Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

October 5, 2022 updated by: Xiaojun Xu, The Children's Hospital of Zhejiang University School of Medicine

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

400

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Zhejiang
      • Hangzhou, Zhejiang, China, 310003
        • Recruiting
        • The Children's Hospital of Zhejiang University School of Medicine
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 day to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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: Ruxolitinib
Single drug in non-severe group; combined with etoposide and dexamethasone in severe group.
Other Names:
  • JAK1/2 inhibitor
Drug: Etoposide
Used in severe group combined with etoposide.
Other Names:
  • VP16

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Children's Hospital of Zhejiang University School of Medicine

Collaborators

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

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2022

Primary Completion (Anticipated)

December 31, 2024

Study Completion (Anticipated)

December 31, 2025

Study Registration Dates

First Submitted

August 4, 2022

First Submitted That Met QC Criteria

August 4, 2022

First Posted (Actual)

August 8, 2022

Study Record Updates

Last Update Posted (Actual)

October 6, 2022

Last Update Submitted That Met QC Criteria

October 5, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022-IRB-057

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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