Major Trials Redefine Treatment Standards for Mantle Cell Lymphoma

The phase III TRIANGLE trial has demonstrated that adding ibrutinib to standard first-line regimens significantly improves failure-free and overall survival in younger patients with mantle cell lymphoma (MCL), while the ECHO trial established a new standard of care for older patients with the combination of acalabrutinib, bendamustine, and rituximab. These landmark findings, alongside advances in CAR T-cell and bispecific antibody therapies, were highlighted at the annual MCL Consortium meeting, signaling a major shift in the treatment landscape for this rare B-cell lymphoma.

The international TRIANGLE trial enrolled 870 patients aged 18 to 65 with untreated stage II to IV MCL who were suitable for autologous stem cell transplantation (ASCT). Patients were randomly assigned between July 2016 and December 2020 to three groups: a control group receiving standard immunochemotherapy followed by ASCT, an experimental group adding ibrutinib to induction and as two-year maintenance after ASCT, and a second experimental group adding ibrutinib without ASCT. After a median follow-up of 54.9 months, both ibrutinib-containing groups showed superior outcomes. The 4-year failure-free survival was 82% in the ibrutinib plus ASCT group and 81% in the ibrutinib-only group, compared to 70% in the control group. Overall survival at 4 years was 88% and 90% in the ibrutinib groups, respectively, versus 81% in the control group. The addition of ASCT to the ibrutinib regimen provided no supplementary benefit but increased toxicity, with grade 3-5 hematologic events occurring in 54% of the ASCT group versus 23% in the control group. The investigators concluded that ibrutinib plus immunochemotherapy followed by ibrutinib maintenance should be considered a new standard of care for younger MCL patients.

For older patients, the phase 3 ECHO clinical trial (NCT02972840) showed favorable progression-free survival data for acalabrutinib plus bendamustine/rituximab (BR) compared to BR plus placebo. This regimen has been approved in the United States and Europe and is now the standard of therapy for patients 65 years or older. Additional data from the meeting included follow-ups on minimal residual disease for acalabrutinib plus lenalidomide plus rituximab in newly diagnosed MCL.

The treatment landscape is further evolving with newer immunotherapies. Two CAR T-cell therapies, brexucabtagene autoleucel (brexu-cel) and lisocabtagene maraleucel (liso-cel), are approved for relapsed MCL. Studies indicate that brexu-cel has greater efficacy but higher rates of cytokine release syndrome and neurotoxicity, while liso-cel shows similar efficacy with reduced toxicity. Other emerging agents discussed at the consortium include a new BTK degrader, the BCL2 inhibitor sonrotoclax, and bispecific antibodies such as glofitamab and epcoritamab. The combination of polatuzumab vedotin and mosunetuzumab has also shown effectiveness for patients who relapse after CAR T-cell therapy.

Mantle cell lymphoma is a rare form of B-cell non-Hodgkin lymphoma, accounting for approximately 6% of all lymphoma diagnoses each year. It is generally considered a fast-growing cancer that tends to affect men more than women and is more common in people over 65. Historically, the disease was managed with intensive chemotherapy regimens like R-CHOP and bendamustine/rituximab, often followed by stem cell transplantation for younger patients. The MCL Consortium, established through philanthropic support, serves as a critical forum for researchers and clinicians to collaborate on advancing treatment. At the recent meeting, a lifetime achievement award was presented for contributions including the development of the MCL International Prognostic Index and leadership of the TRIANGLE study.