-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

240 Role of Autologous Stem Cell Transplantation in the Context of Ibrutinib-Containing First-Line Treatment in Younger Patients with Mantle Cell Lymphoma: Results from the Randomized Triangle Trial By the European MCL Network

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, Combination therapy, Clinical Research, Treatment Considerations
Saturday, December 7, 2024: 3:15 PM

Martin Dreyling, MD1, Jeanette K Doorduijn, MD, PhD2, Eva Gine, MD3, Mats Jerkeman, MD, PhD4, Jan Walewski, MD, Prof.5, Martin Hutchings, MD, PhD6,7, Ulrich Mey, MD, Prof.8,9, Jon Riise, MD, PhD10*, Marek Trneny, Prof., MD, CSc.11, Vibeke KJ Vergote, MD12*, Daniela Donnarumma13*, Ofer Shpilberg, MD, MPH14*, Maria Gomes da Silva, MD, PhD15*, Sirpa Leppä, MD, PhD16, Linmiao Jiang, MSc17*, Christiane Pott, MD18*, Wolfram Klapper, MD, Prof19*, Christian Schmidt, MD20*, Michael Unterhalt, MD21*, Marco Ladetto, MD22 and Eva Hoster, PhD, Prof.23,24*

1Department of Internal Medicine III, LMU University Hospital of Munich, Munich, Germany
2Departement of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
3Hematology Department, Hospital Clínic of Barcelona, IDIBAPS, CIBERONC, Barcelona, Spain
4Division of Oncology, Lund University, Skåne University Hospital, Lund, Sweden
5Maria Sklodowska-Curie National Research Institute of Oncology, Warszawa, Poland
6Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
7Department of Hematology, Rigshospitalet, Copenhagen, Denmark
8Oncology and Hematology, Kantonsspital Graubünden, Chur, Switzerland
9Swiss Group for Clinical Cancer Research (SAKK), Bern, 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
13Hematology-Oncology & Stem Cell Transplantation Unit, National Cancer Institute Fondazione 'G. Pascale', IRCCS, Naples, Italy
14Institute of Hematology, Assuta Medical Center, Tel-Aviv, Israel
15Departamento de Hematologia, Instituto Português de Oncologia, Lisboa, Portugal
16Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
17Institute for Medical Information Processing, Biometry and Epidemiology (IBE), LMU University Munich, Munich, Germany
18Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein, Kiel, Germany
19Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
20Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
21Department of Internal Medicine III, LMU University Hospital Munich, Munich, DEU
22Department of Translational Medicine, Università del Piemonte Orientale ed SCDU Ematologia AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Piedmont, Italy
23Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), LMU Munich, Munich, Germany
24Department of Internal Medicine III, LMU University Hospital Munich, Munich, Germany

On behalf of the European MCL Network, ML and EH contributed equally

Introduction: In younger patients with mantle cell lymphoma (MCL), the addition of ibrutinib during induction immuno-chemotherapy and as 2-years maintenance with and without autologous stem cell transplantation (ASCT) has shown high efficacy in the 3-arm randomized TRIANGLE trial (Dreyling et al., Lancet 2024), establishing a new standard of care induction treatment and maintenance. However, the efficacy comparison of the two ibrutinib-containing treatment arms with and without ASCT was still ongoing. With prolonged follow-up, we now aim to clarify the role of ASCT in the context of ibrutinib-containing treatment, to confirm the previously observed treatment effects and to perform overall survival (OS) comparisons.

Patients and methods: In 2016, the European MCL Network initiated the randomized, open-label, 3-arm TRIANGLE trial to evaluate the addition of ibrutinib to standard treatment with ASCT (arm A+I) in comparison to the previous standard treatment (arm A) and an ibrutinib-containing treatment without ASCT (arm I). Patients with previously untreated, advanced stage II-IV MCL, up to 65 years, and suitable for high-dose cytarabine and ASCT, were randomized 1:1:1 to the 3 trial arms in 13 European countries and Israel. Study treatment consisted of 6 alternating cycles of R-CHOP and R-DHAP without (arm A) or with ibrutinib added to R-CHOP cycles and as 2 years maintenance (arms A+I, I). ASCT was planned for patients of arms A and A+I responding to induction therapy. Rituximab maintenance was recommended to be applied according to national guidelines in responding patients of each trial arm. For the primary outcome, failure-free survival (FFS), stable disease at the end of induction, progression, or death were counted as events. Three pairwise log-rank tests for FFS were monitored with regular pre-planned interim analyses, each maintaining a one-sided 1.67% significance level. A pre-defined decision criterion based on the statistical significance of the treatment comparisons for FFS was established to determine the future treatment recommendation. In 2022, arm A had failed to show FFS-superiority over I and FFS in arm A+I was shown to be superior to A. OS was a secondary outcome and formal pairwise OS comparisons between treatment arms were pre-planned with interim analyses based on O’Brien-Fleming boundaries to maintain pairwise two-sided 5% significance levels.

