Addition of autologous stem-cell transplantation to an ibrutinib-containing

# Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18–65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network *The Lancet 2026* Articles Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18–65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network Martin Dreyling, Jeanette Doorduijn, Eva Giné, Mats Jerkeman, Jan Walewski, Martin Hutchings, Ulrich Mey, Jon Riise, Marek Trneny, Vibeke K J Vergote, Ofer Shpilberg, Maria Gomes da Silva, Sirpa Leppä, Linmiao Jiang, Stephan Stilgenbauer, Andrea Kerkhoff, Ron D Jachimowicz, Georg Heß, Tom van Meerten, Stefan Wirths, Peter Herhaus, Urban Novak, Judith Dierlamm, Mathias Hänel, Christine Hanoun, Kristina Sonnevi, Carlo Visco, Daniela Donnarumma, Andrés J M Ferreri, Caterina Patti, Piero Maria Stefani, Christiane Pott, Wolfram Klapper, Christian Schmidt, Michael Unterhalt, Tobias Tix, Marco Ladetto*, Eva Hoster*, on behalf of the European Mantle Cell Lymphoma Network Summary Background Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival in adult Lancet 2026; 407: 1953–67 patients aged 18–65 years with mantle cell lymphoma, according to the first results from the TRIANGLE trial. With See Comment page 1897 prolonged follow-up, we investigated whether the addition of autologous stem-cell transplantation (ASCT) to an *Contributed equally ibrutinib-containing regimen improves failure-free survival, and evaluated effects on overall survival. Department of Medicine III, LMU University Hospital, Methods We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary Munich, Germany or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or (Prof M Dreyling MD PhD, C Schmidt MD, an association with such a centre, in 13 European countries and Israel. Patients aged 18–65 years with untreated, M Unterhalt MD PhD, T Tix MD); stage II–IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or Department of Hematology, experimental groups A + I or I. Randomisation was done using computer-generated random numbers and stratified Erasmus MC Cancer Institute, University Medical Center by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups. Treatment in group A Rotterdam, Rotterdam, consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m² on day 0 or 1, Netherlands cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1·4 mg/m² on day 1 [up to a (J Doorduijn MD PhD); maximum of 2 mg], and oral prednisone 100 mg on days 1–5) and R-DHAP or R-DHAOx (intravenous rituximab Hematology Department, Hospital Clínic de Barcelona, 375 mg/m² on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1–4, high-dose intravenous cytarabine IDIBAPS, Barcelona, Spain 2 × 2 g/m² for 3 h every 12 h on day 2, plus either intravenous cisplatin 100 mg/m² over 24 h on day 1 [R-DHAP] or (E Giné MD PhD); Cancer Centre, intravenous oxaliplatin 130 mg/m² on day 1 [R-DHAOx]), followed by ASCT. In group A + I, oral ibrutinib (560 mg Lund University Faculty of daily) was added on days 1–19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was Medicine, Lund, Sweden (Prof M Jerkeman MD PhD); given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to Maria Sklodowska-Curie national guidelines. Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were National Research Institute of statistically monitored. The primary analysis was by intention to treat and included all randomly assigned patients, Oncology, Warsaw, Poland ignoring protocol deviations. Safety was assessed in randomly assigned patients who started any trial treatment (Prof J Walewski MD PhD); Department of Haematology component of the respective treatment phase. The trial is registered with ClinicalTrials.gov (NCT02858258) and is and Phase 1 Unit, complete. Rigshospitalet, Copenhagen, Denmark Findings Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were (Prof M Hutchings MD PhD); Oncology and Hematology, randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290). After median follow-up of Kantonsspital Graubuenden, 54·9 months (95% CI 54·4–56·0), group A + I did not show superiority over group I, with 4-year failure-free Chur, Switzerland survival of 82% (95% CI 78–87) versus 81% (76–86; hazard ratio [HR] 0·86 [one-sided 98·33% CI 0·00–1·27]; one- (Prof U Mey MD); Swiss Cancer sided p=0·21). Group A + I remained superior to group A (82% [78–87] vs 70% [65–76]; HR 0·63 [one-sided Institute—formerly Swiss Group for Clinical Cancer 98·33% CI 0·00–0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I Research–SAKK, Bern, (70% [65–76] vs 81% [76–86]; HR 1·45 [one-sided 98·33% CI 0·00–2·02]; one-sided p=0·99). 4-year overall survival Switzerland (Prof U Mey, was 88% (95% CI 84–92) in group A + I versus 81% (76–85) in group A (HR 0·59 [95% CI 0·38–0·92], p=0·0036) Prof U Novak MD); Department and 90% (87–94) in group I versus 81% (76–85) in group A (0·57 [0·36–0·90], p=0·0019). During maintenance or of Oncology, Oslo University Hospital, Oslo, Norway follow-up, the most common grade 3–5 adverse events were haematological disorders, reported in (J Riise MD PhD); First Faculty of 127 (54%) of 234 patients in group A + I versus 74 (28%) of 269 in group I and 56 (23%) of 240 patients in group A, Medicine, Charles University and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in Hospital, Prague, Czech group I and 37 (15%) of 240 patients in group A. Infections and infestations were the most common fatal adverse Republic (Prof M Trneny MD); Department of Hematology, events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of University Hospitals Leuven, 269 patients in group I. Articles Leuven, Belgium Interpretation After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant (V K J Vergote MD PhD); Adelson improvements not only in failure-free survival—a modified form of progression-free survival—but also in overall School of Medicine, Ariel survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but University, Ariel, Israel; increased toxicity. Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years Institute of Hematology, Assuta Medical Center, Tel Aviv, of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with Israel (Prof O Shpilberg MD); mantle cell lymphoma. Department of Hematology, Portuguese Institute of Oncology, Lisbon, Portugal Funding Janssen. (M Gomes da Silva MD PhD); Comprehensive Cancer Center, Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 University of Helsinki and license. Helsinki University Hospital, Helsinki, Finland (Prof S Leppä MD PhD); Institute Introduction patients aged 18–65 years with mantle cell lymphoma for Medical Information Mantle cell lymphoma is a challenging subtype of whether ibrutinib added to R-CHOP (rituximab plus Processing, Biometry, and lymphoma due to the substantial variability in clinical cyclophosphamide, doxorubicin, vincristine, and Epidemiology (IBE), Faculty of Medicine, LMU Munich, course.1,2 Over the last decade, blastoid morphology, high prednisone), alternating with R-DHAP (rituximab plus Munich, Germany (L Jiang MSc, Ki-67 index, and TP53 alterations, in addition to the clinical dexamethasone, high-dose cytarabine, and cisplatin), and Prof E Hoster PhD); Department Mantle Cell Lymphoma International Prognostic Index as maintenance after ASCT (experimental group A + I), or of Internal Medicine III, Ulm (MIPI), have been identified as the most relevant biological ibrutinib added to R-CHOP, alternating with R-DHAP, University Hospital, Ulm, Germany indicators of poor prognosis.3–5 In young (aged ≤65 years) and as maintenance without ASCT (experimental group I), (Prof S Stilgenbauer MD); patients who are medically fit, dose intensification by could replace the pre-trial standard of alternating R-CHOP Medizinische Klinik A, adding autologous stem-cell transplantation (ASCT) and and R-DHAP immunochemotherapy followed by ASCT Universitätsklinikum Münster, cytarabine, and rituximab maintenance, have led to (control group A). Münster, Germany (A Kerkhoff MD); Department I improved long-term outcomes.6–8 In relapsed disease, The previously published TRIANGLE results supported of Internal Medicine, Center for Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib the superior failure-free survival with ibrutinib added to Integrated Oncology and have shown superior efficacy compared with conventional R-CHOP, alternating with R-DHAP, followed by ASCT University Hospital Cologne, chemotherapy.9–11 In the current TRIANGLE trial of the (group A + I) and as time-limited maintenance, over the University of Cologne, Cologne, Germany (R D Jachimowicz MD); European Mantle Cell Lymphoma Network, we pre-trial standard (group A).12 Furthermore, superior Max Planck Institute for investigated in newly diagnosed, transplant-eligible failure-free survival using ASCT without Biology of Ageing, Cologne, Germany (R D Jachimowicz); Department of Hematology Research in context and Medical Oncology, Medical School of the Johannes Evidence before this study Added value of this study Gutenberg-University, Mainz, We did a PubMed search on Oct 30, 2025, without explicit With