The 29th Annual Meeting of the European Hematology Association (EHA) was held from June 13-16, 2024, in Madrid, Spain. As the largest international conference in the field of hematology in Europe, it attracts numerous renowned experts and scholars each year to share and discuss innovative concepts, the latest scientific research, and clinical study results in hematology. At this year's meeting, several research findings from Professor Huilai Zhang's team at Tianjin Medical University Cancer Institute & Hospital were selected. To gain a deeper understanding of the latest research progress in the field of lymphoma, "Oncology Frontier - Hematology Frontier" has invited Professor Lihua Qiu from the same team for an in-depth interpretation.

Oncology Frontier – Hematology Frontier: Can you first introduce the main results and clinical significance of the study on “Epidemiological Characteristics and Prognosis of Primary Gastrointestinal Follicular Lymphoma” (P1136)?

Professor Lihua Qiu:Primary Gastrointestinal Follicular Lymphoma (PGI-FL) is a rare type of extranodal follicular lymphoma. This disease is typically localized and exhibits indolent biological behavior, but there is currently no standardized treatment regimen. This study is based on the U.S. SEER database, a large multicenter population data repository, combined with relevant data from China, providing valuable materials for analysis and summary. Through this study, we have gained profound insights into the biological behavior and prognostic factors of PGI-FL, offering important support and data for exploring optimal treatment models.

The study shows that the incidence of PGI-FL is very low, with an age-adjusted annual incidence rate of 0.111 per 100,000, and the incidence has been increasing annually. This trend is evident in both male and female patients, although the incidence is slightly higher in males. Age distribution shows that the number of patients over 60 years old is significantly higher than those under 60. In terms of primary sites, the small intestine has a significantly higher incidence than the colon and stomach.

Using Cox regression models in univariate and multivariate analyses, we analyzed factors related to survival. The results show that age, gender, grade, Ann Arbor stage, primary site, and radiotherapy are independent prognostic factors (P<0.05). Further, based on the results of multivariate analysis, we constructed nomograms for 1-year, 5-year, and 10-year OS and DSS. Based on the scores generated from the OS nomogram, patients were classified into low-risk, medium-risk, and high-risk groups. These results not only help identify high-risk patients but also provide an important basis for further patient screening and individualized treatment planning.

In conclusion, this study reveals the trend of increasing incidence of PGI-FL over the past 40 years, emphasizing the importance of diagnosis and treatment of PGI-FL by clinicians. Compared to nodal follicular lymphoma, PGI-FL has a better prognosis, with most cases showing indolent progression and a lower likelihood of transformation into diffuse large B-cell lymphoma. The study also identifies independent prognostic factors and categorizes patients into different risk levels based on these factors, providing strong support for clinical treatment. As research on PGI-FL continues to deepen, we are confident that more precise and effective diagnostic and treatment plans will be available to help patients overcome the disease and regain confidence in life.

Oncology Frontier – Hematology Frontier: Another POLARIS study (P1141) showcases the positive results of obinutuzumab combined with lenalidomide and rituximab in untreated mantle cell lymphoma (MCL) patients. What do you think of the potential and application prospects of this triplet therapy in the future treatment of MCL?

Professor Lihua Qiu: Mantle cell lymphoma (MCL) has been considered a low-grade but highly progressive disease with poor prognosis, with a median survival time of about 3 to 5 years. However, with the development of treatment methods, especially the introduction of CD20 monoclonal antibodies, medium- to high-dose cytarabine, and autologous hematopoietic stem cell transplantation, the survival time of MCL patients has significantly extended to more than 10 years. Despite this, the toxicity, accessibility, and suitability of these treatment methods limit their widespread clinical application.

