Final analysis of the CLL2-GIVe trial: obinutuzumab, ibrutinib, and venetoclax for untreated CLL with del(17p)/TP53mut

The final analysis of the open-label, multicenter phase 2 CLL2-GIVe trial shows response and tolerability of the triple combination of obinutuzumab, ibrutinib and venetoclax ("GIVe" regimen) in 41 previously untreated high-risk patients with chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. Induction consisted of 6 cycles of obinutuzumab, ibrutinib, and venetoclax; venetoclax and ibrutinib were continued up to cycle 12 as consolidation. Ibrutinib was given until cycle 15 or up to cycle 36 in patients not achieving a complete response and detectable minimal residual disease (MRD). The primary endpoint was the complete remission (CR) rate at cycle 15, which was achieved in 58.5% (95% CI: 42.1-73.7, p<0.001). The last patient reached end of study in January 2022. After a median observation time of 38.4 (range 3.7 - 44.9) months, the 36-month progression-free survival is 79.9% and the 36-month overall survival is 92.6 %. Only 6 patients continued ibrutinib maintenance. Adverse events of concern were neutropenia (48.8% ≥ grade 3) and infections (19.5% ≥ grade 3). Cardiovascular toxicity grade 3 occurred as atrial fibrillation at a rate of 2.4% in cycles 1-12, as well as hypertension (4.9%) in cycles 1-6. The incidence of adverse events of any grade and ≥ grade 3 was highest during induction and decreased over time. Progressive disease was observed in 7 patients between cycle 27 and cycle 42. In conclusion, the CLL2-GIVe regimen is a promising fixed-duration, first-line treatment for patients with high-risk CLL with a manageable safety profile. Clinical Trial registry: CLL2-GIVe (NCT02758665).