Overall Survival of Patients with Chronic Lymphocytic Leukemia Treated with Frontline Bruton's Tyrosine Kinase Inhibitors: An Analysis of the United States Veterans Health Administration Database
Authors: Fitzgerald Lindsey , Khan Wasiulla , Bokun Alex , Lax Angela , Mu Fan , Lin Yilu , Shi Lizheng , Qureshi Zaina P , Graf Solomon 
Published: December 2024

Introduction:
Three covalent Bruton's tyrosine kinase inhibitors (BTKis) are approved first-line (1L) treatments for patients with chronic lymphocytic leukemia (CLL), including patients with del(17p) and/or TP53 mutation. Limited real-world data, especially in Veterans, evaluate long-term outcomes including overall survival (OS) associated with the different BTKis.
Methods:
This study used the Veterans Health Administration database (2006-2023) to identify patients with CLL who initiated 1L treatment with ibrutinib (ibru), acalabrutinib (acala), or zanubrutinib (zanu) between 11/2019 and 10/2023. The date of 1L treatment initiation was the index date. Eligible patients were required to have ≥2 documentations of CLL via diagnosis codes, have ≥12 months continuous enrollment pre-index and ≥28 days continuous enrollment post-index, and have not received any other antineoplastic agents prescribed. Based on 1L BTKi received, patients were categorized into ibru, acala, and acala or zanu cohorts. Patient characteristics were assessed in the 12 months prior to index. OS was analyzed as time from index until death using Kaplan-Meier analyses, censoring on end of study period or data availability. Cox proportional hazards models adjusting for age, sex, index year, Charlson comorbidity index (CCI), atrial fibrillation, and hypertension were run. A sensitivity model was run adjusting for race, region, and additional baseline comorbidities that were imbalanced: coronary artery disease, stage 3 chronic kidney disease, other malignancy, diabetes, renal disease, congestive heart failure, cerebrovascular disease, dementia, myocardial infarction.
Results:
1,671 patients met the inclusion criteria (N=1,059 ibru, N=504 acala, N=108 zanu). Average age was 72.8 years in the ibru cohort, 74.7 years in the acala cohort, and 74.6 years in the acala/zanu cohort. Patients treated with ibru, acala, and acala/zanu were mostly male (98.0%, 98.6%, 98.5%, respectively) and white, non-Hispanic (75.6%, 77.6%, 77.5%, respectively). Most patients in the ibru cohort initiated treatment in 2019-2021 (72.2%), whereas most patients in the acala and acala/zanu cohorts initiated treatment in 2022-2023 (71.8% and 76.8%, respectively). About two-thirds of the patients in the ibru (66.4%), acala (68.7%), and acala/zanu cohorts (68.6%) had hypertension. Fewer patients in the ibru cohort had atrial fibrillation (7.6%) vs the acala cohort (17.9%) and acala/zanu cohort (16.7%).
For the analysis comparing ibru and acala, median follow-up was 10.9 months in the acala cohort and 25.9 months in the ibru cohort. Median time to death was not reached in either cohort. After adjusting for baseline characteristics, compared to the ibru cohort, patients receiving acala had a statistically significant higher risk of death (hazard ratio [HR]: 1.33; 95% confidence interval [CI]: 1.01, 1.76; p=0.04). The sensitivity analysis found a numerically higher risk of death that did not meet statistical significance (HR: 1.27; 95% CI: 0.96, 1.69; p=0.10).
For the analysis comparing ibru and the combined acala/zanu cohort, median follow-up time was 8.8 months in the acala/zanu cohort. Median time to death was not reached in the ibru or acala/zanu cohorts but was significantly longer in the ibru cohort (p&lt;0.01). After adjustment, the risk of death from any cause was numerically higher among patients treated with acala/zanu than patients treated with ibru (HR: 1.32; 95% CI: 1.00, 1.74; p=0.05). The sensitivity analysis showed a numerically higher risk of death but was not statistically significant (HR: 1.25; 95% CI: 0.94, 1.66; p=0.13).
Conclusion:
In this real-world analysis of the Veteran population, ibru was associated with a lower risk of death as compared with acala and had a comparable risk of death versus patients on acala/zanu. Sensitivity analyses adjusting for baseline characteristics provided numerical favorability for ibru, though findings did not have statistical significance. As safety profiles of the BTKi class continue to evolve, additional real-world evidence is needed to understand long-term outcomes associated with 1L BTKi use in patients with CLL.