On July 20, the 5th Lymphoma & Myeloma Immunotherapy and Targeted Therapy Conference, along with the Gaobo Medical Academic Conference, was successfully held in Beijing. With the core concepts of "Precision, Integration, Innovation," the conference closely followed the latest developments and frontier topics from the 29th European Hematology Association (EHA 2024) and the 2024 American Society of Clinical Oncology (ASCO) annual meetings. To deepen the exchange and discussion, Oncology Frontier - Hematology Frontier invited Dr. Jihao Zhou from Shenzhen People's Hospital for an exclusive interview to discuss advancements in the field and share academic insights.

Oncology Frontier – Hematology Frontier: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoma originating from follicular helper T-cells (TFH) and is clinically challenging to diagnose. Could you first introduce the epidemiology, pathogenesis, and pathological characteristics of AITL?

Dr. Jihao Zhou: AITL is generally considered a relatively rare subtype of lymphoma, accounting for about 14% of all peripheral T-cell lymphomas and only 1-2% of all non-Hodgkin lymphomas. AITL originates from follicular helper T-cells, with high mutation frequencies in genes such as TET2, IDH2, and DNMT3A. Clinically, it typically presents with widespread peripheral lymphadenopathy, often accompanied by B symptoms like fever, night sweats, and weight loss. Extracellular manifestations, including rashes and hepatosplenomegaly, are also common, and bone marrow involvement frequently occurs.

Pathologically, AITL has distinctive features. Morphologically, it can exhibit Reed-Sternberg-like large cells, and the tumor cells display characteristics similar to Hodgkin lymphoma. Immunohistochemically, AITL primarily arises from CD4+ T-cells originating from the germinal center of lymphoid follicles, expressing markers such as CD10 and Bcl-6, typical of germinal center T-cells. These markers aid in distinguishing AITL from other types of T-cell lymphomas. Additionally, AITL exhibits markers of follicular helper T-cells, such as CXCL-13, ICOS, and PD-1, making AITL unique in both morphology and immunohistochemistry.

In molecular genetics, AITL shows a series of genetic features related to disease progression. Specifically, AITL is associated with gene mutations related to DNA methylation, often accompanied by RHOA gene mutations. Moreover, T-cells in AITL patients may have other functional gene mutations affecting T-cell development, differentiation, and immune response. Therefore, the treatment and management of AITL require careful consideration of its molecular genetic background to formulate more precise therapeutic strategies.

Oncology Frontier – Hematology Frontier: Clinically, AITL is often associated with autoimmune diseases. Could you explain the reasons behind this?

Dr. Jihao Zhou: The pathological characteristics of AITL involve dysregulation of follicular helper T-cells (TFH). TFH cells play a crucial role in normal immune responses, located in the germinal centers of lymphoid follicles, where they interact with B-cells to promote their proliferation, differentiation, and antibody production. Therefore, abnormal TFH cells in AITL patients may lead to B-cell dysfunction, causing various autoimmune disorder symptoms.

Clinically, AITL patients often exhibit typical autoimmune disease-related symptoms, such as rashes, fever, and joint pain. Immunologically, AITL patients may show hypergammaglobulinemia, positive Coomb’s test, and positive reactions for multiple rheumatologic autoantibodies. These characteristic manifestations indicate abnormal immune activation and regulatory imbalance. Furthermore, AITL has a significant association with certain viral infections, particularly Epstein-Barr Virus (EBV) infection, which may exacerbate immune system dysregulation by affecting T-cell and B-cell interactions. Hence, the clinical and laboratory findings in AITL patients not only reflect T-cell abnormalities but also highlight the important role of B-cells in the disease pathology.

In summary, AITL is a complex lymphoid malignancy involving intricate interactions between T-cells and B-cells and disruptions in their regulatory mechanisms within the immune system. This dysregulation impacts normal lymphocyte functions and can trigger a range of autoimmune disease symptoms, severely affecting the patient’s health.

Oncology Frontier – Hematology Frontier: Could you provide an overview of the current treatment landscape for first-line and relapsed/refractory AITL, as well as significant advancements in this area?

Dr. Jihao Zhou: Although AITL is not the most common type of lymphoma, its unique pathological characteristics and clinical presentations make it a focal point of research. Despite a deeper understanding of AITL’s biological properties and molecular mechanisms, treatment strategies still face numerous challenges. In first-line treatment, the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) based on anthracyclines remains the mainstay therapy. However, real-world studies indicate that the efficacy of the CHOP regimen is suboptimal. Clinically, efforts are being made to combine new drugs with the CHOP regimen (CHOP+X regimen), but so far, the improvement in efficacy has been limited. Autologous hematopoietic stem cell transplantation (Auto-HSCT) is considered a standard consolidation therapy in first-line treatment for AITL.

When AITL progresses to relapsed or refractory stages, treatment becomes significantly more challenging. Beyond traditional chemotherapy regimens, there have been no major breakthrough advancements. Nevertheless, the emergence of new drugs brings new hope for AITL treatment. In treating relapsed/refractory AITL, new drugs mainly focus on three areas: immunotherapy drugs, epigenetic drugs, and signal transduction pathway inhibitors. Immunotherapy drugs, such as CD30 monoclonal antibodies and immune checkpoint inhibitors (e.g., PD-1/PD-L1 monoclonal antibodies), enhance the immune system’s ability to attack tumor cells. Epigenetic drugs, such as azacitidine and decitabine, or histone deacetylase inhibitors (HDACi) like chidamide, inhibit tumor cell growth and proliferation by altering the epigenetic state of tumor cells. Signal transduction pathway inhibitors, such as PI3K inhibitors and JAK-STAT pathway inhibitors, inhibit tumor cell proliferation and survival by blocking intracellular signaling pathways. Although these new drugs show preliminary efficacy, developing effective treatment strategies by rationally combining these drugs remains an area for further exploration.

For patients difficult to cure, allogeneic hematopoietic stem cell transplantation (Allo-HSCT) may be a potential treatment option, warranting further research and discussion. Overall, while AITL treatment faces many challenges, the continuous emergence of new drugs and optimization of treatment strategies offer hope for more effective and personalized therapies for AITL patients in the future.

Dr. Jihao Zhou

• Chief Physician, Ph.D./Postdoc, Master’s Supervisor
• Head of Hematology, Shenzhen People’s Hospital
• Member of the Hematology Committee and Vice Chairman of the Youth Committee, Guangdong Medical Association
• Member of the Hematology Medication Expert Committee, Guangdong Pharmaceutical Association
• Vice Chairman of the Youth Committee, Blood Rehabilitation Division, Chinese Anti-Cancer Association
• Vice Chairman of the Youth Committee, Precision Diagnosis and Treatment Division of Hematological Diseases, Chinese Research Hospital Association
• Standing Committee Member, Shenzhen Hematology Association
• Standing Director and Secretary, Hematology Division, Shenzhen Medical Doctor Association
• High-level talent of Shenzhen, Young Post Expert of Shenzhen Medical Management Center, Top Ten Outstanding Young Doctors of Shenzhen, First Batch of Outstanding Young Medical Talents of Guangdong Province
• Principal investigator for projects funded by the National Natural Science Foundation, China Postdoctoral Science Foundation, Shenzhen Science and Technology Innovation Committee, and participant in several national, provincial, and municipal projects. Published over 20 academic papers.