What is the treatment for Hemophagocytic Lymphohistiocytosis (HLH) in pediatric patients?

Treatment of Hemophagocytic Lymphohistiocytosis (HLH) in Children

Initiate immediate treatment with dexamethasone 10 mg/m²/day combined with etoposide 150 mg/m² twice weekly for the first 2 weeks, then weekly, while simultaneously treating the underlying trigger. 1

Initial Treatment Protocol

The cornerstone of pediatric HLH treatment is the HLH-94/HLH-2004 protocol, which has improved survival from nearly uniformly fatal to >50% long-term survival. 2 This protocol consists of:

Core immunosuppressive regimen:

• Dexamethasone 10 mg/m²/day to suppress inflammatory cytokine production 1
• Etoposide 150 mg/m² twice weekly for 2 weeks, then weekly - highly effective against T-cell proliferation and cytokine secretion 1
• Cyclosporine A 2-7 mg/kg/day - added after 8 weeks in HLH-94 protocol, or included upfront in HLH-2004 protocol 1, 2

Critical consideration: Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies. 1

Treatment Algorithm Based on Clinical Severity

For rapidly deteriorating or unstable patients:

• Start the full HLH-94 protocol immediately with etoposide, dexamethasone, and consideration of adding IVIG 1
• Transfer to intensive care unit for supportive care 1
• Frequent clinical reassessment (at least every 12 hours) and monitoring of inflammatory parameters and organ function 3

For stable patients with transient HLH:

• Watchful waiting may be considered if responding well to disease-specific treatment alone 1, 2
• Maintain a low threshold to initiate full protocol if deterioration occurs 1

Etiology-Specific Treatment Modifications

Infection-Associated HLH

Anti-infectious treatment is pivotal and must be initiated immediately alongside HLH-directed therapy. 1, 2

• Implement rigorous anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci) 4, 2
• Regular surveillance for secondary infections or reactivations (aspergillus, EBV, CMV) 4, 2
• In some cases of secondary HLH with mild to moderate disease activity, treatment with steroids alone or regimens without cytotoxic drugs may result in resolution 5

EBV-Associated HLH

• Add rituximab (anti-CD20 antibody) 375 mg/m² once weekly for 2-4 doses to clear the viral reservoir 1
• Monitor EBV DNA levels, ferritin, and soluble CD25 to guide the number of rituximab doses 1
• Anti-B-cell therapy should be strongly considered in highly replicative EBV infection 4, 2

Malignancy-Associated HLH

Use a combined approach with HLH-directed therapy and malignancy-directed chemotherapy simultaneously. 1, 2

• Etoposide-containing regimens show superior survival compared to treating the underlying malignancy alone 1, 2
• Lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate may treat both HLH and the underlying neoplasm 4
• Stem cell transplantation should be considered as consolidation in patients with HLH in the context of hematologic malignancy 4, 2

Important prognostic note: For pediatric patients with malignancy-associated HLH, 56% survival following the acute phase and 36% at five years have been reported. 4

Primary (Familial) HLH

• Complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT) is mandatory. 2, 6
• Inactive HLH before transplantation strongly correlates with better survival 2
• Without stem cell transplant, primary HLH has a high mortality rate 5
• Screening for primary HLH needs to be considered in all children with HLH for early referral to HSCT 7

Intrathecal Therapy

Administer intrathecal therapy only for:

• Progressive neurological symptoms after 2 weeks of therapy 2
• Abnormal cerebrospinal fluid that has not improved 2

Early and repeated magnetic resonance imaging of the brain is essential for monitoring central nervous system disease. 6

Refractory or Relapsed Disease

If inadequate response within 24-48 hours to initial therapy, consider: 1, 3

• Intensification of the chemotherapy regimen 2
• Alemtuzumab (anti-CD52 antibody) as salvage therapy 1, 2
• Ruxolitinib (JAK2 inhibitor) for refractory cases - off-label use 1, 2
• Emapalumab (anti-IFN-γ antibody) for refractory cases 1, 2
• Anakinra (2-10 mg/kg/day SC) for inadequate response to corticosteroids 3

Common Pitfalls to Avoid

Delayed diagnosis and treatment significantly increases mortality. 3

• Do not wait for all 5 of 8 HLH-2004 criteria to be met before initiating treatment in a rapidly deteriorating child 1
• Do not neglect the underlying trigger - simultaneous treatment of both HLH and the trigger is essential 1, 3
• Inadequate use of antimicrobials when infection is the primary trigger increases mortality 3
• Do not exceed cumulative etoposide dose of 2-3 g/m² to avoid secondary malignancies 1

Supportive Care Requirements

• Ventilation, vasopressors, renal replacement therapy, and transfusions as needed 3
• Anti-infectious prophylaxis and surveillance are critical in profoundly cytopenic and immunosuppressed patients 4

Key Prognostic Factors

Factors associated with higher mortality: 3, 2

• Shock at ICU admission
• Platelet count <30 g/L
• HLH associated with malignancies (particularly T-cell lymphoma)

Overall outcomes: The most common triggers in children are infections (62%), with bacterial infections (particularly scrub typhus and dengue) and viral infections being most frequent. 5 Overall mortality remains 41% despite treatment. 5