Symposium | Unmet needs in the treatment of MCL

During the 18th International Conference on Malignant Lymphoma (ICML), Jun 17–21, 2025, Lugano, CH, the Lymphoma Hub held a symposium on June 17, 2025, titled Customizing therapy for mantle cell lymphoma (MCL). Here, we share a presentation by Julie Vose, University of Nebraska Medical Center, Omaha, US, discussing unmet needs in the treatment of MCL.

Vose provides an overview of the current treatment landscape for patients with MCL, including Bruton’s tyrosine kinase inhibitors (BTKi), chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies. Vose also discusses mechanisms of resistance to BTKi and the impact on patient outcomes. 

Key points

• The introduction of BTKi has had a major impact on outcomes for patients with MCL over the past decade, including heavily pretreated patients.¹

• BTKi block BTK phosphorylation, leading to a decrease in B-cell proliferation and increased apoptosis in malignant B-cells.²

  • BTKi also interact with the tumor microenvironment, making it less conducive for cancer cell survival and growth.²

• Ibrutinib, a first-generation covalent BTKi, was the first BTKi approved for relapsed/refractory (R/R) MCL; due to low specificity, there can be off-target effects, including cytopenias and cardiovascular toxicities.³

• Acalabrutinib and zanubrutinib are second-generation covalent BTKi with higher specificity for BTK, leading to fewer off-target effects compared with ibrutinib.³

• Several mechanisms of resistance to BTKi in patients with B-cell malignancies have been identified, including⁴:

  • Mutations promoting resistance: BTK, PLCG2, CARD11, CCNDI, TRAF2/BIRC3.

  • Dysregulation of protein expression: upregulation of MYC, ROR1, MALT1, and USP14.

  • Metabolic reprogramming: energy supply shifts to glutamine-fueled oxidative phosphorylation.

  • Microenvironmental factors: direct stromal cell–MCL cell interaction.

• Results from a retrospective analysis of patients with MCL treated with ibrutinib in the US showed an overall discontinuation rate of 83.6%, primarily due to progression (35%) and toxicities (26%).⁵

• Results from an analysis of a US electronic medical record oncology database, which included 946 patients with MCL who were treated with covalent BTKi, demonstrated that 78.1% of patients discontinued covalent BTKi treatment during the follow-up period.⁶

  • The median time from covalent BTKi discontinuation to next treatment discontinuation or death was 3.9 months, while the median overall survival was 10.3 months.⁶

• Outcomes were historically poor for patients relapsing after covalent BTKi therapy, due to a lack of effective treatment options. 

• Recent advancements have led to the development of newer therapies for patients who progress after covalent BTKi:

  • Non-covalent BTKi, such as pirtobrutinib.

  • CAR T-cell therapies, such as brexucabtagene autoleucel and lisocabtagene maraleucel.

  • Bispecific antibodies, such as glofitamab.

• Pirtobrutinib is a highly selective non-covalent BTKi; with a favorable oral pharmacology, it can be delivered effectively in community settings and inhibits fewer off-target kinases compared with covalent BTKi, which may contribute to an improved safety profile.⁷

  • In the phase I/II BRUIN trial, pirtobrutinib showed durable efficacy amd a favorable safety profile in heavily pre-treated patients with R/R MCL.⁷

• CAR T-cell therapies have demonstrated high response rates in patients with R/R MCL; however, they are associated with potential toxicities, including cytokine release syndrome and neurologic toxicities, and require specialist facilities and time for CAR T-cell manufacturing.⁸

• There are currently no specific approvals for bispecific antibodies for the treatment of patients with R/R MCL; however, glofitamab has shown promising activity in patients with R/R MCL and is included in the National Comprehensive Cancer Network guidelines as an option for patients ineligible for CAR T-cell therapy or with progressive disease after CAR T-cell therapy and pirtobrutinib.^9,10

This educational resource is independently supported by Eli Lilly and Company. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.