Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

Cytokine Storm Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05491304
• Other study ID #: 2022-IRB-057
• Status: Recruiting
• Phase: Phase 4
• Start date: September 1, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: October 2022
• Source: The Children's Hospital of Zhejiang University School of Medicine
• Contact: Xiaojun Xu, MD
• Phone: +8657188873617
• Email: xuxiaojun[@]zju.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cytokine Release Syndrome
• Cytokine Storm
• Hemophagocytic Lymphohistiocytoses
• Lymphohistiocytosis, Hemophagocytic

Intervention

Drug:
• Dexamethasone
Single drug in non-severe group; combined with etoposide±ruxolitinib in severe group.
• Etoposide
Used in severe group combined with etoposide.
• Ruxolitinib
Single drug in non-severe group; combined with etoposide and dexamethasone in severe group.

Locations

Country	Name	City	State
China	The Children's Hospital of Zhejiang University School of Medicine	Hangzhou	Zhejiang

Sponsors (21)

Lead Sponsor

Collaborator

The Children's Hospital of Zhejiang University School of Medicine

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

Country where clinical trial is conducted

China, 

References & Publications (9)

Bergsten E, Horne A, Aricó 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. — View Citation

Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, Janka G, Jordan MB, La Rosée 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. Review. — View Citation

Henter JI, Horne A, Aricó 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete remission (CR)	Complete remission rate in 8th week	8th week after the initial of therapy
Primary	Overall survival (OS)	Overall survival rate in one year	One year after enrollment
Primary	overall response rate (ORR)	including the proportion of patients achieving CR, PR and HLH improvement	At the 4th and 8th week of treatment
Primary	Mortality	8-week mortality	At the 8th week of diagnosis
Secondary	Reactivation rate	The relapse rate of disease	Any time during the first year after diagnosis
Secondary	Partial remission (PR)	Partial remission rate in 4th week	4th week after the initial of therapy
Secondary	Rate of Early Death	Death occurred within 2 weeks after diagnosis	2nd week after diagnosis