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1869 Consistently High 5.5-Year Progression-Free Survival (PFS) Rates in Patients with and without Bulky Baseline Lymphadenopathy ≥5 Cm Are Associated with High Undetectable Minimal Residual Disease (uMRD4) Rates after First-Line Treatment with Fixed-Duration Ibrutinib + Venetoclax for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) in the Phase 2 CAPTIVATE Study

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, Combination therapy, CLL, Clinical Research, Diseases, Treatment Considerations, Lymphoid Malignancies, Non-Biological therapies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

William G. Wierda1, Ryan Jacobs2, Paul M Barr, MD3, John N. Allan, MD4, Tanya Siddiqi, MD5, Alessandra Tedeschi, MD6*, Thomas J. Kipps, MD7, Susan M. O'Brien8, Xavier C. Badoux, MBBS, FRACP, FRCPA9, Andrea Visentin, MD, PhD10*, Masa Lasica, MBBS, BMedSci, FRACP, FRCPA11*, Dennis A. Carney, MBBS, FRACP, FRCPA, PhD12*, Anna Elinder Cambrun, MBBS, FRACP, FRCPA13*, Javier De la Serna, MD14, Edith Szafer Glusman, PhD15*, Cathy Zhou, MS16*, Jutta K. Neuenburg, MD, PhD16, Lynne Neumayr, MD16*, Anita Szoke, MD16*, James P. Dean, MD, PhD16*, Paolo Ghia, MD, PhD17,18 and Constantine S. Tam, MBBS, MD19

1The University of Texas MD Anderson Cancer Center, Houston, TX
2Levine Cancer Institute, Charlotte, NC
3University of Rochester, Rochester, NY
4Division of Hematology and Oncology, Weill Cornell Medicine, Long Island City, NY
5City of Hope National Medical Center, Duarte, CA
6Niguarda Ca' Granda Hospital, Milano, ITA
7Moores Cancer Center, University of Californi, San Diego, La Jolla, CA
8UC Irvine, Chao Family Comprehensive Cancer Center, Orange, CA
9Ministry of Health, Kogarah, NSW, Australia
10University of Padova, Padova, Italy
11St Vincent’s Hospital, Melbourne, Australia
12Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
13North Shore Hospital, Auckland, New Zealand
14Hospital Universitario 12 de Octubre, Madrid, Spain
15AbbVie Inc, North Chicago, IL
16AbbVie, North Chicago, IL
17Università Vita-Salute San Raffaele, Milano, Italy
18IRCCS Ospedale San Raffaele, Milan, Italy
19Alfred Hospital and Monash University, Melbourne, VIC, Australia

Introduction: First-line all-oral, once daily ibrutinib (Ibr) + venetoclax (Ven) for CLL/SLL was investigated in 2 cohorts of the phase 2 CAPTIVATE study: Minimal Residual Disease (MRD)–guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). With up to 5.5 years of follow-up, FD Ibr+Ven demonstrated sustained PFS, including in patients (pts) with high-risk genomic features (Wierda et al, ASCO 2024). Explorations of baseline (BL) lymph node (LN) size, depth of LN and MRD response, and outcomes after FD Ibr+Ven are reported.

Methods: Pts aged ≤70 years with previously untreated CLL/SLL received 3 cycles of Ibr, then 12 cycles of Ibr+Ven (Ibr, 420 mg/day orally; Ven, 5-week ramp up to 400 mg/day orally) (FD cohort); the included MRD cohort pts received 1 additional cycle of Ibr+Ven while being randomized to placebo. Post hoc exploratory analyses were performed to evaluate response per iwCLL criteria, undetectable MRD (uMRD4; <10–4 by flow cytometry), PFS, and overall survival efficacy outcomes in pt subgroups defined by maximal LN long diameter (LDi) at BL and at end of treatment (EOT). Treatment-emergent safety outcomes were evaluated in pt subsets defined by BL LN LDi.

Results: Of 202 pts who completed FD Ibr+Ven in the FD cohort (n=159) or MRD cohort placebo arm (n=43), 66 (33%) had BL LDi ≥5 cm. In pts with BL LDi <5 vs ≥5 cm, both groups had median age of 60 years and 29% had Rai stage III/IV, while 60% vs 74% were male, 35% vs 39% had BL cytopenia, and 78% vs 70% had absolute lymphocyte count ≥25 × 109/L, respectively; high-risk genomic features included unmutated IGHV (54% vs 70%), del(17p)/mutated TP53 (18% vs 8%), del(11q) (14% vs 26%), and complex karyotype (≥3 aberrations, 15% vs 21%). BL LN LDi correlated well with BL LN sum of the product of diameters (Pearson correlation, 0.84). At EOT, high uMRD4 rates were achieved in peripheral blood (PB) at 65% and 77% in pts with BL LDi <5 cm and ≥5 cm (66% and 75% bone marrow uMRD4, respectively), while complete response (CR, including CR with incomplete bone marrow recovery) rates were 66% and 21%, respectively. Exploring EOT LN depth of response, LDi ≤1.5 cm and ≤2 cm, respectively, were achieved in 71% and 89% of pts with BL LDi <5 cm and in 27% and 54% of pts with BL LDi ≥5 cm, respectively. EOT uMRD4 rates in pts with EOT LDi of ≤1.5 cm and ≤2 cm, respectively, were consistently high at 71% and 69% in PB, and 72% and 70% in bone marrow (in pts with EOT LDi >2 cm: 71% in PB, 68% in bone marrow). With a median time on study of 69 months (range, 1–84), 5.5-year PFS (67% and 63%) and overall survival (97% in both) rates were very similar in pts with BL LDi <5 or ≥5 cm. Interestingly, 5.5-year PFS rates were high irrespective of EOT LDi ≤1.5 or >1.5 cm (69% vs 64%) or EOT LDi ≤2 or >2 cm (67% vs 63%). On the other hand, as expected, 5.5-year PFS rates were consistently higher in pts with EOT PB uMRD4 vs those with detectable MRD irrespective of depth of EOT LDi: with LDi of ≤1.5 cm, >1.5 to ≤2 cm, or >2 cm, rates were 77% vs 50%, 75% vs 43%, and 72% vs 42%, respectively (corresponding rates with EOT bone marrow uMRD4 vs detectable MRD were very consistent with PB in these subgroups). As previously seen with chemoimmunotherapy, 5.5-year PFS rates were higher in pts with PB uMRD4 irrespective of iwCLL response category (75% whether with CR or partial response [PR]) vs those with detectable MRD (54% with CR and 46% with PR). Again, bone marrow uMRD4 vs detectable MRD outcomes were very consistent with PB. Treatment-emergent grade ≥3 adverse events (AEs) occurred in 64% and 58% of pts with BL LDi <5 cm and ≥5 cm, respectively. AEs leading to discontinuation occurred in 3% and 6% of pts with BL LDi <5 cm and ≥5 cm, respectively.

