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

Abstract

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)

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL

“…Targeted triplet combination regimens are alternative time-limited treatment approaches associated with high rates of BM-uMRD. 2 , 23 , 24 , 25 However, follow-up with such combinations remains short, making it difficult to compare directly with our FCR-based regimen. Potential research designs that could begin to help us understand the relative efficacy and safety of iFCR would need to adapt to current standards of care in which the studies are being performed.…”

Innovative Combinations, Cellular Therapies and Bispecific Antibodies for Chronic Lymphocytic Leukemia: A Narrative Review

“…The CLL2-GIVe study [39], an open-label, single-arm, multicenter trial, explored this triple combination in CLL patients with TP53 abn. Patients received six cycles of obinutuzumab and ibrutinib at standard dose from cycle 1 day 1, while the venetoclax ramp-up phase started from cycle 1 day 22, followed by a consolidation phase with I+V for six additional cycles and then the ibrutinib single agent till cycle 15.…”

Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions

“…33 In the CLL2-GIVe phase 2 trial, a time-limited, responseadapted combination of obinutuzumab, ibrutinib, and venetoclax was evaluated in previously untreated CLL patients with del(17p) and/or TP53 mut. 34 Encouraging results were obtained, and the overall response rate (ORR) at cycle 15 was an impressive 100%, with 58.5% achieving complete response (CR) or CR with incomplete blood count recovery (CRi). Importantly, 87.8% of patients had undetectable MRD at cycles 9 and 12, and after a median follow-up of 38.4 months, the 3-year PFS and OS were 79.9% and 92.6%, respectively.…”

“…Preliminary results obtained in arm D of the SEQUOIA trial show that combining zanubrutinib with venetoclax is a promising treatment option for patients with del(17p) 33 . In the CLL2‐GIVe phase 2 trial, a time‐limited, response‐adapted combination of obinutuzumab, ibrutinib, and venetoclax was evaluated in previously untreated CLL patients with del(17p) and/or TP53 mut 34 . Encouraging results were obtained, and the overall response rate (ORR) at cycle 15 was an impressive 100%, with 58.5% achieving complete response (CR) or CR with incomplete blood count recovery (CRi).…”