Role of Autologous Stem Cell Transplantation in the Context of Ibrutinib-Containing First-Line Treatment in Younger Patients with Mantle Cell Lymphoma: Results from the Randomized Triangle Trial By the European MCL Network
Martin Dreyling, Jeanette K. Doorduijn, Eva Giné, Mats Jerkeman, Jan Walewski, Martin Hutchings, Ulrich Mey, Jon Riise, Marek Trněný, Vibeke Vergote, Daniela Donnarumma, Ofer Shpilberg, María Gomes da Silva, Sirpa Leppä, Linmiao Jiang, Christiane Pott, Wolfgang Hiddemann, Christian Schmidt, Michael Unterhalt, Marco Ladetto, Eva Hoster
Abstract
On behalf of the European MCL Network, ML and EH contributed equally Introduction: In younger patients with mantle cell lymphoma (MCL), the addition of ibrutinib during induction immuno-chemotherapy and as 2-years maintenance with and without autologous stem cell transplantation (ASCT) has shown high efficacy in the 3-arm randomized TRIANGLE trial (Dreyling et al., Lancet 2024), establishing a new standard of care induction treatment and maintenance. However, the efficacy comparison of the two ibrutinib-containing treatment arms with and without ASCT was still ongoing. With prolonged follow-up, we now aim to clarify the role of ASCT in the context of ibrutinib-containing treatment, to confirm the previously observed treatment effects and to perform overall survival (OS) comparisons. Patients and methods: In 2016, the European MCL Network initiated the randomized, open-label, 3-arm TRIANGLE trial to evaluate the addition of ibrutinib to standard treatment with ASCT (arm A+I) in comparison to the previous standard treatment (arm A) and an ibrutinib-containing treatment without ASCT (arm I). Patients with previously untreated, advanced stage II-IV MCL, up to 65 years, and suitable for high-dose cytarabine and ASCT, were randomized 1:1:1 to the 3 trial arms in 13 European countries and Israel. Study treatment consisted of 6 alternating cycles of R-CHOP and R-DHAP without (arm A) or with ibrutinib added to R-CHOP cycles and as 2 years maintenance (arms A+I, I). ASCT was planned for patients of arms A and A+I responding to induction therapy. Rituximab maintenance was recommended to be applied according to national guidelines in responding patients of each trial arm. For the primary outcome, failure-free survival (FFS), stable disease at the end of induction, progression, or death were counted as events. Three pairwise log-rank tests for FFS were monitored with regular pre-planned interim analyses, each maintaining a one-sided 1.67% significance level. A pre-defined decision criterion based on the statistical significance of the treatment comparisons for FFS was established to determine the future treatment recommendation. In 2022, arm A had failed to show FFS-superiority over I and FFS in arm A+I was shown to be superior to A. OS was a secondary outcome and formal pairwise OS comparisons between treatment arms were pre-planned with interim analyses based on O'Brien-Fleming boundaries to maintain pairwise two-sided 5% significance levels. Results: Between July 2016 and December 2020, 870 patients were randomized to arms A (n=288), A+I (n=292), and I (n=290). Median age was 57 years (range 27-68), 76% were male, 87% had stage IV, and 58%/27%/15% had low/intermediate/high risk MIPI. After a median follow-up of 53 months, A+I failed to show FFS-superiority over I (3-year FFS A+I: 86% vs. I: 85%; one-sided p=0.28, hazard ratio: 0.87). FFS-superiority of A over I was again not confirmed with 3-year FFS 75% (A) vs. 85% (I; one-sided p=0.9942, hazard ratio: 1.38). In contrast, the retrospectively calculated two-sided p-value on an overall 5% significance level was consistent with FFS-superiority of I over A (p=0.0102). FFS-superiority of A+I over A was again confirmed with 3-year FFS 86% (A+I) vs. 75% (A; one-sided p=0.0034, hazard ratio: 0.64). Compared with arm A (3-year OS 85%), OS was prolonged in arms A+I and I with 3-year OS of 90% in A+I (p=0.0069, hazard ratio 0.61), and 91% in I (p=0.0041, hazard ratio 0.59). Conclusions: The results confirm superiority of ibrutinib-containing treatment without ASCT (arm I) over ASCT-containing treatment without ibrutinib (arm A) in terms of both, FFS and OS. In the context of ibrutinib- and high-dose cytarabine-containing induction immuno-chemotherapy and ibrutinib maintenance, the addition of ASCT failed to show FFS superiority, while increasing toxicity during maintenance/follow-up. According to the pre-defined decision strategy, ibrutinib+R-CHOP/R-DHAP induction followed by 2 years of ibrutinib maintenance should be the new standard of care in younger MCL patients, thus ending the era of ASCT for MCL patients.