Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis

NCT07497438 · tracked via the Priya Life Science France tracker

Sponsor

Assistance Publique - Hôpitaux de Paris

Phase

Phase 3

Started

2026-04

Last updated

2026-04-23

Condition(s) studied

Hemophagocytic Lymphohistiocytosis

Investigational drug(s) / intervention(s)

Etoposide (Early strategy) →Etoposide (Delayed strategy) →

Etoposide (Early strategy): early strategy arm: patients will receive etoposide treatment within 12 hours of inclusion.

Etoposide (Delayed strategy): 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.

Study 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.

Eligibility

Sex

ALL

Min age

18 Years

Max age

—

Healthy volunteers

Inclusion Criteria: * 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 Exclusion Criteria: * 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.

Primary outcome measure(s)

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

Trial sites (1)

Facility	City	Region	Status
Intensive Care Unit - Avicenne Hospital, Assistance Publique des Hôpitaux de Paris	Bobigny	France

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Official registry record

This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.

View NCT07497438 on ClinicalTrials.gov ↗ ← All trials in France