In recent years, Bruton tyrosine kinase inhibitors (BTKi) like ibrutinib have shown an efficacy rate of about 68% in relapsed/refractory MCL, marking a new era in MCL treatment. The research and application of new-generation BTKi currently present two main trends. First, the development of second-generation BTKi focuses on improving drug efficacy and safety to achieve high efficiency with low toxicity. Second, BTKi combination therapy strategies are becoming a research focus. These combination therapies aim to enhance treatment efficacy while reducing side effects, moving towards a chemo-free treatment model. In combination regimens, traditional medium- to high-dose cytarabine has been replaced with drugs like lenalidomide, rituximab, and BCL-2 inhibitors. The advantage of these comprehensive treatment regimens is that they not only improve treatment efficacy and reduce toxicity but also show significant efficacy in MCL subtypes with poor chemotherapy response, such as those with TP53 mutations.

Second-generation BTKi like acalabrutinib, zanubrutinib, and domestic orelabrutinib have shown high efficiency and low toxicity, further improving the safety and efficacy of MCL treatment.

Orelabrutinib combined with rituximab has been proven to synergistically enhance NK cell-mediated ADCC and promote tumor apoptosis. The treatment regimen of orelabrutinib combined with lenalidomide and rituximab (OLR), as a first-line treatment for untreated MCL patients, has shown significant efficacy and good tolerance in the POLARIS study. As of February 15, 2024, data cutoff, 96.6% of the 29 patients completed six cycles of induction therapy, with 67.9% achieving complete remission (CR) and an overall response rate (ORR) of 85.8%. Additionally, using NGS to detect circulating tumor DNA (ctDNA) in peripheral blood to assess tumor depth of response can help predict prognosis. Lower ctDNA levels indicate fewer residual tumors, suggesting a better prognosis and potential for cure. In 25 MRD analyses, both peripheral blood MRD (PB-MRD) and bone marrow MRD (BM-MRD) were negative. Regarding safety, 96.6% of the 28 patients experienced adverse events, mainly hematologic toxicity, but no deaths were reported. These data indicate that the orelabrutinib combination regimen shows potential in improving response rates while maintaining treatment safety.

Therefore, the results of the POLARIS study confirm the efficacy and safety of the orelabrutinib combination regimen in untreated MCL patients, providing strong evidence for the clinical application of chemo-free treatment regimens. As research on MCL treatment continues and new drugs emerge, we look forward to offering more treatment options and better prognoses for MCL patients.

Oncology Frontier – Hematology Frontier: The P1226 study shows that CD58 gene mutations regulate PD-L1 and IDO through the LYN/CD22/SHP1 axis, impacting antitumor immune responses in diffuse large B-cell lymphoma (DLBCL). Can you interpret this study and its implications for future immunotherapy strategies?

Professor Lihua Qiu: DLBCL is an aggressive hematologic malignancy whose treatment response and patient prognosis are influenced by various factors. This study shows that CD58 gene variations play a critical role in DLBCL, providing a new perspective for individualized treatment of DLBCL.

The study, through an in-depth analysis of CD58’s genetic characteristics, revealed that its mutation rate in DLBCL is 9.1%, with a copy number loss rate of 44.7%. These variations are closely associated with reduced response rates to first-line immunochemotherapy (R-CHOP), shorter progression-free survival (PFS), and overall survival (OS). More importantly, the study found that the downregulation or mutation of CD58 regulates the expression of PD-L1 and IDO through the LYN/CD22/SHP1 axis, promoting tumor cell immune escape and reducing sensitivity to CAR-T cell therapy.

This study not only elucidates a new mechanism by which CD58 impacts antitumor immune responses in DLBCL but also explores potential therapeutic strategies, such as direct activation of CD2 co-stimulatory signals or combination with immune checkpoint inhibitors. These strategies may reverse the immunosuppressive effects caused by CD58 downregulation or mutations, restore T cell proliferation ability, and enhance the efficacy of CAR-T cell therapy. As our understanding of the molecular mechanisms in DLBCL deepens, more patients will likely benefit from precise and individualized medical care, achieving better treatment outcomes and quality of life.