Prospective Study of Immune Function and PD-1 Antibody Therapy Efficacy Predictors on CAEBV and EBV-HLH Patients

Study Overview
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Brief Summary
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This prospective case-control study aims to evaluate the immune function and find PD-1 antibody efficacy predictors on Chronic Active Epstein-Barr Virus Infection and Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis by detecting lymphocyte subsets proportions in peripheral blood mononuclear cells and the positive proportion of PD-1, PD-L1 and other indicators in each lymphocyte subsets in healthy people and patients using flow cytometry before and after the initial PD-1 therapy.

Official Title
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A Prospective Study of Immune Function and PD-1 Antibody Therapy Efficacy Predictors for Chronic Active Epstein-Barr Virus Infection and Epstein-Barr Virus Associated Hemophagocytic Lymphohistiocytosis

Conditions
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Secondary Hemophagocytic Lymphohistiocytosis, Chronic Active Epstein-Barr Virus Infection

Intervention / Treatment
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* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet the diagnostic criteria of EBV-HLH or CAEBV (except B lymphocytes involvement only) after the detection of EBV lymphocyte subsets. EBV-HLH diagnostic criteria: Meet hemophagocytic lymphohistiocytosis (HLH)-04 diagnostic criteria; EBV-DNA in peripheral blood or EBER in tissue were positive, patients were diagnosed with EBV associated HLH (EBV-HLH). CAEBV diagnostic criteria: (1) persistent or recurrent infectious mononucleosis-like symptoms persisting for more than 3 months; (2) EBV-DNA quantitative increase in peripheral blood or tissue lesions; (3) exclusion of other possible Diagnosis, such as primary Epstein-Barr virus infection (infectious mononucleosis), autoimmune disease, congenital immunodeficiency, human immunodeficiency virus (HIV) infection, or other underlying conditions requiring immunosuppressive therapy or underlying immunosuppression. Before the start of the study, total bilirubin ≤10 times the upper limit of normal, serum creatinine ≤1.5 times the normal value; fibrinogen can be corrected to ≥0.6g/L after infusion. Serum HIV antigen or antibody negative. HCV antibody negative, or HCV antibody positive, but HCV RNA negative. HBV surface antigen and HBV core antibody are both negative. If any of the above is positive, peripheral blood hepatitis B virus DNA titer detection is required, and the number of copies less than 1×103 copies/ml can be included in the group. LVEF ≥ 50% by cardiac echocardiography. Women of childbearing age must be confirmed by a pregnancy test that they are not pregnant, and are willing to take effective contraceptive measures during the test period and within ≥ 12 months after the last dose. Women during pregnancy and lactation cannot participate. Contraceptive measures should be taken during the test period and within ≥3 months after the last dose. Informed consent obtained. Exclusion Criteria: According to the New York Heart Association (NYHA) score, patients with heart disease of grade II or above (including grade II); Pregnant or lactating women and patients of childbearing age who refused to take appropriate contraceptive measures during this trial. Those who are allergic to rituximab ingredients or have more severe allergic constitution; Severe hypogammaglobulinemia. Active massive hemorrhage of internal organs (including gastrointestinal hemorrhage, alveolar hemorrhage, intracranial hemorrhage, etc.); Uncontrolled active infection (including lung infection, intestinal infection, etc.); HBV surface antigen and/or HBV core antibody are positive, and the peripheral blood hepatitis B virus DNA test confirms the existence of active hepatitis B patients. Severe mental illness; Patients who were not compliant during the trial and/or follow-up period. Concurrently participate in other clinical investigators.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Control<br>Healthy male or female aged 2-80 years with negative EBV-DNA quantitative test results within the last week. | Other: No intervention<br>* No intervention<br>|
| CAEBV or EBV-HLH Patients<br>Patients aged 2-80 years who fulfilled the diagnostic criteria for CAEBV or EBV-HLH. The diagnostic criteria for CAEBV as defined in the recently revised World Health Organization classification include persistent IM-like symptoms for more than three months, increased EBV DNA (>10^2.5 copies/mg) in peripheral blood, histological evidence of organ disease, and EBV RNA or viral protein in affected tissues. Patients diagnosed with EBV-HLH must meet five of the following eight HLH-2004 diagnostic criteria: temperature 38.5 ℃ and above; splenomegaly; two or three lines of hemocytopenia, i.e. hemoglobin (HB) <90 g/L, platelets (PLT) <100 × 10^9/L or neutrophils (N) <1 × 10^9/L; triacylglycerol (TG) ≥ 3 mmol/ L or fibrinogen (Fbg) <1.5 g/L; serum ferritin (SF) ≥ 500 mg/L; phagocytosis found in bone marrow, spleen, liver or lymph nodes; soluble CD25 (sCD25) ≥ 2400 U/mL; low or absent natural killer (NK) cell activity. | Other: No intervention<br>* No intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EBV-DNA | Treatment effectiveness is defined: EBV-DNA copies/ml in peripheral blood turns negative, and the involved tissues (such as lymph nodes, bone marrow, skin, etc.) are negative in EBER test or the EBV copy number has decreased by more than 2 orders of magnitude, but it is still positive. | Change from before and 2 weeks after initiating PD-1 blockade therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAEBV Evaluation of treatment response | Complete response (CR) was defined as EBV-DNA copy number below the lower limit of detection (<5.0×10^2 copies/ml) for at least 4 weeks. Partial response (PR) was defined as ≤ 1/100 reduction in EBV-DNA copy number, and the CR criterion was not met. Failure to achieve at least PR was defined as no response (NR). Besides, the main clinical manifestation of CAEBV, including fever, asthenia, liver damage (elevation of ALT and AST), skin rash, cytopenia and lymphadenopathy was also evaluated. | Change from before and 2 weeks after initiating PD-1 blockade therapy. | 
| EBV-HLH Evaluation of treatment response | A complete response (CR) was defined as normalization of all of the quantifiable symptoms and laboratory markers of HLH, including levels of sCD25, ferritin, and triglyceride; hemoglobin; neutrophil counts; platelet counts; and alanine aminotransferase (ALT). A partial response (PR) was defined as at least a 25% improvement in 2 or more quantifiable symptoms and laboratory markers as follows: sCD25 response was>1.5-fold decreased; ferritin and triglyceride decreased at least 25%; for patients with an initial neutrophil count of<0.5 ×10^9/L, a response was defined as an increase by at least 100% to>0.5×10^9/L; for patients with a neutrophil count of 0.5 to 2.0× 109/L, an increase by at least 100% to >2.0 × 10^9/L was considered a response; and for patients with ALT >400 U/L, response was defined as an ALT decrease of at least 50%. | Change from before and 2 weeks after initiating PD-1 blockade therapy. | 
| Progression Free Survival | from date of inclusion to date of progression, relapse, or death from any cause | 6 months |