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

Treatment of Primary Hemophagocytic Lymphohistiocytosis (HLH)

Primary HLH requires immediate treatment with the HLH-94 protocol (dexamethasone and etoposide) followed by allogeneic hematopoietic stem cell transplantation (HSCT) for definitive cure. 1

Initial Treatment Approach

First-Line Therapy

• Dexamethasone: 10 mg/m² daily to suppress inflammatory cytokine production 1
• Etoposide: 150 mg/m² twice weekly initially 1
  • Dose reduction required for impaired renal function
  • Consider reduced frequency and/or dose in adults, especially elderly
• IV immunoglobulin (IVIG): Consider adding up to 1.6 g/kg in split doses over 2-3 days 2

Critical Considerations

• Rapid clinical deterioration mandates immediate etoposide treatment without delay 1
• Weekly reevaluation of continued etoposide therapy necessity 2
• Monitor treatment response using:
  • Ferritin levels
  • sCD25 (soluble IL-2 receptor)
  • Cell counts
  • Viral DNA (if applicable) 1

Maintenance and Long-Term Management

Duration of Initial Therapy

• Most patients require 8 weeks of etoposide therapy 2
• Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies 1

Maintenance Therapy

• After initial 8 weeks, HLH-94 maintenance therapy is recommended for those awaiting HSCT 2
• Cyclosporine A may be added after 8 weeks (can be replaced by tacrolimus with careful drug level monitoring) 1

Hematopoietic Stem Cell Transplantation

HSCT Indications and Timing

• Primary (familial) HLH requires HSCT for definitive cure 1
• Inactive HLH before transplantation strongly correlates with better survival 2
• Both reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) are options 2

Donor Selection

• HLA typing of close relatives should include screening for the same gene mutations to avoid a stem cell source with identical pathogenic biallelic mutations 2

Infection Prevention and Management

Prophylaxis

• Antimicrobial prophylaxis against Pneumocystis jirovecii and fungi is essential 2, 1
• Consider antiviral prophylaxis due to severe T-cell depletion 2
• Consider hospitalization in HEPA-filtered rooms 2

Monitoring

• Secondary infections are a major cause of mortality during HLH treatment 1
• Vigilant monitoring for infections is crucial, especially with prolonged cytopenia 2

Salvage Therapy for Refractory Disease

For patients not responding to initial therapy, consider:

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

Prognostic Factors and Pitfalls

Poor Prognostic Factors

• Delayed diagnosis and treatment 1
• Inadequate etoposide dose adjustment 1
• Missing underlying triggers 1
• Overlooking CNS involvement 1, 3

Common Pitfalls to Avoid

• Underestimating infection risk 1
• Exceeding 2-3 g/m² cumulative dose of etoposide 1
• Failing to screen donors for the same genetic mutations 2
• Delaying HSCT consultation in primary HLH 2

Primary HLH is invariably fatal without appropriate treatment, but with prompt initiation of immunochemotherapy followed by HSCT, it has become a potentially curable disease with survival rates exceeding 50% 4.