mature median follow-up of more than 4 years, the Germany (Prof G Heß MD); Department of Hematology, publication date or language restriction, using the search terms TRIANGLE trial shows improvements in both overall survival University Medical Center “(mantle cell lymphoma) AND (ibrutinib OR autologous) AND and failure-free survival when adding ibrutinib to first-line Groningen, Groningen, randomized” to find all randomised, phase 3 trials investigating R-CHOP (rituximab, cyclophosphamide, doxorubicin, Netherlands the role of autologous stem-cell transplantation (ASCT) or the vincristine, and prednisone), alternating with R-DHAP (Prof T van Meerten MD); Department of Hematology, Bruton’s tyrosine kinase inhibitor ibrutinib as part of first-line (rituximab, dexamethasone, high-dose cytarabine, and Oncology, Clinical Immunology treatment for younger, transplant-eligible patients with mantle cisplatin). The addition of ASCT to ibrutinib-containing, first- and Rheumatology, Center for cell lymphoma. Only two trials, both performed by the line treatment did not show superior efficacy and was Internal Medicine, University Hospital Tuebingen, Tübingen, European Mantle Cell Lymphoma Network, matched the search associated with more frequent, severe side-effects. However, Germany (S Wirths MD); criteria. The first randomised trial of the European Mantle Cell preplanned subgroup analyses suggested potentially prolonged Technical University of Munich, Lymphoma Network had established ASCT after response to disease control by ASCT in patients with mantle cell lymphoma School of Medicine and Health, first-line induction with chemotherapy or who have high-risk biology, defined as high-risk combined Department of Internal Medicine III, TUM University immunochemotherapy as standard of care in 2005. In 2024, Mantle Cell Lymphoma International Prognostic Index or high Hospital, Munich, Germany the first results of the three-arm, randomised TRIANGLE trial p53 expression, although these results were not adequately (P Herhaus MD); Department of indicated that the addition of fixed duration ibrutinib should powered given the small sample sizes. Medical Oncology, Inselspital, become part of a cytarabine-containing induction Bern University Hospital, Implications of all the available evidence University of Bern, Bern, immunochemotherapy and maintenance. These conclusions In transplant-eligible adult patients aged 65 years or younger Switzerland (Prof U Novak); from the TRIANGLE trial were based on effects on failure-free with mantle cell lymphoma, first-line treatment should consist Department of Internal survival, whereas results for overall survival had not yet formally Medicine II, UKE Hamburg, of ibrutinib added to R-CHOP, alternating with R-DHAP, and been evaluated. Furthermore, the TRIANGLE trial remained Hamburg, Germany followed by 2 years of ibrutinib maintenance without ASCT. (Prof J Dierlamm MD); ongoing to answer the final question of whether the addition of Future studies are required to clarify the potential role of ASCT Department of Internal ASCT to an ibrutinib-containing first-line treatment was Medicine III, Klinikum effective. in patients with biologically aggressive mantle cell lymphoma. Chemnitz, Chemnitz, Germany 1954 Articles ibrutinib-containing treatment (group A) over ibrutinib- randomisation, or had known CNS involvement of (Prof M Hänel MD); Department containing treatment without ASCT (group I) could not mantle cell lymphoma. Full inclusion and exclusion of Hematology and Stem Cell be shown. These results led to the conclusion that adding criteria are detailed in the trial protocol (appendix 1 Transplantation, University Hospital Essen, Essen, Germany ibrutinib to induction and maintenance treatment pp 42–44). Sex and ethnicity were assessed by site (C Hanoun MD PhD); represents a new standard of care for young (aged investigators. The study adhered to the updated Department of Medicine ≤65 years), transplant-eligible patients with mantle cell Declaration of Helsinki, and all participants provided Huddinge, Karolinska Institutet, Stockholm, Sweden lymphoma. However, the question of whether ASCT adds written informed consent. (K Sonnevi MD PhD); Azienda to the efficacy of the ibrutinib-containing study regimen Ospedaliera Universitaria (group A + I vs group I) remained open for later evaluation, Recruitment, randomisation, and masking Integrata, Ematologia e and effects on overall survival had not yet been After checking inclusion and exclusion criteria, eligible Trapianto di midollo osseo and Department of Engineering for investigated. With an additional 2 years of follow-up, we participants were registered in the trial and randomly Innovative Medicine, Verona, updated the previously observed treatment effects on assigned at a 1:1:1 ratio to one of the three treatment Italy (Prof C Visco MD); Istituto failure-free survival (group A + I vs group A, group A groups by authorised investigators (appendix 1 p 44). Nazionale Tumori - IRCCS vs group I), newly estimated effects on overall survival, Randomisation was done through an electronic data Fondazione G. Pascale, SC Ematologia Oncologica, Napoli, and investigated the last remaining trial question of capture system using computer-generated random Italy (D Donnarumma MD); whether ASCT adds efficacy to ibrutinib-containing numbers with an unpredictable seed. The randomisation Lymphoma Unit, IRCCS San immunochemotherapy and maintenance (group A + I was blocked and stratified by cooperative study groups Raffaele Scientific Institute and vs group I). and MIPI risk groups. Investigators initiated Università Vita-Salute San Raffaele, Milano, Italy randomisation via the electronic case report form and (Prof A J M Ferreri MD); Azienda Methods were unable to predict treatment allocation. Due to the Ospedaliera, Ospedali Riuniti Study design omission of ASCT and earlier initiation of maintenance Villa Sofia – Cervello, UOC TRIANGLE is an investigator-initiated, international, in group I, masking of either ASCT or ibrutinib was not Oncomatologia, Palermo, Italy (C Patti MD); ULSS2 Marca randomised, open-label, phase 3, confirmatory superiority possible. Trevigiana, Ospedale Ca’ trial with three parallel treatment groups, and is sponsored Foncello, Ematologia, Treviso, by Munich University Hospital, Germany. The trial was Procedures Italy (P Maria Stefani MD); conducted across 165 secondary or tertiary university, Participants in all three treatment groups were given Department of Medicine II (Prof C Pott MD PhD), and community, or private hospitals and private clinical centres induction immunoc hemotherapy consisting of Department of Pathology, in Germany, Italy, the Netherlands, Spain, Sweden, Poland, six alternating, 21-day cycles of R-CHOP and either Hematopathology Section and Denmark, Switzerland, Norway, Czech Republic, Belgium, R-DHAP or R-DHAOx (rituximab plus dexamethasone, Lymph Node Registry Israel, Portugal, and Finland. Centres with experience in high-dose cytarabine, and oxaliplatin) regimens. The (Prof W Klapper MD), University Hospital Schleswig-Holstein - mantle cell lymphoma treatment were eligible if they had induction treatments were administered by the clinical Campus Kiel, Kiel, Germany; the capability to perform ASCT or an association with such staff at each investigational site (appendix 1 p 46). The Department of Translational a centre. The trial received ethical approval from the ethics R-CHOP regimen included intravenous rituximab Medicine, Division of committees of all participating centres; the lead ethics 375 mg/m² on day 0 or 1, cyclophosphamide 750 mg/m² Hematology, University of Eastern Piedmont and SCDU committee was the Ethics Committee of the Medical on day 1, doxorubicin 50 mg/m² on day 1, vincristine Ematologia, Azienda Faculty at LMU Munich (659–15 fed). The trial protocol 1·4 mg/m² on day 1 (up to a maximum of 2 mg), and oral Ospedaliera Santi Antonio e and statistical analysis plan are available online (appendix 1 prednisone 100 mg on days 1–5. The R-DHAP and Biagio e Cesare Arrigo, and appendix 2 pp 34–54). After trial start, changes to the R-DHAOx regimens consisted of intravenous rituximab Alessandria, Italy (Prof M Ladetto MD) trial were minor and deviations from the trial protocol 375 mg/m² on day 0 or 1, intravenous or oral Correspondence to: during analysis are reported in the statistical analysis plan dexamethasone 40 mg on days 1–4, high-dose intravenous Prof Martin Dreyling, (appendix 2 pp 52–53). There was no patient or public cytarabine 2 × 2 g/m² for 3 h every 12 h on day 2, plus either Department of Medicine III, LMU involvement in the design, conduct, and reporting of the intravenous cisplatin 100 mg/m² over 24 h on day 1 University Hospital, trial. The trial was registered at ClinicalTrials.gov (R-DHAP) or intravenous oxaliplatin 130 mg/m² on day 1 81377 Munich, Germany martin.dreyling@med. (NCT02858258) and is complete. (R-DHAOx), with subsequent G-CSF support uni-muenchen.de (subcutaneous filgrastim 5 µg/kg daily from day 6 or See Online for appendices 1 and 2 Patients