The 29th European Hematology Association (EHA) Annual Meeting was grandly held in Madrid, Spain, from June 13-16, 2024. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from around the world every year to share and discuss innovative ideas and the latest scientific and clinical research findings in hematology. At this year's EHA conference, multiple studies led by Professor Huilai Zhang from Tianjin Medical University Cancer Institute & Hospital were selected for Poster presentations, covering both clinical and basic research on lymphoma. "Oncology Frontier - Hematology Frontier" conducted an on-site interview with team member Professor Shiyong Zhou to provide in-depth commentary on these studies.Oncology Frontier – Hematology Frontier: Could you talk about your team’s research on the epidemiological characteristics and prognosis of primary gastrointestinal follicular lymphoma (PGI-FL) presented at this EHA meeting (abstract P1136)?
Professor Shiyong Zhou: Primary gastrointestinal follicular lymphoma (PGI-FL) is a relatively rare disease. However, with the advancement of medical technology, especially endoscopic techniques and equipment, PGI-FL is being increasingly discovered and reported. Compared to nodal FL (N-FL), PGI-FL has the same immunohistochemical characteristics and hallmark t(14;18) translocation but often presents as localized lesions with indolent behavior. Furthermore, histological transformation (HT), which is associated with poor prognosis in FL, is extremely rare in PGI-FL, with only a few cases reported to date. Due to its low incidence, most PGI-FL studies have been case reports and retrospective studies with small cohorts, and long-term outcomes remain unclear.
Given this background, Professor Huilai Zhang’s team conducted the largest PGI-FL study to date. Given the rarity of PGI-FL, there is limited data on its incidence, clinical characteristics, and survival. Our team conducted a retrospective study based on the SEER database to analyze epidemiological trends and establish a prognostic nomogram to assist in accurate prognosis assessment. Over the past 40 years, the incidence of PGI-FL has been on the rise, but its prognosis is relatively better compared to FL, with a lower transformation rate to large B-cell lymphoma (LBCL). We validated and predicted outcomes using the established nomogram. To further verify the feasibility of this predictive model, we stratified PGI-FL patients in the training cohort into low, medium, and high-risk groups based on OS nomogram scores, which can help clinicians identify high-risk PGI-FL and select the best individualized treatment plans.
Oncology Frontier – Hematology Frontier: The POLARIS study (abstract P1141) explored the application of orelabrutinib combined with lenalidomide and rituximab in the treatment of newly diagnosed mantle cell lymphoma (MCL). Could you comment on the prospects of this triplet therapy in MCL treatment?
Professor Shiyong Zhou: The POLARIS study, led by Professor Huilai Zhang, is a single-arm, multicenter, open-label phase II clinical trial aimed at exploring the efficacy and safety of the combination of orelabrutinib, lenalidomide, and rituximab in the treatment of newly diagnosed mantle cell lymphoma (MCL). MCL, a type of non-Hodgkin lymphoma (NHL) originating from the mantle zone of lymph nodes, accounts for about 2-10% of NHL cases. In the past decade, significant progress has been made in MCL treatment through high-dose chemotherapy, immunotherapy, and targeted drug combinations. However, traditional chemotherapy has significant toxicity and cannot meet the treatment needs of patients with high mIPI scores, high KI-67 proliferation indices, TP53 gene mutations, and high-grade histology.
In recent years, the development of new drugs has brought new directions for MCL treatment. Orelabrutinib, a new BTK inhibitor with higher kinase selectivity, has been approved in China for the treatment of various lymphomas. Clinical studies have shown that orelabrutinib can precisely target BTK and synergize with CD20 monoclonal antibodies to exert antitumor effects. Based on this, our study explored the efficacy and safety of the combination of orelabrutinib, lenalidomide, and rituximab in the treatment of newly diagnosed MCL. Preliminary data from 28 patients showed an overall response rate (ORR) of 100% and a complete response rate (CR) of 76.2%, with median duration of response (mDOR) and progression-free survival (mPFS) not yet reached. After induction therapy, minimal residual disease (MRD) in bone marrow and peripheral blood was negative. Additionally, this triplet therapy demonstrated good safety, with common adverse events (AEs) being hematologic toxicities. This triplet regimen balances excellent efficacy and good safety, offering more MCL patients a chance for a cure in first-line treatment.
Oncology Frontier – Hematology Frontier: In the POLARIS study, NGS-based ctDNA detection in peripheral blood was used as an exploratory endpoint for prognosis assessment. Is this detection method significantly associated with the survival of MCL patients?
Professor Shiyong Zhou: Based on the POLARIS study results, we summarized and explored the application of NGS-based ctDNA detection in peripheral blood as a practical prognosis assessment and monitoring technique for MCL patients. Preliminary results showed that high levels of ctDNA in peripheral blood were significantly associated with poor prognosis in MCL patients. ctDNA positivity independently predicted poor prognosis, and peripheral blood ctDNA detection helped identify treatment failure and disease progression earlier. Follow-up data indicated that MCL patients with positive ctDNA had significantly shorter median PFS and overall survival (OS) compared to ctDNA-negative patients. The POLARIS study preliminarily validated the significant association between peripheral blood ctDNA levels detected by NGS and the survival of MCL patients. However, larger sample sizes and longer follow-up times in prospective studies are needed to further confirm this. In summary, the POLARIS study suggests that peripheral blood ctDNA detection could be a promising biomarker for prognosis assessment in MCL patients, but more follow-up research is required to clarify its role.
Oncology Frontier – Hematology Frontier: Another study (abstract P1226) showed that CD58 gene mutations regulate the expression of PD-L1 and IDO through the LYN/CD22/SHP1 axis, affecting antitumor effects in diffuse large B-cell lymphoma (DLBCL). Could you explain this study?
Professor Shiyong Zhou: This study, another major breakthrough achieved by our team under the leadership of Professor Huilai Zhang, showed that the CD58 gene mutation rate in DLBCL patients reached 9.1%, with copy number deletions around 44.7%. CD58 gene mutations and low expression were significantly associated with reduced response rates to R-CHOP therapy, shorter progression-free survival, and overall survival. Notably, our study discovered a new mechanism by which CD58 gene mutations influence immune evasion in DLBCL. CD58 gene mutations or downregulation regulated PD-L1 and IDO expression through the LYN/CD22/SHP1 axis, leading to immune evasion mediated by multiple pathways and reduced sensitivity of tumor cells to CAR-T cell therapy. Therefore, this study highlights the critical role of CD58 gene mutations in DLBCL, which can influence the efficacy of antitumor treatments and immune evasion through multiple mechanisms, providing a potential target and therapeutic strategy for improving the treatment outcomes and prognosis of DLBCL patients.
