Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results

ABSTRACT

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is a highly effective therapy for patients (pts) with CLL (Jain, NEJM 2019;Wierda, ASH 2020;Kater, EHA 2021). We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019;Jain, JAMA Oncology 2021). Here we report updated data for these pts with focus on MRD. 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 (yrs). 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 ibrutinib for pts who remained BM MRD+ after Cycle 24. Response assessments were performed using BM and CT imaging 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 in pts off treatment or on ibrutinib monotherapy beyond 24 cycles of combined treatment. Results: A total of 80 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up was 44.1 months. Five pts came off study during 1 st 3 cycles of IBR monotherapy;75 pts initiated VEN. We previously reported that after 12 cycles of the combination, 45/80 (56%) achieved BM U-MRD remission;24/80 (30%) were BM MRD-positive (low MRD+, n=19;high MRD+, n=5). After 24 cycles of the combination, 53/80 (66%) achieved BM U-MRD remission;14/80 (17%) were BM MRD+ (low MRD+, n=13;high MRD+, n=1). Overall, 60/80 (75%) achieved BM U-MRD as the best response. Updated PFS is provided in Figure 1. Of the 53 pts who were BM U-MRD at the end of cycle 24 of the combination, 52 pts had a subsequent blood MRD assessment done in follow-up (1 missed due to COVID-19);51/53 discontinued all therapy, 2 pts continued IBR per treatment physician discretion. With a median time of 18.4 months post Cycle 24, 8 pts had recurrence of blood MRD (defined as MRD ≥ 0.01% in 2 consecutive visits) in follow-up with 1 pt with CLL progression. The sole pt with CLL progression had mutated IGHV with del(11q) and NOTCH1 mutation. The pt had delayed achievement of BM U-MRD with the pt achieving U-MRD for the first time at the end of Cycle 24 of combined therapy. She was noted to have disease progression 22 months off therapy;BTK or PLCG2 mutation were not detected and the patient is currently in clinical remission on acalabrutinib. The time to MRD conversion for these 53 pts is shown in Figure 2. There were 14 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=13;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 13 pts (all low MRD+ in BM, range 0.01-0.56%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of venetoclax;9/13 pts have resumed VEN. 6/9 pts have achieved U-MRD remission. 2 pts had Richter transformation and 3 pts have died (Jain, JAMA Oncology 2021). Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL. Remissions were durable with some pts having recurrence of blood MRD in follow-up, which may be an early indicator of relapse. In a small subset of the pts with BM MRD+ disease at 24 cycles of combined therapy, additional VEN appears to lead to U-MRD remission in majority of the pts. Whether this will lead to improved long-term PFS remains to be determined. [Formula presented] Disclosures Jain TG Therapeutics Honoraria;Beigene Honoraria;Janssen Honoraria;Fate Therapeutics Research Funding;Aprea Therapeutics Research Funding;Precision Biosciences Honoraria, Research Funding;Incyte Research Funding;Adaptive Biotechnologies Honoraria, Research Funding;Cellectis Honoraria, Research Funding;ADC Therapeutics Honoraria, Research Funding;Servier Honoraria, Research Funding;Pfizer Research Funding;Bristol Myers Squibb Honoraria, Research Funding;AstraZeneca Honoraria, Research Funding;Genentech Honoraria, Research Funding;AbbVie Honoraria, Research Funding;Pharmacyclics Research Funding. Thompson AbbVie Other Institution Advisory/Consultancy, Honoraria, Research Grant/Funding;Amgen Other Institution Honoraria, Research Grant/Funding;Genentech Other Institution Advisory/Consultancy, Honoraria, Research Grant/Funding;Adaptive Biotechnologies Other Institution Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony;Pharmacyclics Other Institution Advisory/Consultancy, Honoraria, Research Grant/Funding;Janssen Consultancy, Honoraria;Gilead Other Institution Advisory/Consultancy, Honoraria. Ferrajoli BeiGene Other Advisory Board, Research Funding;Janssen Other Advisory Board;AstraZeneca Other Advisory Board, Research Funding. Burger Novartis Other Travel/Accommodations/Expenses, Speakers Bureau;TG Therapeutics Other Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Janssen Consultancy, Other Travel/Accommodations/Expenses, Speakers Bureau;Beigene Research Funding, Speakers Bureau;Pharmacyclics LLC Consultancy, Other Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Gilead Consultancy, Other Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;AstraZeneca Consultancy. Borthakur GSK Consultancy;ArgenX Membership on an entity's Board of Directors or advisory committees;University of Texas MD Anderson Cancer Center Current Employment;Protagonist Consultancy;Novartis Consultancy, Membership on an entity's Board of Directors or advisory committees;Astex Research Funding;Ryvu Research Funding;Takeda Membership on an entity's Board of Directors or advisory committees. Takahashi Symbio Pharmaceuticals Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis Consultancy;Celgene/BMS Consultancy;GSK Consultancy. Sasaki Daiichi-Sankyo Membership on an entity's Board of Directors or advisory committees;Pfizer Membership on an entity's Board