In the recent European Hematology Association (EHA) Annual Meeting, Professor Mats Jerkeman from Lund University, Sweden, provided an in-depth interpretation of the diagnosis and latest treatment guidelines for Mantle Cell Lymphoma (MCL). With the release of results from several large-scale clinical trials (such as TRIANGLE, ECHO, SHINE, etc.), the treatment landscape for MCL is undergoing a transformation from traditional chemo-immunotherapy to precision targeted therapies centered on BTK inhibitors (BTKi).01 Diagnosis and Staging: Emphasizing the Prognostic Value of TP53 Mutation Screening
Precision treatment of MCL begins with rigorous pathological diagnosis. Professor Mats Jerkeman pointed out that pathologists prefer excisional biopsy for morphological and immunohistochemical analysis to ensure diagnostic accuracy. Regarding staging, traditional CT scans and bone marrow biopsy/aspirate remain standard procedures. Notably, the guidelines specifically emphasize the necessity of performing TP53 mutation analysis at both the initial diagnosis and relapse stages. TP53 mutation is a recognized poor prognostic factor in MCL; for these patients, traditional chemo-immunotherapy and autologous stem cell transplantation (ASCT) offer limited benefit. Additionally, for patients with suspected limited-stage disease, additional PET-CT and endoscopy are recommended to exclude occult extra-nodal lesions. Current data shows that through standardized diagnosis and treatment, the 5-year overall survival (OS) rate for MCL patients has significantly improved from 49% in the first cohort to 83% today.
02 Young Treatment-Naive Patients: The TRIANGLE Study Leading the “De-transplantation” Revolution
For young, fit treatment-naive (front-line) MCL patients, the previous standard of care was: induction immunochemotherapy (high-dose cytarabine combined with R-CHOP/R-DHAP) + autologous stem cell transplantation (ASCT) + rituximab maintenance. However, the landmark TRIANGLE study has rewritten this standard. The TRIANGLE study compared three arms: • Arm A: Standard induction chemotherapy + ASCT. • Arm A+I: Induction chemotherapy combined with Ibrutinib + ASCT + Ibrutinib maintenance. • Arm I: Induction chemotherapy combined with Ibrutinib + Ibrutinib maintenance (omitting ASCT). Key Data: Results showed that adding BTK inhibitors to conventional induction chemotherapy significantly improved failure-free survival (FFS). Even more clinically significant, the efficacy of Arm I (no ASCT) was not inferior to Arm A (with ASCT), suggesting that in the BTK inhibitor era, ASCT may no longer be a necessity for all young patients. Guideline Recommendation: In regions with access to the drug, it is recommended to add BTKi to the induction regimen, followed by 2 years of BTKi combined with 3 years of rituximab maintenance, while the status of ASCT is gradually diminishing.
03 Elderly and Unfit Patients: Diverse Options for BTKi Combination Regimens
For elderly or unfit front-line patients, the goal is to balance efficacy and safety. Professor Jerkeman reviewed several classic and cutting-edge studies:
- STiL Study: Confirmed that rituximab combined with bendamustine (BR regimen) is superior to R-CHOP in terms of progression-free survival (PFS) and tolerability.
- VR-CAP Study: Confirmed that the regimen replacing vincristine with bortezomib significantly improved OS compared to R-CHOP.
- BTKi Combined with Chemotherapy: o SHINE Study: BR combined with ibrutinib significantly extended PFS (6.7 years vs 4.4 years; HR=0.75), but due to more toxicity-related deaths in the experimental arm, this did not translate into an OS benefit. o ECHO Study: Acalabrutinib combined with the BR regimen showed a significant PFS benefit (median PFS not yet reached vs 61.9 months; HR=0.73), with an OS benefit trend observed on the curves and relatively manageable safety. o ENRICH Study: Explored a chemo-free regimen (Rituximab + Ibrutinib); results showed that this regimen was comparable to BR in PFS and clearly superior to R-CHOP. Based on this evidence, BR, VR-CAP, or BTKi combined with rituximab (e.g., BR+Acalabrutinib) are all viable recommended options for elderly patients, supplemented by rituximab maintenance.
04 Relapsed/Refractory MCL: Precision Response Pathways Post-Resistance
Treatment decisions for relapsed/refractory (R/R) MCL depend on the front-line regimen and the nature of resistance:
- Patients who only received front-line chemotherapy: Covalent BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib) are the first choice, with or without venetoclax.
- BTKi-resistant patients: This group faces a very poor prognosis. Current breakthrough measures include: o CAR-T Cell Therapy: Such as Brexu-cel, providing new opportunities for subsequent treatment. o Non-covalent BTKi: Pirtobrutinib has shown positive salvage effects in patients resistant to covalent BTKi. o Novel Inhibitors: Such as Bcl-2 inhibitors like Sonrotoclax in ongoing clinical trials.
- Relapse after fixed-duration BTKi: If a patient relapses a significant time after completing a fixed duration (e.g., 2 years) of BTKi treatment, re-challenge with the original BTKi or switching to another covalent BTKi can be considered.
05 Summary and Outlook: Moving Toward the “Chemo-free” and “Precision” Era
Professor Jerkeman concluded by stating that MCL treatment has entered an era of refined stratification. TP53 mutation status has become a core consideration in formulating treatment plans. For young patients, the TRIANGLE study provides a strong theoretical basis for “de-transplantation”; for elderly patients, optimized combinations of BTKi with chemotherapy and the exploration of chemo-free regimens have further expanded the survival space. In the future, as clinical data for bispecific antibodies, ADC drugs, and next-generation BTK inhibitors continue to accumulate, MCL is expected to achieve higher rates of long-term survival and even clinical cure. Real-time updates to guidelines will continue to lead clinical doctors globally in formulating individualized treatment strategies with better benefit/risk ratios.
Data Check & Glossary • MCL: Mantle Cell Lymphoma • ASCT: Autologous Stem Cell Transplantation • BTKi: Bruton’s Tyrosine Kinase inhibitor • TP53: Tumor Protein p53 • PFS: Progression-Free Survival • OS: Overall Survival • FFS: Failure-Free Survival • HR: Hazard Ratio • BR Regimen: Bendamustine + Rituximab • VR-CAP: Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, Prednisone regimen • Key Trials: TRIANGLE, SHINE, ECHO, ENRICH, STiL
