Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis

NCT07497438 | Not Yet Recruiting Phase 3 DMC

• 2 other identifiers: APHP2308742024-511807-41-01
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 1

Brief Summary

Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder characterized by hyperactivation of the immune system, leading to a cytokine storm responsible for organ failures. Consequently, patients with HLH often require intensive care management, where their short-term prognosis is compromised (1-month mortality: 30 to 40%). Therapeutic management is urgent and consists in treating associated pathologies and employing immunomodulatory therapy. Currently, there are no clear and consistent recommendations for guiding immunomodulatory treatment in HLH due to the lack of high-level evidence studies. Experts recommend corticosteroid therapy for mild forms, whereas etoposide is proposed for severe cases, especially those with organ failures. However, in clinical practice, its use in patients with multi-organ failure is not systematic due to concerns about potential severe side effects and uncertainty regarding the contribution of severe sepsis to the clinical and biological presentation. Consequently, initiation of etoposide is sometimes delayed. Our hypothesis is that early treatment of severe HLH associated with organ failure using etoposide could reduce organ failures associated with this syndrome. Therefore, we aim to compare two strategies for initiating etoposide in severe HLH in intensive care: an early strategy where etoposide is prescribed at the onset of HLH-related organ failure, and a delayed strategy where etoposide is prescribed only if there is unfavorable progression (or lack of improvement) after treating associated pathologies, associated with corticosteroid therapy.

Conditions

Hemophagocytic Lymphohistiocytosis

Keywords

Hemophagocytic lymphohistiocytosis; Etoposide; Intensive care unit; cytokine storm; organe failures

Outcome Measures

Primary Outcomes (1)

• Increase of at least 1 point in the modified SOFA score (excluding the hematologic component) for at least two organ systems compared to Day 0. In the delayed arm, the use of rescue etoposide treatment or in case of secondary aggravation during follow-up

  The occurrence of an event defined as the onset or worsening of organ failures, evaluated using the modified Sequential Organ Failure Assessment (SOFA) score (excluding the hematologic component, from 0 to 20 points), calculated every 12 hours from Day 1 to Day 5 (Day 0 = inclusion), and then every 24 hours from Day 6 to Day 14. An event will be defined as an increase of at least 1 point for at least two organ systems compared to Day 0. In the delayed arm, the use of rescue etoposide treatment or in case of secondary aggravation during follow-up will also be considered an event.

  every 12 hours from Day 1 to Day 5 (Day 0 = inclusion), and then every 24 hours from Day 6 to Day 14

Secondary Outcomes (14)

• Survival

  60 days

• Duration of mechanical ventilation

  14 days after inclusion

• Duration of catecholamine therapy

  14 days after inclusion

• Need for renal replacement therapy.

  14 days after inclusion

• Length of stay in the intensive care unit

  60 days

Study Arms (2)

Early strategy

EXPERIMENTAL

Etoposide treatment will be administered within 12 hours of inclusion.

Drug: Etoposide (Early strategy)

Delayed strategy

ACTIVE COMPARATOR

The need for etoposide treatment will be reassessed after 48 hours of management. If organ failure worsens or fails to improve (modified SOFA increase ≥1 point or stable), etoposide will be administered within 12 hours of reassessment. In cases of rapidly deteriorating clinical status with short-term life-threatening prognosis (defined as an increase of 6 or more points in modified SOFA score), patients may receive rescue treatment (before 48 hours) with etoposide at the discretion of the medical team managing the patient; in such cases, the Day-2 infusion will not be administered.

Drug: Etoposide (Delayed strategy)

Interventions

Etoposide (Early strategy) DRUG

early strategy arm: patients will receive etoposide treatment within 12 hours of inclusion.

Also known as: Etoposide is used at a dose of 100 mg/m², administered via slow intravenous infusion over 30 to 60 minutes on Day 0 or Day 2 depending on the arm.

Early strategy

Etoposide (Delayed strategy) DRUG

delayed strategy arm: patients will be reassessed 48 hours after inclusion. If there is persistence or deterioration of organ failures (similar or higher modified SOFA score), patients will receive etoposide treatment within 12 hours of this reassessment in the absence of formal contraindications. In cases of rapidly deteriorating clinical status with short-term life-threatening prognosis (defined as an increase of 6 or more points in modified SOFA score), patients may receive rescue treatment (before 48 hours) with etoposide at the discretion of the medical team managing the patient; in such cases, the Day-2 infusion will not be administered. This practice will be exceptional and documented, following consultation with the hotline if possible.

Also known as: Etoposide is used at a dose of 100 mg/m², administered via slow intravenous infusion over 30 to 60 minutes on Day 0 or Day 2 depending on the arm.

Delayed strategy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patient
• Confirmed diagnosis of HLH:
• Hscore ≥ 169
• Diagnosis of HLH established by the multidisciplinary team caring for the patient(A 24/7 hotline will be available in case of diagnostic uncertainty: this will be the direct line to the on-call intensivist at Avicenne Hospital, who can contact the coordinating investigator as needed)
• First episode of HLH
• Admission to intensive care unit
• Presence of one or more organ failures:
• Circulatory: mBP \< 65 mmHg with lactate \> 2 mmol/L, or treatment with catecholamines
• Respiratory: oxygen therapy \> 6 L/min or need for non-invasive ventilation, high-flow nasal cannula oxygen therapy, or invasive mechanical ventilation
• Renal: stage 2 or higher according to KDIGO criteria, defined by a creatinine increase ≥ 2 times baseline, or urine output \< 0.5 mL/kg/h for ≥ 12 hours, or initiation of renal replacement therapy
• Neurological: GCS ≤ 13

You may not qualify if:

• Moribund patient with refractory distributive shock: multi-organ failure requiring noradrenaline \> 2.5 µg/kg/min and imminent risk of death.
• Inability to administer etoposide within 12 hours.
• Patient treated with etoposide prior to admission to the intensive care unit.
• Hypersensitivity to etoposide or any of its excipients.
• Hypersensitivity or contraindication to dexamethasone or any of its excipients, as described in the package insert for the dexamethasone specialty used in the trial and in the protocol.
• Patient with a history of CAR-T cell therapy.
• Patient developing HLH within 15 days following chemotherapy for cancer or hematologic malignancy.
• Patient not covered by social security.
• Patient under legal guardianship, tutelage, or curatorship.
• Minor patient.
• Pregnant women (positive βhCG), women for whom pregnancy has not been excluded (βhCG not performed in women of childbearing age), or lactating women.
• Recent vaccination with a live attenuated vaccine.
• Participation in another interventional research study.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Intensive Care Unit - Avicenne Hospital, Assistance Publique des Hôpitaux de Paris

Bobigny, 93000, France

Location

MeSH Terms

Conditions

Lymphohistiocytosis, Hemophagocytic; Cytokine Release Syndrome

Interventions

Etoposide

Condition Hierarchy (Ancestors)

Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Julien SCHMIDT, MD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Julien SCHMIDT, MD

CONTACT

+33 (0)1.48.95.52.41; julien.schmidt@aphp.fr

Stéphane Gaudry, MD, PhD

CONTACT

+33(0)1.48.95.22.81; stephane.gaudry@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2026
• First Posted: March 27, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): February 1, 2030
• Last Updated: April 23, 2026

Record last verified: 2026-03

Locations

FR (1)