alternatively one dose of pegfilgrastim 6 mg on day 6). In Participants were eligible if they were adults aged addition, patients in group A + I and group I received oral 18–65 years of any sex (male or female) with histologically ibrutinib 560 mg daily on days 1–19 during R-CHOP cycles confirmed, previously untreated mantle cell lymphoma only (IR-CHOP; addition to R-DHAP was considered too in Ann Arbor stage II–IV and were suitable for ASCT. toxic)13 and 2 years of continuous maintenance with Additional inclusion criteria included an Eastern ibrutinib 560 mg daily if participants remained failure-free Cooperative Oncology Group performance status of 2 or after ASCT, for participants in group A + I, or after less and at least one measurable lesion. Patients were induction, for participants in group I. For group A and ineligible if they required anticoagulation with warfarin group A + I, ASCT was done after either THAM or equivalent vitamin K antagonists or treatment with conditioning (ie, total body irradiation 10 Gy on days –7 strong CYP3A4 or CYP3A5 inhibitors, had a history of to –5, intravenous cytarabine 1·5 g/m² over 30 min twice intracranial haemorrhage up to 6 months before daily on days –4 to –3, and melphalan 140 mg/m² over 1 h Articles on day –2) or BEAM or TEAM conditioning (ie, intravenous over 1 h on day –2), per investigator discretion. Rituximab carmustine 300 mg/m² over 1 h or thiotepa 5 mg/kg twice maintenance was allowed, according to national on day –7, plus etoposide 100 mg/m² over 1 h every 12 h on guidelines, and should then be given in all three treatment days –6 to –3, cytarabine 200 mg/m² over 30 min every groups. 12 h twice daily on days –6 to –3, and melphalan 140 mg/m² Response assessments, conducted by investigators using Revised Response Criteria for Malignant Lymphoma,14 included physical examinations, pre- Group A (n=288) Group A + I (n=292) Group I (n=290) planned CT scans, laboratory tests, and bone marrow Age, years 57 (52–61) 57 (52–61) 57·5 (52–61) biopsies (mandatory if initial bone marrow infiltration Sex was detected). PET-CT results were not considered for Male 218 (76%) 216 (74%) 228 (79%) response evaluation. Response was assessed after Female 70 (24%) 76 (26%) 62 (21%) four induction cycles, at the end of induction, 4–6 weeks Race after the end of induction, then every 6 months for White 283 (98%) 283 (97%) 290 (100%) 2 years, and annually thereafter until progression. Central Asian 0 1 (<1%) 0 reference pathology laboratories evaluated histo- Black 0 1 (<1%) 0 pathological markers for subgroup analyses of Ki-67 Other 5 (2%) 7 (2%) 0 index (<30% vs ≥30%, <50% vs ≥50%), p53 expression Histology* (≤50% vs >50%), and high-risk biology (defined as MCL 9673/3 286 (99%) 288 (99%) 287 (99%) high-risk combined MIPI or high p53 expression).4,5 ML, NOS 9590/3 0 1 (<1%) 0 Additional procedural details are available in the trial NHL, NOS 9591/3 0 1 (<1%) 0 protocol (appendix 1 pp 46–56). DLBCL 9680/3 0 0 2 (1%) Splenic MZL 9689/3 0 1 (<1%) 0 Outcomes FL 9690/3 1 (<1%) 0 0 The primary outcome was investigator-assessed failure- MZL 9699/3 0 1 (<1%) 0 free survival, defined as the time from randomisation to CLL 9823/3 1 (<1%) 0 0 the first occurrence of stable disease at the end of HCL 9940/3 0 0 1 (<1%) induction immunochemotherapy, progressive disease, or Ann Arbor Stage death from any cause. This endpoint represented a modified progression-free survival endpoint that I 1/287 (<1%) 0 0 specifically included stable disease at the end of induction II 9/287 (3%) 11 (4%) 18 (6%) as an event, representing an indication for salvage III 24/287 (8%) 21 (7%) 28 (10%) treatment at the discretion of the treating physician. IV 253/287 (88%) 260 (89%) 244 (84%) Secondary outcomes included overall survival (time B symptoms 72/285 (25%) 79/291 (27%) 87/285 (31%) from randomisation to death from any cause), ECOG performance status progression-free survival (time from randomisation to 0 214 (74%) 213 (73%) 208 (72%) disease progression or death), duration of remission 1 69 (24%) 77 (26%) 77 (27%) (time from end of successful induction to disease 2 5 (2%) 2 (1%) 5 (2%) progression or death), overall response and complete LDH:ULN ratio 0·94 (0·78–1·19) 0·94 (0·77–1·18) 0·87 (0·74–1·12) remission rates, and the conversion rate from partial to LDH>ULN 122 (42%) 120 (41%) 105 (36%) complete remission following induction therapy. MIPI score 5·62 (5·40–5·91) 5·64 (5·35–5·95) 5·61 (5·38–5·92) Adverse event reporting was required from Low-risk group 168 (58%) 168 (58%) 168 (58%) randomisation until 30 days after the last trial Intermediate-risk group 79 (27%) 80 (27%) 77 (27%) medication was given. As a result, adverse event High-risk group 41 (14%) 44 (15%) 45 (16%) documentation was not mandatory during the Leukocytes (white blood cells, G/L) 7·34 (5·50–10·91) 7·09 (5·28–11·11) 7·40 (5·77–11·92) observation period after ASCT for patients in group A. Ki-67 index 18% (9·75–37·50); 18% (11·56–40·00); 19% (10·25–35·00); Safety outcomes included the frequencies of grade 3–5 n=249 n=262 n=259 adverse events according to Common Terminology Ki-67 index ≥30% 81/249 (33%) 81/262 (31%) 83/259 (32%) Blastoid cytology 28/253 (11%) 34/261 (13%) 31/265 (12%) p53 expression >50% 25/201 (12%) 28/195 (14%) 31/206 (15%) High-risk biology 34/201 (17%) 40/199 (20%) 44/208 (21%) Figure 1: Trial profile ASCT=autologous stem-cell transplantation. CR=complete remission. EOI=end Data are n (%), n/N (%), or median (IQR). CLL=chronic lymphocytic leukaemia. DLBCL=diffuse large B-cell lymphoma. of induction. EX=early death. IR-CHOP=ibrutinib with R-CHOP. MCL=mantle cell ECOG= Eastern Cooperative Oncology Group. FL=follicular lymphoma. G=giga. HCL=hairy cell leukaemia. LDH=lactate lymphoma. NE=not evaluable. PD=progressive disease. PR=partial remission. dehydrogenase. MCL=mantle cell lymphoma. MIPI=Mantle Cell Lymphoma International Prognostic Index. R-CHOP=intravenous rituximab 375 mg/m², intravenous cyclophosphamide ML=malignant lymphoma. MZL=marginal zone lymphoma. NHL=non-Hodgkin lymphoma. NOS=not otherwise 750 mg/m², intravenous doxorubicin 50 mg/m², intravenous vincristine specified. ULN=upper limit of normal. *International Classification of Diseases for Oncology (ICD-O-3) histology code. 1·4 mg/m², and oral prednisone 100 mg. R-DHAP=intravenous rituximab Table 1: Baseline characteristics 375 mg/m², intravenous or oral dexamethasone 40 mg, intravenous cytarabine 2 × 2 g/m², and intravenous cisplatin 100 mg/m². SD=stable disease. 1956 Articles 907 patients assessed for eligibility 37 excluded due to screening failure 870 randomly assigned 288 assigned to group A 292 assigned to group A+I 290 assigned to group I 2 did not start induction 2 did not start induction due to patient decision due to patient decision 286 started R-CHOP/ 291 started IR-CHOP/ 288 started IR-CHOP/ R-DHAP induction R-DHAP induction R-DHAP induction 261 completed six 1 started R-CHOP/R-DHAP 272 completed six cycles of induction induction cycles of induction 25 did not complete 275 completed six 16 did not complete six cycles of cycles of six cycles of induction induction induction 8 progression 40 did not start high-dose 17 did not complete 40 did not start high-dose 10 adverse events 3 started high-dose 6 patient decision treatment six cycles of treatment 2 patient decision treatment 4 physician decision End of induction induction End of induction 2 progression 3 completed ASCT 4 adverse events 7 CR 5 adverse events 15 CR 1 MCL diagnosis 1 MCL diagnosis 4 mobilisation failure 4 MCL diagnosis 3 mobilisation failure rejected rejected 2 physician decision rejected 2 adverse events 1 COVID-19 death 1 COVID-19 death 1 COVID-19 death in CR 4 patient decision 2 physician decision 1 treatment of 11 PR 2 progression 1 MCL diagnosis other malignancy 4 mobilisation failure 1 COVID-19 death rejected 2 physician decision 1 suicide 1 COVID-19 death 2 patient decision 15 PR 2 insufficient 6 adverse events documentation 4 patient decision 1 adverse event 2 MCL diagnosis 2 SD rejected 12 PD 1 physician decision 8 NE 1 mobilisation failure 1 COVID-19 death 1 SD 246 started high-dose 252 started high-dose 3 PD 285 did not start high-dose treatment treatment 1 EX treatment 246 completed ASCT 252 completed ASCT 5 NE 165 started rituximab 10 started rituximab 231 started ibrutinib 10 started ibrutinib 259 started ibrutinib 3 started ibrutinib maintenance maintenance maintenance maintenance maintenance maintenance 153 started ibrutinib 6 started ibrutinib 159 started ibrutinib 1 started ibrutinib plus rituximab plus rituximab plus rituximab plus rituximab maintenance maintenance maintenance maintenance 78 started ibrutinib 4 started ibrutinib 100 started ibrutinib 2 started ibrutinib maintenance maintenance maintenance maintenance 5 started rituximab 9 started rituximab 8 started rituximab maintenance only maintenance only maintenance only 3 adverse events 4 patient decision 3 adverse events 1 physician decision 2 physician decision 3 physician decision 1 NE at end of ASCT 1 MCL diagnosis 1 patient decision 16 did not start