Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. 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, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 4 years.

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. Baseline characteristics are shown in Table 1. The median follow-up is 48.8 months.

Six pts came off study during 1^st 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.

We evaluated baseline pt and disease characteristics (age, gender, IGHV mutation status, CLL FISH panel, complex karyotype, TP53 mutation, del(17p)/TP53 mutation) and rate of bone marrow U-MRD at 6 months, 12 months and at any time during the combined IBR+VEN treatment. At 6 months of combined therapy, presence of TP53 mutation was associated with a lower rate of bone marrow U-MRD (p=0.03); however, none of the aforementioned characteristics, including TP53 mutation were associated with marrow U-MRD responses at 12 months or with best MRD response at any time during the combined therapy. There was a trend towards lower U-MRD rate among pts with mutated IGHV vs. unmutated IGHV at 12 month (p=0.09) and as best response (p=0.09).

The 4-year PFS is 94.5% (95% CI, 90.3%-98.9%) and 4-year OS is 96.6% (95% CI, 93.3%-99.9%). The 4-year PFS by TP53 aberrant status is shown in Figure 1. The 4-year PFS for pts with del(17p)/TP53 mutation (n=27) is 90.9% and for pts without del(17p)/TP53 mutation (n=93) is 95.5%. None of the aforementioned pt/disease characteristics were associated with PFS.

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 time of 23.9 months post Cycle 24, 11 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 11 pts with MRD recurrence, 10 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt had disease progression after 22 months of treatment-free interval and is currently receiving acalabrutinib.

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 recent 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.

Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 4-year PFS of 94.5%. MRD responses and PFS were independent of baseline pt/disease characteristics. Continuation of combined therapy among marrow MRD+ pts during the second and the third year led to achievement of U-MRD in a subset of pts.

Jain:Aprea Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; TransThera Sciences: Research Funding; Fate Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Ipsen: Honoraria; Loxo Oncology: Research Funding; Medisix: Research Funding; Takeda: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; ADC Therapeutics: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Cellectis: Honoraria, Research Funding; Dialectic Therapeutics: Research Funding; Novalgen: Research Funding; Newave: Research Funding; MEI Pharma: Honoraria; TG Therapeutics: Honoraria; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; Mingsight: Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Honoraria. Thompson:AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding. Ferrajoli:Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding. Burger:Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pharmacyclics LLC: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Novartis: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; BeiGene: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Research Funding. Borthakur:Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy; Ostuka Pharmaceuticals: Honoraria; Novartis: Consultancy; Illumina: Honoraria; Mission Bio: Honoraria; Agios: Consultancy; GSK: Consultancy; Celgene/BMS: Consultancy. Sasaki:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Iterion: Research Funding; Astellas: Research Funding; Agios: Consultancy; Amgen: Research Funding; Astex: Honoraria; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Novartis: Consultancy; Pfizer: Research Funding; Genfleet: Research Funding; Servier: Consultancy; PinotBio: Consultancy; JAZZ: Consultancy, Research Funding; Glycomimetics: Research Funding; cyclacel: Research Funding; AstraZeneca: Research Funding; cellenkos: Research Funding; Regeneron: Research Funding; Delta-Fly: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Daver:Syndax: Consultancy; AbbVie: Consultancy, Research Funding; Hanmi: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Trovagene: Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycometrics: Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Servier: Consultancy, Research Funding; Arog: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Shattuck: Consultancy; Agios: Consultancy. Jabbour:AbbVie: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Takeda: Other: Advisory Role, Research Funding. DiNardo:AbbVie: Consultancy, Research Funding; Gilead: Honoraria; LOXO: Research Funding; Novartis: Honoraria; Servier: Consultancy, Honoraria, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; ImmuneOnc: Honoraria, Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria; Foghorn: Honoraria, Research Funding; Cleave: Research Funding; Astex: Research Funding; Forma: Research Funding; Jazz: Honoraria. Alvarado:Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; BerGenBio: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding. Yilmaz:Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Bose:Incyte: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Cogent: Honoraria, Research Funding; Kartos: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Honoraria, Research Funding; Ionis: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Telios: Research Funding; Disc Medicine: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Honoraria; Pharma Essentia: Honoraria; Sierra Oncology (now GSK): Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding. Kanagal-Shamanna:Amgen: Consultancy; Novartis: Consultancy; Aptitude Health: Speakers Bureau; Physicians Education Resource: Speakers Bureau. Kantarjian:AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; ImmunoGen: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Gandhi:Sunesis: Honoraria, Research Funding; Dava Oncology: Honoraria; LOXO: Research Funding; Abbvie: Research Funding; Clear Creek Bio: Consultancy, Research Funding; Pharmacyclics: Research Funding. Wierda:Karyopharm: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Juno: Research Funding; Sanofi: Consultancy; Genzyme: Consultancy; Kite, a Gilead Company: Research Funding; Xencor: Research Funding; Sunesis: Research Funding; Pharmacyclics LLC: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Janssen: Research Funding; GSK/Novartis: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Cyclacel: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; AbbVie: Research Funding.

Combined ibrutinib and venetoclax is not FDA approved