What are the diagnosis and management strategies for Hemophagocytic Lymphohistiocytosis (HLH)?

Diagnosis and Management of Hemophagocytic Lymphohistiocytosis (HLH)

HLH requires prompt diagnosis and aggressive treatment with immunochemotherapy, with management tailored to the specific subtype (primary vs. secondary) and underlying trigger to prevent irreversible organ damage and death. 1, 2

Diagnostic Criteria

HLH diagnosis requires either:

1. Molecular diagnosis consistent with HLH (genetic testing), OR
2. Fulfillment of 5 of the 8 HLH-2004 criteria 1, 3:
   • Fever
   • Splenomegaly
   • Cytopenias affecting ≥2 cell lines
   • Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
   • Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
   • Low or absent NK cell activity
   • Elevated ferritin (≥500 ng/mL)
   • Elevated soluble CD25 (≥2400 U/mL)

Important diagnostic considerations:

• Hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions like septicemia 4
• The combination, extent, and progression of clinical and laboratory abnormalities must be unusual, unexpected, and otherwise unexplained 4
• Testing should be initiated promptly in patients with unexplained or disproportionate inflammatory response 5

Classification of HLH

Primary HLH

• Hereditary genetic defects (familial HLH type 2-5, Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative syndromes) 4
• Predominantly occurs in childhood but increasingly identified in adolescents and adults 4
• May be triggered by infection 4

Secondary HLH

• Triggered by:
  • Infections (particularly EBV, CMV) 4
  • Malignancies 4, 1
  • Autoimmune/autoinflammatory conditions 2
  • Chemotherapy 4

Diagnostic Workup

1. Initial laboratory evaluation:

   • Complete blood count, liver function tests, triglycerides, fibrinogen, ferritin, soluble CD25 1
   • NK cell activity assessment 1

2. Malignancy screening:

   • Peripheral blood and bone marrow examination for blasts 4
   • Chest X-ray, ultrasound and/or CT of abdomen and enlarged lymph nodes 4
   • Biopsy of suspicious lymph nodes or cutaneous lesions 4
   • Consider CT, MRI, and in special cases, PET scan 4

3. CNS evaluation:

   • Cerebrospinal fluid analysis for protein, cell count, and hemophagocytosis 4
   • MRI of brain for patients with neurological signs/symptoms or abnormal CSF 4

4. Genetic testing:

   • Consider in male patients with lymphoma and EBV-driven HLH (for XLP1) 4
   • Case-by-case decision for other hereditary defects 4

Treatment Approach

General Principles

• Treatment must be individualized according to HLH subtype, underlying cause, and clinical severity 2
• Early aggressive critical care interventions are often required for multisystem organ failure 5

First-Line Treatment

• High-dose corticosteroids (methylprednisolone 1g/day for 3-5 days) 2
• Simultaneous treatment of underlying cause 2
• For patients not responding to corticosteroids within 24-48 hours, add etoposide (consider reduced dose of 50-100 mg/m² weekly in adults with comorbidities) 2

Treatment by HLH Subtype

1. Primary HLH:

   • HLH-94/HLH-2004 protocol: etoposide, dexamethasone, cyclosporine A 3
   • Consider intrathecal therapy with methotrexate and corticosteroids in selected patients 3
   • Hematopoietic stem cell transplantation (HSCT) recommended 3

2. Malignancy-Associated HLH:

   • Treatment directed at both the HLH and underlying malignancy 2
   • Etoposide-containing regimens are particularly effective 2
   • Consider stem cell transplantation as consolidation 4
   • Note: T-cell lymphoma-associated HLH has worse prognosis than B-cell lymphoma-associated HLH 1

3. MAS-HLH (Autoimmune/Autoinflammatory):

   • First-line: high-dose corticosteroids 2
   • Second-line: cyclosporine A, anakinra, or tocilizumab 2

4. HLH During Chemotherapy:

   • Consider postponing subsequent chemotherapy blocks or interrupting maintenance therapy 4
   • Rigorous treatment of infectious triggers 4
   • Anti-infectious prophylaxis and surveillance for secondary infections or reactivations 4

Supportive Care

• Frequent clinical reassessment (at least every 12 hours) 2
• Monitor inflammatory parameters and organ function 2
• Provide ventilation, vasopressors, renal replacement therapy, and transfusions as needed 2

Prognosis

• Malignancy-associated HLH has poor prognosis with 30-day survival rates of 56-70% 1
• Pediatric patients with malignancy-associated HLH: 56% survival following acute phase, 36% at five years 4
• Factors associated with higher mortality: shock at ICU admission, platelet count <30 g/L, and malignancy-associated HLH 2

Emerging Therapies

• Ruxolitinib, emapalumab, and alemtuzumab are under investigation 2, 6
• Rituximab may be considered for EBV-triggered HLH 2