What is the recommended initial treatment protocol for hemophagocytic lymphohistiocytosis (HLH)?

Initial Treatment Protocol for Hemophagocytic Lymphohistiocytosis (HLH)

The HLH-94 protocol—consisting of dexamethasone, etoposide, cyclosporine A, and intrathecal therapy (when indicated)—remains the recommended standard of care for initial treatment of HLH, with treatment intensity and components tailored to disease severity and underlying trigger. 1

Immediate Treatment Based on Clinical Stability

For Deteriorating or Unstable Patients

• Initiate corticosteroids immediately, with or without intravenous immunoglobulin (IVIG) 1
• If imminent organ failure is present, immediately administer dexamethasone 10 mg/m² daily combined with etoposide using the modified HLH-94 protocol 2, 3
• Reassess clinical status at least every 12 hours to determine if escalation is needed 2, 4

For Clinically Stable Patients

• Identify and treat the HLH trigger first (infection, malignancy, autoimmune disease) 1
• For mild-to-moderate disease, start with prednisolone 1-2 mg/kg/day or dexamethasone 5-10 mg/m² as monotherapy 2, 4
• Add IVIG 1.6 g/kg divided over 2-3 days for anti-inflammatory effects 2

For Transient HLH Responding to Disease-Specific Treatment

• Watchful waiting approach with close monitoring 1

Core HLH-94 Protocol Components

Dexamethasone

• Standard dose: 10 mg/m² daily for severe disease 1, 4
• Suppresses inflammatory cytokine production and activated T-cell proliferation 3
• No dose adjustment needed for isolated liver dysfunction 4

Etoposide

• Standard dose: 150 mg/m² twice weekly in the original HLH-94 protocol 5
• For adults, especially elderly patients: reduce frequency to once weekly and/or reduce dose to 50-100 mg/m² due to vulnerability to end-organ damage from both cytokine storm and chemotherapy 1, 3
• Critical: The presence of pancytopenia should NOT delay etoposide administration in severe HLH, as mortality from untreated hyperinflammation exceeds the risk of worsening cytopenias 2
• Keep cumulative dose below 2-3 g/m² to minimize risk of secondary malignancies, particularly in non-malignancy HLH 1, 3
• Requires dose reduction for renal impairment but NOT for isolated liver dysfunction 4

Cyclosporine A

• HLH-94 protocol adds cyclosporine A after 8 weeks, not upfront 1
• Early addition (upfront) in HLH-2004 showed trend toward reduced pre-transplant mortality (27% to 19%, p=0.064) but was not statistically significant and is associated with more side effects 1
• Add cyclosporine A 2-7 mg/kg/day earlier if inadequate response to pulse steroids, with therapeutic drug monitoring 2, 4

Intrathecal Therapy

• Only indicated for progressive neurological symptoms after 2 weeks of therapy OR if abnormal cerebrospinal fluid has not improved by then 1
• Consists of methotrexate and corticosteroids 5

Treatment Duration and Monitoring

• Standard intensive phase: 8 weeks with etoposide-based therapy 2, 3, 4
• Weekly reevaluation of the need for continued etoposide therapy 2, 3, 4
• Maintenance therapy with corticosteroids and cyclosporine for patients with residual disease after 8 weeks or those awaiting allogeneic stem cell transplantation 2, 3, 4

Treatment Modifications by HLH Subtype

Malignancy-Associated HLH

• Etoposide-containing regimens show significantly better survival compared to treatment directed only at underlying malignancy 2, 3
• Treat the underlying malignancy concurrently with HLH-directed therapy 2, 3
• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate as they may treat both conditions 3

Infection-Associated HLH

• Anti-infectious treatment is pivotal and must be initiated immediately 3
• For EBV-associated HLH, consider rituximab for highly replicative EBV infection 3

Autoimmune/Autoinflammatory-Associated HLH (MAS-HLH)

• Start with high-dose pulse methylprednisolone 1 g IV daily for 3-5 days as first-line 2, 4
• Add anakinra 2-10 mg/kg/day subcutaneously (divided doses) for steroid-refractory cases 2, 4
• Consider anti-interleukin-1 treatment in addition to standard HLH therapy 3

Primary (Genetic) HLH

• Complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation 3
• Inactive HLH before transplantation strongly correlates with better survival 3

Essential Supportive Care

• Administer prophylaxis against Pneumocystis jirovecii, fungi, and viruses throughout HLH treatment 2, 4
• Monitor vigilantly for fever, persistent symptoms despite antibiotics, or unduly prolonged cytopenia after chemotherapy 2
• Consider hospitalization in HEPA-filtered units to reduce infection risk 4

Refractory/Relapsed HLH Options

• Alemtuzumab (anti-CD52 antibody) 1, 3
• Ruxolitinib (JAK2 inhibitor, off-label) 1, 3
• Emapalumab (anti-IFN-γ antibody) 1, 3
• Cytokine adsorption using filter columns or plasma exchange 1, 3

Critical Pitfalls to Avoid

• Do NOT delay etoposide in severe HLH due to pancytopenia—untreated hyperinflammation is more lethal 2
• Do NOT apply a "one-size-fits-all" approach in adults—the heterogeneity of adult HLH requires tailoring to underlying trigger, disease severity, and comorbidities 1, 6
• Do NOT omit infection prophylaxis—secondary infections are a leading cause of mortality 2, 4
• Do NOT continue etoposide without weekly reassessment—stopping when no longer needed minimizes cumulative toxicity 2, 3, 4