Real-world comparison of BTKi monotherapy and fixed-duration BTKi–Venetoclax for first line treatment of chronic lymphocytic leukemia patients without TP53 mutations or IGHV rearrangement

Abstract

Abstract Background: Targeted regimens incorporating selective inhibitor of BCL-2 like venetoclax and Bruton Tyrosine Kinase inhibitors (BTKi) like ibrutinib have redefined first-line therapy for B-cell chronic lymphocytic leukemia (CLL), demonstrating high rates of undetectable measurable residual disease and durable progression-free survival in randomized trials. Fixed-duration ibrutinib–venetoclax has shown efficacy across risk groups compared to ibrutinib alone, but both regimens carry distinct toxicity profiles, such as neutropenia, infections, and cardiovascular events. Trials often under-represent patients with advanced age, significant comorbidities, or impaired renal function, limiting generalizability to the broader CLL population. We present real-world data for comparative effectiveness and safety of this regimen in broader clinical practice. Methods: TrinetX, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with treatment naive B-CLL excluding ones with TP53 mutation or IGHV gene rearrangements. The population was further divided into two groups, those who received BTKi monotherapy (ibrutinib, zanubrutinib, acalabrutinib) and those who received fixed duration BTKi and venetoclax combination (IV). Further, propensity score matching (PSM) was carried out for age, sex, race, ethnicity, and co-morbidities like IHD, heart failure, diabetes, hypertensive diseases, hyperlipidemia, peripheral vascular disease, atherosclerosis, overweight and obesity, CKD stage 3 and higher, ESRD, cerebrovascular diseases, emphysema, COPD, fibrosis and cirrhosis of liver along with WBC, Hb, platelets and ANC before starting treatment. The primary outcome of interest was overall survival (OS). Secondary outcomes of interest were rate of hospital and ICU admissions, any infection, tumor lysis syndrome (TLS) and cardiovascular outcomes (MACE, Atrial fibrillation/flutter, AV blocks and other arrhythmias). Outcomes were measured from day 1 after administration of BTKi or IV combination. Analysis methods included Kaplan-Meier survival estimates using log-rank test, as well as Cox regression for hazard ratio (HR), measures of association, and number of instances, with T-test statistics assessing differences between cohorts.  Results: After 1:1 propensity score matching, a total of 326 patients were included (163 in each cohort). The median follow-up duration was 730 days for the BTKi monotherapy group and 606 days for the BTKi plus venetoclax (IV) group. Baseline characteristics were well balanced between cohorts. After PSM, both groups had no significant difference in survival probability (90.6% in the BTKi group and 86.3% in the IV group). The Kaplan Meier curves were not separated, with a log-rank test showing p=​​0.167 and HR = 0.61 (0.289-1.248, 95% CI; p = 0.109). Hospital and ICU admissions occurred in 20.2% of BTKi group and 25.2% of IV group, with a mean number of admissions of 1.06 vs 0.47, respectively (p = 0.227). Tumor lysis syndrome was observed in 6.1% of patients in both groups (risk ratio = 1.00; 95% CI: 0.43–2.34). Cardiovascular events (including MACE, AV block, atrial fibrillation/flutter and other arrhythmias) occurred in 20.2% of BTKi group and 23.9% of IV group (odds ratio [OR] = 0.81; 95% CI: 0.48–1.36; p = 0.423). Infection-related complications were slightly more common in the IV group (28.2%) compared to BTKi (24.5%) (OR = 1.21; 95% CI: 0.74–1.99; p = 0.449).  Conclusion: This real-world study suggests that BTKi monotherapy is non-inferior to fixed-duration BTKi and venetoclax combination therapy in terms of 2-year OS for treatment-naive B-CLL patients without TP53 mutations or IGHV gene rearrangement. We noted no statistically significant difference in the safety profiles of BTKi monotherapy and fixed-duration IV combination therapy.