Conclusions: Ibr+Ven is an all-oral, once-daily, chemotherapy-free FD regimen for first-line treatment of CLL/SLL that provides durable PFS and OS with long-term follow-up. In pts with or without bulky baseline LN disease ≥5 cm, similarly durable long-term PFS and OS outcomes were observed and associated with similarly high rates of EOT uMRD4. Assessed at EOT, depth of lymph node responses at LDi ≤1.5 vs ≤2 cm cutoffs were associated with similar 5.5-year PFS outcomes while uMRD4 status was again more strongly correlated with PFS. Long-term PFS was associated most strongly with uMRD4 status while depth of response per iwCLL criteria (CR vs PR) had a minor impact, which was seen only in pts with detectable MRD. The safety profile of FD Ibr+Ven was tolerable and similar irrespective of lymph node bulk at baseline.

Disclosures: Wierda: Oncternal Therapeutics: Research Funding; Genentech, Inc.: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly: Research Funding; Acerta Pharma: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; GSK: Research Funding; Loxo Oncology: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Nurix Therapeutics: Research Funding; Gilead Sciences: Research Funding; Kite: Research Funding; Novartis: Research Funding; Oncternal Therapeutics: Research Funding; Numab Therapeutics: Research Funding; Accutar Biotechnology: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL). Jacobs: Regeneron: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; AbbVie: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding; Lilly: Consultancy, Research Funding; Beigene: Consultancy, Research Funding, Speakers Bureau; Galapagos: Consultancy; Janssen: Consultancy; Adaptive: Speakers Bureau; SecuraBio: Consultancy. Barr: Bristol Myers Squibb: Consultancy; TG Therapeutics: Consultancy, Research Funding; Gilead: Consultancy; Genentech: Consultancy; Merck: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie company: Consultancy; AbbVie: Consultancy; MorphoSys: Consultancy; Seagen: Consultancy. Allan: Janssen: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau. Siddiqi: Gilead/Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tedeschi: AstraZeneca, AbbVie, BeiGene, Janssen, Lilly: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kipps: Abbvie/Janssen/Pharmacyclics/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lymphoma and Leukemia Society: Research Funding; Oncternal Therapeutics: Current equity holder in private company. O'Brien: Alliance: Research Funding; AstraZeneca: Consultancy, Research Funding; Autolus: Consultancy; Beigene, Ltd: Consultancy; Bristol Myers Squibb: Consultancy; Janssen Oncology: Consultancy; Johnson and Johnson: Consultancy; Kite: Research Funding; Loxo Oncology, Inc: Consultancy; Merck: Consultancy; Caribou Biosciences, Inc.: Research Funding; Eli Lilly and Company: Consultancy; Gilead: Research Funding; GlaxoSmithKline: Consultancy; Abbvie: Consultancy; Mustang Bio: Research Funding; Nurix Therapeautics, Inc.: Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy. Badoux: AbbVie, Janssen: Honoraria; AbbVie: Other: Travel, accommodations, expenses. Visentin: Beigene: Consultancy, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; J&J: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZenca SpA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lasica: Celgene: Other: Travel, accommodations, expenses. Szafer Glusman: AbbVie: Current Employment, Other: owns AbbVie stock. Zhou: AbbVie: Current Employment. Neuenburg: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Neumayr: AbbVie: Current Employment, Current holder of stock options in a privately-held company; Novartis: Honoraria; ApoPharma: Consultancy; Forma Therapeutics: Other: travel, accomodations, expenses; Pfizer: Research Funding; Sancilio: Research Funding. Szoke: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Dean: AbbVie Inc.: Current Employment, Current holder of stock options in a privately-held company. Ghia: BeiGen: Consultancy; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Johnson&Johnson: Consultancy, Research Funding; Galapagos: Consultancy; Loxo@Lilly: Consultancy; MSD: Consultancy; Galapagos: Consultancy; AbbvVie: Consultancy, Research Funding; Roche: Consultancy. Tam: AbbVie, BeiGene, Janssen, LOXO: Honoraria; AbbVie, BeiGene, Janssen: Research Funding.

*signifies non-member of ASH