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1010 Minimal Residual Disease (MRD)-Adapted Duration of Front-Line Venetoclax and Obinutuzumab Treatment for Fit Patients with Chronic Lymphocytic Leukemia (CLL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Frontline Targeted Therapy Combinations
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, Combination therapy, Adult, CLL, Clinical Research, Diseases, Treatment Considerations, Lymphoid Malignancies, Study Population, Human, Measurable Residual Disease
Monday, December 9, 2024: 4:45 PM

Lindsey Roeker, MD1, Anthony R. Mato, MD2*, Andrew D. Zelenetz, MD, PhD3, Jae H. Park, MD4, Mark Blaine Geyer, MD1, Andriy Derkach, PhD5*, David Nemirovsky5*, Prioty Islam, MD1*, Lorenzo Falchi, MD6, Maria Lia Palomba, MD3, Anita Kumar, MD3, Gilles Salles, MD, PhD3, Jennifer Kimberly Lue, MD3, Aaron D. Goldberg7, Deborah M. Stephens, DO8, Victoria Duffy6*, Gail Panton6*, Dianna Tyznar6*, Colleen Dorsey6*, Dhara Soni6*, Claire Hutzler6*, Lauren Nogan6*, Alexandra Allen6*, Tenzin Nyima6*, Thu Quynh Nguyen, BSc9*, Monica Shah, BA10*, Tamotha R Cook8*, Jennifer Abillar-Wright6*, Jamila Brutus, NP6*, Carissa Laudati, NP6*, Bejal Kikani11*, Catherine C Coombs, MD12*, Michael R. Silvestrone6*, Christopher E. Jensen8*, Bita Fakhri, MD, MPH13 and Meghan C. Thompson, MD1

1Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Hematology & Oncology, Cayuga Medical Center, Ithaca, NY
3Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
4Cell Therapy Service and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
5Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY
6Memorial Sloan Kettering Cancer Center, New York, NY
7Department of Medicine; Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
8University of North Carolina Chapel Hill, Chapel Hill, NC
9Stanford Cancer Institute, Palo Alto, CA
10Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
11UNC Chapel Hill, Chapel Hill, NC
12University of California Irvine Health, Orange, CA
13Stanford University School of Medicine, Stanford, CA

Introduction: Venetoclax and obinutuzumab (Ven/Obin) is approved as a 1 year fixed-duration treatment regimen in the front-line (1L) setting for patients (pts) with CLL. Extended follow up from the CLL14 study has demonstrated that undetectable measurable residual disease (uMRD) at the end of treatment (EOT) predicts longer progression free survival (PFS). However, whether Ven/Obin treatment duration can be tailored based on an individual pt’s depth of response to optimize outcomes has not been well studied.

Methods: In this phase 2 investigator-initiated study (NCT04447768), pts who required 1L therapy (tx) per iwCLL criteria were treated with Ven/Obin, and tx duration was directed by MRD status. Key inclusion criteria: age ≥ 18 years, CIRS comorbidity score ≤ 6, ECOG ≤ 1, adequate marrow and organ function.

Obin 1000mg was given on Cycle 1 Day 1 (C1D1)/2, 8, 15, and D1 of C2-6. Ven was dose escalated over 5 weeks starting on C1D22 to 400mg daily. Each cycle was 28D. All pts had peripheral blood (PB) MRD testing by next generation sequencing (ClonoSEQ) at C7. For pts who achieved uMRD (defined as <10-6; uMRD6), PB MRD testing was repeated at C9. Pts with uMRD6 in PB at C9 completed 9C of tx and entered treatment free observation (TFO). Pts with detectable MRD (dMRD) at C7 were tested again at C12. Those with uMRD5 (defined as <10-5) in PB at C12 completed 12C of tx and entered TFO. Pts who had dMRD at C12 completed 24C of tx and entered TFO regardless of MRD status. Bone marrow (BM) biopsy was performed at EOT; BM MRD status did not dictate treatment duration. Pts were followed for clinical progression, and next CLL-directed tx was delivered and recorded if iwCLL criteria for therapy were met. Primary endpoint is 36-month (mo) PFS.

Results: As of 7/1/2024, this study has fully accrued 100 pts. Median age at enrollment was 58 years (range 34-81), 71% male, 90% white. Median CIRS score was 3 (range 0-6), 89% had ECOG 0. Rai stage 1/2 for 73%, 3/4 for 27%. Baseline cytogenetics: 7.3% del17p, 19% del11q, 20% trisomy 12, 59% del13q, 12% complex karyotype (CK; ≥3 abnormalities by stimulated karyotype or SNP-ARRAY). 50% unmutated IGHV. 16% TP53 mutated.

With median follow-up (f/u) of 24 mos, 24-mo PFS is 92% and overall survival (OS) is 95% for the entire cohort. Of the 81 pts who have reached C9, 41 pts were uMRD6 at both C7 and C9 and discontinued therapy. Twenty-nine pts were uMRD5 at C12 and discontinued therapy. Three pts remained dMRD (10-5 sensitivity) at C12 and completed 24 cycles of therapy (1 uMRD5, 2 dMRD at C24). Three pts discontinued tx before C9 MRD testing (reasons for discontinuation: 1 intolerance, 1 withdrawal of consent, 1 death unrelated to tx or disease), 16 have not yet reached C9. 8 discontinued tx outside of meeting protocol requirements (6 at C9, 2 at C12) and are included in the intention-to-treat survival analysis. For those who were uMRD in PB at each time point, BM was uMRD6 for 68% at C9 and 67% uMRD5 at C12.

