Ruxolitinib as First Line Treatment in Primary Haemophagocytic Lymphohistiocytosis (R-HLH) (R-HLH)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Haemophagocytic Lymphohistiocytosis
• Intervention / Treatment: Drug: Ruxolitinib

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Despina MOSHOUS, MD, PhD; Phone Number: +33 01 44 49 48 23; Email: despina.moshous@aphp.fr
• Study Contact Backup: Name: Laure CHOUPEAUX; Phone Number: +33 01 44 38 17 11; Email: laure.choupeaux@aphp.fr

Study Locations

• France
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Recruiting
      • Hopital Necker Enfants Malades
      • Contact: Despina MOSHOUS, MD, PHD; Phone Number: +33 01 44 49 48 23; Email: despina.mouhous@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 22 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ruxolitinib	Drug: Ruxolitinib; Form: tablets, 50 mg/m2/day in two administrations. Maximum dose is 100 mg/day. Administration in association with Methylprednisolone IV (or Prednisolone PO) starting at 2 mg/kg/day in two administrations. Duration of treatment: until D-1 of conditioning for allogeneic HSCT OR 9weeks for patients who are not eligible for HSCT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Survival until HSCT	Day 0 until HSCT, up to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients achieving a complete response	To evaluate the efficacy of Ruxolitinib	Day 7, Day 14, Day 21, Day 28, Week 8, and Day-1 of the conditioning for HSCT
Rate of patients achieving a partial response	To evaluate the efficacy of Ruxolitinib	Day 7, Day 14, Day 21, Day 28, Week 8, and Day-1 of the conditioning for HSCT
Delay to obtain complete response	To evaluate the efficacy of Ruxolitinib	Day 0 up to Day-1 of the conditioning for HSCT
Delay to obtain partial response	To evaluate the efficacy of Ruxolitinib	Day 0 up to Day-1 of the conditioning for HSCT
Incidence of HLH reactivation	HLH reactivation after achieving complete or partial response.	Day 0 up to Day-1 of the conditioning for HSCT
Timing of HLH reactivation	HLH reactivation after achieving complete or partial response.	Day 0 up to Day-1 of the conditioning for HSCT
Occurrence of a viral infection de novo or worsening of pre-existing viral infection(s)	To evaluate treatment tolerance	During Ruxolitinib treatment
Occurrence of adverse effects reported in the product information for Ruxolitinib	To evaluate treatment tolerance	During Ruxolitinib treatment
Concentration of Ruxolitinib in blood	to evaluate Pharmacokinetics	Blood sampling: Day 0, weekly until week 8 of treatment and at Day-8 prior to the conditioning for HSCT
Concentration of Ruxolitinib in cerebrospinal fluid	to evaluate Pharmacokinetics	Blood sampling: Day 0, weekly until week 8 of treatment and at Day-8 prior to the conditioning for HSCT
Cytokine profile and gene expression	Assess through measurement of IFNγ, TNFα, Interleukin (IL)-6, IL-2, IL-10, IL-18, IL-1b, and CXCL9	Day 0, Weekly until week 8 of treatment

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Study Chair: Despina MOSHOUS, MD, PhD, Hôpital Necker-Enfants Malades

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: January 3, 2023
• First Submitted That Met QC Criteria: February 28, 2023
• First Posted (Actual): March 9, 2023

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 20, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Ruxolitinib; Jakavi; Haemophagocytic Lymphohistiocytosis; Lymphohistiocytic activation syndrome
• Additional Relevant MeSH Terms: Lymphatic Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Hemic and Lymphatic Diseases; Lymphohistiocytosis, Hemophagocytic; ruxolitinib
• Other Study ID Numbers: APHP200023; 2021-006878-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No