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93 Residual Disease Kinetics Among Patients with High-Risk Factors Treated with First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): The Glow Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Targeted Doublet Combinations
Hematology Disease Topics & Pathways:
adult, Lymphoid Leukemias, clinical trials, Research, CLL, elderly, Combination therapy, Clinical Research, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human, Minimal Residual Disease
Saturday, December 10, 2022: 10:00 AM

Carsten U Niemann, MD1*, Talha Munir, MBBS, MRCP, FRCPath, PhD2*, Carol Moreno, MD, PhD3*, Carolyn Owen, MD4*, George A Follows, MD, PhD5*, Ohad Benjamini6*, Ann Janssens, MD, PhD7*, Mark-David Levin8, Anders Österborg9*, Tadeusz Robak10, Martin Šimkovič11*, Sergey Voloshin12*, Vladimir I. Vorobyev, MD13, Munci Yagci, MD14*, Loic Ysebaert, MD, PhD15*, Keqin Qi16*, Qianaya Qi17*, Lori Parisi17*, Srimathi Srinivasan18*, Natasha Schuier19*, Kurt Baeten20*, Angela Howes, BSc, PhD21, Donne Bennett Caces17* and Arnon P. Kater, MD, PhD22

1Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
2Consultant Haematologist, St James's Hospital, Leeds, United Kingdom
3Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
4Tom Baker Cancer Centre, Calgary, Canada
5Addenbrookes Hospital, Cambridge, United Kingdom
6Sheba Medical Center, Ramat Gan, Israel
7UZ Leuven Gasthuisberg, LEUVEN, Belgium
8Department of Internal Medicine, Albert Schweitzer hospital, Dordrecht, Netherlands
9Karolinska University Hospital, Stockholm, Sweden
10Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland
114th Department of Internal Medicine – Haematology, Faculty of Medicine in Hradec Králové, University Hospital and Charles University in Prague, Hradec Kralove, Czech Republic
12Russian Scientific and Research Institute of Hematology and Transfusiology, St Petersburg, Russian Federation
13Bone Marrow Transplant, Botkin Hospital, Moscow, Russia
14Gazi Universitesi Tip Fakultesi, Ankara, Turkey
15Hematology Department, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
16Janssen Research & Development, Titusville, NJ
17Janssen Research & Development, Raritan, NJ
18Oncology Translational Research, Janssen Research & Development, Lower Gwynedd Township, PA
19Janssen Research & Development, Dusseldorf, Germany
20Janssen Research & Development, Beerse, Belgium
21Janssen Research & Development, Raritan
22Academic Medical Center, Amsterdam Zuidoost, NH, Netherlands

Background: In the GLOW study (NCT03462719), fixed-duration Ibr+Ven demonstrated superior progression-free survival (PFS), deeper, better sustained undetectable minimal residual disease (uMRD) responses, and fewer patients (pts) requiring subsequent anti-cancer treatment versus Clb+O in older and/or comorbid pts with previously untreated chronic lymphocytic leukemia (CLL; Kater AP, et al. NEJM Evidence. 2022). Unmutated IGHV (uIGHV) and TP53 mutations are risk factors associated with worse outcomes for both chemoimmunotherapy and venetoclax plus anti-CD20 therapies for CLL. Here we investigate MRD kinetics and outcomes of Ibr+Ven in GLOW according to these risk factors.

Methods: Pts aged ≥ 65 years or 18 to 64 years with cumulative illness rating scale score > 6 or creatinine clearance < 70 mL/min were enrolled and randomized 1:1 to Ibr+Ven (3 cycles of Ibr lead-in, followed by 12 cycles of Ibr+Ven) or 6 cycles of Clb+O, with a cycle defined as 28 days. Pts with del(17p) or known TP53 mutations at screening were excluded, and central evaluation of TP53 mutational status was performed during the study. The primary end point was PFS by independent review committee. Among pts with partial response or better, MRD in peripheral blood was evaluated using next-generation sequencing via clonoSEQ on-treatment and at 3-6 month intervals post-treatment. uMRD results are reported in peripheral blood (PB) at < 10-4 unless otherwise noted. Since the primary analysis, a post hoc retrospective reclassification of the IGHV status of baseline samples was conducted to reduce the number of unknowns. We used clonoSEQ data as part of CLL clonal testing (Adaptive Biotechnologies, Seattle, WA).

Results: There were 106 pts randomized to Ibr+Ven and 105 to Clb+O. In the Ibr+Ven arm, uMRD rates increased from 46.2% after 6 cycles of the combination to 54.7% at 3 months after end of treatment (EOT+3), demonstrating that the majority of disease clearance in the PB occurred early, during the first 6 months of combination treatment. Post-treatment, 77.6% (45/58) of pts in the Ibr+Ven arm sustained their uMRD status from EOT+3 to EOT+18, compared with 12.2% (5/41) in the Clb+O arm. In the Ibr+Ven arm, 17/24 patients with intermediate MRD ≥ 10-4 to < 10-2 at EOT+3 did not worsen through EOT+18. Among pts with detectable MRD (≥ 10-4) at EOT+3, 6.5% (2/31) clinically progressed by EOT+18 in the Ibr+Ven arm versus 68.1% (32/47) in the Clb+O arm.