ibrutinib rejected 1 NE at EOI or rituximab 1 adverse event 18 did not start ibrutinib maintenance 1 NE at EOI or rituximab 5 adverse events 21 did not start ibrutinib maintenance 2 physician decision or rituximab 2 adverse events 1 patient decision maintenance 2 progression 1 COVID-19 death 4 patient decision 2 deaths 6 EX at end of ASCT 3 physician decision 1 physician decision 1 NE at end of ASCT 2 MCL diagnosis 1 MCL diagnosis rejected rejected 1 SD at EOI 2 deaths 3 PD at EOI 1 adverse event 6 NE at EOI 4 NE at EOI 3 PD at EOI 1 SD at EOI 1 EX at EOI Articles Criteria for Adverse Events version 4.03, deaths, and For overall survival, three pairwise comparisons were cumulative incidence rates of secondary primary conducted, each tested at a two-sided 5% significance malignancies. A complete listing of all secondary level without Bonferroni correction, as the hypotheses endpoints is provided in the trial protocol (appendix 1 were considered independent and not part of the overall pp 40–41). trial decision strategy. To maintain the overall two-sided 5% significance level across several analysis timepoints, Statistical methods an alpha-spending approach using O’Brien–Fleming A prespecified decision strategy was used based on boundaries was applied. We report here the results of the three pairwise, one-sided, log-rank tests for failure-free second interim analysis (Sept 20, 2024) that was survival with a Bonferroni-corrected significance level conducted for comparisons that remained undecided at of 5% divided by 3 for each pairwise comparison: the first interim analysis (May 9, 2024). Over-running group A + I versus group A (null hypothesis: group A + I analyses were done to update previously decided not superior to group A), group A versus group I (null comparisons. hypothesis: group A not superior to group I), and Complete remission and overall response rates were group A + I versus group I (null hypothesis: group A + I compared between group A and the pooled experimental not superior to group I). Separately for each pairwise groups (group A + I plus group I) using Fisher’s exact test test, predefined interim analyses for both futility and on a two-sided 5% significance level. The cumulative superiority were planned biannually using truncated incidence of treatment failure, next lymphoma treatment, sequential probability ratio tests correcting for repeated and secondary malignancies was estimated using the testing.15 The decision boundaries were identical for cumulative incidence function and compared with Gray’s group A + I versus group A and group A + I versus group I. test, with a one-sided significance level of 5% divided by By applying three sequential tests, each maintaining a 3, treating death without the event of interest as a Bonferroni-corrected local significance level, the overall competing event. type I error probability for the decision process was Efficacy analyses were conducted on an intention-to- restricted to 5%. After sample size calculation, a treat basis and included all randomly assigned patients, maximum of 870 patients were planned to be randomly ignoring protocol deviations. Sensitivity analyses assigned to treatment over 5 years, with an additional evaluated the primary hypotheses in a modified intention- 5 years of follow-up, to detect the superiority of to-treat cohort, including all patients with histologically group A + I over group A and group I (12% improvement confirmed mantle cell lymphoma who started induction in 5-year, failure-free survival: 77·1% vs 64·8%, hazard therapy according to randomisation. Subgroup analyses ratio [HR] 0·60) with 90% power, and superiority of for the primary endpoint were conducted in sex, MIPI, group A over group I (16% improvement in 5-year, cytology, Ki-67, p53, biological risk subgroups, and failure-free survival: 64·8% vs 48·5%, HR 0·60) with application of rituximab maintenance. Adverse events 95% power, allowing for 5% dropouts. We report results were assessed by induction, ASCT, and maintenance or using updated data (data cutoff at Sept 20, 2024) after the follow-up phases, and patients who started any trial formal decision of the last of the three statistically treatment component of the respective treatment phase monitored, pairwise tests (group A + I vs group I) at the were analysed descriptively according to the treatment 11th interim analysis on May 9, 2024 (appendix 1, p 22). administered. Induction safety was compared between We did over-running analyses,16 with p values, bias- treatment group A and the pooled group A + I plus corrected maximum-likelihood HR estimates, median group I. unbiased HR estimates, and one-sided 98·33% CIs The p values and HRs for the primary hypotheses were adjusted for the sequential design, which might have calculated using PEST3 software (1994, Reading higher coverage probabilities than indicated.15 University, Reading, UK) to correct for the sequential The Kaplan–Meier method, uncorrected for the statistical design. Decision boundaries for overall survival sequential design, was used to estimate failure-free were calculated using SAS version 9.4 and PEST3. All survival, progression-free survival, and duration of other analyses were conducted using R version 4.2.2. remission, censored at the last event-free date. HRs with More details on statistical methods are provided in the one-sided 98·33% CIs were calculated using Cox statistical analysis plan (appendix 2 pp 34–54). A data regression, applying the Bonferroni correction for safety monitoring committee oversaw the trial progress, three pairwise comparisons. For the comparisons of ensuring patient safety, data integrity, and scientific group I versus group A, two-sided log-rank tests with a validity. significance level of 3·33% and two-sided 96·67% CIs were additionally applied, in line with an overall Role of the funding source two-sided significance level of 10%. Sensitivity analyses The funder of the study had no role in study design, data adjusted for MIPI score (with or without Ki-67 index) or collection, data analysis, data interpretation, or writing of stratified by randomisation factors (study group and the report. The funder supplied ibrutinib for use in the MIPI risk group). study. 1958 Articles Results Between July 29, 2016, and Dec 28, 2020, 907 patients were assessed for eligibility, 870 of whom were randomly assigned to treatment. 288 patients were assigned to A group A, 292 to group A + I, and 290 to group I. The 1·00 median age of the randomly assigned patients was 57 years (IQR 52–61, range 27–68), 662 (76%) were 0·80 male, 208 (24%) were female, and, in 861 (99%), mantle cell lymphoma had been centrally confirmed. 0·60 757 (87%) of 869 patients had stage IV disease, 504 (58%) of 870 were in a low MIPI risk group, and 0·40 236 (27%) of 870 were in an intermediate MIPI risk group. Baseline characteristics for the three treatment 0·20 groups are shown in table 1. By the data cutoff on Sept 20, 2024, 866 patients had initiated induction chemotherapy (286 patients in 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Number at risk group A [including one patient with stage I disease who (censored) started the assigned chemotherapy], 292 in group A + I, Group A and 288 in group I; figure 1), with 808 completing all Group A+I six cycles (261 [91%] in group A, 275 [94%] in group A + I, and 272 [94%] in group I). ASCT was completed in 246 (85%) patients in group A, 252 (86%) in group A + I, and three (1%) in group I (deviating from the assigned treatment), with 238 (97%) patients in group A, 237 (94%) patients in group A + I, and one (33%) patient in group I receiving BEAM or TEAM. Ibrutinib maintenance was initiated in 241 (83%) patients in group A + I, with a median duration of 23·2 months (IQR 11·2–24·0, range 0·1–26·4), and in 262 (90%) in group I, with a median duration of 24·0 months (IQR 21·5–24·0, range 0·2–28·3). All those patients who initiated ibrutinib maintenance had terminated ibrutinib maintenance by time of data cutoff and 110 (46%) patients in group A + I and 156 (60%) in group I had completed the planned 2-year course. The median relative dose intensity of ibrutinib maintenance was 76% (IQR 37 to 97) in group A + I and 94% (70 to >99) in group I. Rituximab maintenance was initiated in 175 (61%) patients in group A, 173 (59%) in group A + I, and in 168 (58%) in group I, with no major biases in patient allocation. By the data cutoff on Sept 20, 2024, median follow-up for the failure-free survival endpoint was 54·9 months (95% CI 54·4–56·0) overall: 54·5 months (95% CI 54·3–56·7) in group A, 55·1 months (54·3–57·6) in group A + I, and 55·0 months (54·0–57·5) in group I (reversed Kaplan–Meier, appendix 2 p 3). Consistent with the last decision of statistical monitoring at the 11th interim analysis on May 9, 2024, group A + I did not show superior failure-free survival over group I, with 4-year failure-free survival of 82% (95% CI 78–87) versus 81% (76–86; corrected for sequential design: HR 0·86 [one-sided 98·33% CI 0·00–1·27]; one-sided p=0·21; figure 2; appendix 2 pp 22–26). Similar