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237 Impact of Rituximab Maintenance Added to Ibrutinib-Containing Regimens with and without ASCT in Younger, Previously Untreated MCL Patients: An Analysis of the Triangle Data Embedded in the Multiply Project

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Therapies for Mantle Cell Lymphoma
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, Diseases, Lymphoid Malignancies
Saturday, December 7, 2024: 2:30 PM

Marco Ladetto1, Katja* Gutmair2*, Jeanette K Doorduijn, MD, PhD3, Eva Gine, MD4, Mats Jerkeman, MD, PhD5, Jan Walewski, MD, Prof.6, Martin Hutchings, MD, PhD7, Ulrich Mey, MD, Prof.8,9, Jon Riise, MD, PhD10*, Marek Trneny, Prof., MD, CSc.11, Vibeke KJ Vergote, MD12*, Piero Maria Stefani, MD13*, Netanel A. Horowitz, MD14,15*, Maria Gomes da Silva, MD, PhD16, Sirpa Leppä, MD, PhD17, Linmiao Jiang, MSc18*, Christiane Pott, MD19*, Wolfram Klapper, MD, Prof20*, Christian Schmidt, MD21*, Michael Unterhalt22*, Martin* Dreyling, MD23 and Eva* Hoster, Prof24,25*

1Department of Translational Medicine, Università del Piemonte Orientale ed SCDU Ematologia AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Piedmont, Italy
2Institute of Medical Information, University of Munich, Munich, Germany
3Departement of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
4Department of Hematology, ICAMS, Hospital Clínic de Barcelona, Barcelona, Spain
5Division of Oncology, Department of Clinical Sciences Lund, Skåne University Hospital, Skane University Hospital, Lund, Skaane Laen, Sweden
6Department of Lymphoid Malignancies, Maria Skłodowska-Curie National Research Institute of Oncology, Warszawa, Poland
7Department of Hematology, Rigshospitalet, Copenhagen, Denmark
8Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland
9Oncology and Hematology, Cantonal Hospital Grisons, Chur, GR, Switzerland
10Department of Oncology, Oslo University Hospital, Oslo, NOR
11First Department of Internal Medicine - Hematology, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
12Department of Hematology, University Hospitals Leuven, Leuven, Belgium
13Ospedale Ca Foncello - S.C di Ematologia, Treviso, ITA
14Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
15The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology,, Haifa, Israel
16Inst. Portuges de Oncologia, Lisbon, PRT
17Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
18Institute for Medical Information Processing, Biometry and Epidemiology (IBE), LMU University Munich, Munich, Germany
19Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein, Kiel, Germany
20Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
21Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
22Department of Internal Medicine III, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany
23Department of Medicine III, University Hospital of the LMU, Munich, Germany
24Department of Internal Medicine III, LMU University Hospital Munich, Munich, Germany
25Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), LMU Munich, Munich, Germany

Introduction

The TRIANGLE trial (Dreyling et al. 2024) has set a novel standard in first-line treatment of mantle cell lymphoma (MCL) patients aged 18-65 years, highlighting the role of ibrutinib in the management of these patients. During the planning stage of TRIANGLE, results of the LYSA-LYMA trial showed a progression-free survival (PFS) benefit with rituximab maintenance (Rm) after a cytarabine-containing induction and autologous stem cell transplantation (ASCT) in younger patients with MCL (Le Gouill et al. 2017). Therefore, the TRIANGLE trial recommended from the beginning the additional non-randomized administration of Rm (every two months for 3 years) to all three treatment arms (arm I: IR-CHOP/ R-DHAP+ Im; arm A+I: IR-CHOP/ R-DHAP followed by ASCT + Im; arm A, i.e. pre-trial standard of care: R-CHOP/ R-DHAP followed by ASCT) according to national guidelines and/or center practice. We retrospectively analyzed the TRIANGLE data to assess the efficacy and toxicity of additional Rm to ibrutinib-containing regimens, with and without ASCT, and to independently confirm the LYSA-LYMA results in younger, untreated MCL patients.

Methods

All patients in remission after induction therapy (arm I) and after ASCT (arms A+I, A) were included in this analysis and assigned to Rm or noRm groups based on the as-treated principle. Every treatment arm (arm I,arm A+I, and arm A) was evaluated separately, thus, no adjustment of the alpha level was necessary. The primary endpoint PFS from end of induction (arm I)/end of ASCT (arm A+I, A) was summarized using Kaplan-Meier curves. Differences between Rm and noRm groups within each treatment arm were evaluated using a two-sided log-rank test with an alpha level of 0.05. To address baseline imbalances and to increase power, Cox regression models were calculated including MCL International Prognostic Index (MIPI) (Hoster et al. 2008), response status at the end of induction therapy (CR vs PR after induction/ASCT), Ki67,and cytology (classical vs.pleomorphic/blastoid variant).

