Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Targeted Doublet Combinations
Hematology Disease Topics & Pathways:
Biological therapies, Lymphoid Leukemias, CLL, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Methods: Pts aged ≤70 y with previously untreated CLL received 3 cycles of Ibr lead-in then 13 cycles of combined Ibr + Ven (oral Ibr 420 mg/d; oral Ven ramp-up to 400 mg/d). Pts achieving Confirmed uMRD (uMRD serially over at least 3 cycles, in both peripheral blood and bone marrow) with Ibr + Ven were then randomly assigned 1:1 to double-blinded tx with PBO or single-agent Ibr. Endpoints included investigator-assessed best response per iwCLL, rates of uMRD (<10–4 by 8-color flow cytometry), DFS rate (time from randomization to MRD relapse [for a confirmed uMRD pt, ≥10-2 CLL cells/leukocytes confirmed on 2 serial visits], PD per investigator assessment, or death, whichever occurs first), PFS, OS, and AEs.
Results: 164 pts were enrolled to receive combined Ibr + Ven tx; after completion, 86 pts with Confirmed uMRD were randomly assigned to PBO or single-agent Ibr (n=43 each). Baseline characteristics were previously reported (Wierda et al. J Clin Oncol. 2021;39:3853). For pts with Confirmed uMRD, median time on study was 56 mo (Ibr arm range, 25‒68 mo; PBO arm range, 40‒65 mo); median post-randomization follow-up was 41.2 mo and 41.5 mo in the PBO and Ibr arms, respectively. In the PBO arm, 63% of pts have now achieved a best response of CR (increased from 60% at 2 y); among pts who continued Ibr, 81% achieved a best response of CR (increased from 72% at 2 y). Rates of uMRD remained stable from y 2 to y 3 post randomization (PBO, 56% [n=24] and 58% [n=25]; Ibr 60% [n=26] and 63% [n=27], respectively). The 3-y DFS rate was 85% (95% CI, 69‒93) with PBO and 93% (95% CI, 80‒98) among pts who continued Ibr (p=0.1621). The 4-y PFS was 88% (95% CI, 74‒95) with PBO and 95% (95% CI, 82‒99) with continued Ibr; 4-y OS was 100% (n=0 deaths) and 98% (95% CI, 84‒100), respectively. Notably, efficacy outcomes in high-risk subgroups were consistent with the total population although low sample size in the PBO arm limits interpretation (Table). Prevalence of AEs during the post-randomization period was generally stable in each arm (Table). New occurrences of hypertension in post randomization ys 1–3 were generally lower with PBO vs Ibr (y 1, n=1/43 vs n=3/43; y 2, n=1/41 vs n=4/41; y 3, n=3/38 vs n=2/41, respectively). No new atrial fibrillation or grade ≥3 hemorrhage events occurred in the PBO arm during the 3-y post randomization period; 1 pt in the Ibr arm had atrial fibrillation in 2nd y post randomization. In the 3rd y post randomization, no pts had dose reduction or discontinuation due to an AE as expected in the PBO arm; 1/41 pts had a dose reduction and 2/41 discontinued Ibr due to an AE. In total, 7 and 2 pts have experienced progressive disease in the PBO and Ibr arms, respectively; 4/7 pts in the PBO arm have initiated subsequent therapy (3 with Ibr, 1 with other agent/s; 0 pts in the Ibr arm have initiated subsequent tx).
Conclusions: First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free regimen that continues to provide deep, durable clinical responses in pts with CLL. With an additional y of follow-up in pts with Confirmed uMRD after Ibr + Ven, 4-y OS rates were ≥98% and 4-y PFS rates were ≥88% in pts randomly assigned to PBO (representing fixed duration) or continued Ibr. The durability of uMRD and the 3-y DFS rate of 85% without ongoing tx are encouraging and support the promising potential for tx-free remission. Together with the safety data, these results demonstrate a favorable benefit-risk profile with fixed duration Ibr + Ven.
