Final Analysis of the Prospective Multicenter CLL2-Give Trial of Obinutuzumab (GA101, G), Ibrutinib (I), and Venetoclax (Ve) in Untreated Patients with CLL with 17p Deletion/TP53 Mutation

Background There is still need for improvement in outcome of high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. The CLL2-GIVe trial tested time limited, response-adapted, fixed duration combination treatment of obinutuzumab, ibrutinib and venetoclax ("GIVe" regimen) in high-risk CLL patients (pts) with a combination of three different agents with distinct mechanisms of action. Here we present the final analysis at the end of the study.

Methods CLL2-GIVe is an open-label, multicenter phase 2 trial including pts with previously untreated CLL with del(17p) and/or TP53 mutation. Induction therapy contained 6 cycles (C) of obinutuzumab (GA-101), ibrutinib, and venetoclax, venetoclax and ibrutinib were continued up to C12 as consolidation. Ibrutinib monotherapy was given for C13 to C36 in pts not achieving a complete response (CR) and undetectable minimal residual disease (uMRD) at cycles 9 and 12. The primary endpoint was CR rate at C15 (final restaging) with a null-hypothesis of 25%. Secondary endpoints included MRD, survival, and safety.

Results Between September 2016 and August 2018, 41 pts were enrolled. The last pt reached end of study in January 2022. Median age was 62 (range 35-85) years, del(17p) was present in 26 pts, TP53mut in 39 pts and 32 pts had an unmutated IGHV status. With a CR rate of 58.5% (24 pts) at final restaging (C15), the primary endpoint was met (95% CI: 42.1-73.7, p<0.001), rate of partial remission (PR) was 41.5% (17 pts). Peripheral blood uMRD at C15 was achieved in 32 pts (78%). After a median observation time of 38.4 (3.7 - 44.9) months, 9 progression-free survival (PFS) events and 3 overall survival (OS) events had occurred. The 36-month OS is 92.6 % (Figure 1a) and median OS is not reached. Three pts died (1 pt at C3 due to retrospectively pre-existing ovarian cancer, 1 pt at C9 due to cardiac failure unrelated to study treatment, 1 pt due to respiratory tract infection after Richter transformation (RT) under subsequent treatment). The PFS rate at 36 months is 79.9% and median PFS is not reached (Figure 1b). Progressive disease (PD) was observed in 7 pts between C27 and C42. PD was nodal (n=3) or lymphocytosis (n=3), and 1 case of RT occurred. Subsequent treatments were administered in 4 pts (1 pt with 3 therapies: venetoclax, idelalisib/rituximab, ibrutinib; obinutuzumab (n=1); acalabrutinib/venetoclax/obinutuzumab (n=2)).

Six pts received complete ibrutinib maintenance treatment after C15 due to PR at final restaging, 3 of these had also detectable MRD. None of these pts progressed. 6 pts with PR and uMRD discontinued treatment at C15 not according to protocol: 2 pts stopped due to adverse event (AE); 4 pts due to other reasons. 5 pts with PR who discontinued treatment at C15 not according to protocol had no uMRD: 2 pts stopped due to AE, 1 pt due to death, 1 pt due to other reasons, 1 pt refused ibrutinib maintenance.

At C36, 18 (43.9%) of pts had uMRD in peripheral blood, while 12 pts (29.3%) had detectable MRD at C36: 8 pts were MRD intermediate (≥ 10^-4 and < 10^-2) (19.5%), 4 pts positive (≥10^-2) (9.8%). In 11 pts (26.8%) analysis was not performed due death (n=2), beginning of a new CLL therapy (n=2), 1 withdrawal of informed consent, missed visits during Covid19 pandemic (n=3), 3 pts were lost to follow-up.

The most frequent grade 3-5 AEs up to the end of study were blood and lymphatic system disorders (58.5%), with neutropenia (48.8%) and thrombocytopenia (17.1%), and infections (19.5%). Most frequent AEs of any grade were gastrointestinal disorders in 85.4% of pts, most of them were low grade. Most common cardiac disorder of any grade was atrial fibrillation in 14.6% of pts.

Conclusion The CLL2-GIVe regimen is a potent and promising fixed-duration, first-line treatment for pts with high-risk CLL with a manageable safety profile worthy of further exploration in phase 3 studies.

Huber:Abbvie, Janssen: Consultancy, Honoraria; Novartis: Other: Travel support. Tausch:Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Schneider:AbbVie, AstraZeneca: Honoraria, Speakers Bureau. Von Tresckow:AbbVie, AstraZeneca, Janssen-Cilag and Roche: Other: Travel support; Janssen-Cilag and Roche: Research Funding; AbbVie, AstraZeneca, Beigene, Janssen-Cilag and Roche: Honoraria; AbbVie, AstraZeneca, Janssen-Cilag, Roche: Consultancy. Robrecht:AstraZeneca: Honoraria. Dreger:AbbVie, AstraZeneca, Bluebird Bio, Gilead, Janssen, Novartis, Riemser, and Roche: Consultancy; AbbVie, AstraZeneca, Gilead, Novartis, Riemser, and Roche: Speakers Bureau. Illert:Roche, AstraZeneca, Ars Tempi, Takeda: Honoraria; Roche, AstraZeneca, Janssen-Cilag, Takeda: Other: Travel support and attending meetings; AbbVie, Janssen-Cilag, Takeda, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees. Böttcher:Janssen Cilag: Research Funding; Roche, AbbVie, Janssen, Astra Zeneca, and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Niemann:Beigene: Consultancy; Takeda: Consultancy; CSL Behring: Consultancy; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Octapharma: Consultancy, Research Funding; Genmab: Consultancy. Fink:Abbvie: Other: Travel Grants; Celegene, AstraZeneca: Research Funding. Fischer:AbbVie: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Döhner:Gilead Sciences, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo Co, LTD: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Syndax Pharmaceuticals Inc.: Consultancy, Honoraria; Kronos Bio, Inc.: Research Funding; Pfizer Inc.: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Brystol Myers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Berlin-Chemie: Consultancy, Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Consultancy, Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hallek:Roche, Janssen: Honoraria, Research Funding; Abbvie, AstraZeneca: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Eichhorst:Janssen, Roche, AbbVie, BeiGene, AstraZeneca: Research Funding; Janssen, Roche, AbbVie, BeiGene, AstraZeneca, MSD: Speakers Bureau; Beigene: Other: Travel Support; Janssen, AbbVie, Lilly, AstraZeneca, BeiGene, MSD: Consultancy. Stilgenbauer:Veristem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVIe: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.