 3-year PFS and OS to be longer for patients receiving first-line venetoclax-based therapy as compared to BTKi, though future research will conduct efficacy assessment in a matched population. Key limitations of our study include unequal cohort sizes, variable follow up time, and potential selection bias of patients in the two treatment groups. Additional future research will explore treatment sequencing post-venetoclax or BTKi to further characterize the evolving treatment landscape.

Barcellos:COTA, Inc: Current Employment. Ambrose:COTA, Inc.: Current Employment. Belli:COTA, Inc: Current Employment, Current equity holder in private company. Fernandes:COTA, Inc: Current Employment. Hansen:COTA, Inc: Current Employment, Current equity holder in private company. Wang:COTA, Inc: Current Employment, Current equity holder in private company. Barr:Merck, abbive, gilead, Beigene, Genentech, Astrazeneca, Janssen, TG therapeutics, Celgene, BMS, Morphosys, Adaptive: Consultancy.