Clinical trial NCT05491304: 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
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hemophagocytic Lymphohistiocytoses
Cytokine Storm
Keywords: Hemophagocytic Lymphohistiocytoses
Cytokine Storm
Ruxolitinib
Interferon-gamma
Interleukin-10
Child
Stratification therapy
Lead sponsor: The Children's Hospital of Zhejiang University School of Medicine
Sponsor class: OTHER
Collaborators: name: The Second Hospital of Anhui Medical University
name: Union hospital of Fujian Medical University
name: Children's Hospital of Fudan University
name: Zunyi Medical College
name: Hunan Provincial People's Hospital
name: Tongji Hospital
name: Children's Hospital of Nanjing Medical University
name: The Affiliated Hospital of Qingdao University
name: Qilu Hospital of Shandong University
name: Shanghai Children's Medical Center
name: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
name: Shanghai Children's Hospital
name: Shenzhen Children's Hospital
name: West China Second University Hospital
name: Children's Hospital of Soochow University
name: Second Affiliated Hospital of Wenzhou Medical University
name: Wuhan Children's Hospital
name: Institute of Hematology & Blood Diseases Hospital, China
name: The Third Xiangya Hospital of Central South University
name: First Affiliated Hospital, Sun Yat-Sen University
First posted: 2022-08-08
Enrollment: 400
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Complete remission (CR)
timeFrame: 8th week after the initial of therapy
measure: Overall survival (OS)
timeFrame: One year after enrollment
measure: overall response rate (ORR)
timeFrame: At the 4th and 8th week of treatment
measure: Mortality
timeFrame: At the 8th week of diagnosis
Secondary outcomes:
measure: Reactivation rate
timeFrame: Any time during the first year after diagnosis
measure: Partial remission (PR)
timeFrame: 4th week after the initial of therapy
measure: Rate of Early Death
timeFrame: 2nd week after diagnosis
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: The Children's Hospital of Zhejiang University School of Medicine
state: Zhejiang
Study officials:
affiliation: The Children's Hospital of Zhejiang University School of Medicine
name: Xiaojun Xu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Children's Hospital of Zhejiang University School of Medicine
name: Yongmin Tang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.
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.
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.
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.
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.
citation: 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.
citation: 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.