Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Targeted Doublet Combinations
Hematology Disease Topics & Pathways:
clinical trials, Research, Lymphoid Leukemias, adult, 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. Baseline characteristics are shown in Table 1. The median follow-up is 48.8 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.
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.
Disclosures: 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: Beigene: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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: cyclacel: Research Funding; PinotBio: Consultancy; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Astex: Honoraria; Genfleet: Research Funding; Agios: Consultancy; Novartis: Consultancy; AstraZeneca: Research Funding; JAZZ: Consultancy, Research Funding; Delta-Fly: Research Funding; cellenkos: Research Funding; Iterion: Research Funding; BMS: Consultancy, Research Funding; Servier: Consultancy; Amgen: Research Funding; Pfizer: Research Funding; Ascentage: Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Regeneron: Research Funding. Pemmaraju: Affymetrix: Research Funding; Plexxikon: Research Funding; Roche Diagnostics: Honoraria; SagerStrong Foundation: Research Funding; LFB Biotechnologies: Honoraria; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte: Research Funding; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding. Daver: Pfizer: Consultancy, Research Funding; Agios: Consultancy; Shattuck: Consultancy; Hanmi: Consultancy, Research Funding; Glycometrics: Research Funding; Trillium: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Research Funding; Arog: Consultancy; FATE Therapeutics: Research Funding; Novimmune: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Syndax: Consultancy; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding. Jabbour: Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Pfizer: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding; AbbVie: 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: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Bose: Kartos: Honoraria, Research Funding; Constellation Pharmaceuticals, Inc./MorphoSys: 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, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celegene: Consultancy, Honoraria, Research Funding; Cogent: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Kanagal-Shamanna: Physicians Education Resource: Speakers Bureau; Aptitude Health: Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy. 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.
OffLabel Disclosure: Combined ibrutinib and venetoclax is not FDA approved