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

Treatment of Primary Hemophagocytic Lymphohistiocytosis (HLH)

Primary HLH requires immediate initiation of the HLH-94 protocol (dexamethasone 10 mg/m² plus etoposide) followed by allogeneic hematopoietic stem cell transplantation (alloSCT) for cure, as this is the only definitive treatment that corrects the underlying genetic defect. 1

Initial Immunochemotherapy: The HLH-94 Protocol

The HLH-94 protocol remains the standard of care for primary HLH and consists of: 1, 2

• Dexamethasone 10 mg/m² to suppress inflammatory cytokine production 2
• Etoposide (highly effective against T-cell proliferation and cytokine secretion) at standard dosing 1, 2
• Duration: 8 weeks of initial therapy with weekly reassessment 1
• Cyclosporine A added after 8 weeks (not upfront) at 2-7 mg/kg/day with careful drug level monitoring 1, 3, 2

Critical Dosing Considerations

• Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies 1, 2
• Etoposide is primarily cleared by the kidneys; dose reduction is required if renal function is impaired, but no dose reduction needed for isolated hyperbilirubinemia or elevated transaminases 1
• The median cumulative etoposide dose in successful treatment is approximately 1500 mg/m² body surface area 1

Intrathecal Therapy

Intrathecal therapy is only indicated for: 1, 2

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

Definitive Curative Treatment: Allogeneic Stem Cell Transplantation

AlloSCT is mandatory for cure in primary HLH after achieving disease control with chemotherapy. 1, 4

Pre-Transplant Requirements

• Inactive HLH before transplantation is strongly associated with better survival 1
• Decisions regarding transplantation should be made in consultation with experts in HLH and alloSCT 1
• Patients with primary HLH are candidates for either reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) 1

Genetic Screening Considerations

In patients with confirmed HLH-causing mutations, HLA typing of close relatives must integrate screening for the same gene mutations to avoid a stem cell source with the same pathogenic biallelic mutation(s). 1

Conditioning Regimen Selection

• Transplant-related mortality in children using RIC has been reported to compare favorably to MAC 1
• A retrospective European Society of Blood and Marrow Transplantation study did not show superiority of RIC over MAC in adults 1
• The choice between RIC and MAC should be made on clinical grounds 1

Management of Severe Presentation with Organ Failure

For severe HLH presenting with imminent organ failure, immediately administer dexamethasone 10 mg/m² combined with etoposide without delay. 1, 3

• High-dose pulse methylprednisolone 1 g/day IV for 3-5 consecutive days can be used as first-line therapy, escalating to dexamethasone plus etoposide for severe disease 3
• Do not delay etoposide in severe HLH with organ failure—mortality increases significantly with treatment delay 3

Maintenance Therapy

After the initial 8-week treatment course: 1, 3

• Patients with residual disease benefit from maintenance therapy with corticosteroids and cyclosporine 1, 3
• Continue weekly reevaluation of the need for continued etoposide therapy 1
• Many patients require the full 8 weeks of etoposide, but this should be individualized based on response and toxicity 1

Refractory or Relapsed Primary HLH

If HLH reactivates or is refractory to initial treatment, consider: 1

• Treatment intensification with chemotherapy 1, 2
• Anti-CD52 antibody (alemtuzumab) 1, 2
• JAK2 inhibitor (ruxolitinib) - off-label use 1, 2
• Anti-IFN-γ antibody (emapalumab) 1, 2
• Cytokine adsorption using filter columns or plasma exchange 1, 2
• Proceed to alloSCT as soon as possible after achieving disease control 5

Essential Supportive Care

Administer prophylaxis against Pneumocystis jirovecii, fungi, and viruses throughout HLH treatment due to severe T-cell depletion. 3

• Monitor for secondary infections as a major cause of mortality during chemotherapy 3
• Frequent clinical reassessment and monitoring of inflammatory parameters and organ function are essential 2

Common Pitfalls to Avoid

• Never apply pediatric HLH-2004 protocols directly to adults without dose modifications 1, 3
• Do not delay etoposide in severe disease—this is a critical error that increases mortality 3
• Do not proceed to transplant with active HLH—achieving inactive disease first is strongly associated with better survival 1
• Do not use a stem cell donor with the same genetic mutation—screen all potential related donors for the causative mutation 1

Prognosis

• The HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival 2, 4, 6
• Familial HLH has become a curable disease with immunochemotherapy followed by HSCT 6
• Reduced intensity conditioning for HSCT is associated with less transplantation-related mortality and will further improve cure rates 6