What are the diagnostic criteria and treatment options for Hemophagocytic Lymphohistiocytosis (HLH)?

Diagnostic Criteria and Treatment Options for Hemophagocytic Lymphohistiocytosis (HLH)

The diagnosis of HLH should be based on the HLH-2004 diagnostic criteria, which requires either a molecular diagnosis consistent with HLH or fulfillment of 5 of 8 specific clinical and laboratory parameters, while treatment should follow the HLH-94 protocol with modifications based on the underlying trigger and patient characteristics. 1, 2

Diagnostic Criteria for HLH

The diagnosis of HLH can be established if either of the following is fulfilled:

1. Molecular diagnosis consistent with HLH 1, 3

2. At least 5 of the following 8 criteria 1, 4:

   • Fever 1
   • Splenomegaly 1
   • Cytopenias affecting ≥2 of 3 lineages in peripheral blood 1, 3:
     • Hemoglobin <90 g/L (<100 g/L in infants <4 weeks)
     • Platelets <100 × 10^9/L
     • Neutrophils <1.0 × 10^9/L
   • Hypertriglyceridemia and/or hypofibrinogenemia 1:
     • Fasting triglycerides ≥3.0 mmol/L (≥265 mg/dL)
     • Fibrinogen ≤1.5 g/L
   • Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver 1
   • Low or absent NK cell activity 1, 3
   • Ferritin ≥500 μg/L (values >10,000 μg/L are highly suspicious in adults) 1
   • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL 1, 3

Important Diagnostic Considerations

• Hyperferritinemia should always prompt consideration of HLH in the differential diagnosis, with levels >10,000 μg/L being highly suspicious in adults 1

• Hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions such as septicemia 1

• Soluble IL-2 receptor (sCD25) has been reported as an excellent diagnostic test for adult HLH 1

• For clinical purposes, it is crucial to judge whether the combination, extent, and progression of clinical and laboratory abnormalities are unusual, unexpected, and otherwise unexplained 1

Classification of HLH

Primary (Genetic) HLH

• Caused by mutations affecting lymphocyte cytotoxicity and immune regulation 2, 5
• Most common in children but can occur in adolescents and young adults 2, 3
• Includes familial HLH types 2-5, Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative syndromes 1

Secondary (Acquired) HLH

• Most common in adults 2
• Triggered by:
  • Infections (particularly EBV) 2, 5
  • Malignancies (particularly lymphomas) 1, 3
  • Autoinflammatory/autoimmune disorders 2, 5
  • Immunotherapies 2

Diagnostic Workup

• In all patients with HLH, screen peripheral blood and bone marrow for blasts 1

• Imaging studies recommended 1:

  • Chest X-ray
  • Ultrasound and/or CT of abdomen and enlarged lymph nodes
  • Consider CT, MRI, and in special cases, PET for patients with elevated likelihood of malignancy

• Biopsy suspicious lymph nodes or cutaneous lesions indicative of lymphoma 1

• Screen cerebrospinal fluid for features of CNS involvement (elevated protein, cell count, hemophagocytosis) 1

• Consider MRI of the brain in patients with neurological signs/symptoms or abnormal CSF 1

• Consider genetic or flow cytometric analysis for primary HLH, especially in male patients with lymphoma and EBV-driven HLH 1

Treatment Approach

General Principles

• The HLH-94 protocol is the recommended standard treatment for HLH 2, 4

• Treatment components include 2, 4, 6:

  • Dexamethasone (to suppress inflammatory cytokine production)
  • Etoposide (effective against T-cell proliferation and cytokine secretion)
  • Cyclosporine A (added after 8 weeks in HLH-94)
  • Intrathecal therapy (for progressive neurological symptoms)

• Treatment should be tailored according to the underlying condition and HLH-triggering factor 2, 6

Treatment Based on HLH Subtype

Primary (Genetic) HLH

• Complete HLH-94 protocol followed by allogeneic hematopoietic stem cell transplantation (alloSCT) 2, 5
• Achieving inactive HLH before transplantation strongly correlates with better survival 2

Malignancy-Associated HLH

• Combined approach with HLH-directed and malignancy-directed therapy 2, 1
• Etoposide-containing regimens show better survival compared to treatment directed only at underlying pathology 2, 1
• Consider lymphoma regimens containing etoposide, cyclophosphamide, or methotrexate as they may treat both HLH and underlying neoplasm 1, 2
• AlloSCT may be considered as consolidation in patients with HLH in the context of hematologic malignancy 2, 3

Infection-Associated HLH

• Anti-infectious treatment is pivotal 2
• For EBV-associated HLH: Consider anti-B-cell therapy (rituximab) for highly replicative EBV infection 1, 2

Autoimmune/Autoinflammatory-Associated HLH

• Anti-interleukin-1 treatment in addition to glucocorticosteroids, cyclosporin A, and etoposide 2, 5

Treatment Modifications for Adults

• For adults, especially elderly patients: Consider reduced etoposide frequency (once weekly instead of twice weekly) and/or reduced dosing (50-100 mg/m² instead of 150 mg/m²) 2

• Keep cumulative etoposide dose below 2-3 g/m² to minimize risk of secondary malignancies, particularly in non-malignancy associated HLH 2

Refractory/Relapsed HLH

• Treatment intensification options include 2:
  • Chemotherapy intensification
  • Anti-CD52 antibody (alemtuzumab)
  • Cytokine adsorption using filter columns or plasma exchange
  • JAK2 inhibitor (ruxolitinib) - off-label use
  • Anti-IFN-γ antibody (emapalumab)

Prognosis

• Factors associated with higher mortality include malignancy-associated HLH (particularly T-cell lymphoma) 2, 3

• T-cell lymphoma-associated HLH has a worse prognosis than B-cell lymphoma-associated HLH 3

• Survival rates for malignancy-associated HLH are generally poor, with 30-day survival rates of 56-70% and median overall survival of 36-230 days 3

• The HLH-94 protocol has improved survival from nearly uniformly fatal to >50% long-term survival 2, 5