Type: Oral
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Therapies for Mantle Cell Lymphoma
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Clinical Research, Treatment Considerations
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.
Disclosures: Dreyling: AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding. Gine: Astra-Zeneca: Honoraria; Lilly: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria; Roche: Honoraria. Jerkeman: Janssen: Honoraria; Roche: Research Funding; AstraZeneca: Honoraria, Research Funding; Kite/Gilead: Honoraria; Abbvie: Honoraria, Research Funding. Walewski: Astrazeneca, Celgene/BMS, Epizyme, Gilead, GSK, Incyte, Janssen, Karyopharm, Morphosys, MSD, NanoVector, PLRG, Polish Myeloma Consortium, Regeneron, Seagen, Takeda, TG Therapeutics, Vanda Pharm: Research Funding; Gilead, Roche: Honoraria; Gilead, MSD, Regeneron: Consultancy. Hutchings: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen/J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Mey: Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche: Other: Travel support; German-Swiss-Austrian Guideline for Mantle Cell Lymphoma: Other: participation in national Guideline committee; Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda: Membership on an entity's Board of Directors or advisory committees. Riise: AstraZeneca, Roche: Membership on an entity's Board of Directors or advisory committees. Trneny: Gilead Sciences, Takeda, Bristol-Myers Squibb, Roche, Janssen, Abbvie, SOBI: Other: Travel, Accommodations, Expenses; Takeda, Bristol-Myers Squibb, Incyte, Abbvie, Amgen, Roche, Gilead Sciences, Janssen, MorphoSys, Novartis, Genmab, SOBI, Autolus, Caribou Biosciences: Consultancy; Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, Abbvie, Roche, MorphoSys, Novartis, SOBI, Swixx BioPharma: Honoraria. Vergote: Janssen, Abbvie: Honoraria; Beigene, Celgene, Gilead, Roche, Lilly Oncology, Abbvie, Johnson & Johnson: Consultancy; Amgen, Abbvie, Gilead, Roche: Other: Travel Support. da Silva: Janssen, Roche, Gilead Sciences, Lilly, Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen, Abbvie: Other: Institutional payments; Gilead Sciences, AstraZeneca: Research Funding; Roche, Abbvie, Janssen, Gilead, Takeda: Other: Travel Support. Leppä: Abbvie, BeiGene, Genmab, Gilead, Incyte, Novartis, Orion, Roche: Membership on an entity's Board of Directors or advisory committees. Klapper: Roche, Janssen, Amgen, InCyte: Research Funding. Schmidt: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Janssen: Honoraria. Unterhalt: AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding. Ladetto: Abbvie, Amgen, BMS, EUSA Pharma, GSK, Gentili, Gilead/Kite, Novartis, Incyte, Jazz, Lilly, Ellipses: Consultancy, Honoraria, Speakers Bureau; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, Roche, Janssen, ADC Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta, Sandoz: Honoraria.
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