Results

In the different study arms, 59% (n=159; arm I), 64% (n=151; arm A+I) and 67% (n=155; arm A) started Rm. In general, baseline characteristics were well balanced between the Rm and noRm groups in all treatment arms except for more frequent pleomorphic/blastoid cytology in the noRm group of arm I; higher Ki67 in the Rm group of arm A and A+I; and a higher Ann-Arbor stage, and more frequent CR after ASCT in the noRm group of arm A. After a median follow-up time of 4.0 years, median duration of Rm, excluding patients who relapsed, died, or withdrew, was 26 months for arm I and 30 months for arms A+I and A. The Kaplan-Meier curves for PFS and adjusted Cox regression analyses indicated a significantly longer PFS with additional Rm administration in all three treatment arms. The adjusted hazard ratio (Rm vs. noRm) for arm I was 0.50 (95% CI: 0.28 – 0.90, p-value 0.019), for arm A+I 0.26 (95% CI: 0.13 – 0.51, p-value <0.001), and for arm A 0.29 (95% CI: 0.16 – 0.52, p-value <0.001), respectively. Accordingly, the 4-year PFS rate estimated from the Kaplan-Meier curves were for arm I 86% (95% CI: 80% - 92%) in the Rm group vs. 76% (95% CI: 67% - 85%; log rank p=0.016) in the noRm group, for arm A+I 89% (95% CI: 84% - 95%) in the Rm group vs. 75% (95% CI: 65% - 87%; log rank p <0.001) in the noRm group; and for arm A 83% (95% CI: 77% - 89%) in the Rm group vs. 54% (95% CI: 42% - 68%; log-rank p <0.001) in the noRm group. Rm was associated with a modest increase in infectious complications (grade 3 or greater) in all arms (arm I: 25% in the Rm group vs. 12% in the noRm group; arm A+I: 30% in the Rm group vs. 13% in the noRm group; arm A: 19% in the Rm group vs. 1% in the noRm group). In contrast hematological toxicity (grade 3 or greater) was increased only in arm A (28% in the Rm group vs. 11% in the noRm group), whereas comparable frequencies were observed in the other study arms (arm A+I: 46% in the Rm group vs. 52% in the noRm group; arm I: 27% in the Rm group vs 23% in the noRm group).

Conclusion

This analysis confirms the benefit of Rm, as single maintenance (arm A) as well as in combination with ibrutinib (arms A+ I and I). No unexpected toxicity signals were observed, supporting its use also in combination with novel regimens.

On behalf of the European MCL Network

*: shared first/senior authorship

Disclosures: Ladetto: GSK: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Gentili: Consultancy, Honoraria, Speakers Bureau; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ellipses: Consultancy, Honoraria, Speakers Bureau. Gine: Janssen: Honoraria, Research Funding; Astra-Zeneca: Honoraria; Gilead/Kite: Honoraria; Lilly: Honoraria, Research Funding; Roche: Honoraria. Jerkeman: Janssen: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Roche: Research Funding; Kite/Gilead: Honoraria. Walewski: Gilead, Roche: Honoraria; Gilead, MSD, Regeneron: Consultancy; Astrazeneca, Celgene/BMS, Epizyme, Gilead, GSK, Incyte, Janssen, Karyopharm, Morphosys, MSD, NanoVector, PLRG, Polish Myeloma Consortium, Regeneron, Seagen, Takeda, TG Therapeutics, Vanda Pharm: Research Funding. Hutchings: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen/J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Mey: Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche: Other: Travel support; German-Swiss-Austrian Guideline for Mantle Cell Lymphoma: Other: participation in national Guideline committee; Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda: Membership on an entity's Board of Directors or advisory committees. Riise: AstraZeneca, Roche: Membership on an entity's Board of Directors or advisory committees. Trneny: Gilead Sciences, Takeda, Bristol-Myers Squibb, Roche, Janssen, Abbvie, SOBI: Other: Travel, Accommodations, Expenses; Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, Abbvie, Roche, MorphoSys, Novartis, SOBI, Swixx BioPharma: Honoraria; Takeda, Bristol-Myers Squibb, Incyte, Abbvie, Amgen, Roche, Gilead Sciences, Janssen, MorphoSys, Novartis, Genmab, SOBI, Autolus, Caribou Biosciences: Consultancy. Vergote: Janssen, Abbvie: Honoraria; Beigene, Celgene, Gilead, Roche, Lilly Oncology, Abbvie, Johnson & Johnson: Consultancy; Amgen, Abbvie, Gilead, Roche: Other: Travel Support. Stefani: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. da Silva: Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Research Funding; Celgene/BMS, MSD, Roche: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Research Funding. Leppä: Abbvie, BeiGene, Genmab, Gilead, Incyte, Novartis, Orion, Roche: Membership on an entity's Board of Directors or advisory committees. Klapper: Roche, Janssen, Amgen, InCyte: Research Funding. Schmidt: Janssen: Honoraria; Bayer: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dreyling: AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding.

*signifies non-member of ASH