Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, adult, Research, clinical trials, CLL, Clinical Research, Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human, Minimal Residual Disease
Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy.
Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Median age was 64.5 years (range, 26-88 years). 86% had IGHV-unmutated CLL. 23% had del(17p)/TP53 mutation. The median follow-up is 61.5 months.
Six pts came off study during 1st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. One pt had DLBCL transformation and 1 pt had CLL progression during the first 2 year of therapy (details below).
The 5-year PFS is 90.1% and 5-year OS is 95.6% (Figure 1). The 5-year PFS for pts with del(17p)/TP53 mutation (n=27) is 86.1%.
Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median follow-up of 40 months post Cycle 24, 22 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 22 pts with MRD recurrence, 5 pt had CLL progression at a median of 18 months (range, 6-30 months) from MRD recurrence (details below); 16 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt died from mesothelioma. Among the 55 pts who remain in blood U-MRD remission, 53 remain in long-term follow-up in U-MRD remission; 1 pt had B-PLL transformation and 1 patient died (found unresponsive at home; was off therapy for 2 years).
There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Only 2/23 pts are still receiving IBR (remaining pts have d/c IBR; all pts have d/c venetoclax); none of these 23 pts had clinical relapse.
A total of 6 pts had CLL progression (1 during the first 2 yr of therapy; remaining 5 during off-therapy phase). 3/6 had evaluation of BTK, PLGG2 and BCL2 mutations at the time of relapse and none were detected. 5 pts have started subsequent therapy (acalabrutinib, n=4; ibrutinib, n=1; all are clinically responding); 1 pt has not yet started therapy.
Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 5-year PFS of 90.1%. The 5-year PFS for pts with del(17p)/TP53 mutation is 86.1%. Retreatment with BTK inhibitor appears effective for pts with disease relapse.
Disclosures: Jain: Mingsight: Research Funding; Medisix: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Loxo Oncology: Research Funding; Newave: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Servier: Research Funding; ADC Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novalgen: Research Funding; Dialectic Therapeutics: Research Funding; TransThera Sciences: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Thompson: abbvie: Consultancy; adaptive biotechnologies: Consultancy, Research Funding, Speakers Bureau; astrazeneca: Consultancy, Speakers Bureau; beigene: Consultancy; genentech: Consultancy; janssen: Consultancy, Speakers Bureau; Lilly: Consultancy; merck: Consultancy, Speakers Bureau; pharmacyclics: Consultancy. Ferrajoli: Beigene: Research Funding; GenMab: Research Funding; Genetech: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Senapati: Kite Pharma: Other: Advisory Board. Burger: AstraZeneca, Pharmacyclics: Other: Advisory Board, Research Funding; Janssen: Other: Speaker fees and Travel Support; Abbvie, Beigene: Research Funding. Borthakur: 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; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Konopleva: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trials Support, Research Funding. Kadia: Liberum: Consultancy; Delta-Fly Pharma, Inc.: Research Funding; SELLAS Life Sciences Group: Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Astex: Honoraria; BMS: Consultancy, Research Funding; Pinotb-Bio: Consultancy; Agios: Consultancy; Servier: Consultancy; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; 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; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Genzyme: Honoraria; Amgen, Inc.: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Ascentage Pharma Group: Research Funding; Astellas Pharma Global Development: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Cellenkos Inc.: Research Funding; Cure: Speakers Bureau; Cyclacel: Research Funding; GenFleet Therapeutics: Research Funding; Glycomimetics: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; Janssen Research and Development: Research Funding; Pfizer: Consultancy, Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Regeneron Pharmaceuticals: Research Funding; Sanofi-Aventis: Consultancy. Pemmaraju: Menarini Group: 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; Neopharm: 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; Medscape: 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; Novartis Pharmaceuticals: 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; EUSA Pharma: 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; 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; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareDx: 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; Blueprint: 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; Harborside Press: 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; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Imedex: 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; Celgene: 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; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Aplastic Anemia & MDS International Foundation: 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; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: 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; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASH Committee on Communications: Other: Leadership; ASCO Cancer.Net Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; United States Department of Defense (DOD): Research Funding; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Daver: Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Trovagene: Research Funding; FATE: Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; AROG: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Celgene: Consultancy; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Jabbour: Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Astex: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. DiNardo: Schrödinger: Consultancy; Takeda: Honoraria; Fogham: Honoraria; Notable Labs: Honoraria; Novartis: Honoraria; BMS: Honoraria; ImmuniOnc: Honoraria; Servier: Honoraria; AbbVie/Genentech: Honoraria; Astellas: Honoraria. Alvarado Valero: BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Jazz: Research Funding; Astex: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Bose: Kartos, Telios, Disc, Janssen, Geron: Research Funding; GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria; Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo, Ionis: Honoraria, Research Funding. Kantarjian: Shenzhen Target Rx: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Labcorp: Honoraria, Research Funding; KAHR medical: Honoraria, Research Funding; Ipsen Biopharmaceuticals: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biologix: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Ascentage: Honoraria, Research Funding; Amphista: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Stemline: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding. Gandhi: Dava Oncology: Honoraria; Sunesis: Honoraria, Research Funding; AbbVie: Research Funding; LOXO: Research Funding; Clear Creek Bio: Consultancy, Research Funding; Pharmacyclics: Research Funding. Wierda: Accutar Biotechnology: Research Funding; Numab THerapeutics: Research Funding; Nurix THerapeutics: Research Funding; Juno Therapeutics: Research Funding; Janssens Biotech: Research Funding; Janssens Biotech Inc: Research Funding; GlaxoSmithKline: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Cyclacel: Consultancy, Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Research Funding; GSK/Novartis: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: 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.
OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved
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