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Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

Primary Purpose

Hemophagocytic Lymphohistiocytoses, Cytokine Storm

Status
Recruiting
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Dexamethasone
Etoposide
Ruxolitinib
Sponsored by
The Children's Hospital of Zhejiang University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophagocytic Lymphohistiocytoses focused on measuring Hemophagocytic Lymphohistiocytoses, Cytokine Storm, Ruxolitinib, Interferon-gamma, Interleukin-10, Child, Stratification therapy

Eligibility Criteria

1 Day - 18 Years (Child, Adult)All SexesDoes not accept 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.

Sites / Locations

  • The Children's Hospital of Zhejiang University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Non-severe DXM group

Non-severe Ruxo group

Severe HLH-94 group

Severe HLH-94 plus ruxolitinib group

Arm Description

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.

Ruxolitinib(Ruxo): body weight (BW)<10kg: 2.5mg Bid; 10-20kg: 5mg Bid; >20kg: 10mg Bid; Orally for 4 weeks.

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.

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.

Outcomes

Primary Outcome Measures

Complete remission (CR)
Complete remission rate in 8th week
Overall survival (OS)
Overall survival rate in one year
overall response rate (ORR)
including the proportion of patients achieving CR, PR and HLH improvement
Mortality
8-week mortality

Secondary Outcome Measures

Reactivation rate
The relapse rate of disease
Partial remission (PR)
Partial remission rate in 4th week
Rate of Early Death
Death occurred within 2 weeks after diagnosis

Full Information

First Posted
August 4, 2022
Last Updated
October 5, 2022
Sponsor
The Children's Hospital of Zhejiang University School of Medicine
Collaborators
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, China, The Third Xiangya Hospital of Central South University, First Affiliated Hospital, Sun Yat-Sen University
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1. Study Identification

Unique Protocol Identification Number
NCT05491304
Brief Title
Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis
Official Title
Clinical Study on the Treatment of Pediatric Hemophagocytic Lymphohistiocytosis Based on Cytokine Guided Risk Stratification:A Multicenter Randomized Controlled Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 1, 2022 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Children's Hospital of Zhejiang University School of Medicine
Collaborators
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, China, The Third Xiangya Hospital of Central South University, First Affiliated Hospital, Sun Yat-Sen University

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophagocytic Lymphohistiocytoses, Cytokine Storm
Keywords
Hemophagocytic Lymphohistiocytoses, Cytokine Storm, Ruxolitinib, Interferon-gamma, Interleukin-10, Child, Stratification therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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)
Masking Description
Open Label
Allocation
Randomized
Enrollment
400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Non-severe DXM group
Arm Type
Experimental
Arm Description
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.
Arm Title
Non-severe Ruxo group
Arm Type
Experimental
Arm Description
Ruxolitinib(Ruxo): body weight (BW)<10kg: 2.5mg Bid; 10-20kg: 5mg Bid; >20kg: 10mg Bid; Orally for 4 weeks.
Arm Title
Severe HLH-94 group
Arm Type
Experimental
Arm Description
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.
Arm Title
Severe HLH-94 plus ruxolitinib group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Steroid, Corticosteroid
Intervention Description
Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group.
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
VP16
Intervention Description
Used in severe group combined with etoposide.
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
JAK1/2 inhibitor
Intervention Description
Single drug in non-severe group; combined with etoposide and dexamethasone in severe group.
Primary Outcome Measure Information:
Title
Complete remission (CR)
Description
Complete remission rate in 8th week
Time Frame
8th week after the initial of therapy
Title
Overall survival (OS)
Description
Overall survival rate in one year
Time Frame
One year after enrollment
Title
overall response rate (ORR)
Description
including the proportion of patients achieving CR, PR and HLH improvement
Time Frame
At the 4th and 8th week of treatment
Title
Mortality
Description
8-week mortality
Time Frame
At the 8th week of diagnosis
Secondary Outcome Measure Information:
Title
Reactivation rate
Description
The relapse rate of disease
Time Frame
Any time during the first year after diagnosis
Title
Partial remission (PR)
Description
Partial remission rate in 4th week
Time Frame
4th week after the initial of therapy
Title
Rate of Early Death
Description
Death occurred within 2 weeks after diagnosis
Time Frame
2nd week after diagnosis

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Xiaojun Xu, MD
Phone
+8657188873617
Email
xuxiaojun@zju.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Zebin Luo, MD
Phone
+8618758196529
Email
645747676@qq.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xiaojun Xu, MD
Organizational Affiliation
The Children's Hospital of Zhejiang University School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Yongmin Tang, MD
Organizational Affiliation
The Children's Hospital of Zhejiang University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital of Zhejiang University School of Medicine
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310003
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aimei Ma, bachelor
Phone
+8657180070072
Email
zuchiec@163.com

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
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28935695
Citation
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Results Reference
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Citation
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Results Reference
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Citation
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Citation
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Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

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