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

Initial Treatment for Hemophagocytic Lymphohistiocytosis (HLH)

The initial treatment for Hemophagocytic Lymphohistiocytosis (HLH) should include etoposide (150 mg/m² twice weekly) and dexamethasone (10 mg/m² daily), with the addition of intravenous immunoglobulin (IVIG) up to 1.6 g/kg in split doses over 2-3 days. 1

Treatment Algorithm Based on HLH Subtype

Primary (Familial) HLH

• Start HLH-94 protocol immediately:
  • Etoposide 150 mg/m² twice weekly
  • Dexamethasone 10 mg/m² daily
  • IVIG up to 1.6 g/kg over 2-3 days
• Plan for hematopoietic stem cell transplantation (HSCT) as definitive treatment
• Continue treatment for 8 weeks, then transition to maintenance therapy while awaiting HSCT 1

Secondary HLH

Treatment depends on the underlying trigger:

EBV-Associated HLH

• For severe disease or rapid deterioration: Etoposide + dexamethasone + IVIG
• For less severe disease: Short course of corticosteroids with/without IVIG
• Add rituximab (375 mg/m² weekly for 2-4 doses) to clear EBV if it replicates in B cells
• Monitor ferritin, sCD25, cell counts, and EBV DNA to assess response 2

Malignancy-Associated HLH

• Most aggressive approach needed (worst prognosis subtype)
• Etoposide + dexamethasone + treatment of underlying malignancy
• Consider combined regimens that treat both HLH and malignancy (containing etoposide, cyclophosphamide, or methotrexate) 1

Macrophage Activation Syndrome (MAS-HLH)

• High-dose pulse methylprednisolone (1 g/day for 3-5 days)
• Add cyclosporine A (2-7 mg/kg/day) for insufficient response
• Consider anakinra (2-10 mg/kg/day subcutaneously in divided doses) 2

Infection-Associated HLH (non-EBV)

• Treat the underlying infection aggressively
• For severe disease: Add immunosuppressive therapy (corticosteroids ± etoposide)
• For infections targeting monocyte-macrophage system (Leishmania, Rickettsia, TB): Avoid HLH-94 protocol and focus on antimicrobial treatment 2

Monitoring and Dose Adjustments

• Weekly reevaluation of need for continued etoposide therapy
• Monitor ferritin, sCD25, cell counts, and viral DNA (if applicable) to assess treatment response
• Reduce etoposide dose for impaired renal function
• Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies 1

Critical Supportive Care

• Antimicrobial prophylaxis against Pneumocystis jirovecii and fungi
• Consider antiviral prophylaxis due to severe T-cell depletion
• Consider hospitalization in HEPA-filtered rooms to minimize infection risk
• Vigilant monitoring for secondary infections, a major cause of mortality 1

Treatment of Refractory HLH

For patients not responding to initial therapy:

• Anti-CD52 antibody (alemtuzumab)
• Cytokine adsorption using filter columns or plasma exchange
• JAK2 inhibitor (ruxolitinib) (off-label)
• Anti-IFN-γ antibody (emapalumab) 1

Important Caveats

1. Don't delay treatment if clinical suspicion is high - mortality in adult HLH ranges from 20-88%
2. Recognize that HLH can coexist with sepsis - consider HLH in patients with disproportionate inflammatory response
3. Secondary infections are a major cause of fatality - aggressive prophylaxis and monitoring are essential
4. Tailor treatment intensity to disease severity - not all patients need full HLH-94 protocol
5. Weekly reassessment is crucial - adjust therapy based on clinical and laboratory response 2, 1

The approach to HLH treatment has evolved significantly since the original HLH-94 protocol, with more nuanced strategies based on underlying triggers and disease severity. While etoposide and dexamethasone remain the backbone of therapy, early identification of the underlying cause and appropriate trigger-specific treatment are essential for improving outcomes.