Target dose delivery comparison: Ibrutinib + venetoclax vs. acalabrutinib + venetoclax in treatment-Naïve CLL patients in prospective clinical trials

Abstract Introduction: Combination therapies with venetoclax (VEN) + CD20 monoclonal antibody or Bruton tyrosine kinase inhibitors (BTKi) + VEN are preferred, time-limited treatments for treatment-naïve (TN) chronic lymphocytic leukemia (CLL). Ibrutinib (IBR) + VEN achieves a 75% undetectable measurable residual disease (uMRD4, 10⁻⁴ sensitivity) rate in peripheral blood (PB) at 1 year in TN-CLL. The AMPLIFY study reported a 45% uMRD4 rate with acalabrutinib (A) + VEN, lower than reported for IBR + VEN (IV), despite A's comparable efficacy and better safety profile. Reasons for this difference are unclear. We compared cumulative dose delivery of IV vs. A + VEN (AV) in TN-CLL from two phase 2 trials conducted at MD Anderson Cancer Center. Methods: TN-CLL patients from the IV study (Jain et al., NEJM 2019) and AV ± O study (NCT04169737) were included. IV patients received IBR (C1-3), VEN ramp-up (C4), and IV (C4-27). AV ± late O patients received A monotherapy (C1-2), VEN ramp-up (C3), and AV±O (C3-26). Cumulative BTKi and VEN doses relative to intended doses were categorized: 1–24.9%, 25–49.9%, 50–74.9%, 75–99.9%, 100%. Reasons for dose reductions/interruptions were recorded. Fisher's exact test compared dose delivery distributions across all levels as well as between 1-74.9% and 75-100% levels (two-sided, p < 0.05 significant). Statistical analyses were conducted using R version 4.2.1 within RStudio (version 2022.7.1.554). Results: Of 120 IV patients, 117 received IBR (C1-3), 114 IBR (C4-27), and 112 VEN (C5-27). Of AV ± late O patients, all received A (C1-2) and AV ± O (C3-26). Thirty-two (32/42, 76%) patients received O at C15. BTKi lead-in phase showed no dose delivery difference (p = 0.516). BTKi dose delivery differed significantly in the combination phase (p < 0.0001), with more AV patients receiving ≥75% BTKi dose (<75%: 56% vs. 14%; ≥75%: 44% vs. 13%, p < 0.0001). VEN dose delivery also differed between IV and AV (p < 0.0001). However, there was no difference in cumulative VEN dose when stratified by <75% and ≥75% between IV and AV (<75%, 25% vs. 31%; ≥75%, 75% vs. 69%, p = 0.540). For IV, IBR dose reductions were due to neutropenia (12%), atrial fibrillation (9%), bleeding (9%), and rash (8%); interruptions (≤14 days) were due to surgery (11%), non-adherence (6%), and neutropenia (5%). Long-term (>14 days) IBR interruptions were due to neutropenia (20%) and infections (9%). VEN dose reductions in IV were due to neutropenia (14%) and infections (4%); interruptions were due to non-adherence (23%) and neutropenia (11% ≤14 days, 13% >14 days). For AV, A dose reductions were due to thrombocytopenia (7%) and neutropenia (5%); interruptions ≤14 days were due to non-adherence (17%), surgery (10%), and >14 days were due to thrombocytopenia (10%) and neutropenia (10%). VEN dose reductions in AV were due to neutropenia (41%) and gastrointestinal issues (12%); interruptions ≤14 days were due to non-adherence (45%), neutropenia (14%), and >14 days were due to infections (29%), neutropenia (21%). Conclusion: AV ± O patients received significantly higher cumulative BTKi than IV patients. However, there was no difference in the cumulative VEN dose between patients treated with IV and AV. Despite this, lower uMRD4 rates with AV suggest factors beyond dose delivery may influence efficacy. Further studies are needed.