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.
Adult patient
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
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.
Parallel
Etoposide (Early strategy)
Drugearly strategy arm: patients will receive etoposide treatment within 12 hours of inclusion.
Etoposide (Delayed strategy)
Drugdelayed 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.
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.
Survival
Time to death after inclusion (with a maximum follow-up duration of 60 days)
Duration of mechanical ventilation
Number of ventilator-free days between inclusion and Day 14. A live discharge from the intensive care unit will be considered equivalent to no mechanical ventilation (event) from the date of discharge. Patients who died before day 14 will be assigned a value of 0 days, corresponding to no days alive without ventilation.
Duration of catecholamine therapy
Number of catecholamine-free days between inclusion and Day 14. A live discharge from the intensive care unit will be considered equivalent to an absence of catecholamines (event) from the date of discharge. Patients who died before D14 will be assigned a value of 0 days, corresponding to an absence of live days without catecholamines.
Need for renal replacement therapy.
Proportion of patients receiving at least one session of renal replacement therapy between inclusion and Day 14. Discharge from intensive care without prior extrarenal purification will be considered a non-event. Death without prior extrarenal purification will be considered a non-event.
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