results were observed in the modified intention-to-treat cohort (uncorrected for sequential design: HR 0·92 [one-sided 98·33% CI 0·00–1·33]; one-sided p=0·31; appendix 2 pp 25–26). ytilibaborp lavivrus eerf-eruliaF HR 0·63 (one-sided 98·33% CI 0·00–0·89); one-sided p=0·0026 B 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Number at risk (censored) Group I Group A ytilibaborp lavivrus eerf-eruliaF HR 1·45 (one-sided 98·33% CI 0·00–2·02); one-sided p=0·9890 C 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time since randomisation (months) Number at risk (censored) Group I Group A+I ytilibaborp lavivrus eerf-eruliaF Group A Group A+I 288 255 245 235 219 211 200 187 159 121 74 57 32 20 4 1 (0) (11) (12) (13) (13) (14) (17) (27) (49) (83) (124)(140)(165)(176) (192)(195) 292 274 259 252 245 236 230 217 180 141 89 70 28 24 6 2 (0) (11) (14) (17) (18) (19) (23) (32) (64) (99) (143)(160)(200)(204) (222)(226) Group I Group A 290 273 263 250 246 237 228 213 167 129 89 67 31 20 7 2 (0) (9) (11) (12) (14) (16) (20) (30) (71) (107)(138)(154)(189)(200) (213)(218) 288 255 245 235 219 211 200 187 159 121 74 57 32 20 4 1 (0) (11) (12) (13) (13) (14) (17) (27) (49) (83) (124)(140)(165)(176) (192)(195) Group I Group A+I HR 0·86 (one-sided 98·33% CI 0·00–1·27); one-sided p=0·21 290 273 263 250 246 237 228 213 167 129 89 67 31 20 7 2 (0) (9) (11) (12) (14) (16) (20) (30) (71) (107)(138)(154)(189)(200) (213)(218) 292 274 259 252 245 236 230 217 180 141 89 70 28 24 6 2 (0) (11) (14) (17) (18) (19) (23) (32) (64) (99) (143)(160)(200)(204) (222)(226) Figure 2: Failure-free survival for group A + I vs group A (A), group A vs group I (B), and group A + I vs group I (C) HR=hazard ratio. Articles A Group A + I remained superior to group A with 4-year failure-free survival of 82% (95% CI 78–87) for group A + I versus 70% (65–76) for group A (corrected for sequential design: HR 0·63 [one-sided 98·33% CI 0·00–0·89]; one-sided p=0·0026; figure 2; appendix 2 pp 25–26). The benefit in group A + I was particularly pronounced in patients with high p53 expression compared with group A (HR 0·23 [one-sided 98·33% CI 0·00–0·57]; appendix 2 pp 4–6, 17–18). The superiority of group A + I over group A was further observed in progression-free survival (HR 0·64, one-sided 98·33% CI 0·00–0·91; one-sided p=0·0032; appendix 2 pp 7–8, 17–18), duration of remission (HR 0·69, one-sided 98·33% CI 0·00–1·001; one-sided p=0·0170; appendix 2 pp 9–10, 17–18), and duration of remission after ASCT (HR 0·66, one-sided 98·33% CI 0·00–0·98; one-sided p=0·014; appendix 2 pp 11–12, 17–18). As was the case with the results for failure-free survival after the shorter follow-up time,12 superiority of group A compared with group I was not shown with failure-free survival after 4 years (70% [95% CI 65–76] vs 81% [76–86]; corrected for sequential design: HR 1·45 [one- B sided 98·33% CI 0·00–2·02]; one-sided p=0·99; figure 2; 1·00 appendix 2 pp 25–26). A post-hoc, two-sided comparison with a significance level of 3·33% revealed the superiority 0·80 of group I over group A (corrected for sequential design: HR 0·69 [two-sided 96·67% CI 0·45–0·97]; two-sided 0·60 p=0·021; appendix 2 pp 25–26). The absence of superiority of group A versus group I was consistently observed for 0·40 failure-free survival across all analysed subgroups (appendix 2 pp 17–18), for progression-free survival 0·20 (HR 1·42 [one-sided 98·33% CI 0·00–2·00]; one-sided 0 p=0·99; appendix 2 pp 7–8, 25–26), and for duration of 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 remission (HR 1·27 [one-sided 98·33% CI 0·00–1·81]; Number at risk one-sided p=0·92; appendix 2 pp 9–10, 25–26). Of note, (censored) Group I subgroup analyses by rituximab maintenance also did not show superior failure-free survival for group A compared Group A+I with group I (appendix 2 pp 4–6). The absence of superiority in failure-free survival for group A + I versus group I was seen in most of the analysed subgroups (figure 3A). However, failure-free survival results for group A + I versus group I were only hypothesis-generating rather than confirmatory in patients with blastoid cytology (HR 0·58 [one-sided 98·33% CI 0·00–1·33]), Ki-67 of at least 50% (HR 0·59 [one-sided 98·33% CI 0·00–1·21]), high p53 expression (HR 0·57 [one-sided 98·33% CI 0·00–1·49]), and high-risk biology (HR 0·61 [one-sided 98·33% CI 0·00–1·29]; figure 3B–F; appendix 2 pp 4–6). Of note, subgroup analyses by rituximab maintenance also revealed overlapping failure-free survival curves for group A + I versus group I during the first 4 years (appendix 2 pp 4–6). Similar to failure-free survival, 4-year progression-free survival was 83% (95% CI 78–87) in group A + I and 81% (77–86) in group I, with an uncorrected HR of 0·90 (one- (Figure 3 continues on next page) sided 98·33% CI 0·00–1·31; one-sided p=0·28) for the 1960 ytilibaborp lavivrus eerf-eruliaF HR 0·58 (one-sided 98·33% CI 0·00–1·33) C 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time since randomisation (months) Number at risk (censored) Group I Group A+I ytilibaborp lavivrus eerf-eruliaF Events/patients HR (one-sided p interaction 98·33% CI) All 134/582 0·90 (0–1·30) Sex 0·71 Female 30/138 1·02 (0–2·23) Male 104/444 0·88 (0–1·33) MIPI Low 62/336 0·76 (0–1·31) Intermediate 37/157 1·15 (0–2·32) 0·33 High 35/89 1·03 (0–2·12) 0·56 Cytology 0·15 Non-blastoid 92/461 1·00 (0–1·56) Blastoid 27/65 0·58 (0–1·33) Ki-67 0·41 <30% 71/357 1·05 (0–1·74) ≥30% 54/164 0·79 (0–1·42) Ki-67 0·10 <50% 89/433 1·07 (0–1·69) ≥50% 36/88 0·59 (0–1·21) p53 expression 0·43 Low 67/342 0·83 (0–1·41) High 21/59 0·57 (0–1·49) High-risk biology 0·33 Low 60/323 0·88 (0–1·53) High 34/84 0·61 (0–1·29) 0·10 0·25 0·50 1·0 2·0 4·0 Group A+I superior to group I Group A+I not superior to group I Group I Group A+I 31 28 24 21 21 18 16 14 11 9 6 5 2 2 0 0 (0) (1) (1) (1) (1) (1) (3) (5) (7) (8) (10) (10) (13) (13) (15) (15) 34 29 26 25 24 21 21 20 17 13 11 10 2 1 0 0 (0) (2) (3) (3) (3) (3) (3) (3) (6) (10) (12) (13) (21) (22) (23) (23) HR 0·79 (one-sided 98·33% CI 0·00−1·42) 83 77 72 65 65 60 58 53 42 33 21 16 7 5 1 1 (0) (3) (3) (4) (4) (4) (5) (9) (18) (26) (33) (36) (45) (47) (51) (51) 81 72 68 64 61 55 54 50 39 28 22 19 7 5 2 0 (0) (5) (6) (7) (7) (7) (8) (10) (20) (30) (36) (39) (51) (53) (56) (58) Articles comparison between group A + I and group I (appendix 2 (over-running analysis corrected for interim analysis: HR pp 7–8, 25–26). Complete response was seen in 0·57 [two-sided 95% CI 0·36–0·90]; two-sided p=0·0019; 250 (44%) of 566 patients in group A + I plus group I figure 4; appendix 2 pp 25–26). The pairwise overall combined compared with 101 (36%) of 277 patients in survival comparison between group A + I and group I is group A (p=0·037). Overall response was seen in 556 (98%) patients in group A + I plus group I combined D compared with 260 (94%) patients in group A (p=0·0013). 1·00 Among patients who had a partial or complete response at the end of induction, the 4-year duration of remission 0·80 was 83% (78–87) in 279 patients in group A + I and 81% (76–86) in 277 patients in group I, with an HR of 0·87 0·60 (one-sided 98·33% CI 0·00–1·27; one-sided p=0·22) for group A + I versus group I (appendix 2 pp 9–10, 25–26). 0·40 After selection of patients who had a partial or complete response after ASCT only (248 in group A + I) or 4–6 weeks 0·20 post-induction (169 in group I), the 4-year duration of remission was 84% (79–89) in group A + I and 82% 0 (76–89) in group I (HR 0·88 [one-sided 98·33% CI 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Number at risk 0·00–1·40]; one-sided p=0·28; appendix 2 pp 9–10, (censored) 25–26). Group I 4-year cumulative incidence of treatment failure was Group A+I 11% (95% CI 7–15) in group A + I versus 16% (11–20) in group I (p=0·089); risk of death without treatment failure was 7% (4–10) in group A + I versus 4% (2–6) in group I (p=0·099; appendix 2 pp 13–14). Among those who were alive and had a first treatment failure, 35 (80%) of 44 patients in group A + I and 50 (85%) of 59 in group I received subsequent lymphoma treatment. 