What is the initial treatment for Hemophagocytic Lymphohistiocytosis (HLH)?

Initial Treatment for Hemophagocytic Lymphohistiocytosis (HLH)

High-dose corticosteroids (methylprednisolone 1g/day for 3-5 consecutive days) should be initiated immediately as first-line treatment for HLH, with simultaneous aggressive treatment of any underlying trigger. 1

Treatment Algorithm by Clinical Severity

Rapidly Deteriorating or Unstable Patients

• Start corticosteroids immediately with or without intravenous immunoglobulin (IVIG 1.6 g/kg over 2-3 days) 2, 3
• For patients not responding within 24-48 hours, add etoposide (consider reduced dose of 50-100 mg/m² weekly in adults with comorbidities) 1
• The HLH-94 protocol (etoposide + dexamethasone + cyclosporine A + intrathecal therapy) remains the standard for severe cases requiring treatment intensification 2

Stable Patients with Transient HLH

• Watchful waiting may be appropriate if the patient responds to disease-specific treatment alone 2
• However, frequent clinical reassessment (at least every 12 hours) with monitoring of inflammatory parameters is essential 1

Treatment Based on HLH Subtype

Infection-Associated HLH

• Anti-infectious treatment is pivotal and must be initiated simultaneously with HLH-directed therapy 2
• For EBV-associated HLH: add rituximab 375 mg/m² once weekly for 2-4 doses to clear the viral reservoir 1, 3
• Monitor ferritin, soluble CD25, cell counts, and EBV DNA levels to guide rituximab dosing 3
• For CMV or tuberculosis-associated HLH: specific antimicrobial therapy (ganciclovir/valganciclovir or anti-TB therapy) combined with dexamethasone 4, 5

Malignancy-Associated HLH

• Combined approach targeting both HLH and the underlying malignancy is mandatory 2
• Etoposide-containing regimens show superior survival compared to treatment directed only at the malignancy 2
• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate as they may treat both conditions simultaneously 2
• Stem cell transplantation should be considered as consolidation in hematologic malignancy-associated HLH 6, 2

Autoimmune/Autoinflammatory-Associated HLH (MAS-HLH)

• First-line: high-dose corticosteroids 1
• Second-line options: cyclosporine A (2-7 mg/kg/day), anakinra (2-10 mg/kg/day SC), or tocilizumab 1

HLH During Chemotherapy

• Strongly consider postponing subsequent chemotherapy blocks or interrupting maintenance therapy, except in cases of neoplasm relapse 6
• The necessity and extent of HLH-directed treatment depends on clinical severity 6
• Implement rigorous anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci) and regular surveillance for secondary infections (aspergillus, EBV, CMV) 6

Second-Line Treatment for Inadequate Response

If corticosteroids alone are insufficient:

• Cyclosporine A (2-7 mg/kg/day) 1
• Anakinra (2-10 mg/kg/day subcutaneously) 1
• Etoposide (if not already initiated) 1, 2

Refractory HLH Options

For patients failing standard therapy:

• Alemtuzumab (anti-CD52 antibody) 2
• Ruxolitinib (JAK2 inhibitor, off-label) 2
• Emapalumab (anti-IFN-γ antibody) 2
• Cytokine adsorption or plasma exchange 2

Critical Supportive Care

• Ventilation, vasopressors, renal replacement therapy, and transfusions as needed 1
• Frequent clinical reassessment at least every 12 hours 1
• Monitor inflammatory parameters and organ function continuously 1

Common Pitfalls to Avoid

• Delayed diagnosis and treatment significantly increases mortality 2
• Do not apply pediatric protocols directly to adults without dose adjustments, particularly for etoposide 2
• In adults, especially elderly patients, reduce etoposide frequency (once weekly instead of twice weekly) and/or dosing (50-100 mg/m² instead of 150 mg/m²) to prevent end-organ damage 2
• Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies 2
• Never delay HLH-specific treatment while working up for differential diagnosis in critically ill patients 5
• Inadequate antimicrobial therapy when infection is the primary trigger is a critical error 2

Prognostic Considerations

• Factors associated with higher mortality: shock at ICU admission, platelet count <30 g/L, and malignancy-associated HLH (particularly T-cell lymphoma) 1, 2
• Malignancy-associated HLH has 30-day survival of 56-70%, median overall survival of 36-230 days, and 3-year survival of 18-55% 6, 2
• Inactive HLH before transplantation strongly correlates with better survival in primary HLH 2