Ruxolitinib as first-line treatment for primary haemophagocytic lymphohistiocytosis

Efficacy of Ruxolitinib as First Line Treatment in Primary Haemophagocytic Lymphohistiocytosis (HLH) in Children: a Phase 2, Multicentre, Non-comparative Study

This will test whether ruxolitinib plus corticosteroids helps children and young adults with primary HLH survive until they can receive a stem cell transplant.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: N/A to 22 Years
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (Academic / other)
• Drugs / interventions: Alemtuzumab, Ruxolitinib
• Locations: 1 site (Paris, Île-de-France Region)
• Trial ID: NCT05762640 on ClinicalTrials.gov

What this trial studies

This Phase 2 interventional study gives ruxolitinib together with corticosteroids as first-line induction therapy for patients with primary HLH aged 0–22 years, with the main outcome being survival until allogeneic haematopoietic stem cell transplantation (HSCT). The approach aims to suppress the life-threatening hyperinflammation while using a targeted JAK1/2 inhibitor that may be less myeloablative than conventional etoposide- or ATG-based regimens. Ruxolitinib has reduced disease manifestations and improved survival in HLH animal models and has been used in isolated human cases, so this protocol tests it prospectively as initial therapy. Patients are treated and followed at a tertiary pediatric centre in Paris, with standardized criteria for HLH diagnosis and requirement for HSCT once remission is achieved.

Who should consider this trial

Good fit: Children and young adults aged 0–22 with genetically confirmed primary HLH or who meet at least five of the standard HLH diagnostic criteria are the intended candidates.

Not a fit: Patients with secondary HLH due to an active malignancy or rheumatic disease, those older than 22, or patients with contraindications to JAK inhibitors are unlikely to benefit from this specific protocol.

Why it matters

Potential benefit: If successful, this approach could increase survival to HSCT and lower the short-term toxicity of induction therapy versus conventional regimens.

How similar studies have performed: Ruxolitinib showed efficacy in HLH mouse models and there are encouraging human case reports, but prospective randomized data as first-line therapy in primary HLH are lacking.

Eligibility criteria

Inclusion Criteria

* Patient aged 0 to 22 years
* Patient with HLH syndrome confirmed by at least one of the two criteria:

  1. Confirmed genetic diagnosis of a condition predisposing to primary HLH (see table 1 and table 2) or abnormal expression of perforin, MUNC13-4, SAP or XIAP in FACS and/or positive family history OR
  2. Presence of at least 5 of the 8 following HLH diagnostic 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

* Previous treatment with ATG, Alemtuzumab, Etoposide, JAK-inhibitors, rifampicin and/or anti-Interferon gamma antibodies. St. John's Wort, or any other strong CYP3A4 inducers.
* Previous treatment with corticosteroids and/or cyclosporine A for more than 14 days
* Isolated CNS disease.
* Contraindication to receive Ruxolitinib:
* History of hypersensitivity to the active substance or to any of the excipients
* Pregnant or lactating female patient
* Contraindication to receive methylprednisolone or prednisolone
* History of hypersensitivity to the active substance or to any of the excipients
* Any infectious condition with the exception of infections, which are the trigger for lymphohistiocytic activation.
* Patient with acute very severe renal impairment (Creatinine Clearance \<15 mL/min/1.73m²) who are NOT receiving dialysis.
* Patient with Grade 4 hepatic failure according to the CTCAE v5.0 of 27 November 2017 (Life-threatening consequences; moderate to severe encephalopathy; coma)
* Past or know active tuberculosis
* Known rheumatologic disorder.
* Known active malignancy.
* Patient who is taking another investigational agent or is enrolled in another treatment protocol.
* Patient who cannot tolerate administration of drugs PO or through NG

Where this trial is running

Paris, Île-de-France Region

• Hopital Necker Enfants malades — Paris, Île-de-France Region, France (Recruiting)

Study contacts

• Study coordinator: Despina MOSHOUS, MD, PhD

Conditions Haemophagocytic Lymphohistiocytosis; Lymphohistiocytic activation syndrome; Ruxolitinib; Jakavi