Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

Sponsor

The Children's Hospital of Zhejiang University School of Medicine (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05491304

Collaborator

The Second Hospital of Anhui Medical University (Other), Union hospital of Fujian Medical University (Other), Children's Hospital of Fudan University (Other), Zunyi Medical College (Other), Hunan Provincial People's Hospital (Other), Tongji Hospital (Other), Children's Hospital of Nanjing Medical University (Other), The Affiliated Hospital of Qingdao University (Other), Qilu Hospital of Shandong University (Other), Shanghai Children's Medical Center (Other), Xinhua Hospital, Shanghai Jiao Tong University School of Medicine (Other), Shanghai Children's Hospital (Other), Shenzhen Children's Hospital (Other), West China Second University Hospital (Other), Children's Hospital Of Soochow University (Other), Second Affiliated Hospital of Wenzhou Medical University (Other), Wuhan Children's Hospital (Other), Institute of Hematology & Blood Diseases Hospital (Other), The Third Xiangya Hospital of Central South University (Other), First Affiliated Hospital, Sun Yat-Sen University (Other)

400

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hemophagocytic Lymphohistiocytoses Cytokine Storm	Drug: Dexamethasone Drug: Etoposide Drug: Ruxolitinib	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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)

Masking Description:

Open Label

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Non-severe DXM group 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 Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group. Other Names: Steroid Corticosteroid
Experimental: Non-severe Ruxo group Ruxolitinib(Ruxo): body weight (BW)<10kg: 2.5mg Bid; 10-20kg: 5mg Bid; >20kg: 10mg Bid; Orally for 4 weeks.	Drug: Ruxolitinib Single drug in non-severe group; combined with etoposide and dexamethasone in severe group. Other Names: JAK1/2 inhibitor
Experimental: Severe HLH-94 group 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 Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group. Other Names: Steroid Corticosteroid Drug: Etoposide Used in severe group combined with etoposide. Other Names: VP16
Experimental: Severe HLH-94 plus ruxolitinib group 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 Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group. Other Names: Steroid Corticosteroid Drug: Etoposide Used in severe group combined with etoposide. Other Names: VP16 Drug: Ruxolitinib Single drug in non-severe group; combined with etoposide and dexamethasone in severe group. Other Names: JAK1/2 inhibitor

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Reactivation rate [Any time during the first year after diagnosis]
The relapse rate of disease
Partial remission (PR) [4th week after the initial of therapy]
Partial remission rate in 4th week
Rate of Early Death [2nd week after diagnosis]
Death occurred within 2 weeks after diagnosis

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital of Zhejiang University School of Medicine	Hangzhou	Zhejiang	China	310003

Sponsors and Collaborators

The Children's Hospital of Zhejiang University School of Medicine
The Second Hospital of Anhui Medical University
Union hospital of Fujian Medical University
Children's Hospital of Fudan University
Zunyi Medical College
Hunan Provincial People's Hospital
Tongji Hospital
Children's Hospital of Nanjing Medical University
The Affiliated Hospital of Qingdao University
Qilu Hospital of Shandong University
Shanghai Children's Medical Center
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Shanghai Children's Hospital
Shenzhen Children's Hospital
West China Second University Hospital
Children's Hospital Of Soochow University
Second Affiliated Hospital of Wenzhou Medical University
Wuhan Children's Hospital
Institute of Hematology & Blood Diseases Hospital
The Third Xiangya Hospital of Central South University
First Affiliated Hospital, Sun Yat-Sen University

Investigators

Principal Investigator: Xiaojun Xu, MD, The Children's Hospital of Zhejiang University School of Medicine
Principal Investigator: Yongmin Tang, MD, The Children's Hospital of Zhejiang University School of Medicine