What is the treatment for Hemophagocytic Lymphohistiocytosis (HLH)?

Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

The HLH-94 protocol, consisting of etoposide, dexamethasone, and cyclosporine A, is the recommended standard treatment for HLH, with individualized modifications based on the underlying trigger, disease severity, and patient characteristics. 1

Classification and Initial Approach

Treatment of HLH should be tailored based on:

1. Patient stability and disease severity:

   • Clinically stable patients: Identify and treat the HLH trigger
   • Deteriorating/unstable patients: Start corticosteroids (±IVIG)
   • Transient HLH responding to disease-specific treatment: Monitor closely 1

2. Type of HLH:

   • Primary (genetic) HLH: Requires full HLH-directed therapy followed by stem cell transplantation
   • Secondary HLH: Treatment depends on underlying cause (infection, malignancy, autoimmune disease)

Standard Treatment Protocol (HLH-94)

The HLH-94 protocol includes:

• Etoposide: Highly effective against T-cell proliferation and cytokine secretion

  • Standard dose: 150 mg/m² twice weekly
  • For adults (especially elderly): Consider reduced frequency (once weekly) and/or reduced dose (50-100 mg/m²) 1
  • Cumulative dose should stay below 2-3 g/m², particularly in non-malignancy HLH 1

• Dexamethasone: Suppresses inflammatory cytokine production

• Cyclosporine A: Added after 8 weeks in HLH-94 (or upfront in HLH-2004)

  • Note: HLH-94 remains the recommended standard despite HLH-2004 modifications 1

• Intrathecal therapy: Only for progressive neurological symptoms after 2 weeks or if abnormal CSF hasn't improved by then 1

Treatment Modifications Based on HLH Subtype

Malignancy-Associated HLH:

• Consider combined HLH-directed and malignancy-directed approach
• Etoposide has shown better survival compared to treatment directed only at underlying pathology 1
• Lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate may treat both HLH and the underlying neoplasm 1
• Consider allogeneic stem cell transplantation for consolidation in malignancy-associated HLH 1

Infection-Associated HLH:

• Aggressive treatment of the underlying infection is crucial
• For EBV-driven HLH: Consider rituximab (anti-B-cell therapy) 1
• Anti-infectious prophylaxis and screening (antifungal, pneumocystis jiroveci, aspergillus, EBV, CMV) 1

Autoimmune/Autoinflammatory HLH:

• Anti-interleukin-1 treatment can be used in addition to standard therapy 1

Stem Cell Transplantation

• Indications for allogeneic HSCT:

  • Primary (familial) HLH
  • Persistent or recurrent disease
  • High-risk malignancy-associated HLH 1

• Conditioning regimens:

  • No clear superiority of reduced-intensity conditioning over myeloablative conditioning in adults 1
  • Inactive HLH before transplantation strongly associated with better survival 1

Salvage Therapy for Refractory HLH

For patients not responding to initial therapy:

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

Monitoring Response to Treatment

Early response markers at day 7 of therapy predict outcomes:

• Improvement in soluble CD25 (sCD25) of at least 25% from pre-therapy levels
• Platelet count
• Absolute lymphocyte count
• Blood urea nitrogen 2

Prognosis

• 5-year survival with HLH-94 protocol: approximately 54% 3
• Primary HLH: 50% 5-year survival with HSCT; none survive without HSCT 3
• Malignancy-associated HLH: 30-day survival 56-70%, with T-cell lymphoma having worse prognosis than B-cell lymphoma 1

Important Considerations and Pitfalls

1. Early mortality risk factors:

   • Jaundice, edema, elevated creatinine 3
   • Failure to improve sCD25 levels by day 7 2

2. Treatment challenges in adults:

   • Chronic comorbidities may increase vulnerability to cytokine storm and chemotherapy toxicity
   • Requires more individualized approach than in pediatric patients 4

3. Interdisciplinary care:

   • Collaboration with rheumatologists, gastroenterologists, neurologists, transplant team, and pathologists is essential 4

4. Common pitfalls:

   • Delayed diagnosis and treatment initiation
   • Failure to identify and treat underlying trigger
   • Inadequate monitoring of response markers
   • Not considering HSCT in appropriate cases

The heterogeneity of HLH in adults necessitates a disease- and risk-adapted treatment approach with continuous reassessment of therapeutic measures to improve outcomes in this life-threatening condition.