In recent years, the field of hematologic oncology has experienced remarkable breakthroughs, with significant advancements in mantle cell lymphoma (MCL). Chinese researchers have increasingly contributed to this progress, playing a pivotal role in driving academic development and clinical practice in the field. As we step into the new year, Hematology Frontier invited Professor Shuhua Yi from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, to review the major events and breakthroughs in MCL during 2024. This comprehensive summary aims to provide valuable insights for clinical practice and future research directions.

Advances in BTK Inhibitor Therapy: Reducing the Role of Chemotherapy and Transplantation

In 2024, the role of Bruton tyrosine kinase (BTK) inhibitors in the frontline treatment of MCL was further solidified. This was particularly evident for elderly patients, where BTK inhibitors combined with CD20 monoclonal antibodies have become a standard therapy, significantly improving both treatment outcomes and patient experiences.

At the 2024 ASH Annual Meeting, two pivotal studies underscored the potential of BTK inhibitors to reduce the reliance on high-dose chemotherapy. The first was the ENRICH study, a randomized controlled trial focusing on elderly patients. It demonstrated that ibrutinib combined with rituximab (IR) significantly improved progression-free survival (PFS) compared to traditional R-chemo regimens. The IR regimen also exhibited lower hematologic toxicity and improved quality of life during treatment, providing a promising new frontline option for elderly patients newly diagnosed with MCL. The second study, ECOG-ACRIN EA4181, revealed that for patients aged ≤70 years with newly diagnosed MCL, adding acalabrutinib to bendamustine and rituximab (BR) was comparable in efficacy to BR or cyclophosphamide plus rituximab (RC). This suggests that acalabrutinib could be a viable treatment option that avoids the use of high-dose cytarabine.

The application of BTK inhibitors has also diminished the role of autologous stem cell transplantation (ASCT) in MCL treatment. Results from the TRIANGLE study indicated that the benefits of ASCT were not significant in the context of BTK inhibitor-based therapy. These findings may lead to a reevaluation of ASCT’s role as frontline consolidation therapy in future guidelines and consensus documents.

New Treatment Landscape: Stratification, Immunotherapy, and Novel Drug Approaches

Stratified treatment has become increasingly critical in MCL management. For high-risk patients, particularly those with cytogenetic abnormalities, ASCT has shown limited survival benefits, and BTK inhibitors alone cannot fully overcome the negative prognostic impact. Developing effective strategies for this subgroup remains a key focus in current research.

Cellular immunotherapy continues to revolutionize the treatment paradigm, with early use of bispecific antibodies and CAR-T cell therapy emerging as effective strategies. These innovative therapies hold promise for significantly improving outcomes in high-risk MCL patients.

In 2024, several advancements in drug development and new indications further strengthened the MCL treatment landscape. Pirtobrutinib, a non-covalent BTK inhibitor, was approved for relapsed or refractory MCL, offering an alternative for patients who have failed first-generation BTK inhibitors. In cellular immunotherapy, relmacabtagene autoleucel, a representative CAR-T product, was approved for treating relapsed or refractory MCL, providing renewed hope for these patients. Bispecific antibodies also showed encouraging efficacy in MCL, offering valuable alternatives for patients who have failed BTK inhibitor therapy.

Research efforts are now focused on advancing the use of cellular immunotherapy in high-risk patients earlier in the treatment process to maximize its benefits. Continuous exploration and innovation are expected to pave the way for more personalized and precise MCL treatments, improving patient outcomes and quality of life.

Breakthroughs in Resistance Mechanisms: New Targets and New Strategies

Significant progress was made in understanding the mechanisms of resistance in MCL during 2024. At the ASH Annual Meeting, Prof. Yi’s team presented findings on how SMARCA2 regulates TENT5C, influencing ATP metabolism, MCL proliferation, and resistance to BTK inhibitors. This research provided a new perspective on the molecular mechanisms driving MCL growth and resistance.

The team also discovered that isoginkgetin (IGK) reduces ATP production and synergistically enhances the efficacy of BTK inhibitors. This finding highlights IGK’s potential as a therapeutic target for overcoming BTK inhibitor resistance, offering new treatment avenues with strong clinical translation potential.

Milestones in MCL Research and Clinical Framework in China

A landmark event in MCL research in China occurred on November 9, 2024, at the 5th Peking Union International Lymphoma Symposium, where the Chinese Mantle Cell Lymphoma Working Group was officially established. This milestone marks a new era in the development of MCL research and clinical practice in China. Bringing together leading researchers and institutions across the country, the working group aims to foster collaboration in clinical and translational research, ultimately improving patient outcomes.

In line with ongoing advancements in research and the emergence of new evidence, the Chinese guidelines for MCL diagnosis and treatment are scheduled for an update in 2025. This revision will integrate cutting-edge international developments and incorporate valuable insights from Chinese studies and clinical experience, ensuring the guidelines remain both advanced and practical. The efforts of the Chinese Mantle Cell Lymphoma Working Group, combined with the continuous refinement of treatment guidelines, are expected to significantly advance MCL care in China.

Conclusion

In 2024, remarkable strides were made in understanding and treating mantle cell lymphoma. Advances in BTK inhibitors, cellular immunotherapy, and resistance mechanisms have reshaped the treatment paradigm, while landmark developments in China’s MCL research framework and guidelines underscore the country’s growing role in driving global progress. These advancements bring hope for more effective, personalized, and precise treatments, setting the stage for improved outcomes and quality of life for MCL patients.