Results: Between July 2016 and December 2020, 870 patients were randomized to arms A (n=288), A+I (n=292), and I (n=290). Median age was 57 years (range 27-68), 76% were male, 87% had stage IV, and 58%/27%/15% had low/intermediate/high risk MIPI. After a median follow-up of 53 months, A+I failed to show FFS-superiority over I (3-year FFS A+I: 86% vs. I: 85%; one-sided p=0.28, hazard ratio: 0.87). FFS-superiority of A over I was again not confirmed with 3-year FFS 75% (A) vs. 85% (I; one-sided p=0.9942, hazard ratio: 1.38). In contrast, the retrospectively calculated two-sided p-value on an overall 5% significance level was consistent with FFS-superiority of I over A (p=0.0102). FFS-superiority of A+I over A was again confirmed with 3-year FFS 86% (A+I) vs. 75% (A; one-sided p=0.0034, hazard ratio: 0.64). Compared with arm A (3-year OS 85%), OS was prolonged in arms A+I and I with 3-year OS of 90% in A+I (p=0.0069, hazard ratio 0.61), and 91% in I (p=0.0041, hazard ratio 0.59).

Conclusions: The results confirm superiority of ibrutinib-containing treatment without ASCT (arm I) over ASCT-containing treatment without ibrutinib (arm A) in terms of both, FFS and OS. In the context of ibrutinib- and high-dose cytarabine-containing induction immuno-chemotherapy and ibrutinib maintenance, the addition of ASCT failed to show FFS superiority, while increasing toxicity during maintenance/follow-up. According to the pre-defined decision strategy, ibrutinib+R-CHOP/R-DHAP induction followed by 2 years of ibrutinib maintenance should be the new standard of care in younger MCL patients, thus ending the era of ASCT for MCL patients.

Disclosures: Dreyling: AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; 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; AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding. Gine: Astra-Zeneca: Honoraria; Lilly: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria; Roche: Honoraria. Jerkeman: Janssen: Honoraria; Roche: Research Funding; AstraZeneca: Honoraria, Research Funding; Kite/Gilead: Honoraria; Abbvie: Honoraria, Research Funding. Walewski: 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; Gilead, Roche: Honoraria; Gilead, MSD, Regeneron: Consultancy. Hutchings: Takeda: Honoraria, 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; AstraZeneca: 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; Takeda, Bristol-Myers Squibb, Incyte, Abbvie, Amgen, Roche, Gilead Sciences, Janssen, MorphoSys, Novartis, Genmab, SOBI, Autolus, Caribou Biosciences: Consultancy; Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, Abbvie, Roche, MorphoSys, Novartis, SOBI, Swixx BioPharma: Honoraria. Vergote: Janssen, Abbvie: Honoraria; Beigene, Celgene, Gilead, Roche, Lilly Oncology, Abbvie, Johnson & Johnson: Consultancy; Amgen, Abbvie, Gilead, Roche: Other: Travel Support. da Silva: Janssen, Roche, Gilead Sciences, Lilly, Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen, Abbvie: Other: Institutional payments; Gilead Sciences, AstraZeneca: Research Funding; Roche, Abbvie, Janssen, Gilead, Takeda: Other: Travel Support. 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: 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; Bayer: Research Funding; Janssen: Honoraria. Unterhalt: AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding. Ladetto: Abbvie, Amgen, BMS, EUSA Pharma, GSK, Gentili, Gilead/Kite, Novartis, Incyte, Jazz, Lilly, Ellipses: Consultancy, Honoraria, Speakers Bureau; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, Roche, Janssen, ADC Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta, Sandoz: Honoraria.

<< Previous Abstract | Next Abstract
*signifies non-member of ASH