Ibrutinib versus acalabrutinib in fixed-duration chronic lymphocytic leukemia therapy: a comparative analysis of efficacy

Sep 30, 2026

Letter to the editor presenting an indirect comparative analysis of fixed-duration (FD) chronic lymphocytic leukemia therapy using reconstructed individual patient data from phase III AMPLIFY and phase II CAPTIVATE trial cohorts. The primary endpoint, progression-free survival, is assessed over a common 3-year follow-up using restricted mean survival time (RMST) and RMST difference (Δ), including sensitivity analyses excluding COVID-19-related deaths and excluding TP53-mutated patients. Results show a significant PFS advantage for ibrutinib-based FD venetoclax combinations over acalabrutinib-based regimens, particularly after adjustment for COVID-19 mortality effects and among unmutated IGHV subgroups.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages4

Reading Time10 min

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Letter to the Editor

Indirect comparative analysis and methods

Endpoint assessment with RMST

Sensitivity analyses and key findings

LETTER TO THE EDITOR Ibrutinib versus acalabrutinib in fixed-duration chronic lymphocytic leukemia therapy: a comparative analysis of efficacy The phase III AMPLIFY trial ([clinicaltrials.gov](clinicaltrials.gov) 03836261) provides important evidence on the efficacy of fixed-duration (FD) acalabrutinib-venetoclax (AV), with or without obinutuzumab, demonstrating improved progression-free survival (PFS) compared to standard chemoimmunotherapy in treatment-naïve chronic lymphocytic leukemia (CLL) patients without 17p deletion or TP53 mutations 1 These findings have informed recent updates to the National Comprehensive Cancer Network (NCCN) guidelines, resulting in a Category 1 recommendation for the FD AV regimen for previously untreated CLL patients requiring therapy.2 Notably, comparable findings have been documented in the phase II CAPTIVATE trial ([clinicaltrials.gov](clinicaltrials.gov) 02910583) and the phase III GLOW trial ([clinicaltrials.gov](clinicaltrials.gov) 03462719), both of which investigated FD combinations of venetoclax with ibrutinib.3,4 Acalabrutinib is generally preferred over ibrutinib in continuous Bruton’s tyrosine kinase inhibitor (BTKi)-based approaches, primarily due to its comparable efficacy and an improved safety profile.5 However, it remains unclear whether acalabrutinib should be preferred over ibrutinib in FD combinations with venetoclax, as the degree of synergy between BTKi and venetoclax therapy may differ among different BTKi. In the absence of direct comparative studies, we conducted an indirect analysis to assess the relative efficacy of FD venetoclax in combination with ibrutinib or acalabrutinib. Data from the FD cohort of the CAPTIVATE trial, which features a patient population closely aligned with that of the AMPLIFY trial, served as a benchmark for this indirect comparative analysis 1,3 To enable a rigorous yet indirect comparison, individual patient data (IPD) from the FD AV arm of the AMPLIFY trial and the FD ibrutinib-venetoclax (IV) cohort of the CAPTIVATE trial were reconstructed using the methodology outlined by Liu et al.6 The IPD utilized for sensitivity analyses (specifically, those excluding COVID-19-related deaths in the AMPLIFY study and patients with TP53 mutations in the CAPTIVATE study) were obtained from the IPD employed in the Kaplan-Meier subgroup plots presented in the original published reports 1,3 The primary endpoint of this analysis, PFS, was evaluated through restricted mean survival time (RMST) analysis over a common 3-year follow-up period. Restricted mean survival time offers an alternative to hazard ratios and median survival times by directly quantifying the entire observed survival curve.7 Specifically, RMST is calculated as the area under the Kaplan-Meier survival curve up to a pre-specified time point (t) which corresponds to the duration of follow-up in the study.7 Unlike median survival, RMST summarizes the average survival experience and does not depend on the proportional hazards assumption, thereby capturing treatment benefits across the entire follow-up period.8 In the present study, the difference (Δ) in RMSTwas used to quantify and compare the area between the PFS curves of the IV and AV treatment regimens, using the previously reported approach.8 Baseline demographic and clinical characteristics of the patient cohorts were compared using c2 tests or Fisher exact tests, as appropriate. This indirect comparative analysis was conducted using publicly available, published data and did not involve the collection of new primary data from human participants. Therefore, ethical approval was not required in accordance with institutional guidelines and national regulations 1,3 In aggregate, 450 patients undergoing combination therapy with a BTKi in combination with venetoclax were included in the analysis. BTKi-venetoclax treated patients were divided into two groups: 159 patients treated with IV in the FD cohort of CAPTIVATE trial, and 291 pa

FAQs

What trials and patient cohorts were used for the indirect comparison?

The analysis reconstructed individual patient data from the FD acalabrutinib-venetoclax (AV) arm of the phase III AMPLIFY trial and from the FD ibrutinib-venetoclax (IV) cohort of the phase II CAPTIVATE trial.

How was progression-free survival evaluated in the study?

Progression-free survival was assessed over a common 3-year follow-up using restricted mean survival time (RMST) analysis, with RMST difference (Δ) used to compare the area between the PFS curves.

What overall conclusion does the analysis reach about IV versus AV therapy?

After excluding TP53-mutated patients for cohort homogeneity and conducting sensitivity analyses around COVID-19-related deaths, the IV (ibrutinib-based) regimen demonstrated a statistically significant PFS advantage over AV.

Sep 30, 2026

Uploaded by River Wang