What are the key parameters for diagnosing and treating Hemophagocytic Lymphohistiocytosis (HLH)?

Key Parameters for Diagnosing and Treating Hemophagocytic Lymphohistiocytosis (HLH)

The diagnosis of HLH requires a combination of specific clinical and laboratory parameters, with treatment decisions based on disease severity, underlying triggers, and patient age. 1

Diagnostic Parameters

HLH-2004 Diagnostic Criteria

• While originally developed for pediatric patients, the HLH-2004 criteria serve as the primary diagnostic framework for HLH in all age groups, despite having substantial weaknesses in malignancy contexts 1
• Diagnosis requires either:
  • Molecular diagnosis consistent with HLH (genetic testing) 1
  • OR fulfillment of 5 of the 8 following criteria:

Clinical Criteria

• Fever (typically persistent and high) 1, 2
• Splenomegaly 1, 2

Laboratory Criteria

• Cytopenias affecting ≥2 cell lines 1
• Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL) 1, 2
• Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver 1
• Low or absent NK cell activity 1, 2
• Ferritin ≥500 ng/mL (often markedly elevated >10,000 ng/mL) 1, 2
• Elevated soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL 1, 2

Important Diagnostic Considerations

• Hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions like septicemia 1
• The combination, extent, and progression of abnormalities must be unusual, unexpected, and otherwise unexplained 1
• Ferritin elevation must be differentiated from transfusion-related iron overload in patients receiving blood products 1

Diagnostic Workup

Initial Evaluation

• Complete blood count with differential 3, 2
• Liver function tests (elevated transaminases are common) 2
• Coagulation studies (fibrinogen, D-dimer) 1, 2
• Triglycerides 2
• Ferritin (often markedly elevated) 1, 2
• Soluble IL-2 receptor (sCD25) level 1, 2
• NK cell function testing 1

Underlying Cause Investigation

• Screen peripheral blood and bone marrow for blasts 1
• Bone marrow aspiration and biopsy to assess for hemophagocytosis and underlying malignancy 1, 3
• Chest X-ray, abdominal ultrasound and/or CT scan 1
• Biopsy of suspicious lymph nodes or cutaneous lesions 1
• In patients with elevated likelihood of malignancy, consider CT, MRI, and in special cases, PET scan 1
• Cerebrospinal fluid analysis for CNS involvement (protein, cell count, hemophagocytosis) 1
• Brain MRI for patients with neurological signs/symptoms or abnormal CSF 1
• Infectious disease workup, particularly for EBV, CMV, tuberculosis, and other pathogens 4, 2

Genetic Testing Considerations

• Consider genetic testing for primary HLH, particularly in:
  • Children and young adults 1
  • Patients with family history of HLH 1
  • Male patients with lymphoma and EBV-driven HLH (consider XLP1) 1
  • Flow cytometric analysis to detect NK/T-cell degranulation defects 1

Treatment Parameters

Treatment Approach Based on Underlying Cause

• Primary (Familial) HLH:

  • Chemotherapy as bridge to hematopoietic stem cell transplantation 2

• Malignancy-Associated HLH:

  • Treatment of underlying malignancy is essential 1, 5
  • HLH-94 protocol with etoposide and corticosteroids is commonly used 5
  • T-cell lymphoma-associated HLH has worse prognosis than B-cell lymphoma-associated HLH 1
  • Consider stem cell transplantation as consolidation in patients with hematologic malignancy-associated HLH 1

• HLH During Chemotherapy:

  • Consider postponing subsequent chemotherapy blocks except in case of neoplasm relapse 1
  • HLH-directed treatment intensity depends on clinical severity 1
  • Rigorously treat infectious triggers 1
  • Implement anti-infectious prophylaxis (anti-fungal, pneumocystis jiroveci) 1
  • Regular surveillance for secondary infections or reactivations (aspergillus, EBV, CMV) 1

• Rheumatic Disease-Associated HLH (Macrophage Activation Syndrome):

  • Glucocorticoids, IL-1 blockade, or cyclosporine A 2

Age-Related Treatment Considerations

• Malignancy as HLH trigger correlates strongly with age:
  • 68% in patients >60 years 1
  • 38% in patients 30-59 years 1
  • 10% in patients 15-29 years 1
  • 0% in patients <14 years 1
• In children and adolescents, malignancy accounts for only 8% of HLH cases 1

Prognostic Parameters

• Survival rates for malignancy-associated HLH:
  • 30-day survival: 56-70% 1
  • Median overall survival: 36-230 days 1
  • 3-year survival: 18-55% (depending on malignancy subtype) 1
• T-cell lymphoma-associated HLH has worse prognosis than B-cell lymphoma-associated HLH 1
• For pediatric patients with malignancy-associated HLH:
  • 56% survival following acute phase 1
  • 36% survival at five years 1

Common Pitfalls and Caveats

• Delayed diagnosis due to rarity and variable presentation 6, 7
• Hemophagocytosis may be absent initially and is not required for diagnosis 1
• HLH features may overlap with or be attributed to underlying malignancy or infection 1, 7
• HLH may be underrecognized in adults 7, 5
• Treatment decisions must be made on a case-by-case basis due to lack of robust evidence on optimal therapeutic interventions 1
• Malignancy should be considered as a possible underlying disease in any patient with HLH, especially in older adults 1