of Directors or advisory committees;Novartis Consultancy, Research Funding. Kadia Cellonkos Other;Aglos Consultancy;Dalichi Sankyo Consultancy;AbbVie Consultancy, Other Grant/research support;BMS Other Grant/research support;Amgen Other Grant/research support;Cure Speakers Bureau;Jazz Consultancy;Genentech Consultancy, Other Grant/research support;Liberum Consultancy;Novartis Consultancy;Pfizer Consultancy, Other;Pulmotech Other;Sanofi-Aventis Consultancy;AstraZeneca Other;Astellas Other;Genfleet Other;Ascentage Other. Konopleva Sanofi Other grant support, Research Funding;Cellectis Other grant support;Calithera Other grant support, Research Funding;KisoJi Research Funding;Agios Other grant support, Research Funding;Ascentage Other grant support, Research Funding;AbbVie Consultancy, Honoraria, Other Grant Support, Research Funding;Ablynx Other grant support, Research Funding;Stemline Therapeutics Research Funding;Eli Lilly Patents & Royalties intellectual property rights, Research Funding;AstraZeneca Other grant support, Research Funding;Rafael Pharmaceuticals Other grant support, Research Funding;Genentech Consultancy, Honoraria, Other grant support, Research Funding;F. Hoffmann-La Roche Consultancy, Honoraria, Other grant support;Forty Seven Other grant support, Research Funding;Novartis Other research funding pending, Patents & Royalties intellectual property rights;Reata Pharmaceuticals Current holder of stock options in a privately-held company, Patents & Royalties intellectual property rights. Alvarado BerGenBio Research Funding;Jazz Pharmaceuticals Research Funding;Astex Pharmaceuticals Research Funding;Sun Pharma Consultancy, Research Funding;MEI Pharma Research Funding;FibroGen Research Funding;Daiichi-Sankyo Research Funding;CytomX Therapeutics Consultancy. Yilmaz Pfizer Research Funding;Daiichi-Sankyo Research Funding. DiNardo Notable Labs Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;Novartis Honoraria;Takeda Honoraria;Celgene, a Bristol Myers Squibb company Honoraria, Research Funding;Forma Honoraria, Research Funding;AbbVie Consultancy, Research Funding;GlaxoSmithKline Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb Honoraria, Research Funding;ImmuneOnc Honoraria, Research Funding;Agios/Servier Consultancy, Honoraria, Research Funding;Foghorn Honoraria, Research Funding. Bose Kartos Therapeutics Honoraria, Research Funding;Sierra Oncology Honoraria;Novartis Honoraria;Constellation Pharmaceuticals Research Funding;NS Pharma Research Funding;Celgene Corporation Honoraria, Research Funding;Blueprint Medicines Honoraria, Research Funding;Pfizer Research Funding;Promedior Research Funding;Astellas Research Funding;Incyte Corporation Honoraria, Research Funding;BMS Honoraria, Research Funding;CTI BioPharma Honoraria, Research Funding. Pemmaraju Blueprint Medicines Consultancy;LFB Biotechnologies Consultancy;Novartis Pharmaceuticals Consultancy, Other Research Support, Research Funding;ASCO Leukemia Advisory Panel Membership on an entity's Board of Directors or advisory committees;Dan's House of Hope Membership on an entity's Board of Directors or advisorycommittees;Roche Diagnostics Consultancy;MustangBio Consultancy, Other;Affymetrix Consultancy, Research Funding;Samus Other, Research Funding;ImmunoGen, Inc Consultancy;ASH Communications Committee Membership on an entity's Board of Directors or advisory committees;Aptitude Health Consultancy;Plexxicon Other, Research Funding;Springer Science + Business Media Other;Protagonist Therapeutics, Inc. Consultancy;HemOnc Times/Oncology Times Membership on an entity's Board of Directors or advisory committees;Clearview Healthcare Partners Consultancy;Abbvie Pharmaceuticals Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding;CareDx, Inc. Consultancy;Sager Strong Foundation Other;Daiichi Sankyo, Inc. Other, Research Funding;Incyte Consultancy;Stemline Therapeutics, Inc. Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding;Bristol-Myers Squibb Co. Consultancy;DAVA Oncology Consultancy;Pacylex Pharmaceuticals Consultancy;Celgene Corporation Consultancy;Cellectis S.A. ADR Other, Research Funding. Jabbour Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech Research Funding. Wang Stemline Therapeutics Honoraria. Kantarjian Taiho Pharmaceutical Canada Honoraria;Precision Biosciences Honoraria;Immunogen Research Funding;Daiichi-Sankyo Research Funding;Jazz Research Funding;BMS Research Funding;AbbVie Honoraria, Research Funding;Pfizer Honoraria, Research Funding;Novartis Honoraria, Research Funding;NOVA Research Honoraria;KAHR Medical Ltd Honoraria;Ipsen Pharmaceuticals Honoraria;Astra Zeneca Honoraria;Astellas Health Honoraria;Aptitude Health Honoraria;Amgen Honoraria, Research Funding;Ascentage Research Funding. Wierda Juno Therapeutics Research Funding;AstraZeneca Research Funding;Xencor Research Funding;Janssen Research Funding;Loxo Oncology, Inc. Research Funding;Cyclacel Research Funding;Oncternal Therapeutics, Inc. Research Funding;Miragen Research Funding;KITE Pharma Research Funding;Sunesis Research Funding;Gilead Sciences Research Funding;Acerta Pharma Inc. Rese rch Funding;Pharmacyclics LLC, an AbbVie Company Research Funding;Karyopharm Research Funding;Genentech Research Funding;GSK/Novartis Research Funding;Genzyme Corporation Consultancy;AbbVie Research Funding. OffLabel Disclosure The combination of ibrutinib and venetoclax is not FDA approved