Disclosures: Allan: Genentech: Consultancy, Research Funding; PCYC: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Epizyme: Consultancy; ADC Therapeutics: Consultancy; Ascentage: Consultancy; Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Siddiqi: Beigene: Consultancy, Research Funding, Speakers Bureau; Astrazeneca: Consultancy, Research Funding, Speakers Bureau; Ascentage Pharm: Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Jannsen: Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau. Kipps: Pharmacyclics, LLC an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech-Roch: Consultancy, Research Funding; Oncternal: Research Funding; Gilead: Consultancy; Celgene: Consultancy. Kuss: Mundipharma: Consultancy, Honoraria; Roche Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Commonwealth Serum Laboratories: Current equity holder in private company, Current holder of stock options in a privately-held company; AbbVie: Consultancy, Honoraria, Other: expert textinomy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria. Badoux: AbbVie: Honoraria, Other: travel, accomodations, expenses; Janssen: Honoraria. Barrientos: Janssen: Honoraria; Beigene: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; MEI: Consultancy; Oncternal: Research Funding; Velosbio: Research Funding; Pharmacyclics, LLC an AbbVie Company: Research Funding. Tedeschi: Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau. Opat: Pharmacyclics, LLC an AbbVie Company: Research Funding; Antegene: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Belgene: Research Funding. Flinn: Fate Therapeutics: Research Funding; Biopath: Research Funding; Hutchison MediPharma: Consultancy; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Curis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding; Incyte: Research Funding; IGM Biosciences: Research Funding; Merck: Research Funding; Loxo@Lilly: Research Funding; Infinity Pharmaceuticals: Research Funding; 2seventy bio: Research Funding; Triphase Research & Development Corp: Research Funding; ArQule: Research Funding; Agios: Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; TCR2 Therapeutics: Research Funding; City of Hope National Medical Center: Research Funding; Tessa Therapeutics: Research Funding; Pfizer: Research Funding; Portola Pharmaceuticals: Research Funding; Trillium Therapeutics: Research Funding; Rhizen Pharmaceuticals: Research Funding; Myeloid Therapeutics: Research Funding; Epizyme: Research Funding; Iksuda Therapeutics: Consultancy; CTI Biopharma: Research Funding; Millenium Pharmaceuticals: Research Funding; Genentech: Consultancy, Research Funding; Acerta Pharma: Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Research Funding; Servier Pharmaceuticals: Consultancy; Unum Therapeutics: Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Xencor: Consultancy; CALIBR: Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; CALGB: Research Funding; InnoCare Pharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Genmab: Consultancy; Gilead Sciences: Research Funding; Century Therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Gonzalez Barca: Takeda: Honoraria; Incyte: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; EUSA Pharma: Honoraria, Other: travel, accommodations, expenses; Roche: Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Novartis: Consultancy; Beigene: Consultancy; Gilead: Consultancy; Kiowa: Consultancy; Lilly: Consultancy. Jacobs: TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Beigene: Speakers Bureau; Teneobio: Research Funding; Verastem: Consultancy; MEI Pharma: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics, an AbbAvie Company: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Szafer-Glusman: AbbVie: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Zhou: AbbVie: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Szoke: Pharmacyclics, an AbbVie Company: Current Employment; AbbVie: Current equity holder in private company, Current holder of stock options in a privately-held company. Wierda: GSK/Novartis: Research Funding; AbbVie: Research Funding; Oncternal Therapeutics: Research Funding; Miragen: Research Funding; Kite Pharma: Research Funding; Bristol Myers Squibb (June and Celgene): Research Funding; Cyclacel: Research Funding; Sunesis: Research Funding; Loxo Oncology/Lilly: Research Funding; Gilead Sciences: Research Funding; AstraZeneca/Acerta Pharma: Research Funding; Pharmacyclics, LLC an AbbVie Company: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Genentech: Research Funding. Ghia: Lilly/Loxo: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Tam: Beigene: Honoraria, Research Funding; AstraZeneca: Honoraria; LOXO: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding.
OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication.