Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

Introduction to HLH Treatment

• 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, 2

Treatment Algorithm Based on Clinical Presentation

• For deteriorating or unstable patients: Start corticosteroids with or without intravenous immunoglobulin (IVIG) immediately 2
• For transient HLH responding to disease-specific treatment: Watchful waiting approach 2

Primary Treatment Components

• Dexamethasone: To suppress inflammatory cytokine production 1, 2
• Etoposide: Highly effective against T-cell proliferation and cytokine secretion 1, 2
• 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, 2
• 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, 2
• Intrathecal therapy: Only for progressive neurological symptoms after 2 weeks of therapy or if abnormal cerebrospinal fluid has not improved 1, 2

Treatment Based on HLH Subtype

• Complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT) for primary (genetic) HLH 1
• Inactive HLH before transplantation strongly correlates with better survival 1
• Malignancy-associated HLH: Combined approach with HLH-directed and malignancy-directed therapy 3
• Etoposide-containing regimens show better survival compared to treatment directed only at underlying pathology in malignancy-associated HLH 3, 4
• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate as they may treat both HLH and underlying neoplasm 4, 5
• AlloSCT may be considered as consolidation in patients with HLH in the context of hematologic malignancy 3
• Infection-associated HLH: Anti-infectious treatment is pivotal 3, 4
• For EBV-associated HLH: Consider anti-B-cell therapy (rituximab) for highly replicative EBV infection 3, 6
• Autoimmune/autoinflammatory-associated HLH: Anti-interleukin-1 treatment in addition to glucocorticosteroids, cyclosporin A, and etoposide 5

Refractory/Relapsed HLH

• Treatment intensification options include chemotherapy intensification 2
• Anti-CD52 antibody (alemtuzumab) 2, 5
• Cytokine adsorption using filter columns or plasma exchange 2
• JAK2 inhibitor (ruxolitinib) - off-label use 2
• Anti-IFN-γ antibody (emapalumab) 2

Prognosis

• Factors associated with higher mortality: Malignancy-associated HLH (particularly T-cell lymphoma) 3
• HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival 1

Diagnosis and Treatment of Hemophagocytic Lymphohistiocytosis (HLH)

Diagnostic Criteria

• The American Society of Hematology recommends that HLH is diagnosed using the HLH-2004 criteria, which requires either molecular diagnosis consistent with HLH or fulfillment of 5 of the 8 following criteria, including fever, splenomegaly, cytopenias, hypertriglyceridemia, hemophagocytosis, low or absent NK cell activity, elevated ferritin, and elevated soluble CD25 7
• The European Hematology Association notes that hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions like sepsis 7
• HLH can present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome, according to the American College of Physicians 8, 9

Classification of HLH

• Primary (genetic) HLH is most common in children but can occur in adolescents and young adults, and is caused by mutations affecting lymphocyte cytotoxicity and immune regulation, as stated by the American Academy of Pediatrics 8, 9
• Secondary (acquired) HLH is most common in adults and can be triggered by infections, malignancies, autoinflammatory/autoimmune disorders, and novel immunotherapies, according to the American Society of Clinical Oncology 8, 9

Treatment Approach

• The National Comprehensive Cancer Network recommends treating the underlying cause while simultaneously initiating HLH-directed therapy, with first-line treatment being high-dose corticosteroids 10
• The European Society for Medical Oncology suggests that second-line treatment should be based on clinical response and HLH subtype 10
• For malignancy-associated HLH, the American Society of Hematology recommends a combined approach with HLH-directed and malignancy-directed therapy, with etoposide-containing regimens showing better survival compared to treatment directed only at underlying pathology 11, 12

Prognosis and Monitoring

• The American College of Physicians states that frequent clinical reassessment and monitoring of inflammatory parameters and organ function are essential, with malignancy-associated HLH having a poor prognosis, including 30-day survival of 56-70%, median overall survival of 36-230 days, and 3-year survival of 18-55% depending on subtype 13, 12
• The American Society of Hematology notes that factors associated with higher mortality include shock at ICU admission, platelet count <30 g/L, and HLH associated with malignancies 10

Initial Treatment for Hemophagocytic Lymphohistiocytosis (HLH)

Treatment Based on HLH Subtype

• Stem cell transplantation should be considered as consolidation in hematologic malignancy-associated HLH, according to the Haematologica guideline 14
• Strongly consider postponing subsequent chemotherapy blocks or interrupting maintenance therapy, except in cases of neoplasm relapse, as recommended by the Haematologica guideline 14
• Implement rigorous anti-infectious prophylaxis and regular surveillance for secondary infections, as suggested by the Haematologica guideline 14
• The necessity and extent of HLH-directed treatment depends on clinical severity, according to the Haematologica guideline 14
• Implement rigorous anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci) and regular surveillance for secondary infections (aspergillus, EBV, CMV), as recommended by the Haematologica guideline 15

Prognostic Considerations

• Malignancy-associated HLH has 30-day survival of 56-70%, median overall survival of 36-230 days, and 3-year survival of 18-55%, according to the Haematologica guideline 14

Management of Secondary HLH Prior to Trigger Identification

Initial Treatment Strategy

• Initiate high‑dose corticosteroids immediately in any deteriorating or unstable patient; if organ failure is imminent or there is inadequate response within 24–48 h, escalate to dexamethasone 10 mg/m² daily plus etoposide while a rapid diagnostic work‑up proceeds. 16
• The decision to start HLH‑directed therapy should be based on clinical severity rather than waiting for trigger identification, because untreated hyperinflammation carries a higher mortality than the risks of therapy. 16
• For patients with severe disease and imminent organ failure, begin dexamethasone 10 mg/m² daily together with etoposide according to the modified HLH‑94 protocol without delay. 16
• Add intravenous immunoglobulin (IVIG) 1.6 g/kg divided over 2–3 days to provide additional anti‑inflammatory effects (complement inhibition, Fc‑receptor blockade, cytokine neutralization). 16

Adjunctive Immunosuppression

• Introduce cyclosporine A at 2–7 mg/kg/day when the immediate response to pulse steroids is insufficient, with therapeutic drug‑level monitoring to ensure adequate T‑cell suppression. 16

Etoposide Dosing and Safety

• The above etoposide recommendations are based on the modified HLH‑94 protocol. 16

Guidance on Avoiding Common Pitfalls

• Do not postpone corticosteroids or etoposide for isolated liver dysfunction; dexamethasone dose does not need adjustment for hyperbilirubinemia or elevated transaminases. 16
• Do not withhold etoposide because of pancytopenia in severe HLH; the mortality risk from untreated hyperinflammation outweighs the potential worsening of cytopenias. 16

Refractory Disease Options

• If the initial regimen fails while awaiting trigger identification, consider escalation to: