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

Initial Treatment for Hemophagocytic Lymphohistiocytosis (HLH)

Start high-dose corticosteroids immediately for all HLH patients, with dexamethasone or methylprednisolone 1g/day for 3-5 consecutive days being the first-line treatment, while simultaneously addressing the underlying trigger. 1, 2

Immediate Management Based on Clinical Stability

For deteriorating or unstable patients:

• Begin corticosteroids with or without intravenous immunoglobulin (IVIG) immediately without waiting for diagnostic confirmation 1
• If no response within 24-48 hours, add etoposide at reduced adult dosing (50-100 mg/m² weekly rather than the pediatric 150 mg/m² twice weekly) 2
• Frequent clinical reassessment every 12 hours with monitoring of inflammatory parameters and organ function 2

For stable patients with transient HLH:

• Watchful waiting may be appropriate if the condition responds to disease-specific treatment alone 1

The HLH-94 Protocol: Standard of Care

The HLH-94 protocol remains the recommended standard treatment, consisting of: 1

• Dexamethasone (5-10 mg/m²) to suppress inflammatory cytokine production
• Etoposide (highly effective against T-cell proliferation and cytokine secretion)
• Cyclosporine A (added after 8 weeks, not upfront as in HLH-2004)
• Intrathecal therapy (only for progressive neurological symptoms after 2 weeks or persistent abnormal cerebrospinal fluid)

Critical dosing considerations for adults: 1

• Reduce etoposide frequency to once weekly instead of twice weekly
• Reduce etoposide dose to 50-100 mg/m² instead of 150 mg/m² due to vulnerability to end-organ damage
• Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies

Treatment Modifications by HLH Subtype

Primary (Genetic) HLH: 1

• Complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT)
• Achieving inactive HLH before transplantation strongly correlates with better survival

Malignancy-Associated HLH: 1

• Combined approach with both HLH-directed and malignancy-directed therapy
• Etoposide-containing regimens show better survival compared to treatment directed only at underlying pathology
• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate as they may treat both conditions simultaneously
• AlloSCT may be considered as consolidation

Infection-Associated HLH: 1, 3

• Anti-infectious treatment is pivotal and must not be delayed
• For EBV-associated HLH: Add rituximab (375 mg/m² once weekly for 2-4 doses) to clear the viral reservoir
• Monitor ferritin, soluble CD25, cell counts, and EBV DNA levels to guide rituximab dosing
• For tuberculosis-associated HLH: Combine anti-TB therapy with dexamethasone and IVIG 4

Autoimmune/Autoinflammatory-Associated HLH (Macrophage Activation Syndrome): 1, 2

• First-line: High-dose corticosteroids
• Second-line: Cyclosporine A (2-7 mg/kg/day) and/or anakinra (2-10 mg/kg/day subcutaneously)
• Consider tocilizumab as alternative
• Anti-interleukin-1 treatment in addition to glucocorticosteroids, cyclosporin A, and etoposide for severe cases

Second-Line and Refractory Treatment Options

If inadequate response to initial therapy: 1, 2

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

Critical Supportive Care Measures

Essential monitoring and support: 2

• Ventilation, vasopressors, renal replacement therapy, and transfusions as needed
• Rigorous anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci)
• Regular surveillance for secondary infections (aspergillus, EBV, CMV) 1

Common Pitfalls to Avoid

Do not delay treatment: 2, 5

• Delayed diagnosis and treatment significantly increases mortality
• Start steroids immediately even before complete diagnostic workup in deteriorating patients
• Do not wait for bone marrow biopsy showing hemophagocytosis, as this finding is neither sensitive nor specific 1

Do not directly apply pediatric protocols to adults: 1, 2

• Adults, especially elderly patients, require dose reductions and frequency modifications
• Adult HLH is more heterogeneous and requires tailoring to underlying condition

Do not neglect the underlying trigger: 2, 6

• Inadequate use of antimicrobials when infection is the primary trigger is a critical error
• Treatment of HLH alone without addressing the underlying cause leads to poor outcomes

Prognostic Factors

Higher mortality is associated with: 1, 2

• Malignancy-associated HLH (particularly T-cell lymphoma) with 30-day survival of 56-70%
• Shock at ICU admission
• Platelet count <30 g/L
• Median overall survival of 36-230 days in malignancy-associated HLH

The HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival in genetic HLH. 1