What is the treatment for Hemophagocytic Lymphohistiocytosis (HLH)?

Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

The HLH-94 protocol, consisting of etoposide, dexamethasone, cyclosporine A, and intrathecal therapy, is the recommended standard treatment for HLH, with treatment needing to be tailored according to the underlying condition and HLH-initiating trigger in adults. 1

Treatment Algorithm Based on Clinical Presentation

Initial Assessment and Stabilization

• For clinically stable patients: Identify and treat the underlying HLH trigger (infection, malignancy, autoimmune/autoinflammatory condition, drug-induced) 1, 2
• For deteriorating or unstable patients: Start corticosteroids with or without intravenous immunoglobulin (IVIG) immediately 1
• For transient HLH responding to disease-specific treatment: Watchful waiting approach 1

Primary Treatment Components

HLH-94 Protocol (Standard of Care)

• Dexamethasone: To suppress inflammatory cytokine production 1
• Etoposide: Highly effective against T-cell proliferation and cytokine secretion 1
  • For adults, especially elderly patients: Consider reduced etoposide frequency (once weekly instead of twice weekly) and/or reduced dosing (50-100 mg/m² instead of 150 mg/m²) due to vulnerability to end-organ damage 1
  • Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies, particularly in non-malignancy associated HLH 1
• Cyclosporine A: Added after 8 weeks in HLH-94 (not upfront as in HLH-2004) 1
• Intrathecal therapy: Only for progressive neurological symptoms after 2 weeks of therapy or if abnormal cerebrospinal fluid has not improved 1

Treatment Based on HLH Subtype

Primary (Genetic) HLH

• Complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT) 1, 2
• No patients with familial disease survive without HSCT 3
• Inactive HLH before transplantation strongly correlates with better survival 1

Secondary (Acquired) HLH

• Malignancy-associated HLH:

  • Combined approach with HLH-directed and malignancy-directed therapy 1, 2
  • Etoposide-containing regimens show better survival compared to treatment directed only at underlying pathology 1
  • Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate as they may treat both HLH and underlying neoplasm 1
  • AlloSCT may be considered as consolidation in patients with HLH in the context of hematologic malignancy 1

• Infection-associated HLH:

  • Anti-infectious treatment is pivotal 1
  • For EBV-associated HLH: Consider anti-B-cell therapy (rituximab) for highly replicative EBV infection 1

• Autoimmune/autoinflammatory-associated HLH:

  • Anti-interleukin-1 treatment in addition to glucocorticosteroids, cyclosporin A, and etoposide 1

Refractory/Relapsed HLH

• Treatment intensification options include:
  • Chemotherapy intensification 1
  • Anti-CD52 antibody (alemtuzumab) 1
  • Cytokine adsorption using filter columns or plasma exchange 1
  • JAK2 inhibitor (ruxolitinib) - off-label use 1
  • Anti-IFN-γ antibody (emapalumab) 1

Monitoring and Prognosis

• Early response markers by day 7 of therapy strongly predict outcomes 4
• Key prognostic indicators include:
  • Improvement in soluble CD25 (sCD25) of less than 25% from pre-therapy levels 4
  • Absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen 4
• Factors associated with higher mortality:
  • Jaundice, edema, and elevated creatinine within first 2 months 3
  • Malignancy-associated HLH (particularly T-cell lymphoma) 1, 2

Important Considerations and Caveats

• HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival 1, 3
• Adult HLH requires more individualized approach than pediatric HLH due to heterogeneity, comorbidities, and varied triggers 5
• Interdisciplinary care is essential for successful treatment 5
• Patients with CNS involvement require special attention as they have worse outcomes 3
• Early identification of poor responders (by day 7) may allow for earlier implementation of alternative therapeutic strategies 4