What is the appropriate treatment approach for a patient diagnosed with secondary hemophagocytic lymphohistiocytosis (sHLH)?

Treatment Approach for Secondary Hemophagocytic Lymphohistiocytosis (sHLH)

The treatment of secondary hemophagocytic lymphohistiocytosis (sHLH) must be tailored to the underlying trigger, with a combination of etoposide, dexamethasone, and IVIG forming the cornerstone of therapy for most cases, while simultaneously treating the underlying cause. 1

Case Scenario

A 45-year-old male presents to the emergency department with a 2-week history of persistent high fever (39.5°C), fatigue, and abdominal discomfort. Laboratory findings reveal:

• Bicytopenia (hemoglobin 8.5 g/dL, platelets 65,000/μL)
• Elevated ferritin (15,000 μg/L)
• Hypertriglyceridemia (450 mg/dL)
• Hypofibrinogenemia (120 mg/dL)
• Elevated soluble IL-2 receptor (sCD25) at 5,000 U/mL

Bone marrow biopsy shows hemophagocytosis. Further workup reveals EBV viremia with high viral load. The patient is diagnosed with EBV-triggered secondary HLH.

Diagnostic Approach

Diagnosis requires fulfilling 5 of 8 HLH-2004 criteria:

• Fever ≥38.5°C
• Splenomegaly
• Cytopenias affecting ≥2 lineages
• Hypertriglyceridemia and/or hypofibrinogenemia
• Hemophagocytosis in bone marrow, spleen, or lymph nodes
• Low/absent NK cell activity
• Ferritin ≥500 μg/L (often >10,000 μg/L in adults)
• Elevated sCD25 ≥2400 U/mL 1

Treatment Algorithm for sHLH

Step 1: Identify and Treat the Underlying Trigger

• Malignancy-associated HLH: Requires aggressive treatment due to worst prognosis (30-day survival 56-70%) 1
• Infection-associated HLH:
  • Viral (especially EBV, CMV, HIV): Specific antiviral therapy plus HLH-directed therapy 2
  • Bacterial/fungal/parasitic: Targeted antimicrobial therapy 2

Step 2: Initiate HLH-Directed Therapy Based on Severity and Trigger

For Severe Disease (rapid deterioration, high ferritin, multi-organ dysfunction):

1. Etoposide-based regimen (HLH-94 protocol):
   • Etoposide 150 mg/m² twice weekly (consider dose reduction in elderly or renal impairment)
   • Dexamethasone 10 mg/m² daily (to suppress inflammatory cytokines)
   • IV immunoglobulin (IVIG) 1.6 g/kg in split doses over 2-3 days 1
   • Weekly reevaluation of need for continued etoposide therapy
   • Most patients require 8 weeks of etoposide 2

For Less Severe Disease or Improving Clinical Manifestations:

1. Conservative approach:
   • Short course of corticosteroids with/without IVIG
   • Monitor ferritin, sCD25, cell counts, and viral DNA (if applicable) 2

For EBV-HLH (as in our case scenario):

1. Standard HLH therapy plus:
   • Rituximab (375 mg/m² once weekly, 2-4 times) to clear B-cell viral reservoir
   • Note: If EBV infects T/NK cells, rituximab cannot replace anti-T-cell therapy 2
   • Monitor EBV DNA levels (>10³ copies/mL relevant for HLH development) 2

Step 3: Supportive Care and Infection Prevention

• Antimicrobial prophylaxis against Pneumocystis jirovecii and fungi
• Consider antiviral prophylaxis due to T-cell depletion
• Consider HEPA-filtered room hospitalization
• Vigilant monitoring for secondary infections (major cause of mortality) 2, 1

Step 4: Evaluate Response and Consider Salvage Therapy

• Monitor ferritin, sCD25, cell counts, and clinical parameters
• For refractory cases, consider:
  • Anti-CD52 antibody (alemtuzumab)
  • Cytokine adsorption or plasma exchange
  • JAK2 inhibitor (ruxolitinib) - especially with renal dysfunction 3
  • Anti-IFN-γ antibody (emapalumab)
  • Anakinra (IL-1 receptor antagonist) - particularly effective in some sHLH cases 4, 5

Step 5: Consider Hematopoietic Stem Cell Transplantation (HSCT)

• Indications:
  • Primary (familial) HLH
  • Persistent or recurrent disease
  • High-risk malignancy-associated HLH 1

Special Considerations and Pitfalls

1. Avoid treatment delay: Mortality in adult HLH ranges from 20-88%; early intervention is critical 2

2. Etoposide toxicity:

   • Keep cumulative dose below 2-3 g/m² to minimize risk of secondary malignancies
   • Consider dose reduction in renal impairment 1
   • Ruxolitinib may be an alternative in cases with acute renal injury 3

3. Secondary infections:

   • Major cause of mortality during HLH treatment
   • Aggressive antimicrobial prophylaxis essential 2

4. Balancing immunosuppression:

   • For infections that target monocyte-macrophage system (Leishmania, Rickettsia, tuberculosis), avoid excessive immunosuppression and focus on antimicrobial treatment 2

5. Alternative therapies:

   • IVIG and corticosteroids alone have shown efficacy in some cases (76% resolution rate in one study) 6
   • Anakinra may allow avoidance of etoposide in selected cases 4

For our case scenario with EBV-triggered sHLH, the recommended approach would be:

1. Initiate etoposide, dexamethasone, and IVIG per HLH-94 protocol
2. Add rituximab to target EBV in B cells
3. Implement infection prophylaxis
4. Monitor response through clinical parameters, ferritin, sCD25, and EBV DNA levels
5. Adjust therapy based on response

This approach addresses both the hyperinflammatory state and the underlying trigger, maximizing chances for survival and recovery.