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3031 Ibrutinib Maintenance (I-M) Following Intensive Induction in Mantle Cell Lymphoma (MCL): Efficacy, Safety and Changes in Minimal Residual Disease

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster III
Hematology Disease Topics & Pathways:
Diseases, Mantle Cell Lymphoma, Therapies, Combinations, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Lymphoid Malignancies, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Reem Karmali, MD, MSc1, Jeremy S Abramson, MD, MMSc2, Deborah M. Stephens, DO3, Jeffrey A Barnes, MD, PhD2, Jason Kaplan, MD4, Jane N. Winter, MD5, Shuo Ma, MD, PhD6, Juehua Gao, MD, PhD7*, Adam M Petrich, MD8,9, Ephraim Hochberg, MD2, Ronald Takvorian10*, Frank Kuhr, PhD11*, Valerie Nelson, MD, MBA6*, Leo I. Gordon, MD6 and Barbara Pro, MD12

1Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL
2Massachusetts General Hospital Cancer Center, Boston, MA
3University of Utah/Huntsman Cancer Institute, Salt Lake City, UT
4Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
5Division of Hematology and Oncology, Northwestern University, Chicago, IL
6Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine; Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
7Department of Pathology, Northwestern University, Chicago, IL
8Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
9Daiichi-Sankyo, Inc., Basking Ridge, NJ
10Massachusetts General Hospital, Harvard Medical School, Boston, MA
11Adaptive Biotechnologies, Seattle, WA
12Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL

BACKGROUND: Ibrutinib is a BTK inhibitor approved for relapsed/refractory MCL. We evaluated the safety and efficacy of single-agent ibrutinib maintenance (I-M) following frontline chemo-immunotherapy for MCL in a multicenter phase II trial. Herein, we report preliminary results.

METHODS: Patients (Pts) received I-M 560 mg daily for up to 4 years after complete/partial response (CR/PR) to frontline chemo-immunotherapy (+/- autoSCT). The 3-year PFS rate was the primary endpoint. Secondary endpoints were PR to CR conversions, median OS and toxicity. After identifying a trackable clone using archived tissue obtained at diagnosis, minimal residual disease (MRD) was measured using NGS (detection resolution of 1 cell per million; clonoSEQ®; Adaptive Biotechnologies) on peripheral blood at 4 time-points: baseline (after induction but prior to starting I-M) and then at 1, 6 and 18-24 mo(s) after initiation of I-M.

RESULTS: 36 pts were enrolled between 7/2014-7/2018. Median age was 60 years (range 46-90). For induction, 17 (47%) received BR, 18 (50%) a cytarabine-containing regimen and 1 (3%) R-CHOP. Eighteen (50%) had autoSCT in CR1. Post-induction +/- autoSCT, 33 (92%) had a CR and 3 (8%) had a PR as best response respectively. One patient converted from PR to CR on I-M.

Median f/u was 34.6 months. 5 (14%) pts completed the 4-year I-M course and 15 (42%) remain on I-M (median 31 cycles, range 2-52). Sixteen (44%) pts discontinued I-M early due to: treatment related adverse events (TRAEs; n=12), second malignancies considered unrelated to I-M (n=2), PD (n=1) and death of unknown cause (n=1). Three pts died, 2 deaths deemed unrelated to I-M (aspiration pneumonia, 2nd malignancy) and 1 from unknown cause; 1 pt was lost to follow-up.

The most common grade ≥ 3 TRAEs during I-M were neutropenia, HTN, infection, bleeding and atrial fibrillation/flutter (Table 1). TRAEs led to permanent dose reductions in 9 (25%) pts, most commonly for neutropenia (n=3), and I-M discontinuation in 12 (33%), 6 for new onset atrial fibrillation/flutter, 1 each for myalgias, rash, pericardial effusion, mucositis, TIA, subdural hematoma/bleed. Notably, I-M was discontinued in the majority of pts with new onset atrial fibrillation/flutter though not typical of current practice.

At the time of data cut-off, MRD was assessed in 21 of 36 pts at varying time points (Figure 1) with remaining samples not yet collected/analyzed. After induction but prior to I-M, 16 pts were confirmed MRD (-), 4 were MRD indeterminate and 1 was MRD (+). Four pts MRD (-) prior to I-M became MRD (+) with follow-up, 2 induced with hyperCVAD, 1 with BR and 1 with R-CHOP + autoSCT prior to I-M; 2 of these pts reverted back to MRD (-) status with ongoing I-M. Of the 2 pts with persistent MRD (+) disease, 1 had clinical progression and the other maintains radiographic CR. Post induction, all MRD indeterminate pts were MRD (-) when checked after 1 month on I-M. The pt who was MRD (+) after front-line treatment (Nordic regimen + autoSCT) remains MRD (+) after 30 cycles of I-M without clinical relapse. MRD correlations with PFS and OS have not yet been performed.

CONCLUSION: I-M 560 mg daily is feasible in pts with MCL after response to frontline chemo-immunotherapy. Grade ≥ 3 rates of atrial fibrillation/flutter are consistent with ibrutinib’s known safety profile. NGS-based assessments demonstrate that most pts are MRD negative after intensive induction. Longer follow-up and correlation of MRD with PFS and OS are needed to determine the clinical relevance of I-M and MRD status.

Disclosures: Karmali: Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Takeda: Research Funding. Stephens: Arqule: Research Funding; Innate: Consultancy; Juno: Research Funding; Acerta: Research Funding; MingSight: Research Funding; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Beigene: Consultancy; Pharmacyclics: Consultancy; Gilead: Research Funding; Verastem: Research Funding. Winter: Norvartis: Consultancy, Other: DSMB; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Epizyme: Other: DSMB; Delta Fly Pharma: Consultancy; Amgen: Consultancy; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Ma: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Bioverativ: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Juno: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; TG Therapeutics: Research Funding. Petrich: AbbVie: Current equity holder in publicly-traded company; Daiichi-Sankyo: Current Employment. Hochberg: Intervention Insights: Consultancy; Leuko: Consultancy. Kuhr: Adaptive Biotechnologies: Current Employment. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Pro: Verastem Oncology: Research Funding.

OffLabel Disclosure: maintenance ibrutinib after frontline therapy in MCL

*signifies non-member of ASH