Real-world study on the impact of continuous treatment dose interruption or reduction of COVALENT BTK inhibitors on efficacy: A 7-year follow-up in chronic lymphocytic leukemia specialized clinics at tertiary hospitals in shanghai, China

Abstract Introduction: Since the introduction of first-generation Bruton tyrosine kinase inhibitors (BTKis) nearly a decade ago, BTKis have become foundational agents in both first- and second-line therapies for CLL/SLL. Continuous BTKi treatment is often complicated by dose reductions or treatment interruptions due to various factors, which clinical and real-world studies have linked to patient prognosis, potentially affecting progression-free survival (PFS) and overall survival (OS). However, comprehensive real-world analyses addressing the characteristics, clinical outcomes, and long-term efficacy and safety implications of varied dose modification and interruption scenarios remain scarce. To address challenges such as the low incidence of CLL/SLL in Asian populations and incomplete electronic medical records, we established a standardized outpatient treatment management system for CLL/SLL. This system aims to standardize therapeutic protocols, enhance treatment adherence, and ensure comprehensive and accurate clinical data collection, thereby providing robust real-world evidence. Within this framework, dose reductions and interruptions during BTKi therapy are meticulously documented, and their impact on clinical outcomes is systematically evaluated. Methods: This retrospective study included CLL patients aged 18 years and older who received care at the CLL/SLL specialized clinics affiliated with Shanghai Jiao Tong University School of Medicine between January 2018 and April 2025. Eligible patients had undergone at least one month of covalent BTKi therapy, including ibrutinib, zanubrutinib, or orelabrutinib. Patients enrolled in clinical trials were excluded. All patients were included irrespective of their treatment status at enrollment. Results: A total of 324 patients under specialized outpatient observation were enrolled; among BTKi-treated patients, the median age was 65 years (range, 25–91), with a male-to-female ratio of 2.6:1. Treatment-naïve (TN) patients numbered 225 (69.44%), and relapsed/refractory (R/R) patients numbered 99 (30.56%). The proportion of TN patients receiving BTKi increased from 22.7% in 2018 to 100% in 2024. Patients younger than 65 years accounted for 40.74% (132/324), and 43.5% (87/200) exhibited del(17p)/TP53 aberrations, reflecting the evolution of BTKi-based regimens in clinical practice in China.With a median follow-up of 42 months, the median OS was not reached, and the 42-month PFS rate was 70.22%. Among all patients, 88 received full-dose BTKi, 231 were in the dose reduction/interruption group, and 5 were lost to follow-up.A total of 352 dose reduction or temporary interruption events were recorded, attributed to non-hematologic adverse events (AEs) in 68.8%, hematologic AEs in 4.5%, concomitant hematologic and non-hematologic AEs in 10.5%, social factors in 5.4%, and physician judgement in 10.8%. The proportion of AE-related dose modifications or interruptions by year were: 83.33% (20/24) in 2019, 86.08% (68/79) in 2020, 87.23% (82/94) in 2021, 76.40% (68/89) in 2022, 51.85% (42/81) in 2023, and 38.46% (15/39) in 2024. COVID-19-related events accounted for 38.6% (136/352) of all events.Among 295 adverse event (AE)-related dose reduction or interruption events, 82 involved switching between covalent BTK inhibitors (defined as switching events; 76 single switches, 3 involving 2 switches), while 213 did not involve switching (non-switching events). Statistical comparison of duration categories of dose modification/interruption (≤7 days, 7–14 days, >14 days) revealed that the duration in the switching group was significantly shorter than that in the non-switching group (χ² = 50.8, df = 2, p = 9.31×10⁻¹²).Early (0 to 3 months) dose reduction/interruption events were significantly associated with worse OS (hazard ratio [HR] = 3.29, p = 0.014) and PFS (HR = 3.93, p = 0.008). Additionally, comparison between non-switching (n = 124) and switching (n = 51) groups demonstrated significant impact on PFS (HR = 0.36, p = 0.022) and OS (HR = 0.34, p = 0.018), favoring the switching group. This study underscores the critical role of standardized management and comprehensive real-world monitoring in elucidating and mitigating the impact of dose modifications and treatment interruptions during BTKi therapy for CLL/SLL.