Association Between Dose Reduction and Duration of Therapy in Patients Receiving Ibrutinib or Acalabrutinib for Chronic Lymphocytic Leukemia: A Medical Chart Review Study
Authors: Shadman Mazyar , Roeker Lindsey , Pinilla-Ibarz Javier , Srivastava Bhavini , Karve Sudeep , Krigsfeld Gabriel S. , Franceschini Erin , Saifan Chadi , Karanth Siddharth , Goyal Ravi K. , Rombi Julien , Stephens Deborah M. 
Published: December 2024

Background: Bruton tyrosine kinase inhibitors including ibrutinib (ibr) and acalabrutinib (acala) are first-line (1L) treatments (tx) for chronic lymphocytic leukemia (CLL); however, adverse events (AEs) commonly lead to dose reduction (DR). Recent real-world studies suggest that DR of ibr can optimize tx outcomes, reducing the rate of tx failure regardless of cardiac or noncardiac AEs (Shadman et al, EHA 2023). However, outcomes of DR with acala are less well described. In this study, we analyzed the association between DR and duration of therapy (DOT) in patients (pts) with CLL receiving ibr or acala.
Methods: This retrospective chart review was conducted at 142 community and academic oncology sites treating pts with CLL. Eligible pts aged ≥18 years diagnosed with CLL/small lymphocytic lymphoma were included if they initiated 1L tx with standard-dose ibr (420 mg/day) or acala (100 mg twice daily) after October 1, 2017. This analysis focused on pts treated with ibr or acala with DR due to AEs of interest, defined as those that lead to DR (including cardiac and noncardiac). Data on baseline demographics, clinical characteristics, and tx patterns, including occurrence of AEs and subsequent dosing status (DR or remained on standard dose), were abstracted from medical records and analyzed until the prespecified quota was filled. Differences in DOT for pts with DR due to AEs of interest, measured as time to discontinuation or death, between ibr and acala were analyzed using the Kaplan-Meier method. Multivariable Cox regression analyses were performed, adjusting for baseline pt characteristics including demographics, risk factors, genomic factors, and time from diagnosis to tx. Adjusted hazard ratios (aHRs) with 95% CIs were estimated. Restricted mean survival time (RMST) is defined as the area under the survival curve up to a specific time point and is a novel alternative measure in survival analyses that may be useful when proportional hazards assumptions cannot be made. Here RMST was estimated where proportional hazard assumptions were violated and average time on therapy was reported (Kloecker et al, Ann Intern Med 2020).
Results: Medical record data were abstracted for pts with CLL with DR due to AEs of interest: 102 pts treated with ibr (median age: 66 years; 59.8% men; del(17p) 15.7%) and 56 pts treated with acala (median age: 60.4 years; 67.9% men, del(17p) 32.1%). The median (range) follow-up of 1L tx for ibr and acala DR due to AEs of interest was 35.1 mo (13.8-76.0) and 32.6 mo (14.3-76.8) respectively. The ibr and acala pts with DR due to AEs of interest had the same median Charlson Comorbidity Index score (1.0). The most common baseline comorbidity was hypertension (ibr: 30.4%; acala: 41.1%) and the median time to first recorded AE of interest and DR during 1L tx was 5.7 mo and 6.7 mo for ibr and 4.3 mo and 5.3 mo for acala. The most common reduced daily dose was 280 mg for ibr (94.9%) and 100 mg daily for acala (98.7%). Per physician reports, the most common AEs leading to DR were hypertension (26%), diarrhea (22%), and rash (14%) for ibr, and hypertension (29%), diarrhea (27%), and anemia (21%) for acala. The median DOT from tx initiation in pts with DR due to AEs of interest was 35.7 mo (95% CI: 25.6-38.5) for ibr and 18.0 mo (95% CI: 13.5-32.4) for acala; (aHR [ibr vs acala] = 0.93; 95% CI: 0.52-1.65, P=0.805). Average time on therapy from RMST analysis was 27.5 mo for ibr and 22.6 mo for acala (P&lt;0.01). At 12 mo, 88.2% (95% CI: 80.2-93.1) of pts with DR due to AEs of interest remained on ibr therapy; 75.0% (95% CI: 61.5-84.4) remained on acala. The median DOT in pts after the DR due to AEs of interest was 29.2 mo (95% CI: 20.3-40.0) for ibr and 12.2 mo (95% CI: 8.2-20.3) for acala; (aHR [ibr vs acala] = 0.800; 95% CI: 0.35-1.8, P=0.592); average time on therapy from RMST analysis was 20.1 mo for ibr and 14.9 mo for acala (P=0.008).
Conclusions: In this real-world study, pts with CLL who initiated 1L tx with ibr and underwent a DR due to an AE of interest and stayed on therapy longer than pts undergoing a DR with acala. Findings from this and prior studies support ibr DR strategies; however, additional information is needed to assess the effectiveness of DR for acala and to evaluate the impact of drug availability and options for DR on pts who dose reduce.