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fever, lymphadenopathy or hepatosplenomegaly, cytope- nia, coagulopathy, and potentially life-threatening multi- system organ dysfunction. If left untreated, HLH can result in a high risk of death.1
before screening; (iv) were male or female, less than 18 years of age and (v) signed an informed consent form before participating in the study. Patients who had any one of the following were inel- igible: serious renal dysfunction (creatinine clearance <15 mL/min or glomerular filtration rate <15 mL/min), liver cirrhosis with a Model for End-stage Liver Disease (MELD) score >20, heart func- tion above grade II (New York Heart Association), presence of a malignancy, parasitic infection, or a history of severe allergic, ana- phylactic, or other hypersensitivity reactions to chemicals.
Epstein-Barr virus-associated HLH (EBV-HLH) patients were defined as patients who met the HLH diagnosis criteria and whose EBV infection was confirmed by identifying increased EBV-DNA copy numbers (500 copies/L) in the peripheral blood or plasma (cell-free). Anti-EBV serological pattern showed the EBV status. In brief, EBNA-IgG-negative and EBCA-IgG (or IgM)-posi- tive antibodies would indicate the first exposure to EBV, while positive EBNA-IgG, EBCA-IgG and EBCA-IgM antibodies would indicate EBV reactivation from a previous infection. Autoinflammatory disorder (AID)-HLH patients were defined as patients who met HLH diagnosis criteria and had excessive sys- temic inflammation, leading to recurrent fever, rashes, and IL-6 overproduction and no evidence of infection, tumor or specific antibody involvement.
Patients were categorized into high- and low-risk groups. High risk was defined as any central nervous system involvement or accordance with at least three of the following criteria: i) age ≤2 years; ii) serious non-laboratory manifestations: severe hepatosplenomegaly, active bleeding, or icterus; iii) absolute neu- trophil count <0.5×109/L; iv) soluble CD25 >25,000 pg/mL; v) fer- ritin >2,000 g/L; vi) a >10-fold increase in IFN-γ from normal lev- els; and vii) alanine aminotransferase (ALT) >200 U/L. Patients who do not meet the above criteria are considered low risk
Study design and ruxolitinib treatment protocol
The study was registered in the Chinese Clinical Trials Registry Platform (clinicaltrials gov. Identifier: ChiCTR2000029977) and approved by the Ethics Committee of Beijing Children’s Hospital. This is a single-arm, open-label, pilot study to investigate the effi- cacy and safety of RUX as a front-line therapy in children with secondary HLH. Twelve patients were enrolled in this study. Patients in this study received oral RUX phosphate tablets on a 28-day cycle for one cycle. The dose was 2.5 mg, 5 mg or 10 mg twice daily depending on the body weight (≤10 kg, ≤20 kg or >20 kg, respectively). Therapy was changed immediately when there was no response after 3 days of treatment or at any time during treatment due to disease progression, relapse or toxic effects requiring drug discontinuation. The data cutoff for the primary analysis occurred when all patients completed day 28 of or dis- continued therapy.
Study end points
The primary efficacy endpoint was the overall response (OR) rate at day 28 of the last dose, including the proportion of patients achieving a complete response (CR), a partial response (PR) and HLH improvement. Secondary efficacy endpoints included the 6-month event-free survival (EFS, defined as the time from initial RUX treatment to the first occurrence of dis- ease progression, relapse or death; for non-responders, EFS was defined as date of enrollment plus 1 day). Other end points included the durability of response, symptom reduction, dynamic changes of key biomarkers during treatment, the rela- tionship between treatment response and risk stratification, and safety. In addition, for patients who discontinued and changed therapy regimens, we also counted the subsequent treatment responses and outcomes.
Currently, HLH-1994 or HLH-2004 regimen is the stan- dard HLH treatment strategy. In this regimen, etoposide and dexamethasone, with or without cyclosporine A, are used to treat active HLH. Long-term results of the HLH-1994 regi- men showed that patients had a 5-year survival of 54±6%;2 compared with the HLH-1994 data, the HLH-2004 protocol did not improve HLH outcome significantly with a 5-year survival of 61%,3 which indicates that HLH treatment has not progressed significantly in the past few decades. Furthermore, based on the HLH-1994 or HLH-2004 regi- men, intense cytotoxic chemotherapy can induce serious myelosuppressive or broadly immunosuppressive effects leading to severe infection and even death. In addition, the long-term side effect of etoposide in the regimen, secondary tumor risk, also deserves more attention.4-6 Therefore, prospective clinical trials investigating novel pharmacologic treatments for HLH are urgently needed. Recently, inter- leukin-1 (IL-1) inhibitors, interferon-γ (IFN-γ) monoclonal antibody and others have been suggested as possible treat- ment options, with varying clinical effects.7,8
Excessive production of cytokines, including IFN-γ, IL-10 and IL-6, contributes greatly to the pathogenesis of HLH. These overproduced cytokines bind to a broad array of spe- cific receptors and activate the downstream JAK-STAT dependent signal pathway, which finally promotes the tran- scription of numerous downstream proinflammatory genes.9,10 Based on their essential roles in transmitting cytokine-induced signals, JAK inhibition might serve as a valid therapeutic approach in HLH. Recently, ruxolitinib (RUX), an oral selective JAK1/2 inhibitor, has shown prom- ise in mouse models of primary and secondary HLH.11-13 When RUX is administered, cytokine production and tissue damage are decreased, leading to improved survival in mice. These data have led to interest in the use of RUX clinically for HLH treatment. Recently, RUX was used to treat refrac- tory HLH patients in several case studies.14-16 There are also reports that RUX was used as a first-line treatment in one adult and one childhood HLH patient, and led to clinical remission.17, 18 In addition, a phase I clinical trial (clinicaltrails gov. Identifier: NCT02400463) using RUX in newly diag- nosed adult HLH patients is ongoing and has published its preliminary data from the first five enrolled patients, which suggests that RUX is active and safe in that setting.19
However, since the etiology of HLH is complex and the severity of illness varies, the clinical outcome of RUX in the treatment of HLH still needs further investigation to identi- fy the optimal dose and duration. Meanwhile, the specific subtypes of HLH which might show better sensitivity to RUX and the association between treatment response and risk stratification are still unclear. Therefore, we performed an open-label, single-arm, pilot study to investigate the effi- cacy and safety of RUX as a first-line agent in pediatric HLH and try to clarify the above uncertainties.
Methods
Patients
Patients who were enrolled in this study fulfilled the following criteria: (i) met HLH-2004 diagnostic criteria;20 (ii) had a new diag- nosis of HLH; (iii) had no prior chemotherapy treatment for HLH
haematologica | 2021; 106(7)
Study of Ruxolitinib as a front-line therapy for pediatric HLH
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