Article, 2024
Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network
The Lancet,
ISSN
0140-6736,
1474-547X,
Volume 403,
10441,
Pages 2293-2306,
10.1016/s0140-6736(24)00184-3
Contributors
Dreyling, Martin
(Corresponding author)
[1]
Doorduijn, Jeanette K
0000-0002-1014-0918
[2]
Giné, Eva
[3]
Jerkeman, Mats Ingvar
0000-0003-4509-6707
[4]
Walewski, Jan Andrzej
0000-0003-4247-2674
[5]
Hutchings, Martin
[6]
Mey, Ulrich J M
[7]
Riise, Jon
0000-0002-0024-0093
[8]
Trneny, Marek
0000-0002-6952-6073
[9]
Vergote, Vibeke K J
0000-0003-1100-5600
[10]
Shpilberg, Ofer
[11]
[12]
Gomes Da Silva, Maria
0000-0002-6993-2450
[13]
Leppä, Sirpa M
0000-0002-8265-511X
[14]
Jiang, Linmiao
[15]
Stilgenbauer, Stephan
0000-0002-6830-9296
[16]
Kerkhoff, Andrea
[17]
Jachimowicz, Ron Daniel
[18]
Celli, Melania
[19]
Hess, Georg
[20]
Arcaini, Luca L
0000-0002-9504-991X
[21]
[22]
Visco, Carlo
[23]
[24]
Van Meerten, Tom
0000-0002-5581-6950
[25]
Wirths, Stefan
[26]
Zinzani, Pier Luigi
[27]
Novak, Urban
0000-0001-7642-2101
[28]
[29]
Herhaus, Peter
[30]
Benedetti, Fabio
[24]
Sonnevi, Kristina
0000-0002-7306-2371
[31]
Hanoun, Christine
[32]
Hänel, Matthias
[33]
Dierlamm, Judith
[34]
Pott, Christiane
[35]
Klapper, Wolfram
[35]
Gözel, Döndü
[1]
Schmidt, Christian
[1]
Unterhalt, Michael
[1]
Ladetto, Marco
0000-0002-8283-2681
[36]
Hoster, Eva
0000-0002-0749-1389
[15]
Affiliations
- [1]
LMU Klinikum
[NORA names:
Germany; Europe, EU; OECD];
- [2]
Erasmus MC Cancer Institute
[NORA names:
Netherlands; Europe, EU; OECD];
- [3]
August Pi i Sunyer Biomedical Research Institute
[NORA names:
Spain; Europe, EU; OECD];
- [4]
Lund University
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [5]
The Maria Sklodowska-Curie National Research Institute of Oncology
[NORA names:
Poland; Europe, EU; OECD];
(... more)
- [6]
Rigshospitalet
[NORA names:
Capital Region of Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [7]
Kantonsspital Graubünden
[NORA names:
Switzerland; Europe, Non-EU; OECD];
- [8]
Oslo University Hospital
[NORA names:
Norway; Europe, Non-EU; Nordic; OECD];
- [9]
General University Hospital in Prague
[NORA names:
Czechia; Europe, EU; OECD];
- [10]
Universitair Ziekenhuis Leuven
[NORA names:
Belgium; Europe, EU; OECD];
- [11]
Ariel University
[NORA names:
Israel; Asia, Middle East; OECD];
- [12]
Assuta Medical Center
[NORA names:
Israel; Asia, Middle East; OECD];
- [13]
Portuguese Oncology Institute
[NORA names:
Portugal; Europe, EU; OECD];
- [14]
Helsinki University Hospital
[NORA names:
Finland; Europe, EU; Nordic; OECD];
- [15]
Ludwig-Maximilians-Universität München
[NORA names:
Germany; Europe, EU; OECD];
- [16]
University Hospital Ulm
[NORA names:
Germany; Europe, EU; OECD];
- [17]
University Hospital Münster
[NORA names:
Germany; Europe, EU; OECD];
- [18]
University of Cologne
[NORA names:
Germany; Europe, EU; OECD];
- [19]
Ospedale Infermi di Rimini
[NORA names:
Italy; Europe, EU; OECD];
- [20]
Johannes Gutenberg University Mainz
[NORA names:
Germany; Europe, EU; OECD];
- [21]
Policlinico San Matteo Fondazione
[NORA names:
Italy; Europe, EU; OECD];
- [22]
University of Pavia
[NORA names:
Italy; Europe, EU; OECD];
- [23]
Ospedale San Bortolo
[NORA names:
Italy; Europe, EU; OECD];
- [24]
University of Verona
[NORA names:
Italy; Europe, EU; OECD];
- [25]
University Medical Center Groningen
[NORA names:
Netherlands; Europe, EU; OECD];
- [26]
Universitätsklinikum Tübingen
[NORA names:
Germany; Europe, EU; OECD];
- [27]
University of Bologna
[NORA names:
Italy; Europe, EU; OECD];
- [28]
University Hospital of Bern
[NORA names:
Switzerland; Europe, Non-EU; OECD];
- [29]
University of Bern
[NORA names:
Switzerland; Europe, Non-EU; OECD];
- [30]
Technical University of Munich
[NORA names:
Germany; Europe, EU; OECD];
- [31]
Karolinska Institutet
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [32]
Essen University Hospital
[NORA names:
Germany; Europe, EU; OECD];
- [33]
Klinikum Chemnitz
[NORA names:
Germany; Europe, EU; OECD];
- [34]
University Medical Center Hamburg-Eppendorf
[NORA names:
Germany; Europe, EU; OECD];
- [35]
University Hospital Schleswig-Holstein
[NORA names:
Germany; Europe, EU; OECD];
- [36]
University of Eastern Piedmont Amadeo Avogadro
[NORA names:
Italy; Europe, EU; OECD]
(less)
Abstract
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.
Keywords
A+I,
European,
European Mantle Cell Lymphoma Network,
European countries,
International Prognostic Index risk groups,
Israel,
R-CHOP,
R-CHOP cycles,
R-DHAP,
adverse events,
analysis,
autologous stem-cell transplantation,
cell lymphoma,
cell lymphoma patients,
centre,
clinical centres,
clinical outcomes,
comparison,
control group A,
countries,
cycle,
cycles of R-CHOP,
day 1,
days,
differences,
efficacy,
events,
failure-free survival,
first-line treatment,
follow-up,
grade,
grade 3,
group,
group A,
group I,
haematological adverse events,
ibrutinib,
immunochemotherapy,
improve outcomes,
increased toxicity,
induction,
infection,
intention-to-treat,
log-rank test,
lymphoma,
lymphoma patients,
maintenance,
mantle,
mantle cell lymphoma,
mantle cell lymphoma patients,
median follow-up,
months,
months median follow-up,
network,
one-sided log-rank test,
open-label,
outcomes,
pairwise,
parallel-group,
patients,
period,
phase,
phase 3 superiority trial,
primary analysis,
primary outcome,
regimens,
risk groups,
stage,
standard immunochemotherapy,
standard treatment,
standards,
stem-cell transplantation,
study,
study group,
superiority,
survival,
tertiary clinical centre,
test,
three-arm,
toxicity,
transplantation,
treatment,
treatment period,
trials,
untreated patients,
years
Funders
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