BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.

1st Faculty of Medicine Charles University Hospital Prague Czech Republic

Adelson School of Medicine Ariel University Ariel Israel; Institute of Hematology Assuta Medical Center Tel Aviv Israel

Cancer Centre Lund University Faculty of Medicine Lund Sweden

Comprehensive Cancer Center University of Helsinki and Helsinki University Hospital Helsinki Finland

Department 1 of Internal Medicine Center for Integrated Oncology and University Hospital Cologne University of Cologne Cologne Germany

Department of Haematology and Phase 1 Unit Rigshospitalet Copenhagen Denmark

Department of Hematology and Medical Oncology Medical School of the Johannes Gutenberg University Mainz Germany

Department of Hematology and Stem Cell Transplantation University Hospital Essen Essen Germany

Department of Hematology Erasmus MC Cancer Institute University Medical Center Rotterdam Rotterdam Netherlands

Department of Hematology Oncology Clinical Immunology and Rheumatology Center for Internal Medicine University Hospital Tuebingen Tübingen Germany

Department of Hematology Portuguese Institute of Oncology Lisbon Portugal

Department of Hematology University Hospitals Leuven Leuven Belgium

Department of Hematology University Medical Center Groningen Groningen Netherlands

Department of Internal Medicine 2 UKE Hamburg Hamburg Germany

Department of Internal Medicine 3 Klinikum Chemnitz Chemnitz Germany

Department of Internal Medicine 3 Technical University Munich Germany TU Munich Munich Germany

Department of Internal Medicine 3 Ulm University Hospital Ulm Germany

Department of Medical Oncology Inselspital Bern University Hospital University of Bern Bern Switzerland

Department of Medicine 2 University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Medicine 3 LMU University Hospital Munich Germany

Department of Medicine Huddinge Karolinska Institutet Stockholm Sweden

Department of Molecular Medicine University of Pavia Pavia Italy; Division of Hematology Fondazione IRCCS Policlinico San Matteo Pavia Italy

Department of Oncology Oslo University Hospital Oslo Norway

Department of Pathology Hematopathology Section and Lymph Node Registry University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Translational Medicine Division of Hematology University of Eastern Piedmont and SCDU Ematologia Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo Alessandria Italy

Division of Hematology Infermi Hospital Rimini Italy

Hematology and Stem Cell Transplantation Azienda Ospedaliera Universitaria di Verona Verona Italy

Hematology Department Hospital Clínic de Barcelona IDIBAPS Barcelona Spain

Hematology Department San Bortolo Hospital Vicenza Italy; Department of Medicine University of Verona Verona Italy

Institute for Medical Information Processing Biometry and Epidemiology Faculty of Medicine LMU Munich Munich Germany

Istituto di Ematologia Seràgnoli IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy; Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna Bologna Italy

Maria Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Medizinische Klinik A Universitätsklinikum Münster Münster Germany

Oncology and Hematology Kantonsspital Graubuenden Chur Switzerland

Lancet. 2024 May 25;403(10441):2264-2265. doi: 10.1016/S0140-6736(24)00301-5. PubMed

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ClinicalTrials.gov
NCT02858258