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The European Commission has expanded the indication for ibrutinib (Imbruvica) for use 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 the frontline treatment of patients with mantle cell lymphoma (MCL) who are eligible for autologous stem cell transplant (ASCT).1
The expanded approval is based on data from the phase 3 TRIANGLE trial (NCT02858258), which showed that ibrutinib plus chemoimmunotherapy improved both failure-free survival (FFS; HR, 0.639; 98% CI, 0.428-0.953; 2-sided P = .0068) and overall survival (OS; HR, 0.522; 95% CI, 0.341-0.799; 2-sided P = .0023) vs ASCT plus chemoimmunotherapy. At a median follow-up of 55 months, the 54-month FFS rates were 77% and 68% with ibrutinib plus chemoimmunotherapy vs ASCT plus chemoimmunotherapy. The respective 54-month OS rates were 88% and 78%.
“MCL is still an aggressive, incurable disease, and patients suffer under the burden associated with transplant,” Martin Dreyling, MD, PhD, Ludwig Maximilian University of Munich, stated in a news release. “As a targeted therapy, ibrutinib represents an opportunity to improve long-term outcomes earlier in the treatment pathway. Patients now have a new standard of care in first-line treatment that not only offers prolonged survival but also avoids short and long-term toxicities associated with high-dose chemotherapy and autologous stem cell transplant.”
With respect to safety, the adverse effect (AE) profile of ibrutinib plus chemoimmunotherapy was similar to that of ibrutinib monotherapy. The most frequent grade 3 to 5 AEs in the ibrutinib plus chemoimmunotherapy (n = 265) and ASCT plus chemoimmunotherapy (n = 268) arms, respectively, were blood and lymphatic system disorders (64.9% vs 75.0%), decreased neutrophil counts (24.2% vs 23.1%), decreased platelet counts (29.4% vs 33.2%), and infections and infestations (28.7% vs 23.1%).
“For more than a decade, ibrutinib has been the standard of care in relapsed or refractory MCL, transforming patient outcomes in later lines. Today’s approval for frontline use offers patients facing this aggressive blood cancer improved survival outcomes from the outset of treatment,” Ester in ‘t Groen, EMEA, Therapeutic Area Head Hematology, Johnson & Johnson Innovative Medicine, said. “This milestone reinforces our commitment to evolving treatment paradigms in hematological malignancies through targeted, science-driven innovation.”
The European MCL Network–led TRIANGLE study is an ongoing, open-label, randomized trial designed to evaluate the activity of ibrutinib plus chemoimmunotherapy with or without ASCT vs ASCT plus chemoimmunotherapy alone.
Investigators enrolled 870 patients between the ages of 18 and 65 years of age with treatment-naive MCL.2 Eligible patients had a histologically confirmed diagnosis of MCL according to World Health Organization classification, Ann Arbor stage II to IV disease, and at least 1 measurable lesion. In addition to an ECOG/WHO performance status of 2 or lower, patients had to be suitable for high-dose treatment.
Patients who underwent major surgery within 4 weeks prior to randomization or required anticoagulation with warfarin or an equivalent vitamin K antagonist would be excluded from enrollment, as well as those who had a history of stroke or intracranial hemorrhage within 6 months before randomization. Additional exclusion criteria included treatment with strong CYP3A4/5 inhibitors, known central nervous system involvement, and clinically significant hypersensitivity to ibrutinib, among others.
The primary end point was FFS. Secondary end points included OS, safety and tolerability, progression-free survival, and the number of secondary primary malignancies.
“Until now, fit patients with MCL have only had the option of frontline treatment with ASCT and chemotherapy.1 We’re incredibly proud that with this approval, ibrutinib has become the first alternative therapy for this patient population after demonstrating superior outcomes compared to the current standard of care,” Jessica Vermeulen, vice president, Lymphoma & Leukemia Disease Area Stronghold Leader, Johnson & Johnson Innovative Medicine, said. “This approval reinforces our ongoing commitment to hematological malignancies, and the power of our collaborations with academics and researchers to bring cutting edge science to areas of high unmet need.”
References
- European Commission approves Imbruvica (ibrutinib) as the first targeted therapy for patients with previously untreated mantle cell lymphoma who would be eligible for autologous stem cell transplant. News release. Johnson & Johnson. July 23, 2025. Accessed July 23, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-imbruvica-ibrutinib-as-the-first-targeted-therapy-for-patients-with-previously-untreated-mantle-cell-lymphoma-who-would-be-eligible-for-autologous-stem-cell-transplant
- ASCT after a rituximab/ibrutinib/Ara-c containing iNduction in generalized mantle cell lymphoma. ClinicalTrials.gov. Updated December 19, 2017. Accessed July 23, 2025. https://clinicaltrials.gov/study/NCT02858258