On July 20, 2024, the 5th Lymphoma & Myeloma Immunotherapy and Targeted Therapy Conference, part of the Gaobo Medical Academic Conference, was successfully held in Beijing. With the core themes of "Precision, Integration, and Innovation," the conference closely followed the latest developments and cutting-edge topics from the 29th Annual Congress of the European Hematology Association (EHA 2024) and the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. During the event, Dr. Kai Fu from Roswell Park Comprehensive Cancer Center delivered an insightful presentation on "Progress Reports From the Northern American MCL Consortium." In an exclusive interview with Hematology Frontier, Professor Fu discussed the research progress of the North American Mantle Cell Lymphoma Program (NAMCLP) and the significance of a novel prognostic model for mantle cell lymphoma (MCL). The following is a summary of the interview.Hematology Frontier: Could you provide an update on the latest developments in the North American Mantle Cell Lymphoma Program?
Dr. Kai Fu: In recent years, the North American Mantle Cell Lymphoma Consortium has made significant progress in various clinical studies. Our team has been involved in the research projects of the consortium and has collected data on the diagnosis and treatment of 800-900 MCL patients. Comparative analysis has revealed a significant improvement in the median overall survival (mOS) of MCL patients over the past 10-20 years. Statistics from the consortium indicate that the 3-5 year survival rates for MCL patients around 2004 were approximately 30-50%, with an mOS of around three years. However, survival data post-2010-2012 show significant improvement. A study conducted by NAMCLP, which included 586 MCL patients, demonstrated a 5-year survival rate of 64%, with an mOS of 7-8 years and a 3-year progression-free survival (PFS) rate of 52%. Notably, younger MCL patients (<65 years) had a survival advantage compared to older patients (≥65 years), with 5-year OS rates of 78% versus 48% and 3-year PFS rates of 64% versus 38%, respectively.
The effectiveness of MCL treatment has improved significantly in recent years, mainly due to advances in understanding the pathogenesis of MCL, breakthroughs in basic research, and the development of immuno-targeted therapies such as CAR-T. Additionally, the application of hematopoietic stem cell transplantation (HSCT) has greatly improved the OS and PFS of MCL patients. Overall, the increasing variety of treatment options has led to significant improvements in treatment outcomes and prognosis. Compared to Western countries, there is still some disparity in the precision diagnosis and treatment of MCL in China, which needs further standardization. However, China’s progress in CAR-T therapy is impressive and unmatched by other countries.
Hematology Frontier: Can you discuss the significant advancements made by the North American Mantle Cell Lymphoma Consortium in establishing prognostic models and treatments for MCL in recent years?
Dr. Kai Fu: The North American Mantle Cell Lymphoma Consortium, established in 2010 at the University of Nebraska Medical Center, is a collaborative project involving 23 medical centers across North America. The consortium has collected approximately 1,000 MCL cases and conducted a series of clinical and pathological studies. Research has shown that TP53 mutations significantly impact the OS and PFS of MCL patients. One study explored the relationship between P53 scores and MCL patient outcomes, revealing that patients with a P53 score of 90 or above had significantly worse OS and PFS.
Building on previous research, our team has proposed a new approach to MCL prognostic evaluation, establishing a novel prognostic model based on TP53 gene expression (see figure below). This research was published last year in the Journal of Hematology & Oncology. This year, we conducted further studies, performing whole-genome sequencing on case samples. The results indicated that TP53 mutations and deletions have a significant impact on MCL prognosis. TP53 mutations further activate and enhance signaling in the B-cell receptor (BCR) pathway, which may reduce the efficacy of BTK inhibitors (BTKi). Therefore, when encountering MCL patients with poor BTKi response, clinicians should consider the possibility of TP53 mutations. Overall, our MCL prognostic research has the following value: (1) It established the North American Mantle Cell Lymphoma Prognostic Index (NAMPI), a new prognostic index for MCL, which can be used in clinical management. (2) This model further confirms the significant impact of TP53 inactivation on the clinical efficacy and prognosis of MCL patients. (3) Through next-generation sequencing, we can classify MCL into seven subtypes, with the C2 subtype (TP53 inactivation) characterized by reduced TP53 expression, significant activation of the BCR signaling pathway, and upregulation of NF-kB and DNA repair signaling pathways, which is crucial for MCL clinical treatment and prognostic evaluation.
Hematology Frontier: Do you believe this prognostic model is suitable for assessing the prognosis of Chinese MCL patients?
Dr. Kai Fu: The majority of MCL patients included in the North American Mantle Cell Lymphoma Program (NAMCLP) are Caucasians, with less than 5% being Asian. Therefore, whether this prognostic model applies to Chinese MCL patients requires further investigation. However, the fundamental principle of the model remains the same: the inactivation of TP53 mutations significantly impacts MCL treatment outcomes and prognosis.
