Addition of obinutuzumab after one year of combined acalabrutinib and venetoclax is safer and effective than early obinutuzumab in a randomized Phase II trial for treatment naïve CLL Free

Introduction: The treatment landscape of chronic lymphocytic leukemia (CLL) includes Bruton tyrosine kinase inhibitors (BTKi), B-cell lymphoma 2 (BCL2) inhibitor and CD20 monoclonal antibodies (mAb). Several studies explored the safety and efficacy of these agents as combined targeted therapy. Recently, combined acalabrutinib (A) and venetoclax (VEN) ± obinutuzumab (O, AV ± O) was added to the NCCN guidelines as a preferred regimen for treatment-naïve (TN) CLL, supported by the AMPLIFY study and a phase II study (Davids et al. JCO2025). Patients (pts) treated with AVO triplet achieved undetectable measurable residual disease (10^-4 sensitivity, uMRD4) rates of 83%-95% in blood and 78% in bone marrow (BM), at the end of 1 year (Y) of treatment. Despite higher rates of uMRD4, the use of triplet therapy in TN CLL pts is challenging due to the concerns of higher rates of side effects, especially neutropenia and infections. We conducted a randomized phase II trial of A + VEN (AV) with and without early O in TN CLL (NCT04169737). We reported a BM uMRD4 rate of 73% at the end of 1 Y of AV + early O (Swaminathan et al. Blood 2024). To understand if the toxicity profile of AVO triplet therapy differs by the timing of O, we compared the toxicities of patients (pts) randomized to early O vs. late O.

Methods: In this phase II trial, pts were randomized to receive 6 cycles (C) standard dose early O starting C1, with A starting in C2 vs. no early O, with A starting C1. Standard VEN ramp-up started in C3 for both arms. All pts could receive a total of 24 C of AV. Pts with detectable MRD4 or partial response at C14 assessment could receive 6 C of O starting C15, regardless of prior O. The TN cohort enrolled high-risk pts, defined as: age >65 Y or unmutated IGHV or del(17p)/TP53-mutated or del(11q). The primary endpoint was BM uMRD4 status at the end of C9. The study enrolled pts from July 2020. For this post-hoc analysis, adverse events (AEs) were compared at 2 time points: C1-14, when no pts in the late O arm received O, and C15-26. Fisher's Exact Test was used to compare differences in AEs at a significance level of p<0.05.

Results: Eighty-four pts were enrolled, 42 in each arm. The median age was 59 Y (41-77) in AV ± late O and 62 Y (29-79, p=0.301) in AV + early O. Nine (21%) and 11 (26%) pts had TP53 aberration, respectively. Forty-one (98%) in AV ± late O and 37 (88%) pts in AV + early O completed 1 Y of combination therapy; 39 (93%) and 32 (76%), respectively, completed 2 Y of treatment. Thirty-two (76%) pts in AV ± late O arm received O. Notably, 3 (7%) pts in AV + early O died during study treatment due to COVID-19. In the intention-to-treat population, in the AV ± late O arm, the most frequent AEs of any grade in the 1^st Y were: diarrhea, 34 (81%); headache, 26 (62%); nausea, 22 (52%); infections,16 (38%); in the 2^nd Y; thrombocytopenia,12 (29%); infections, 9 (21%); diarrhea, 8 (19%); neutropenia, 5 (12%). Among grade ≥3 AEs in the 1^st Y: neutropenia, 5 (12%); non-melanoma skin cancers and infections, each 2 (5%); in the 2^nd Y: thrombocytopenia, 9 (21%); neutropenia, 4 (10%). In the AV + early O arm, most frequent AEs of any grade in the 1^st Y were: neutropenia, 29 (69%); infections, 27 (64%); diarrhea, 25 (60%); headache,18 (43%); in the 2^nd Y: infections,17 (40%); diarrhea, 7 (17%); fever, 6 (14%). Among grade ≥3 AEs in the 1^st Y: neutropenia, 27 (64%); infections,11 (26%); non-melanoma skin cancers, 5 (12%); in the 2^nd Y: infections, 7 (17%); neutropenia, 4 (10%). Grade ≥3 infections (p=0.013) and neutropenia (p<0.00001) were significantly higher in the 1^st Y in the AV + early O arm. Grade ≥3 thrombocytopenia was significantly higher in the AV ± late O arm in the 2^nd year (p=0.002). There were no differences in neutropenia (p=1.0) or infection (any grade, p=0.098 and grade ≥3, p=0.057) rates between the 2 arms in the 2^nd Y, suggesting better tolerance of AVO triplet therapy when O is added after the 1^st Y. The BM uMRD4 rate at the end of C26 was 90% in the AV ± late O arm and 94% the AV + early O arm (p=0.683).

Conclusion: AVO triplet is very effective in TN CLL. Addition of O after 1 Y of AV may improve tolerability, with lower rates of grade ≥3 neutropenia and infection.