The TRIANGLE trial supports ibrutinib as part of the first-line treatment for transplant-eligible mantle cell lymphoma

In a trial conducted by the European MCL Network, patients with mantle cell lymphoma (MCL) who were treated with ibrutinib in first line obtained comparable rates of failure-free survival (FFS) than patients who underwent the current standard of care (i.e., high-dose immunochemotherapy followed by an autologous stem cell transplantation [ASCT]), regardless of whether they received a stem cell transplantation. In a next step this study will further assess whether an ASCT following ibrutinib-based induction still has clinical value. However, the current data already provide support for the use of ibrutinib in transplant-eligible newly diagnosed MCL patients.

Introduction

The current standard of care for fit patients with MCL consists of high-dose cytarabine-based chemoimmunotherapy, followed by an ASCT and rituximab maintenance. In recent years, BTK inhibitors, such as ibrutinib, have become standard of care for MCL patients in first relapse and recently also showed potential in the frontline treatment of older or frail MCL patients. In 2016, the European MCL Network initiated the randomized, open-label, 3-arm TRIANGLE trial to evaluated the effect of adding ibrutinib to the current standard of care for fit untreated MCL patients (Arm A + I) and to assess the potential of an ibrutinib-based first line regimen without ASCT (Arm I).

Study design

The study at hand enrolled 870 patients with previously untreated, advanced stage II-IV MCL. In order to be eligible, patients had to be ≥65 years and be suitable for high-dose cytarabine and ASCT. Patients were randomized (1:1:1) to receive standard of care (Arm A), standard of care plus ibrutinib (A+I), or the same ibrutinib-based regimen without an ASCT (Arm I). The treatment regimen that was used in this trial consists of 3 cycles R-CHOP/R-DHAP without (arm A) or with ibrutinib added to the R-CHOP cycles and 2 years ibrutinib maintenance (arms A+I, I). ASCT was planned for responding patients of arms A and A+I. Rituximab maintenance could be applied according to national guidelines in all responding patients irrespective of the trial arm. The primary endpoint of the study was failure-free survival (FFS), with a failure being defined as stable disease at the end of induction, any progression, or death. Secondary study objectives consisted of overall response rate (ORR), complete remission (CR) rate, overall survival (OS), and the incidence of grade 3-5 adverse events (AEs).

Results

Patients in the study had a median age of 57 years (range 27-68), 76% of them were male, and 87% had stage IV disease. Furthermore, 58%, 27% and 15% of study participants had a low, intermediate, or high risk MIPI score, respectively. After a median follow-up of 2.5 years, the TRIANGLE trial demonstrated superiority of the A+I regimen over A alone, with 3-year FFS rates of 88% and 72%, respectively (HR: 0.52; p= 0.0008). Interestingly, A failed to show superiority over I in terms of FFS with 3-year FFS rates of 72% for A and 86% for I (HR: 1.77; p= 0.9979). OR and CR rates were reported at 94% and 36% in arm A as compared to 98% and 45% in the combined A+I and I arms.

There were no substantial differences in the occurrence of grade 3-5 AEs during induction with R-CHOP/R-DHAP vs. ibrutinib-R-CHOP/R-DHAP (neutropenia: 47% vs. 49%, leukopenia: 15% for both, febrile neutropenia: 9% vs. 12%, infections and infestations: 9% vs. 12%). Similarly, there were also no substantial differences in the incidence of grade 3-5 AEs between the two ASCT-containing arms. In contrast, during maintenance therapy there were substantially more grade 3-5 AEs in the A+I arm as compared to A and I (e.g., grade 3-5 neutropenia: 44%, 17% and with A+I, A and I, respectively).

Conclusions

These results of the TRIANGLE study show that the addition of ibrutinib during induction and as maintenance with or without ASCT comes with a strong efficacy and an acceptable toxicity profile. Furthermore, it has been shown that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. As such, one could conclude that ibrutinib may be best used as a replacement for, rather than an augment to, stem cell transplantation. More follow-up is needed to further clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support standard chemotherapy plus ibrutinib (with or without ASCT) as the new standard of care for first-line MCL patients,”

Reference

M. Dreyling, et al. 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. Presented at ASH 2022; Abstract 1.