Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis

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.

1. Objectives Primary Objective: To compare the effect on the evolution of organ failures of two initiation strategies of etoposide in severe HLH in intensive care: * An early strategy where etoposide is initiated within 12 hours after inclusion. * A delayed strategy where this treatment is initiated only in case of unfavorable evolution (or lack of improvement) after 48 hours. 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. Secondary objectives: * Evaluate the effect of these 2 strategies on: 1. Survival 2. Duration of mechanical ventilation 3. Duration of catecholamine therapy 4. Need for renal replacement therapy 5. Length of stay in the intensive care unit 6. Length of hospital stay 7. Proportion of patients receiving etoposide treatment 8. Cumulative dose of etoposide 9. Time to initiation of etoposide treatment 10. Number of patients receiving another immunosuppressive treatment 11. Normalization of HLH-related biological abnormalities 12. Evolution of the HScore (probability score for HLH) 13. Potential side effects attributable to etoposide, such as healthcare-associated infections, incidence of neutropenia, and bleeding events. 14. Evolution of the SOFA score and modified SOFA score * Identify risk factors for mortality in severe HLH in intensive care. * Identify and describe comorbidities associated with severe HLH in intensive care, and their prognostic impact. 2. Investigational treatment 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 or delayed strategy). Patients in the "early strategy" arm will receive etoposide treatment within 12 hours of inclusion. In the "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 trial.show_full_description

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.