4-year cumulative incidence of next lymphoma treatment was 10% (7–14) in group A + I versus 16% (12–21) in group I (p=0·074), which might be explained by the risk of death without next lymphoma treatment in group A + I versus group I (8% [5–11] vs 4% [2–6], p=0·052; appendix 2 pp 15–16). After a median follow-up of 55·4 months (95% CI 54·8–56·7, reversed Kaplan–Meier; appendix 2 p 3), 4-year overall survival was 81% (95% CI 76–85) in group A, 88% (84–92) in group A + I, and 90% (87–94) in group I (figure 4). Compared with group A, overall survival was significantly longer in group A + I (over- running analysis corrected for interim analysis: HR 0·59 [two-sided 95% CI 0·38–0·92]; two-sided p=0·0036; figure 4; appendix 2 pp 25–26) and in group I Figure 3: Failure-free survival in subgroups for group A + I vs group I (A), in subgroups of patients with blastoid cytology (B), high Ki-67 with 30% cutoff (C), high Ki-67 with 50% cut-off (D), high p53 expression (E), and high-risk biology (F) for group A + I vs group I p values are for interactions. High-risk biology was classified as low (low, low intermediate, or high intermediate combined MIPI and low p53 expression) or high (high combined MIPI or high p53 expression). All results are uncorrected for the sequential design, and HRs are unadjusted and shown with one-sided 98·33% CIs corresponding to the primary one-sided hypotheses. No lower confidence limits for the treatment efficacy estimates are given. Superiority of group A + I versus group I would have been confirmed by an upper confidence limit smaller than 1·0 (A); due to reduced statistical power in the subgroups, the results are only hypothesis generating and not confirmatory. HR=hazard ratio. MIPI=Mantle Cell Lymphoma International Prognostic Index. ytilibaborp lavivrus eerf-eruliaF HR 0·59 (one-sided 98·33% CI 0·00–1·21) E 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Number at risk (censored) Group I Group A+I ytilibaborp lavivrus eerf-eruliaF HR 0·57 (one-sided 98·33% CI 0·00–1·49) F 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time since randomisation (months) Number at risk (censored) Group I Group A+I ytilibaborp lavivrus eerf-eruliaF Group I Group A+I 42 38 33 29 29 24 23 21 19 16 9 6 3 2 0 0 (0) (1) (1) (1) (1) (1) (2) (4) (5) (7) (12) (14) (17) (18) (20) (20) 46 39 36 32 32 28 27 24 19 14 13 11 5 4 2 0 (0) (4) (5) (6) (6) (6) (7) (8) (13) (18) (19) (21) (27) (28) (30) (32) 31 2 24 22 22 20 18 1 10 9 6 6 2 2 0 0 (0) (2) (2) (2) (2) (2) (3) (5) (9) (10) (12) (12) (16) (16) (18) (18) 28 26 24 23 22 20 19 17 15 12 8 7 1 1 0 0 (0) (2) (3) (3) (3) (3) (4) (5) (7) (10) (13) (13) (19) (19) (20) (20) HR 0·61 (one-sided 98·33% CI 0·00–1·29) 44 39 34 28 28 25 23 19 13 11 7 7 2 2 0 0 (0) (2) (2) (3) (3) (3) (4) (7) (12) (13) (16) (16) (21) (21) (23) (23) 40 35 32 28 27 25 24 22 18 15 10 9 2 2 0 0 (0) (3) (4) (5) (5) (5) (6) (7) (11) (14) (18) (18) (25) (25) (27) (27) Articles ongoing and will be reported at the final analysis on trial completion. Investigator-reported causes of death included progressive lymphoma in 31 (11%) of 288 patients in A group A, nine (3%) of 292 patients in group A + I, and 1·00 14 (5%) of 290 patients in group I, and comorbidities in 16 (6%) patients in group A, 13 (4%) patients in 0·80 group A + I, and 15 patients (5%) patients in group I (appendix 2 p 27). Medical review revealed expected risks 0·60 for ASCT-related deaths in seven (3%) of 246 patients in group A and in eight (3%) of 252 in group A + I. 0·40 During ASCT in patients treated with alternating IR-CHOP and R-DHAP, blood and lymphatic system 0·20 disorders were the most common grade 3–5 adverse events, reported in 163 (64%) of 254 patients. Of these, 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 the most common blood and lymphatic system disorder Number at risk was decreased platelet count in 112 (44%) of 254 patients. (censored) Group I Grade 3–5 gastrointestinal disorders were observed in 54 (21%) patients, general disorders and Group A+I administration-site conditions in 54 (21%) patients, and infections and infestations in 53 patients (21%; table 2). Infections were the most common fatal adverse events during ASCT, occurring in five (2%) of 254 patients treated with alternating IR-CHOP and R-DHAP (appendix 2 p 28). During maintenance or follow-up, more grade 3–5 adverse events were observed in patients receiving ibrutinib after ASCT (group A + I) compared with patients receiving ibrutinib without ASCT (group I; table 2). Blood and lymphatic system disorders were the most common grade 3–5 adverse events, affecting 127 (54%) of 234 patients in group A + I and 74 (28%) of 269 patients in group I, with decreased neutrophil count being the most common cause of blood and lymphatic system disorders in 110 (47%) patients in group A + I versus 61 (23%) in group I (table 2). Grade 3–5 infections and infestations were reported in 80 (34%) patients in group A + I and 71 (26%) in group I (table 2). Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) patients in group A + I and five (2%) patients in group I (appendix 2 p 29). The grade 3–5 adverse events in patients treated with alternating IR-CHOP and R-DHAP during induction, ASCT, and maintenance or follow-up are summarised in appendix 2 (pp 30–31). Secondary haematological malignancies occurred in four (1%) of 288 patients treated in group A (three with acute myeloid leukaemia and one with myelodysplastic syndrome), two (1%) of 292 in group A + I (myelodysplastic syndrome), and one (<1%) of 290 in group I (multiple myeloma; appendix 2 pp 19–21). Secondary non- haematological malignancies were observed in 20 (7%) patients in group A + I, 20 (7%) patients in group I, and seven (2%) in group A. The 4-year cumulative Figure 4: Overall survival for group A + I vs group I (A), group A + I vs group A (B), and group A vs group I (C) HR=hazard ratio. incidences of secondary haematological and 1962 ytilibaborp lavivrus llarevO B 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Number at risk (censored) Group A Group A+I ytilibaborp lavivrus llarevO HR 0·59 (two-sided 95% CI 0·38–0·92); two-sided p=0·0036 C 1·00 0·80 0·60 0·40 0·20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time since randomisation (months) Number at risk (censored) Group I Group A ytilibaborp lavivrus llarevO Group I Group A+I 290 282 273 266 264 259 253 243 194 147 101 78 41 21 7 2 (0) (6) (8) (9) (10) (11) (13) (23) (69) (112)(156) (179)(216)(236) (250)(255) 292 281 267 262 257 253 248 235 201 160 107 83 39 26 8 2 (0) (7) (10) (13) (14) (15) (16) (26) (58) (99) (151) (175)(219)(232) (250)(256) Group A Group A+I 288 270 260 255 243 238 233 222 187 145 92 73 41 23 5 1 (0) (8) (9) (9) (12) (13) (14) (20) (49) (87) (137) (156)(188)(205) (223)(227) 292 281 267 262 257 253 248 235 201 160 107 83 39 26 8 2 (0) (7) (10) (13) (14) (15) (16) (26) (58) (99) (151) (175)(219)(232) (250)(256) Group I Group A HR 0·57 (two-sided 95% CI 0·36–0·90); two-sided p=0·0019 290 282 273 266 264 259 253 243 194 147 101 78 41 21 7 2 (0) (6) (8) (9) (10) (11) (13) (23) (69) (112)(156) (179)(216)(236) (250)(255) 288 270 260 255 243 238 233 222 187 145 92 73 41 23 5 1 (0) (8) (9) (9) (12) (13) (14) (20) (49) (87) (137) (156)(188)(205) (223)(227) Articles non-haematological malignancies were 0·7% (95% CI 0·7% (0·1–2·4) and 2·5% (1·1–4·9) in group A (appendix 2 0·1–2·5) and 6·1% (3·7–9·3) in group A + I, respectively, pp 19–21). The lower incidence of non-haematological 0·4% (0·03–1·9) and 6·5% (4·0–9·8) in group I, and malignancies in group A might be explained by a During induction, During ASCT, During maintenance or follow-up IR-CHOP/R-DHAP IR-CHOP/R-DHAP (n=579) (n=254) Group A+I Group I (n=234) (n=269) Blood and lymphatic system disorders 449 (78%) 163 (64%) 127 (54%) 74 (28%) Neutrophil count decreased 301 (52%) 85 (33%) 110 (47%) 61 (23%) Platelet count decreased 355 (61%) 112 (44%) 17 (7%) 9 (3%) Anaemia 150 (26%) 58 (23%) 8 (3%) 5 (2%) Febrile neutropenia 73 (13%) 73 (29%) 16 (7%) 7 (3%) White blood cell decreased 93 (16%) 41 (16%) 13 (6%) 7 (3%) Lymphocyte count decreased 41 (7%) 8 (3%) 2 (1%) 6 (2%) Infections and infestations 73 (13%) 53 (21%) 80 (34%) 71 (26%) Lung infection 9 (2%) 13 (5%) 37 (16%) 30 (11%) Coronavirus infection 4 (1%) 0 12 (5%) 24 (9%) Sepsis 12 (2%) 17 (7%) 5 (2%) 4 (1%) Other 10 (2%) 12 (5%) 1 (<1%) 3 (1%) Device-related infection 5 (1%) 7 (3%) 2 (1%) 1 (<1%) Shingles 0 0 10 (4%) 1 (<1%) Gastrointestinal disorders 69 (12%) 54 (21%) 15 (6%) 13 (5%) Diarrhoea 21 (4%) 7 (3%) 7 (3%) 5 (2%) Oral mucositis 9 (2%) 23 (9%) 0 2 (1%) Nausea 18 (3%) 18 (7%) 0 0 Vomiting 18 (3%) 2 (1%) 1 (<1%) 2 (1%) General disorders and administration-site conditions 38 (7%) 54 (21%) 7 (3%) 13 (5%) Mucosal inflammation 6 (1%) 45 (18%) 2 (1%) 2 (1%) Fever 6 (1%) 8 (3%) 0 5 (2%) Fatigue 16 (3%) 3 (1%) 1 (<1%) 0 Metabolism and nutrition disorders 76 (13%) 22 (9%) 7 (3%) 8 (3%) Hypokalaemia 34 (6%) 13 (5%) 2 (1%) 1 (<1%) Investigations 36 (6%) 12 (5%) 13 (6%) 2 (1%) γ-glutamyl transferase increased 11 (2%) 3 (1%) 7 (3%) 0 Nervous system disorders 28 (5%) 1 (<1%) 16 (7%) 13 (5%) Syncope 9 (2%) 1 (<1%) 6 (3%) 3 (1%) Respiratory, thoracic, and mediastinal disorders 17 (3%) 13 (5%) 8 (3%) 9 (3%) Vascular disorders 33 (6%) 8 (3%) 5 (2%) 9 (3%) Hypertension 24 (4%) 6 (2%) 1 (<1%) 4 (1%) Cardiac disorders 19 (3%) 2 (1%) 9 (4%) 14 (5%) Atrial fibrillation 11 (2%) 1 (<1%) 4 (2%) 7 (3%) Injury, poisoning, and procedural complications 8 (1%) 4 (2%) 4 (2%) 10 (4%) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 2 (<1%) 0 8 (3%) 16 (6%) Renal and urinary disorders 40 (7%) 3 (1%) 0 4 (1%) Acute kidney injury 36 (6%) 2 (1%) 0 2 (1%) Skin and subcutaneous tissue disorders 5 (1%) 11 (4%) 9 (4%) 1 (<1%) Musculoskeletal and connective tissue disorders 8 (1%) 0 6 (3%) 10 (4%) Grade 3–5 adverse events and preferred terms occurring in at least 3% of patients in any treatment group shown. MedDRA coded preferred terms and system organ class were reclassified to match Common Terminology Criteria for Adverse Events version 4.03 for all preferred terms that had occurred in more than