What is the initial treatment approach for Hemophagocytic Lymphohistiocytosis (HLH) when the underlying cause is unknown?

Initial Treatment of Hemophagocytic Lymphohistiocytosis (HLH) with Unknown Cause

For HLH with unknown underlying cause, initial treatment should include high-dose corticosteroids with etoposide, following the HLH-94/HLH-2004 protocol framework, while simultaneously pursuing diagnostic workup to identify potential triggers. 1

Initial Treatment Approach

First-line Therapy

• Corticosteroids:
  • High-dose pulse methylprednisolone 1 g/day for 3-5 consecutive days 1
  • OR dexamethasone if CNS involvement is suspected
• Etoposide (VP16):
  • Add to corticosteroids as part of initial therapy 1
  • Particularly important in severe cases with rapid progression
  • Dosing based on HLH-94/2004 protocols with adjustments for renal function

Additional First-line Agents

• Cyclosporine A:
  • 2-7 mg/kg/day (oral or IV in critical settings) 1
  • Can be added to the initial regimen or for insufficient response to steroids/etoposide

Supportive Care

• Aggressive supportive care is essential
• Frequent monitoring (at least every 12 hours in critically ill patients) 1
• Monitor ferritin, sCD25, cell counts to assess treatment response

Treatment Based on Suspected Triggers

Infection-Associated HLH

• Viral triggers (especially EBV):

  • Add rituximab (375 mg/m² weekly for 2-4 doses) if EBV-associated 1
  • Monitor EBV DNA levels (>10³ copies/mL considered relevant)
  • Note: EBV may infect T/NK cells, so rituximab cannot replace etoposide/steroids 1

• Bacterial/fungal triggers:

  • Targeted antimicrobial therapy is crucial
  • For pathogens targeting monocyte-macrophage system (Leishmania, Rickettsia, TB), specific antimicrobial treatment may be sufficient without full HLH-directed immunosuppression 1

Malignancy-Associated HLH

• If malignancy is suspected but not confirmed:
  • Etoposide is particularly important as it treats both HLH and potential underlying lymphoma 1
  • Lymphoma protocols containing etoposide, cyclophosphamide, or methotrexate may treat both conditions simultaneously 1

Rheumatic Disease-Associated HLH (MAS-HLH)

• If rheumatic disease is suspected:
  • High-dose corticosteroids remain first-line
  • Consider early addition of IL-1 blockade with anakinra (2-10 mg/kg/day in divided doses) 1, 2
  • Cyclosporine A is particularly effective in this context 2

Refractory HLH Management

• For inadequate response to initial therapy:
  • Consider adding anakinra (IL-1 blockade) 1, 2
  • Consider tocilizumab (IL-6 blockade) in selected cases 1
  • Alemtuzumab (anti-CD52) has shown efficacy as a salvage agent 1
  • Newer agents under investigation include ruxolitinib (JAK1/2 inhibitor) and emapalumab (anti-IFN-γ antibody) 1

Common Pitfalls and Caveats

1. Delayed recognition: HLH mortality remains high, especially in adults with underlying malignancies. Early diagnosis and treatment are critical 1, 3

2. Confusing with sepsis: HLH, multi-organ dysfunction syndrome, and sepsis can coexist. Consider HLH in patients with disproportionate inflammatory response to infection 1

3. Inadequate treatment intensity: Adult HLH often requires more aggressive initial therapy than pediatric protocols suggest 4

4. Missing the underlying trigger: Continuous diagnostic workup must occur simultaneously with treatment 3

5. One-size-fits-all approach: Unlike pediatric HLH, adult HLH is heterogeneous and requires a more individualized approach based on suspected triggers and disease severity 4

The mortality of untreated HLH approaches 100%, and even with treatment, mortality remains high in adults. Consultation with an HLH reference center is strongly recommended whenever possible 1.