PFS at 12 mos following completion of tx was 91% for those who discontinued tx after 9C (median f/u 27 mos from C1D1) vs. 95% for those who discontinued tx after 12C (median f/u 27 mos from C1D1). PFS at 24 mos following tx completion is identical to 12 mos, though only 33 pts have reached this landmark. There is no significant difference in PFS between those who completed 9 and 12 C of therapy (p=0.7). Two pts treated with 9C of tx required subsequent treatment; one pt required CLL-directed treatment after 10 mos of TFO (later diagnosed with Richter’s transformation and died) and one pt experienced Richter’s transformation and was treated after 5 mos of TFO. No pt receiving 12C or more of tx have progressed.

Pts who had early uMRD6 at C7 vs. those who did not were more likely to have tri12 (31% vs. 8%, p=0.012) and less likely to have del13q (50% vs. 73%, p=0.035). There was no significant difference in rates of TP53 aberrations, CK, or IGHV mutational status.

Conclusion: This study supports the use of MRD testing to guide duration of Ven / Obin therapy in the 1L setting. Early discontinuation of Ven/Obin for pts who are uMRD6 at C9 achieves similar PFS to pts who completed 12C of Ven/Obin and have uMRD5 status before entering TFO. In this study, concordance rate between PB and BM was relatively low (approximately two-thirds concordance) at 10-6 (C9) and 10-5 (C12) sensitivities. Longer follow-up from this study will inform the impact of PB and BM MRD status on PFS and if additional Ven/Obin beyond 12C improves outcomes for those who remain dMRD.

Disclosures: Roeker: Pharmacyclics LLC, an AbbVie Company: Consultancy; Pfizer: Consultancy, Research Funding; PeerView: Honoraria, Speakers Bureau; Medscape: Honoraria, Speakers Bureau; Loxo Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Genentech: Research Funding; Dren Bio: Research Funding; Dava Oncology: Honoraria, Speakers Bureau; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Research Funding; Adaptive Biotechnologies: Research Funding; AbbVie: Consultancy, Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; TG Therapeutics: Consultancy; Qilu Puget Sound Biotherapeutics: Research Funding; Curio: Honoraria, Speakers Bureau. Mato: AstraZeneca: Consultancy. Zelenetz: Genentech/Roche: Consultancy, Research Funding; Abbvie: Consultancy; Gilead/Kite: Consultancy; Novartis: Consultancy; BeiGene: Consultancy, Research Funding; BMS/Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy; Adaptive Biotechnology: Consultancy. Park: Curocell: Current equity holder in publicly-traded company; Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; Adaptive Biotechnologies, Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, Bright Pharmaceutical Services, BMS, Caribou Biosciences, Curocell, Galapagos, Gilead Sciences, Intellia, In8Bio, Kite, Novartis, Pfizer, Servier, Sobi, Synthekine: Consultancy; Takeda: Consultancy. Geyer: Actinium Pharmaceuticals, Inc: Research Funding; Amgen: Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Tigen Pharma: Research Funding. Islam: Disc Medicine: Consultancy. Falchi: Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; Genmab: Consultancy, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taylor Francis: Other: Journal Editor; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EvolveImmune: Consultancy; Kaplan: Other: CME Presentation: Projects in Knowledge. Palomba: Novartis: Consultancy; Synthekine: Consultancy; Bristo Meyer Squibb: Consultancy; Cellectar: Consultancy. Kumar: Genentech, Inc.: Consultancy, Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Seattle Genetics: Research Funding; BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Kite Pharmaceuticals, Janssen: Honoraria; Loxo Oncology/Lily Pharmaceuticals: Honoraria, Research Funding; Adaptive Biotechnologies, Celgene, Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Salles: Molecular Partners: Consultancy; Incyte: Consultancy; Ipsen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Genmab: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Nurix: Research Funding. Lue: GenMab: Consultancy; ADC Therapeutics: Consultancy; Merck Pharmaceuticals: Consultancy; Kymera Therapeutics: Research Funding; Lumanity: Consultancy. Goldberg: Ikena Oncology: Consultancy; Pfizer: Research Funding; Molecular Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Aptose: Research Funding; AROG: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celularity: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura Oncology: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stephens: AstraZeneca, Beigene, Novartis: Research Funding; Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics: Consultancy. Coombs: AbbVie, AstraZeneca, Beigene, Genentech, Lilly: Speakers Bureau; Bluebird Bio, Geron, Pfizer: Current equity holder in publicly-traded company; AbbVie, Allogene, AstraZeneca, Beigene, Genentech, Janssen, LOXO/Lilly, MEI Pharma, Mingsight, Octapharma, TG Therapeutics, have served on speaker’s bureaus for AbbVie, AstraZeneca, Beigene, Genentech, Lilly: Consultancy, Honoraria; AbbVie, AstraZeneca, CarnaBio, LOXO/Lilly: Research Funding. Jensen: Abbvie: Consultancy, Research Funding. Fakhri: Loxo/Lilly: Research Funding; AbbVie/Genmab, Loxo-Lilly, BMS, Angiocrine: Research Funding; AbbVie, ADC therapeutics, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thompson: AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Nurix Therapeutics: Other: Reimbursed travel, Research Funding; Dava Oncology: Honoraria, Other: Reimbursed travel; Pharmacyclics/Janssen Pharmaceuticals: Consultancy; Loxo Oncology at Lilly: Consultancy; Genentech: Research Funding; Genmab: Other: Reimbursed travel, Research Funding; Peerview Institute for Medical Education: Honoraria; Mashup Media LLC: Honoraria, Other: Reimbursed Travel; Clinical Care Options: Honoraria; AstraZeneca: Consultancy, Research Funding; eScientiq: Honoraria; Adaptive Biotechnologies: Research Funding.

OffLabel Disclosure: Use of MRD-adapted Venetoclax / Obinutuzumab, rather than the standard of care fixed-duration approach

*signifies non-member of ASH