ten patients. ASCT=autologous stem-cell transplantation. MedDRA=Medical Dictionary for Regulatory Activities. IR-CHOP=ibrutinib combined with R-CHOP. R-CHOP=intravenous rituximab 375 mg/m², intravenous cyclophosphamide 750 mg/m², intravenous doxorubicin 50 mg/m², intravenous vincristine 1·4 mg/m², and oral prednisone 100 mg. R-DHAP=intravenous rituximab 375 mg/m², intravenous or oral dexamethasone 40 mg, intravenous cytarabine 2 × 2 g/m², and intravenous cisplatin 100 mg/m². Table 2: Frequency of patients with at least one grade 3–5 adverse event by system organ class and preferred terms during induction, ASCT, and maintenance or follow-up in group A+I and group I Articles potentially higher risk of death due to competing events improved progression-free survival as well as a non- (appendix 2 pp 19–21). significant trend towards better overall survival in a study population aged 65 years and older.20 Discussion In 2023, ibrutinib was withdrawn in the USA for In this large, randomised, phase 3 trial, the pre-trial treatment of relapsed mantle cell lymphoma, but standard treatment for mantle cell lymphoma of two additional, second-generation BTK inhibitors in the immunochemotherapy followed by ASCT in adult USA and one in Europe are registered for relapsed patients (aged ≤65 years) was challenged by ibrutinib, mantle cell lymphoma.21,22 Given their greater selectivity either in addition to or instead of ASCT. After a prolonged and improved tolerability in other entities, it is tempting follow-up of 55 months, both ibrutinib-containing to speculate about their potential as part of a TRIANGLE- groups showed clinically relevant improvements not only like regimen instead of ibrutinib.23 However, no phase 3 in failure-free survival—a modified form of progression- data on such combinations are available. free survival—but also in overall survival. In line with Based on the new standard of an ibrutinib-containing previous reports on immunochemotherapy-only regimen, salvage treatment in patients might be more regimens, the addition of ibrutinib resulted in a clinically challenging. In historical series, patients with disease important improvement in efficacy.3,4 progression under ibrutinib showed a dismal outcome Furthermore, we re-evaluated the efficacy of ASCT- independent of conventional salvage treatment.24 It is containing treatment in the context of current clinical important to emphasise that ibrutinib maintenance in the standards, which now include induction with rituximab, current trial was applied for a fixed duration of 2 years, high-dose cytarabine, and platinum-based agents, with the majority of patients still in remission after rituximab maintenance, and ibrutinib—approaches that completing maintenance. Thus, re-exposure with BTK were not established when the original randomised trial inhibitors might be worthwhile, either alone or in showing the superiority of ASCT was done.6 In the overall combination, but data on salvage treatment after time- patient population of the TRIANGLE trial, ASCT did not restricted exposure to ibrutinib are currently scarce. In improve the overall outcome, with only a small efficacy addition, immunological approaches that include gain that was counterbalanced by an expected chimeric antigen receptor (CAR) T cells and bispecific ASCT-related mortality of about 3% and additional toxicity antibodies, as well as non-covalent BTK inhibitor or BTK during ibrutinib with or without rituximab maintenance protein degraders, might at least partially overcome the after ASCT. Consistent with our results, a randomised US poor outcomes of relapses after covalent BTK inhibitors.25–27 intergroup trial reporting in 2024 showed that ASCT did A limitation of our study is that no patient-reported not improve the outcomes of patients who had already outcomes were collected in this complex academic trial. reached a molecular remission after induction.17 In addition, despite the relatively large overall sample Of note, in the 19% of patients in the study with size, analyses of patient subsets, especially those with high-risk biology, the hypothesis was generated that the high-risk features, are mostly only hypothesis-generating addition of ASCT could improve failure-free survival, rather than confirmatory due to the small patient although this finding warrants further investigation in numbers. There are still insufficient data on follow-up, larger cohorts. Again, such potentially improved efficacy which is substantially shorter than in trials evaluating the must be weighed against the increased toxicity observed role of ASCT. Finally, staging procedures were based on after ASCT. Similarly, in patients with p53 alterations, a CT scans only. potentially improved outcome following ASCT was However, based on our results, it is tempting to observed, whereas dose-intensified chemotherapy speculate whether chemotherapy might be omitted in typically achieves short-term responses.3–5 However, this first-line treatment overall. In the ENRICH phase 3 study observation should be interpreted with caution given the in patients 60 years and older, a significant improvement very small patient numbers (n=53). In 2025, the BOVEN in progression-free survival has been reported with an phase 2 trial reported an excellent outcome of 72% ibrutinib–rituximab regimen.28 Of note, the progression-free survival and 76% overall survival after chemotherapy control group was superior to an 2 years in patients with mantle cell lymphoma with p53 ibrutinib–rituximab regimen in patients with high mutations, applying a well tolerated triple regimen biological risk. Combined targeted approaches might combining a second-generation BTK inhibitor further overcome potential resistance mechanisms of (zanubrutinib), a BLC2 antagonist (venetoclax), and a BTK inhibitor monotherapy. Accordingly, encouraging CD20 antibody (obinutuzumab).18 Although the results in results have been reported for the combination of a BTK our study appear even more favourable, future trials are inhibitor with the pro-apoptotic BCL2 antagonist, required to define the optimal treatment strategy for this venetoclax, in patients with relapsed mantle cell patient subset.19 lymphoma,29,30 and a triple combination with anti-CD20 Interestingly, the ECHO trial evaluating the more antibodies that achieved impressive and ongoing specific, second-generation BTK inhibitor, acalabrutinib, remission rates as a first-line treatment.18 Similarly, in combination with bendamustine–rituximab showed immunotherapeutic approaches, including CAR T cells 1964 Articles or bispecific antibodies, have been shown to at least monitoring board or advisory board for AbbVie, AstraZeneca, Genmab, partially overcome the negative prognostic effect of Johnson & Johnson, Roche, and Takeda. UM reports travel support from Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche; biological high-risk parameters.24,25 Support for these participation in advisory boards for Bristol-Myers Squibb/Celgene, results is required from currently recruiting randomised Gilead, Janssen-Cilag, and Roche; and participation in a national trials.31 guideline committee for the German–Swiss–Austrian Guideline for In conclusion, based on the prespecified decision Mantle Cell Lymphoma. JR reports participation on an advisory board for Johnson & Johnson. MT reports consulting fees from AbbVie, strategy along with significantly improved survival after Amgen, Autolus, Bristol-Myers Squibb, Caribou Biosciences, Genmab, prolonged follow-up, this trial provides evidence Gilead, Incyte, Janssen, MorphoSys, Novartis, Roche, Swedish Orphan supporting ibrutinib-containing chemotherapy without Biovitrum, and Takeda; payment or honoraria for lectures, presentations, ASCT as a practice-informing alternative to ASCT-based speakers bureaus, manuscript writing, or educational events from AbbVie, Amgen, Bristol-Myers Squibb, Gilead, Janssen, MorphoSys, consolidation in first-line treatment of adult patients Novartis, Roche, Swedish Orphan Biovitrum, Swixx BioPharma, and 65 years or younger with mantle cell lymphoma. In the Takeda; support for attending meetings or travel from AbbVie, Gilead, context of ibrutinib-containing induction and Janssen, Roche, Swedish Orphan Biovitrum, and Takeda; and maintenance, ASCT does not improve the outcome of an participation on a data safety monitoring board or advisory board for AbbVie, Amgen, Autolus, Bristol-Myers Squibb, Caribou Biosciences, ibrutinib-based treatment in general. The hypothesis- Genmab, Gilead, Incyte, Janssen, MorphoSys, Novartis, Roche, Swedish generating results on potentially improved failure-free Orphan Biovitrum, and Takeda. VKJV reports payment to her institution survival in patients with mantle cell lymphoma with for lectures for Johnson & Johnson. OS reports an institutional research high-risk biology emphasise the need for further grant from Johnson & Johnson and honoraria for lectures from Johnson & Johnson. MGdS reports grants or contracts from AstraZeneca; research. consulting fees from Janssen, Lilly, and Roche; payment or honoraria