On July 20, 2024, 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. Li Bao from Beijing Jishuitan Hospital for an exclusive interview to discuss advancements in the field and share academic insights.

Oncology Frontier – Hematology Frontier: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory syndrome caused by genetic or acquired immune dysregulation, with a relatively high diagnostic difficulty and risk of misdiagnosis. Could you first discuss the current clinical diagnostic pathways for HLH?

Dr. Li Bao: Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic lymphohistiocytosis (HLH), is a severe inflammatory syndrome caused by genetic or acquired immune dysregulation. The main clinical features include fever, cytopenia, hepatosplenomegaly, and hemophagocytosis in the liver, spleen, lymph nodes, and bone marrow. The widely adopted diagnostic criteria for HLH are from the revised version by the Histiocyte Society in 2004. HLH can be diagnosed if any of the following conditions are met:

1. Molecular diagnosis consistent with HLH, showing pathogenic mutations in known HLH-related genes such as PRF1, UNC13D, STX11, STXBP2, Rab27a, LYST, SH2D1A, BIRC4, ITK, AP3β1, MAGT1, CD27, etc.
2. Fulfillment of at least five of the following eight criteria: Fever: temperature >38.5℃ for more than 7 days Splenomegaly Cytopenia involving at least two of three lineages in peripheral blood: hemoglobin <90 g/L (or <100 g/L in infants under 4 weeks), platelets <100×10^9/L, neutrophils <1.0×10^9/L not due to bone marrow hypoplasia Hypertriglyceridemia and/or hypofibrinogenemia: triglycerides >3 mmol/L or >3 standard deviations above normal for age, fibrinogen <1.5 g/L or below 3 standard deviations for age Hemophagocytosis in bone marrow, spleen, liver, or lymph nodes Decreased or absent NK cell activity Elevated ferritin: ferritin ≥500 μg/L Elevated sCD25 (soluble IL-2 receptor)

While there is a clear set of diagnostic criteria for HLH, the core clinical challenge lies in understanding the underlying pathogenesis. For instance, if a patient presents with fever, splenomegaly, and cytopenia in two or three blood cell lines, accompanied by elevated ferritin, hypertriglyceridemia, or hypofibrinogenemia, they likely meet the diagnostic criteria for HLH. However, the critical aspect in clinical practice is identifying the root cause of HLH, including infections, immune disorders, or hematologic malignancies, or determining if it is a primary disease.

Secondary HLH is an inflammatory syndrome triggered by factors such as tumors, rheumatic immune diseases, and infections. For patients who do not test positive for known HLH-related pathogenic genes and have no clear secondary cause, they are temporarily classified as having idiopathic HLH, requiring ongoing investigation into the primary cause during treatment and follow-up. Primary HLH is caused by genetic defects in lymphocyte cytotoxic function or inflammation-related genes and includes familial HLH, immunodeficiency syndrome-related HLH, X-linked lymphoproliferative disease, and EBV-driven HLH.

Current guidelines and pathways provide clinicians with a clear diagnostic framework, enabling systematic diagnosis in the face of complex and diverse clinical manifestations, ensuring each suspected case is thoroughly and comprehensively evaluated. Adhering to standardized guidelines and clinical diagnostic pathways can significantly reduce the risk of misdiagnosis and missed diagnosis, improving diagnostic accuracy and efficiency. Through standardized procedures, clinicians can quickly gather crucial diagnostic information, including patient history, family history, clinical symptoms, and necessary laboratory and imaging results. This approach not only enhances the accuracy of initial diagnoses and reduces unnecessary repeated tests and treatment delays but also provides timely and effective treatment plans for patients, improving their prognosis. Therefore, the use of standardized diagnostic processes is crucial for improving the overall diagnostic and treatment standards for HLH.

Oncology Frontier – Hematology Frontier: After confirming an HLH diagnosis, could you discuss the current guideline-recommended first-line and salvage treatment strategies? What are the recent significant advances in HLH treatment?

Dr. Li Bao: Before treatment, the primary step is to confirm the HLH diagnosis and then determine its cause. Given the impact of different causes on treatment strategies, clinicians need to develop personalized treatment plans for each patient. For non-genetic and idiopathic HLH patients, corticosteroids and intravenous immunoglobulin (IVIG) might be appropriate. If the cause is a viral infection, such as EBV infection, the treatment should be adjusted based on the type of infected cells (e.g., T-cells or B-cells). If the cause is lymphoma, the HLH-94 regimen combined with chemotherapy may be used. For HLH caused by rheumatic immune diseases, high-dose corticosteroids are recommended to treat the underlying condition.

Historically, the HLH-94 regimen (etoposide + dexamethasone) has been widely used as a treatment strategy, playing a critical role. However, with ongoing medical research and advancements, recent discoveries have shown that JAK inhibitors like ruxolitinib have significant efficacy in treating HLH. The advantage of this new treatment method is that patients can receive oral medication at relatively low doses while achieving satisfactory results. This breakthrough brings great hope to patients, as it allows them to avoid the discomfort and pain associated with chemotherapy. Overall, new therapeutic drugs like ruxolitinib, with their unique administration mechanisms and significant efficacy, are gradually reshaping the HLH treatment landscape, leading to profound changes in treatment paradigms.

Oncology Frontier – Hematology Frontier: Hemophagocytic syndrome related to CAR-T cell infusion is common among patient populations and CAR-T cell constructs. Could you discuss the severity grading and clinical treatment strategies for this type of HLH?

Dr. Li Bao: Following CAR-T therapy, patients may face various complications, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Notably, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) occurring after CAR-T therapy is classified separately. Its characteristics include abnormal activation of macrophages and lymphocytes, significant elevation of inflammatory cytokines, lymphocyte tissue infiltration, and immune-mediated multi-organ dysfunction. Therefore, treatment strategies for this condition must consider both HLH remission and the regulation of post-CAR-T therapy inflammatory responses. In such cases, corticosteroids and tocilizumab are appropriate treatment choices, while the combined use of ruxolitinib may further enhance therapeutic outcomes.

CRS grading consists of four levels: Grade 1 CRS may only present with fever and mild inflammatory responses without hemodynamic changes. When CRS progresses to Grade 2, it may involve mild hypotension and hypoxia, requiring treatment with tocilizumab or corticosteroids. Grade 3 CRS shows further exacerbation of hypotension and hypoxia, potentially necessitating high-flow oxygen or vasopressor intervention. Grade 4 CRS may require more complex treatments, including mechanical ventilation. Therefore, treatment strategies should be adjusted stepwise based on CRS severity. When clear signs of HLH transformation are observed post-CAR-T therapy, in addition to corticosteroids and tocilizumab, ruxolitinib should be administered promptly, combined with other strong symptomatic treatments to ensure timely and effective patient care.

Dr. Li Bao

• Director of the Department of Hematology, Beijing Jishuitan Hospital, Capital Medical University
• Chief Physician
• Chairman of the Translational Medicine Professional Committee, China Medical Education Association
• Chairman of the Hematology Professional Committee, Beijing Perioperative Medicine Research Association
• Chairman of the Hematology Professional Committee, Beijing Chronic Disease Prevention and Health Education Research Association
• Member of the Expert Database in the Medical and Health Field, Beijing Municipal Science and Technology Commission