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Frontline ibrutinib for younger patients with MCL: Results from the phase III TRIANGLE trial

Jan 20, 2023
Learning objective: After reading this article, learners will be able to cite a new clinical development in MCL.

Mantle cell lymphoma (MCL) is an uncommon form of non-Hodgkin lymphoma, occurring 5–10% of patients with non-Hodgkin lymphoma globally. The treatment landscape for MCL is rapidly evolving. Currently, high-dose cytarabine-containing immunochemotherapy followed by autologous stem cell transplantation (ASCT) and rituximab maintenance therapy represents the standard of care (SOC) for younger patients with MCL. In recent years, Bruton's tyrosine kinase (BTK) inhibitors have shown promise as a more effective treatment protocol than SOC treatments, with ibrutinib demonstrating promising efficacy in relapsed and previously untreated older patients with MCL.

In younger patients with advanced MCL, it is unclear whether incorporation of ibrutinib into frontline therapy could improve outcomes. To address this, the European MCL Network is conducting the phase III, randomized, open-label TRIANGLE trial (NCT02858258) evaluating the addition of ibrutinib to standard treatment in comparison to the previous standard treatment and an ibrutinib regimen without ASCT.

Here, we report a summary of results from the ongoing phase III TRIANGLE trial of ibrutinib in younger patients with MCL presented by Dreyling at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2022, as part of the plenary scientific session.

Study design

The trial design is shown in Figure 1.

Figure 1. Trial design*† 

ASCT, autologous stem cell transplantation; l, ibrutinib; R, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin.
*Adapted from Dreyling, et al.1
†Rituximab maintenance was added in all three arms and was started (+/− ibrutinib) in 58%/57%/54% of A/A+I/I randomized patients, respectively. 

TRIANGLE is an ongoing phase III, randomized, open-label, three-arm trial of ibrutinib to compare the effectiveness and safety of adding ibrutinib to standard treatment (arm A + I) vs previous standard treatment (arm A) and an ibrutinib containing treatment without ASCT (arm I) (Figure 1).

Between July 2016 and December 2020, 870 patients were selected for enrolment and randomized 1:1:1 to the three trial arms. Eligible patients were aged ≤65 years, had advanced previously untreated Stage II–IV MCL, an Eastern Cooperative Oncology Group Performance Score of 0­–2, and were suitable for high-dose cytarabine and ASCT therapy.

The primary outcome was failure-free survival (FFS), with stable disease at the end of induction, progression, and death constituting qualifying events. Key secondary outcomes included response rates, progression-free survival, overall survival, and safety.


Figure 2. Efficacy outcomes* 

CR, complete response; FFS, failure-free survival; OR, overall response; OS, overall survival.
*Adapted from Dreyling, et al.1


  • OR and CR rates were 94% and 36% in arm A vs 98% and 45% in the A+I/I arms combined, respectively.
  • After a median follow-up of 31 months, 3-year FFS was 72% vs 86% in arm A vs arm I; this showed that previous standard treatment was not superior to ibrutinib containing treatment without ASCT. Arm A + I showed improved FFS over arm A, with a 3-year FFS of 88% vs 72%, respectively (Figure 2).
  • Three-year overall survival for arms A, A + l, and l was 86%, 91%, and 92%, respectively.
  • Subgroup analyses by the intention to apply rituximab maintenance did not affect the study results.
  • Statistical monitoring for the FFS comparison of arm A + I vs arm I is ongoing.


  • No significant differences in the occurrence of Grade 3­–5 adverse events (AEs) were detected between induction with R-CHOP/R-DHAP vs ibrutinib-R-CHOP/R-DHAP patient groups.
  • The two ASCT-containing arms (arm A and arm A + l) did not show significant differences in the occurrence of Grade 3­–5 AEs.
  • During the maintenance phase, patients in the A + I arm experienced more AEs than those in arms A and l, with
    • 44%, 17%, and 23% experiencing neutropenia;
    • 4%, 2%, and 2% experiencing leukopenia;
    • 6%, 3%, and 3% experiencing febrile neutropenia;
    • 25%, 13%, and 19% experiencing infections and infestations; and
    • 3%, 1%, and 4% experiencing cardiac disorders, respectively.


These results show that addition of ibrutinib to ASCT leads to improved FFS outcomes. In addition, neither ASCT-containing arm (arm A and arm A + l) had significantly better outcomes compared with the ibrutinib alone arm (arm l); however, therapy with ibrutinib alone had a more favorable safety profile. Longer-term follow-up results will indicate if these results remain consistent in younger patients with MCL.

  1. Dreyling M. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized TRIANGLE trial by the European MCL Network. Plenary scientific session. 64th American Society of Hematology Annual Meeting and Exposition; Dec 11, 2022; New Orleans, US. 

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