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About
The purpose of this project is to study the survival of patients until Haematopoietic Stem Cell Transplantation following the use of Ruxolitinib as first-line treatment associated to corticosteroids in primary HLH.
Full description
Haemophagocytic lymphohistiocytosis (HLH) is a devastating inflammatory condition caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting an excess of inflammatory cytokines.
Treatment of HLH aims at decreasing inflammation and requires also treatment of the underlying trigger, if any.
The principal goal of the induction therapy is to suppress the life-threatening inflammatory process. Once remission of HLH achieved, patients require allogeneic haematopoietic stem cell transplantation (HSCT), the only curative therapy to date.
Despite significant treatment progress, mortality remains high. The study aims to implement a targeted treatment that is less aggressive than conventional approaches (Etoposide / ATG / Alemtuzumab).
A better understanding of the pathophysiology of primary HLH has opened new avenues for targeted therapy. The central cytokine of the HLH process is IFNγ. IFNγ as well as most cytokines that are elevated in HLH, signal via Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-associated receptors. Ruxolitinib, a selective JAK1/2 inhibitor has shown its efficacy in mouse models of HLH, where it significantly reduced disease manifestations and enhanced survival. Notably, Ruxolitinib diminished CD8+ T-cell accumulation and cytokine production, while sparing degranulation and cytotoxicity. Recently, Ruxolitinib has also been used successfully in humans in isolated cases of refractory primary and secondary HLH.
This is a National, phase II, non-comparative and non-randomized, study in France with 9 participating centers. The chosen experimental plan is a Simon's Optimal 2-Step Design.
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Inclusion and exclusion criteria
Inclusion Criteria
Patient aged 0 to 22 years
Patient with HLH syndrome confirmed by at least one of the two criteria:
Fever
Splenomegaly
Cytopenia (affecting at least two cell lineages)
Haemoglobin < 9 g/dl (<10 g/dL in neonates)
Platelets < 100,000/µL
Absolute neutrophil count (ANC) < 1,000/µL
Hypertriglyceridemia and/or hypofibrinogenemia
Fasting triglycerides ≥ 3 mmol/l
Fibrinogen <1.5 g/L
Haemophagocytosis found in a histological sample (without evidence of a malignant process or an underlying rheumatic disorder)
Decreased or absent NK function
Ferritin ≥ 500 µg/l
Presence of activated T cells in the immune phenotyping as evidenced by expression of the activation marker DR (superior to the normal value of the laboratory) OR CD25 soluble (sIL-2 receptor) ≥ 2,400 U/mL.
Patient with no previous specific treatment for HLH syndrome
For patients of childbearing age : using an effective method of contraception during the trial, and through to 90 days after EOS for male participants and 30 days after EOS for female participants
Freely given, informed and written consent of legal representative of the participant or consent of the adult participant
Affiliation to Social Security.
Exclusion Criteria
Primary purpose
Allocation
Interventional model
Masking
20 participants in 1 patient group
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Central trial contact
Jinmi BAEK, Master; Despina MOSHOUS, MD, PhD
Data sourced from clinicaltrials.gov
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