CHMP Recommends Ibrutinib Plus Chemoimmunotherapy for Frontline, Transplant-Eligible Mantle Cell Lymphoma

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The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of ibrutinib (Imbruvica) in combination with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisolone), alternating with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) or R-DHAOx (rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin) without ibrutinib, followed by ibrutinib monotherapy, for adult patients with previously untreated mantle cell lymphoma (MCL) who are eligible for autologous stem cell transplant (ASCT).¹

The recommendation is based on findings from the phase 3 TRIANGLE study (NCT02858258), which enrolled 870 patients with previously untreated MCL across 3 arms. Investigators evaluated ibrutinib plus chemoimmunotherapy with or without ASCT vs standard chemoimmunotherapy followed by ASCT.

Results presented at the 2024 ASH Annual Meeting demonstrated that patients who received ibrutinib plus chemoimmunotherapy followed by ASCT (n = 292) achieved a 4-year failure-free survival (FFS) rate of 82% compared with 70% for patients given chemoimmunotherapy alone followed by ASCT (n = 288; HR, 0.64; P = .0026).2

Notably, patients given ibrutinib plus chemoimmunotherapy without ASCT (n = 290) achieved a 4-year FFS rate of 81% (HR vs ibrutinib/chemoimmunotherapy plus ASCT, 0.83; P = .21). The addition of ASCT to ibrutinib plus chemoimmunotherapy was not superior to ibrutinib/chemoimmunotherapy without ASCT across subgroups, but trends toward superiority with the addition of ASCT were seen in those with a Ki-67 expression of more than 30%; those with blastoid cytology; and patients with high p53 expression.

The 4-year OS rates were 90% for the ibrutinib/no ASCT arm vs 81% for the chemoimmunotherapy/ASCT arm (HR, 0.565; P = .0019). The 4-year OS rate was 88% for ibrutinib/chemoimmunotherapy/ASCT (HR vs chemoimmunotherapy/ASCT, 0.587; P = .0036).

“Today’s CHMP recommendation is an important milestone for patients with previously untreated MCL, an aggressive disease which requires complex and challenging treatment,” Ester in't Groen, EMEA Therapeutic Area Head of Haematology at Johnson & Johnson Innovative Medicine, stated in a news release.1 “We are excited by the innovation that ibrutinib continues to bring and hope to soon offer patients this frontline option that has demonstrated improved OS without the burden, toxicity, and time in hospital associated [with] an ASCT-based treatment regimen.”

TRIANGLE Study Breakdown

The TRIANGLE study is an ongoing, multicenter, randomized, open-label, phase 3, investigator-initiated trial led by the European MCL Network. Designed to evaluate the role of ibrutinib in first-line treatment, the trial enrolled patients between 18 and 65 years of age deemed suitable for high-dose therapy, including ASCT.2 Patients needed to have stage II to IV disease and an ECOG performance status of 0 to 2.

Patients were randomly assigned to 1 of 3 treatment arms: standard induction immunochemotherapy with ASCT; induction immunochemotherapy combined with ibrutinib and ASCT; or induction immunochemotherapy combined with ibrutinib without ASCT.

The primary end point of the study was FFS. Key secondary end points included OS, overall response rate, progression-free survival, and safety.

Safety Information

Safety data revealed that the addition of ASCT to ibrutinib plus chemoimmunotherapy was associated with increased toxicity. Specifically, the rates of grade 3 or higher blood and lymphatic disorders were 54% with ibrutinib/chemoimmunotherapy followed by ASCT, 28% for ibrutinib/chemoimmunotherapy without ASCT, and 23% for chemoimmunotherapy with ASCT. The rates of grade 3 or higher infections and infestations were 34%, 26%, and 15%, respectively.

“At Johnson & Johnson, we are committed to improving outcomes for patients facing complex blood cancers,” Jessica Vermeulen, vice president and Lymphoma & Leukemia Disease Area Stronghold Leader at Johnson & Johnson Innovative Medicine, added in a news release.1 “The TRIANGLE study, conducted by the European MCL Network, affirms the potential emergence of a new standard of care for transplant-eligible patients diagnosed with MCL and represents the first major step forward for these patients in many years. We look forward to working together to bring this transplant-free therapeutic option to the MCL community.”

References

1. Imbruvica (ibrutinib) receives positive CHMP opinion for the treatment of patients with previously untreated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplant. News Release. Johnson & Johnson. June 20, 2025 https://www.jnj.com/media-center/press-releases/imbruvica-ibrutinib-receives-positive-chmp-opinion-for-the-treatment-of-patients-with-previously-untreated-mantle-cell-lymphoma-mcl-who-would-be-eligible-for-autologous-stem-cell-transplant
2. Dreyling M, Doorduijn JK, Gine E, et al. Role of ASCT 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. Blood. 2024;144(Supp 1):240. doi:10.1182/blood-2024-200735