Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

NCT05491304 | Unknown Phase 4 DMC

• 1 other identifier: 2022-IRB-057
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 1

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.

Conditions

Hemophagocytic Lymphohistiocytoses; Cytokine Storm

Keywords

Hemophagocytic Lymphohistiocytoses; Cytokine Storm; Ruxolitinib; Interferon-gamma; Interleukin-10; Child; Stratification therapy

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (3)

• Reactivation rate

  Any time during the first year after diagnosis

• Partial remission (PR)

  4th week after the initial of therapy

• Rate of Early Death

  2nd week after diagnosis

Study Arms (4)

Non-severe DXM group

EXPERIMENTAL

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

Non-severe Ruxo group

EXPERIMENTAL

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

Drug: Ruxolitinib

Severe HLH-94 group

EXPERIMENTAL

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; Drug: Etoposide

Severe HLH-94 plus ruxolitinib group

EXPERIMENTAL

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; Drug: Etoposide; Drug: Ruxolitinib

Interventions

Dexamethasone DRUG

Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group.

Also known as: Steroid, Corticosteroid

Non-severe DXM group; Severe HLH-94 group; Severe HLH-94 plus ruxolitinib group

Etoposide DRUG

Used in severe group combined with etoposide.

Also known as: VP16

Severe HLH-94 group; Severe HLH-94 plus ruxolitinib group

Ruxolitinib DRUG

Single drug in non-severe group; combined with etoposide and dexamethasone in severe group.

Also known as: JAK1/2 inhibitor

Non-severe Ruxo group; Severe HLH-94 plus ruxolitinib group

Eligibility Criteria

• Age: 1 Day - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• treated with steroids or etoposide within 72 hours before diagnosis.

Sponsors & Collaborators

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

Study Sites (1)

The Children's Hospital of Zhejiang University School of Medicine

Hangzhou, Zhejiang, 310003, China

RECRUITING

Related Publications (9)

• Bergsten E, Horne A, Arico M, Astigarraga I, Egeler RM, Filipovich AH, Ishii E, Janka G, Ladisch S, Lehmberg K, McClain KL, Minkov M, Montgomery S, Nanduri V, Rosso D, Henter JI. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017 Dec 21;130(25):2728-2738. doi: 10.1182/blood-2017-06-788349. Epub 2017 Sep 21.

  PMID: 28935695 BACKGROUND

• Xu XJ, Tang YM. Dilemmas in diagnosis and management of hemophagocytic lymphohistiocytosis in children. World J Pediatr. 2020 Aug;16(4):333-340. doi: 10.1007/s12519-019-00299-3. Epub 2019 Sep 10.

  PMID: 31506890 BACKGROUND

• Tang Y, Xu X, Song H, Yang S, Shi S, Wei J, Pan B, Zhao F, Liao C, Luo C. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol. 2008 Oct;143(1):84-91. doi: 10.1111/j.1365-2141.2008.07298.x. Epub 2008 Jul 31.

  PMID: 18673367 BACKGROUND

• Xu XJ, Tang YM, Song H, Yang SL, Xu WQ, Zhao N, Shi SW, Shen HP, Mao JQ, Zhang LY, Pan BH. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012 Jun;160(6):984-90.e1. doi: 10.1016/j.jpeds.2011.11.046. Epub 2012 Jan 9.

  PMID: 22226576 BACKGROUND

• Xu XJ, Luo ZB, Song H, Xu WQ, Henter JI, Zhao N, Wu MH, Tang YM. Simple Evaluation of Clinical Situation and Subtypes of Pediatric Hemophagocytic Lymphohistiocytosis by Cytokine Patterns. Front Immunol. 2022 Feb 28;13:850443. doi: 10.3389/fimmu.2022.850443. eCollection 2022.

  PMID: 35296096 BACKGROUND

• Wang J, Zhang R, Wu X, Li F, Yang H, Liu L, Guo H, Zhang X, Mai H, Li H, Wang Z. Ruxolitinib-combined doxorubicin-etoposide-methylprednisolone regimen as a salvage therapy for refractory/relapsed haemophagocytic lymphohistiocytosis: a single-arm, multicentre, phase 2 trial. Br J Haematol. 2021 May;193(4):761-768. doi: 10.1111/bjh.17331. Epub 2021 Feb 9.

  PMID: 33559893 BACKGROUND

• Zhang Q, Zhao YZ, Ma HH, Wang D, Cui L, Li WJ, Wei A, Wang CJ, Wang TY, Li ZG, Zhang R. A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis. Blood. 2022 Jun 16;139(24):3493-3504. doi: 10.1182/blood.2021014860.

  PMID: 35344583 BACKGROUND

• Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, Janka G, Jordan MB, La Rosee P, Lehmberg K, Machowicz R, Nichols KE, Sieni E, Wang Z, Henter JI. Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1508-1517. doi: 10.1016/j.jaip.2018.05.031. Epub 2018 Jul 4.

  PMID: 30201097 BACKGROUND

• Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.1002/pbc.21039.

  PMID: 16937360 BACKGROUND

MeSH Terms

Conditions

Lymphohistiocytosis, Hemophagocytic; Cytokine Release Syndrome

Interventions

Dexamethasone; Steroids; Adrenal Cortex Hormones; Etoposide; ruxolitinib

Condition Hierarchy (Ancestors)

Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Glucosides; Glycosides; Carbohydrates

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xiaojun Xu, MD

CONTACT

+8657188873617; xuxiaojun@zju.edu.cn

Zebin Luo, MD

CONTACT

+8618758196529; 645747676@qq.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open Label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: chief physician

Model Details: 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.

Study Record Dates

• First Submitted: August 4, 2022
• First Posted: August 8, 2022
• Study Start: September 1, 2022
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2025
• Last Updated: October 6, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)