Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

Study Overview
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Brief Summary
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Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by immune-dysregulation characterized by hypercytokinemia, with about 30%-40% of patients suffering death in children. Stratification strategy and individualized treatment is important to improve the survival. In our recent retrospective study, risk stratification based on IL-10 and IFN-γ levels well distinguished patients with different outcomes. In this multicenter prospective study, we will enroll the newly diagnosed pediatric HLH patients and divide them into low, intermediate and high-risk cytokine groups according to IFN-γ and IL-10 levels. The patients'clinical manifestation and laboratory findings will be further evaluated into severe and non-severe groups. For low/intermediate risk and non-severe patients, steroid or ruxolitinib will be used initially; while those with high risk or severe diseases, DXM+VP16±ruxolitinib will be administered. The treatment strategy could be adjusted after evaluation 48-72 hours later.

Detailed Description
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Background and objectives: Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by immune-dysregulation characterized by hypercytokinemia, with about 30%-40% of patients suffering death in children. Early death is an important issue in HLH treatment, which is greatly caused by hypercytokinemia resulting in multi-organ disfunction and partially due to the treatment toxicities. Thus, stratification strategy and individualized treatment is important to improve the survival. In our recent retrospective study which enrolled 256 pediatric patients, the patients were stratified into low, intermediate and high risk according to their IL-10 and IFN-γ levels. The 8-week mortality for low, intermediate and high-risk patients were 5.4±2.4%, 16.9±3.4% and 48.7±8.0%, and the 5-year OS rate were 82.9±40%, 67.0±4.3% and 51.3±8.0%, respectively. This indicated that IFN-γ and IL-10 are helpful for stratifying HLH patients into different risk groups to receive individualized therapies. However, evidence of cytokine application based on multi-center prospective study is still lacking. The aim of this protocol is to establish a model to early identify the patients with low and high mortality and to guide the precise treatment of pediatric HLH. Methods and protocol design: A multicenter prospective study in Asian countries is to be launched for children with HLH. The inclusion criterion is newly diagnosed pediatric HLH patients who has not received steroids or etoposide when enrollment. In this study, the patients are identified as low, intermediate and high-risk cytokine groups according to their cytokine levels: (1) low-risk: IFN-γ<3700pg/mL and IL-10<200pg/mL; (2) intermediate-risk: IFN-γ<3700pg/mL and IL-10≥200pg/mL; (3) high-risk: IFN-γ≥3700pg/mL. The patients' clinical manifestation and laboratory findings were evaluated as well and those fulfill either one of the following criteria were considered as severe: (1) present ≥2 out of 3 ⅰ, albumin<26.0 g/L; ⅱ, direct bilirubin>55.0μmol/L; ⅲ, fibrinogen<0.75g/L. (2) CNS involvement, shock, mechanical ventilation, renal failure. Based on the cytokine risk and disease severity, different intensity of treatment will be started. For low/intermediate risk and not severe patients, steroid or ruxolitinib will be used initially; while those with high risk or severe disease, DXM+VP16±ruxolitinib will be administered. The treatment strategy could be adjusted after evaluation 48-72 hours later based on treatment respose and cytokine levels. A total of 400 pediatric patients under 18 years old are to be recruited. The primary end-point of the study is the 8-week responsive rates and mortality, and one-year overall survival.

Official Title
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Clinical Study on the Treatment of Pediatric Hemophagocytic Lymphohistiocytosis Based on Cytokine Guided Risk Stratification：A Multicenter Randomized Controlled Study

Conditions
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Hemophagocytic Lymphohistiocytoses, Cytokine Storm

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Etoposide
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from one day to 18 years old； Newly diagnosed HLH, fulfilling the HLH criteria; To observed the early diagnosis role of cytokines, patients who is suspected to be HLH and fulfill 3 out of 8 criteria can be pre-enrolled. Exclusion Criteria: treated with steroids or etoposide within 72 hours before diagnosis.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The patients will be divide into different risk groups according to cytokine concentration, clinical manifestation and laboratory findings. For low/intermediate risk and not severe patients, steroid or ruxolitinib will be used initially; while those with high risk or severe disease, DXM+VP16±ruxolitinib will be administered.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-severe DXM group<br>Dexamethasone (DXM): week1-2: 10 mg/m2.d, week 3-4: 5 mg/m2.d, week5-6: 2.5 mg/m2.d, week7: 1.25 mg/m2.d, week8: tapering. | Drug: Dexamethasone<br>* Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group.<br>* Other names: Corticosteroid;|
| Experimental: Non-severe Ruxo group<br>Ruxolitinib(Ruxo): body weight (BW)<10kg: 2.5mg Bid; 10-20kg: 5mg Bid; >20kg: 10mg Bid; Orally for 4 weeks. | Drug: Ruxolitinib<br>* Single drug in non-severe group; combined with etoposide and dexamethasone in severe group.<br>* Other names: JAK1/2 inhibitor;|
| Experimental: Severe HLH-94 group<br>DXM: week1-2: 10 mg/m2.d, week 3-4: 5 mg/m2.d, week5-6: 2.5 mg/m2.d, week7: 1.25 mg/m2.d, week8: tapering. Etoposide (VP16): 100-150mg/m2 twice in the first two weeks, and once every week to week 8. | Drug: Dexamethasone<br>* Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group.<br>* Other names: Corticosteroid;Drug: Etoposide<br>* Used in severe group combined with etoposide.<br>* Other names: VP16;|
| Experimental: Severe HLH-94 plus ruxolitinib group<br>DXM: week1-2: 10 mg/m2.d, week 3-4: 5 mg/m2.d, week5-6: 2.5 mg/m2.d, week7: 1.25 mg/m2.d, week8: tapering. Etoposide (VP16): 100-150mg/m2 twice in the first two weeks, and once every week to week 8. Ruxolitinib(Ruxo): body weight (BW)<10kg: 2.5mg Bid; 10-20kg: 5mg Bid; >20kg: 10mg Bid; Orally for 4 weeks. | Drug: Dexamethasone<br>* Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group.<br>* Other names: Corticosteroid;Drug: Etoposide<br>* Used in severe group combined with etoposide.<br>* Other names: VP16;Drug: Ruxolitinib<br>* Single drug in non-severe group; combined with etoposide and dexamethasone in severe group.<br>* Other names: JAK1/2 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission (CR) | Complete remission rate in 8th week | 8th week after the initial of therapy | 
| Overall survival (OS) | Overall survival rate in one year | One year after enrollment | 
| overall response rate (ORR) | including the proportion of patients achieving CR, PR and HLH improvement | At the 4th and 8th week of treatment | 
| Mortality | 8-week mortality | At the 8th week of diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reactivation rate | The relapse rate of disease | Any time during the first year after diagnosis | 
| Partial remission (PR) | Partial remission rate in 4th week | 4th week after the initial of therapy | 
| Rate of Early Death | Death occurred within 2 weeks after diagnosis | 2nd week after diagnosis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophagocytic Lymphohistiocytoses, Cytokine Storm, Ruxolitinib, Interferon-gamma, Interleukin-10, Child, Stratification therapy