Comparison of Early versus Delayed Etoposide Initiation Strategies in Critically Ill Patients with Severe Sporadic Hemophagocytic Lymphohistiocytosis: A Randomized Trial

Trial ID: 2024-511807-41-01
Protocol: APHP230874
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Haemophagocytic lymphohistiocytosis

Objectives

The primary objective is to compare the effect on the evolution of organ failures between two different initiation strategies of etoposide in patients with severe hemophagocytic lymphohistiocytosis receiving intensive care. The strategies involve an early initiation within 12 hours of inclusion versus a delayed initiation based on unfavorable clinical evolution after 48 hours. 3

Secondary objectives include:

Survival and evolution of the HScore.
Clinical parameters such as mechanical ventilation duration, catecholamine therapy duration, need for renal replacement therapy, and length of stay in the intensive care unit or hospital.
Evaluation of etoposide administration, including the proportion of patients treated, cumulative dose, and time to initiation.
Use of other immunosuppressive treatments and normalization of biological abnormalities.
Safety assessment via the evolution of the SOFA score and potential adverse effects such as neutropenia, healthcare-associated infections, and bleeding events.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of adults of both genders diagnosed with hemophagocytic lymphohistiocytosis. Inclusion requires a confirmed diagnosis based on Henter criteria, the presence of a first episode of the disease, and admission to an intensive care unit. Participants must exhibit one or more organ failures involving the circulatory, respiratory, renal, or neurological systems. Eligible individuals must present with specific clinical indicators such as cytopenias, hyperferritinemia, or impaired Glasgow Coma Scale scores.

Plans and Procedures

This randomized trial evaluates two initiation strategies of etoposide for the management of severe sporadic hemophagocytic lymphohistiocytosis in patients admitted to an intensive care unit. Participants undergo a screening process to confirm diagnosis based on Henter criteria, a first episode of the disease, and the presence of organ failure. The study compares an early strategy, where etoposide is administered within 12 hours of inclusion, against a delayed strategy, where treatment is initiated only if there is an unfavorable evolution after 48 hours. Dexamethasone is utilized as a background therapy. The primary endpoint is the occurrence or worsening of organ failures, assessed via the modified Sequential Organ Failure Assessment score. Secondary outcomes include time to death, ventilator-free days, and the duration of hospital stay. The follow-up period extends up to 60 days after inclusion to monitor mortality and clinical stabilization. Participant involvement is centered on the intensive care stay and subsequent clinical monitoring.

Treatment

The experimental treatment consists of etoposide administered in the pharmaceutical form PHF675. The dosage is 100 mg/m², delivered via intravenous injection or intravenous infusion. This medication is evaluated based on two initiation strategies for the management of severe sporadic hemophagocytic lymphohistiocytosis: an early initiation within 12 hours of inclusion or a delayed initiation following unfavorable clinical evolution after 48 hours.

The auxiliary background therapy involves dexamethasone acetate in the pharmaceutical form PHF00245MIG. This substance is administered through intravenous use at a dosage of 10 mg/m².

Efficacy

The primary efficacy endpoint is the occurrence of an event characterized by the onset or worsening of organ failures. This is evaluated using the modified Sequential Organ Failure Assessment score, excluding the hematologic component. An event is defined as an increase of at least 1 point for at least two organ systems relative to Day 0. In the delayed treatment arm, the administration of rescue etoposide or secondary aggravation during follow-up is also categorized as an event.

Secondary endpoints include:

Time to death following inclusion, with a maximum follow-up of 60 days.
Number of ventilator-free days and catecholamine-free days between inclusion and Day 14.
Proportion of patients requiring renal replacement therapy between inclusion and Day 14.
Length of intensive care unit stay and total hospital stay.
Proportion of patients receiving at least one dose of etoposide, the cumulative dose of etoposide over the first 14 days, and the time from inclusion to treatment initiation.
Number of patients receiving additional immunosuppressive treatment during the intensive care unit stay up to Day 14.
Time from inclusion to the normalization of fibrinogen, ferritin, and triglycerides during the intensive care unit stay up to Day 14.
HScore assessment at Days 2, 7, and 14.
Proportion of patients experiencing healthcare-associated infections, acquired neutropenia, and bleeding events requiring transfusion or surgical intervention.
Delta SOFA at Days 2 and 5, and the maximum SOFA score, including both SOFA and modified SOFA.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adult patient
Confirmed diagnosis of HLH: • Presence of 5 or more Henter criteria (HLH-04) out of the 6 achievable in routine care (fever, splenomegaly, cytopenias affecting 2 or 3 blood lineages, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, hyperferritinemia) • Diagnosis of HLH established by the multidisciplinary team caring for the patient
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 > 6L/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, either creatinine 2-2.9 times baseline, or urine output < 0.5 mL/kg/h for 12 hours • Neurological: GCS ≤ 13

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Exclusion Criteria

Moribund patient with refractory distributive shock: multi-organ failure requiring noradrenaline >2.5 μg/kg/min and imminent risk of death
Participation in another interventional research study
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
Patient not covered by social security
Patient under legal guardianship, tutelage, or curatorship
Minor patient
Pregnant or lactating woman
Recent vaccination with a live attenuated vaccine
Hypersensitivityor contraindication to dexamethasone or any of its excipients
Patients developing SAM within 15 days ofchemotherapy for cancer or malignant blood disease