After reclassification of baseline samples, uIGHV / mutated IGHV (mIGHV) / unknown status was 63.2%/30.2%/6.6% in the Ibr+Ven arm and 54.3%/33.3%/12.4% in the Clb+O arm. In the Ibr+Ven arm, rates of uMRD after 6 cycles of combination treatment and at EOT+3, respectively, were 52.2% and 59.7% in pts with uIGHV and 31.3% and 40.6% in pts with mIGHV (Fig A). On-treatment MRD kinetics differed by IGHV status in the Ibr+Ven arm, with uMRD achieved at a higher rate and earlier in pts with uIGHV.

In the Ibr+Ven arm, uMRD was sustained post-treatment (from EOT+3 and EOT+18) in 80.0% (32/40) of pts with uIGHV and 76.9% (10/13) of pts with mIGHV. Among pts with detectable MRD (≥ 10-4) at EOT+3, 2/16 with uIGHV and 0/14 with mIGHV had clinically progressed by EOT+18 in the Ibr+Ven arm; corresponding rates were 83.3% (25/30) and 42.9% (6/14) in the Clb+O arm. Five of 7 pts with TP53-mutated CLL achieved uMRD at EOT+3 in the Ibr+Ven arm; TP53 variant allele frequencies ranged between 5.9% and 29.6% for these 5 pts and all maintained uMRD through EOT+18.

With a median study follow-up of 34.1 months, PFS rates after IGHV reclassification were well sustained post-treatment regardless of IGHV status in the Ibr+Ven arm, while uIGHV pts in the Clb+O arm relapsed more quickly (Fig B).

PFS, overall survival, and subgroup analyses with longer study follow-up will be presented.

Conclusion: All-oral, once-daily, fixed-duration Ibr+Ven achieved uMRD responses that were better sustained than Clb+O during the first 18 months post-treatment. Notably, with Ibr+Ven, uMRD rates were higher and achieved earlier in pts with uIGHV CLL versus mIGHV CLL, while uMRD was similarly sustained post-treatment irrespective of IGHV status. Clinical progressions in the first 18 months post-treatment with Ibr+Ven were uncommon even among pts with detectable MRD ≥ 10-4. MRD kinetics and sustained responses demonstrate strong efficacy of the fixed-duration Ibr+Ven combination in older pts with high-risk genomic features.

Disclosures: Niemann: AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding; Roche: Consultancy; CSL Behring: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Octapharma: Consultancy. Munir: Janssen, AstraZeneca, Alexion, Sobi, Novartis, Roche, Abbvie, Gilead: Honoraria; Janssen, AstraZeneca, Alexion, Abbvie, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Moreno: Janssen, Abbvie: Research Funding; Abbvie, Janssen, AstraZeneca, Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Owen: Abbvie, AstraZeneca: Consultancy, Honoraria; Janssen, Roche, Merck, Gilead, Servier: Honoraria. Follows: Roche: Consultancy, Speakers Bureau; Janpix: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Lilly: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau. Benjamini: AbbVie,Janssen,Astrazeneca: Consultancy. Janssens: Genmab: Current Employment; Abbvie: Consultancy, Other: Travel Grants, Speakers Bureau; Amgen: Consultancy, Other: travel grants, Speakers Bureau; Astra-Zeneca: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene: Other: travel grants. Levin: AbbVie, Roche and Janssen: Other: Travel expenses. Robak: Regeneron: Honoraria, Research Funding; GSK: Honoraria, Research Funding; OctaPharma: Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Šimkovič: Janssen-Cilag, Gilead, Roche, AstraZeneca, Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Voloshin: Janssen, Abbvie, Sanofi: Honoraria, Other: Clinical trials, Non-financial support; Novartis, Pfizer: Other: Clinical Trials, Non-financial support. Ysebaert: Abbvie, Astra-Zeneca, Janssen, Roche, Beigene, BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Qi: Janssen: Current Employment. Qi: Janssen: Current Employment. Parisi: Janssen: Current Employment. Srinivasan: Janssen: Current Employment. Schuier: Janssen: Current Employment. Baeten: Janssen: Current Employment. Howes: Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Bennett Caces: Janssen: Current Employment. Kater: Abbvie, Astra Zeneca, BMS, Janssen, Roche/Genentech: Research Funding; Janssen, LAVA: Patents & Royalties: Pending; Astra Zeneca, BMS, Roche/Gennetech, Janssen, Abbvie, LAVA: Membership on an entity's Board of Directors or advisory committees; Abbvie, Astra Zeneca, Janssen: Other: Speakers fee; Amsterdam UMC, University of Amsterdam: Current Employment.

OffLabel Disclosure: The combination of ibrutinib and venetoclax is an investigational treatment for patients with previously untreated CLL. Ibrutinib and venetoclax are each individually approved for previously untreated CLL

*signifies non-member of ASH