All-Trans Retinoic Acid for the Treatment of Hemophagocytic Lymphohistiocytosis

An Open-Label Study Evaluating the Safety and Efficacy of All-Trans Retinoic Acid in Patients With Hemophagocytic Lymphohistiocytosis

This study is designed to evaluate the safety and preliminary efficacy of all-trans retinoic acid (ATRA) as an initial treatment for patients with active hemophagocytic lymphohistiocytosis (HLH). HLH is a severe hyperinflammatory syndrome caused by excessive activation of immune cells and uncontrolled cytokine release. Current treatment often requires intensive immunosuppressive or cytotoxic therapy, which may be associated with significant toxicity.

ATRA is an orally available agent that has been widely used in other hematologic diseases and has immunomodulatory effects. Preclinical studies suggest that ATRA may help control HLH-related inflammation and improve immune dysregulation. In this study, patients with newly diagnosed or treatment-naïve active HLH will receive ATRA-based initial therapy. The study will assess clinical response, changes in HLH-related inflammatory markers, organ function, viral or disease-related parameters when applicable, and treatment-related adverse events.

The goal of this study is to determine whether ATRA can provide a safe and feasible initial therapeutic approach for active HLH and support further clinical development of ATRA-based treatment strategies in this disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Hemophagocytic Lymphohistiocytosis (HLH)
• Intervention / Treatment: Drug: ATRA

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• Inclusion Criteria

  1. Age ≥18 years.
  2. Patients diagnosed with active hemophagocytic lymphohistiocytosis according to HLH-2004 diagnostic criteria or the investigator's clinical assessment.
  3. Newly diagnosed or treatment-naïve active HLH requiring initial HLH-directed therapy.
  4. Presence of active disease manifestations, including at least one of the following: persistent fever, cytopenia, hyperferritinemia, splenomegaly, hypofibrinogenemia and/or hypertriglyceridemia, elevated soluble CD25, hemophagocytosis, reduced or absent NK-cell activity, or other HLH-related organ involvement.
  5. Eastern Cooperative Oncology Group performance status of 0-3, or performance status considered acceptable by the investigator in the context of active HLH.
  6. Adequate ability to receive oral medication, or ability to receive ATRA through an appropriate enteral route.
  7. Expected survival of more than 48 hours in the judgment of the investigator.
  8. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use effective contraception during treatment and for an appropriate period after the last dose of ATRA.
  9. Ability to understand and willingness to sign written informed consent. For patients unable to provide consent because of disease severity, consent may be provided by a legally authorized representative according to local regulations.

• Exclusion Criteria

  1. Prior systemic HLH-directed therapy for the current HLH episode, including etoposide-based therapy, ruxolitinib, emapalumab, alemtuzumab, PD-1 blockade, or other investigational HLH-directed treatment. Short-term corticosteroids, supportive care, anti-infective therapy, or emergency treatment before enrollment may be allowed at the investigator's discretion.
  2. Known hypersensitivity to all-trans retinoic acid, tretinoin, retinoids, or any component of the study drug.
  3. Pregnant or breastfeeding women.
  4. Patients with acute promyelocytic leukemia or other diseases for which ATRA is being used as standard leukemia-directed therapy.
  5. Severe uncontrolled infection, shock, respiratory failure, bleeding, or organ failure that, in the investigator's judgment, would make participation unsafe or prevent assessment of study treatment.
  6. Severe hepatic dysfunction not primarily attributed to HLH, such as total bilirubin or transaminase levels considered unsafe for ATRA administration by the investigator.
  7. Severe renal dysfunction requiring dialysis before enrollment, unless considered related to HLH and acceptable by the investigator.
  8. Active intracranial hypertension, pseudotumor cerebri, or uncontrolled severe neurologic disease that may increase the risk of ATRA-related toxicity.
  9. Uncontrolled hypertriglyceridemia or other metabolic abnormality that, in the investigator's judgment, would make ATRA treatment unsafe.
  10. Concomitant use of vitamin A supplements, other systemic retinoids, or medications with unacceptable interaction risk that cannot be discontinued.
  11. Any other condition that, in the investigator's judgment, would interfere with patient safety, protocol compliance, or interpretation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment

Drug: ATRA; All-trans retinoic acid (ATRA) will be administered orally as frontline treatment for patients with active hemophagocytic lymphohistiocytosis (HLH). ATRA will be given at a dose of 45 mg/m²/day in two divided doses, according to the study protocol. Dose rounding, dose reduction, temporary interruption, or discontinuation will be allowed based on toxicity, organ function, and investigator assessment. Standard supportive care, anti-infective treatment, transfusion support, organ function support, and treatment of underlying triggers or diseases are permitted. Additional HLH-directed therapy or rescue treatment may be introduced at the investigator's discretion for patients with inadequate response, disease progression, or life-threatening clinical deterioration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ATRA Efficacy for HLH	Overall response rate will be assessed at Week 4 and week 8 after initiation of ATRA treatment. Overall response is defined as achievement of complete response, partial response, or HLH improvement. Complete response is defined as normalization of HLH-related clinical and laboratory abnormalities, including resolution of fever and splenomegaly, recovery of cytopenias, improvement of coagulation abnormalities, reduction of hyperferritinemia, absence of active central nervous system manifestations, and no sustained worsening of soluble CD25 levels. Partial response is defined as normalization of at least three HLH-related abnormalities. HLH improvement is defined as at least 50% improvement from baseline in at least three HLH-related abnormalities. HLH-related abnormalities to be assessed include fever, splenomegaly, central nervous system symptoms when present, complete blood count, fibrinogen and/or D-dimer, serum ferritin, and soluble CD25.	From enrollment to the end of treatment at 8 weeks
Adverse effects of ATRA	Safety will be assessed by the incidence, severity, seriousness, and relationship to study treatment of treatment-emergent adverse events. An adverse event is defined as any unfavorable and unintended sign, symptom, disease, or abnormal laboratory finding that occurs after initiation of ATRA treatment, whether or not considered related to ATRA. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Serious adverse events, grade 3 or higher adverse events, adverse events leading to dose interruption, dose reduction, treatment discontinuation, rescue HLH-directed therapy, hospitalization, or death will be recorded and summarized.	From enrollment to the end of treatment at 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival of HLH patients	Overall survival will be assessed from the date of initiation of ATRA treatment to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the date of last follow-up. Survival status will be recorded during the study treatment period and follow-up period.	From initiation of ATRA treatment up to 6 months

Collaborators and Investigators

• Sponsor: Beijing Anzhen Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: May 27, 2026
• First Submitted That Met QC Criteria: June 2, 2026
• First Posted (Actual): June 4, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Lymphatic Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Hemic and Lymphatic Diseases; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: ATRA-HLH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No