Cytokine Guided Risk Stratification and Treatment in Pediatric Hemophagocytic Lymphohistiocytosis

Zhejiang University

Status and phase: Enrolling; Phase 4

Conditions: Cytokine Storm; Hemophagocytic Lymphohistiocytoses

Treatments: Drug: Ruxolitinib; Drug: Etoposide; Drug: Dexamethasone

Study type: Interventional

Funder types: Other

Identifiers

NCT05491304

2022-IRB-057

Details and patient eligibility

About

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.

Full 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.

Enrollment: 400 estimated patients

Sex: All

Ages: 1 day to 18 years old

Volunteers: No 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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400 participants in 4 patient groups

Non-severe DXM group

Experimental group

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.

Treatment:

Drug: Dexamethasone

Non-severe Ruxo group

Experimental group

Description:

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

Treatment:

Drug: Ruxolitinib

Severe HLH-94 group

Experimental group

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.

Treatment:

Drug: Dexamethasone

Drug: Etoposide

Severe HLH-94 plus ruxolitinib group

Experimental group

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.

Treatment:

Drug: Dexamethasone

Drug: Etoposide

Drug: Ruxolitinib