Background

Patients (pts) with IGHV-mutated ( IGHV-M) CLL have favorable long-term outcomes after receiving first-line FCR (fludarabine, cyclophosphamide and rituximab). We designed an investigator-initiated, phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809), and we report here an updated analysis with a median follow-up of 72 months.

Methods

Inclusion criteria included diagnosis of previously untreated CLL/SLL needing treatment per iwCLL criteria, age ≥18, IGHV-M, absence of both del(17p) and TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (BM) (4-color flow-cytometry, sensitivity 10 -4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with U-MRD (CR/CRi or PR) at end of Cycle 12 stopped all therapy, including ibrutinib. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by clinical examination, blood counts and peripheral blood MRD every 6 months.

Results

Between March 2016 and August 2018, 45 pts initiated treatment. Data cutoff was July 15, 2023. Baseline characteristics are shown in Table 1. All pts per study inclusion criterion had IGHV-M; however, 1 enrolled pt was later reclassified as IGHV-unmutated. A total of 69% pts had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. Median follow-up duration is 72 months.

41/45 pts completed 12 cycles of treatment (4 pts came off study prior to Cycle 12). All 41 pts achieved marrow U-MRD and per protocol, discontinued ibrutinib. After a median follow-up of 61 mos post-discontinuing ibrutinib, 8 pts had MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 32 mos (range, 20-67 mos) after stopping all therapy. Of the 8 pts with MRD recurrence, 2 pts had clinical relapse (described below); remaining 6 pts are being monitored with no clinical progression or active therapy.

The 6-year PFS and OS are 92.2% (95% CI= 77.7-97.4) and 97.7% (95% CI= 84.9-99.6), respectively. Two pts had clinical progression: one pt had IGHV 3-21; MRD recurred 28 mos after discontinuing ibrutinib, with clinical relapse 59 mos after discontinuing ibrutinib; this pt is now in remission with venetoclax-based therapy; the second pt with clinical relapse had IGHV-unmutated CLL, MRD recurred 24 mos after discontinuing ibrutinib, with clinical relapse 48 mos after discontinuing ibrutinib; this pt has not yet required therapy for relapse. No pt had progression to Richter transformation. One pt developed therapy-related myelodysplastic syndrome; this pt is being monitored for 58+ months without any active therapy for MDS with normal blood counts. One pt died from congestive heart failure during month 9 of the study.

Conclusions

iFCG regimen with only three cycles of combination chemotherapy achieves U-MRD rates of 98% in bone marrow on an intent-to-treat analysis and a 6-year PFS of 92% in IGHV-M CLL. These results are favorable compared to the 5-year PFS of approximately 65% with FCR (CLL10 trial) for the same genomic subgroup. Additionally, these results also appear favorable to the current targeted therapy regimens (such as BTKi, BCL2i+CD20 antibody) for IGHV-M CLL. With the caveat that the role of chemoimmunotherapy in CLL has significantly declined, the iFCG regimen provides for a very high rate of durable remissions among a chemo-sensitive subgroup of pts with CLL.

Jain:AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; ADC Therapeutics: Research Funding; Servier: Research Funding; TransThera Sciences: Research Funding; Mingsight: Research Funding; Aprea Therapeutics: Research Funding; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Medisix: Research Funding; Incyte: Research Funding; Newave: Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Fate Therapeutics: Research Funding; Dialectic Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Novalgen: Research Funding; Loxo Oncology: Research Funding; Pfizer: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Burger:Janssen: Other: Speaker fees and Travel Support; Abbvie, Beigene: Research Funding; AstraZeneca, Pharmacyclics: Other: Advisory Board, Research Funding. Ferrajoli:Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Genetech: Honoraria; GenMab: Research Funding; Beigene: Research Funding; AstraZeneca: Honoraria, Research Funding. Senapati:Kite Pharma: Other: Advisory Board. Borthakur:Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees. Bose:Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo: Honoraria, Research Funding; Kartos, Telios, Ionis, Disc, Janssen, Geron: Research Funding; GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria. Kadia:Genentech: Consultancy, Research Funding; GenFleet Therapeutics: Research Funding; AstraZeneca: Research Funding; Astellas Pharma Global Development: Research Funding; Glycomimetics: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Agios: Consultancy; Iterion: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Janssen Research and Development: Research Funding; Liberum: Consultancy; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Ascentage Pharma Group: Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Consultancy; Regeneron Pharmaceuticals: Research Funding; SELLAS Life Sciences Group: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Cellenkos Inc.: Research Funding; Amgen, Inc.: Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Cure: Speakers Bureau; Cyclacel: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Genzyme: Honoraria; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Pemmaraju:Karger Publishers: Other: Licenses; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; United States Department of Defense (DOD): Research Funding; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASH Committee on Communications: Other: Leadership; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASCO Cancer.Net Editorial Board: Other: Leadership; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Konopleva:AbbVie, Forty Seven, Precision Biosciences, Gilead Sciences, Genentech, Janssen, Sanofi, MEI Pharma, Daiichi Sankyo Pharmaceutical, AstraZeneca Co., Menarini.: Consultancy; Abbvie, Allogene Therapeutics, Cellectis, Forty Seven, Gilead Sciences, Genentech, Sanofi, MEI Pharma, Rafael Pharmaceuticals, Daiichi Sankyo Pharmaceutical, AstraZeneca Co., Menarini, Precision BioSciences.: Research Funding; Reata Pharmaceuticals.: Current holder of stock options in a privately-held company, Patents & Royalties. Jabbour:Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Gandhi:Dava Oncology: Honoraria; AbbVie: Research Funding; LOXO: Research Funding; Clear Creek Bio: Consultancy, Research Funding; Pharmacyclics: Research Funding; Sunesis: Honoraria, Research Funding. O'Brien:Regeneron: Research Funding; Pharmacyclics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Johnson & Johnson: Consultancy; Janssen: Consultancy; Lilly: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Astrazeneca: Consultancy; Abbvie: Consultancy. Wierda:AstraZeneca/Acerta Pharma: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Janssens Biotech: Research Funding; Nurix THerapeutics: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Accutar Biotechnology: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Janssens Biotech Inc: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; GSK/Novartis: Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel: Consultancy, Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; Numab THerapeutics: Research Funding; Sunesis: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding.

Combination of ibrutinib with FCG regimen is not FDA approved

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2023
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