for Contributors lectures, presentations, speakers bureaus, manuscript writing or MD, JDo, EG, MJ, JW, MHu, UM, JR, MT, VKJV, OS, MGdS, SL, StS, educational events from Clinical Care Options; support for attending AK, RDJ, GH, TvM, SW, PH, UN, JDi, MHa, CH, KS, CV, DD, AJMF, meetings or travel from AbbVie, BeOne, Gilead, Janssen, Lilly, and CPa, PMS, CPo, WK, CS, MU, TT, and ML were involved in Roche; and participation on a data safety monitoring board or advisory investigation. MD, JDo, EG, MJ, JW, MHu, UM, JR, MT, VKJV, OS, board for Munich University and Italian Lymphoma Foundation. MGdS, SL, GH, CS, ML, and EH were involved providing resources. All SL reports grants or contracts to their institution from Bristol-Myers authors were involved in writing the manuscript—reviewing and Squibb, Galapagos, Genmab, Novartis, and Roche; consulting fees from editing. MD, JDo, EG, MJ, JW, UM, MT, OS, MGdS, GH, CS, MU, ML, Bristol-Myers Squibb and Roche; payment or honoraria for lectures, and EH were involved in conceptualisation. MD, LJ, CS, and EH were presentations, speakers bureaus, manuscript writing, or educational involved in methodology. MD, JDo, EG, MJ, JW, MHu, UM, JR, MT, events from AbbVie, Gilead, and Roche; participation on a data safety VKJV, OS, MGdS, SL, CS, MU, and ML were involved in project monitoring board or advisory board for AbbVie, AstraZeneca, Gilead, administration. MD, JDo, EG, MJ, JW, MHu, UM, JR, MT, VKJV, OS, Incyte, and Roche; and leadership or fiduciary roles in other board, MGdS, SL, StS, AK, RDJ, GH, TvM, SW, PH, UN, JDi, MHa, CH, KS, society, committee, or advocacy group, paid or unpaid, for Nordic CV, DD, AJMF, CPa, PMS, CPo, WK, CS, MU, TT, ML, and EH were Lymphoma Group and European Hematology Association. SS reports involved in supervision. MD was involved in funding acquisition. LJ, grants or contracts from AbbVie, AstraZeneca, BeOne, Bristol-Myers MU, and EH were involved in software. MD, CS, MU, and TT were Squibb, Galapagos, F Hoffmann-La Roche, Gilead, GSK, Johnson & involved in data curation. All authors were involved in validation. MD, Johnson, Lilly, Novartis, and Sunesis Pharmaceuticals; consulting fees LJ, MU, and EH were involved in formal analysis. MD, LJ, and EH were from AbbVie, AstraZeneca, BeOne, Bristol-Myers Squibb, Galapagos, involved in writing the original manuscript draft. LJ and EH were F Hoffmann-La Roche, Gilead, GSK, Johnson & Johnson, Lilly, Novartis, involved in visualisation. All authors had full access to all data in the and Sunesis Pharmaceuticals; payment or honoraria for lectures, study and had final responsibility for the decision to submit for presentations, speakers bureaus, manuscript writing, or educational publication. LJ, MU, and EH directly assessed and verified the events from AbbVie, AstraZeneca, BeOne, Bristol-Myers Squibb, underlying data reported in the manuscript. Galapagos, F Hoffmann-La Roche, Gilead, GSK, Johnson & Johnson, Lilly, Novartis, and Sunesis Pharmaceuticals; support for attending Declaration of interests meetings or travel from AbbVie, AstraZeneca, BeOne, Bristol-Myers MD reports (institutional) support of academic studies from AbbVie, Squibb, Galapagos, F Hoffmann-La Roche, Gilead, GSK, Johnson & Gilead/Kite, Janssen, Lilly, and Roche; honoraria for independent Johnson, Lilly, Novartis, and Sunesis Pharmaceuticals; participation on a academic presentation from AbbVie, AstraZeneca, BeOne, Bristol-Myers data safety monitoring board or advisory board for AbbVie, AstraZeneca, Squibb, Gilead/Kite, Janssen, Lilly, and Swedish Orphan Biovitrum; BeOne, Bristol-Myers Squibb, Galapagos, F Hoffmann-La Roche, Gilead, congress travel support from Janssen and Roche; and participation on a GSK, Johnson & Johnson, Lilly, Novartis, and Sunesis Pharmaceuticals; scientific advisory board for AbbVie, AstraZeneca, AvenCell, BeOne, and receipt of equipment, materials, drugs, medical writing support, Bristol-Myers Squibb, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, gifts, or other services from AbbVie, AstraZeneca, BeOne, Bristol-Myers Novartis, Roche, and Swedish Orphan Biovitrum. EG reports grants or Squibb, Galapagos, F Hoffmann-La Roche, Gilead, GSK, Johnson & contracts from Janssen and Lilly; payment or honoraria for lectures, Johnson, Lilly, Novartis, and Sunesis Pharmaceuticals. AK reports presentations, speakers bureaus, manuscript writing, or educational consulting fees from Roche; payment or honoraria for lectures, events from AstraZeneca, Gilead, Janssen, and Lilly; support for presentations, speakers bureaus, manuscript writing, or educational attending meetings or travel from AstraZeneca and Lilly; and events from AbbVie, Alexion, Amgen, AstraZeneca, BeOne, Bristol- participation on a data safety monitoring board or advisory board for Myers Squibb, Lilly, Novartis, Recordati, Swedish Orphan Biovitrum, Gilead. MJ reports payment or honoraria for lectures, presentations, and Takeda; and support for attending meetings or travel from AbbVie, participation in speakers bureaus, manuscript writing, or attendance at Roche, and Swedish Orphan Biovitrum. RDJ reports travel support for educational events from Bristol-Myers Squibb, Gilead/Kite, and Lilly; meeting attendance from AstraZeneca, BeOne, Celgene, and Janssen; payment for expert testimony from AstraZeneca and Johnson & payment or honoraria for lectures, presentations, speakers bureaus, Johnson; and participation on a data safety monitoring board or advisory manuscript writing, or educational events from AstraZeneca, BeOne, board for BeOne, Galapagos, Gilead/Kite, Lilly, and Roche. JW reports Celgene, Janssen, Lilly, and Roche; support for attending meetings or consulting fees from Gilead, MSD, and Regeneron; and lecture travel from BeOne and Janssen; and participation on a data safety honoraria from Gilead. MHu reports financial support of the present monitoring board or advisory board for Celgene. GH reports grants or study from Janssen/Johnson & Johnson; honoraria for lectures from contracts for clinical research from AbbVie, Gilead/Kite, Janssen, Lilly, AbbVie, Genmab, Roche, and Takeda; and participation on a data safety Articles and Roche; consulting fees from AbbVie, AstraZeneca, Beigene (BeOne), The following study groups supported the trial by providing resources Bristol-Myers Squibb, Gilead/Kite, Incyte, Janssen, Miltenyi Biotec, and by project administration and supervision: Czech Lymphoma Study MSD, Pierre Fabre, Regeneron, Roche, and Swedish Orphan Biovitrum; Group, Dutch-Belgian Cooperative Trial Group for Hematology payment or honoraria for lectures, presentations, speakers bureaus, Oncology, Fondazione Italiana Linfomi, Grupo Español de Linfoma/ manuscript writing, or educational events from AbbVie, ADC Trasplante Autólogo de Médula Ósea, Instituto Português de Oncologia, Therapeutics, AstraZeneca, BeiGene (BeOne), Bristol-Myers Squibb, Israeli Lymphoma Group, Nordic Lymphoma Group, Polish Lymphoma Gilead/Kite, Incyte, Janssen, Lilly, MSD, Novartis, Roche, and Swedish Research Group, and Swiss Cancer Institute (formerly Swiss Group for Orphan Biovitrum; support for attending meetings or travel from Incyte, Clinical Cancer Research). During the preparation of this work, we used Janssen, and Pierre Fabre; and participation on a data safety monitoring ChatGPT (GPT-5, OpenAI) to assist with minor language editing and board or advisory board for AstraZeneca. TvM reports payment or improving readability of the manuscript. The tool was used under honoraria for lectures, presentations, speakers bureaus, manuscript human oversight for language editing and paraphrasing only. No part of writing or educational events from Gilead/Kite and Lilly; and the analysis, interpretation, or scientific conclusions was generated by participation on a data safety monitoring board or advisory board for artificial intelligence. After using this tool, we reviewed and edited the GE HealthCare and Gilead/Kite. UN reports consulting fees to or content as needed and take full responsibility for the content of the through institution from AstraZeneca, BeiGene, Bristol-Myers Squibb/ publication. 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The MCL elderly III trial Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. protocol: an international, randomized, open-label phase II trial to Version 3.2025. investigate the combinations of venetoclax, ibrutinib and rituximab 24 Hess G, Dreyling M, Oberic L, et al. Real-world experience among or bendamustine, ibrutinib and rituximab in patients with patients with relapsed/refractory mantle cell lymphoma after treatment naive mantle cell lymphoma not eligible for dose- Bruton tyrosine kinase inhibitor failure in Europe: the SCHOLAR-2 intensive treatment. BMC Cancer 2025; 25: 1370. retrospective chart review study. Br J Haematol 2023; 202: 749–59. --- [PDF原文](https://sci-net.xyz/storage/7932541/3819400569f73699f0ac8a7bec0a3d90443fecd083d1a89327418251b60755d7/Addition-of-autologous-stem-cell-transplantation-to-an-ibrutinib-containing-first-line-treatment.pdf) DOI: 10.1016/S0140-6736(26)00362-4