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

Background: Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival in adult patients aged 18-65 years with mantle cell lymphoma, according to the first results from the TRIANGLE trial. With prolonged follow-up, we investigated whether the addition of autologous stem-cell transplantation (ASCT) to an ibrutinib-containing regimen improves failure-free survival, and evaluated effects on overall survival. Methods: We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or an association with such a centre, in 13 European countries and Israel. Patients aged 18-65 years with untreated, stage II-IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or experimental groups A + I or I. Randomisation was done using computer-generated random numbers and stratified by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups. Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, 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 maximum of 2 mg], 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, high-dose intravenous cytarabine 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 intravenous oxaliplatin 130 mg/m2 on day 1 [R-DHAOx]), followed by ASCT. In group A + I, oral ibrutinib (560 mg daily) was added on days 1-19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to national guidelines. Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were statistically monitored. The primary analysis was by intention to treat and included all randomly assigned patients, ignoring protocol deviations. Safety was assessed in randomly assigned patients who started any trial treatment component of the respective treatment phase. The trial is registered with ClinicalTrials.gov (NCT02858258) and is complete. Findings: Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290). After median follow-up of 54·9 months (95% CI 54·4-56·0), group A + I did not show superiority over group I, with 4-year failure-free 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-sided p=0·21). Group A + I remained superior to group A (82% [78-87] vs 70% [65-76]; HR 0·63 [one-sided 98·33% CI 0·00-0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I (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 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) 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 follow-up, the most common grade 3-5 adverse events were haematological disorders, reported in 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, and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in group I and 37 (15%) of 240 patients in group A. Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I. Interpretation: After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant improvements not only in failure-free survival-a modified form of progression-free survival-but also in overall survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but increased toxicity. Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with mantle cell lymphoma. Funding: Janssen.