From the Guidelines
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that requires prompt diagnosis and treatment with dexamethasone and etoposide as the first-line therapy, following the HLH-94/2004 protocol, as recommended by the most recent and highest quality study 1.
Key Considerations
- The decision to start HLH-directed treatment depends on clinical judgment and assessment of organ function, with pulsed corticosteroids and elements of HLH-94 (dexamethasone 10 mg/m2 with/without a modified dose of etoposide) being considered 1.
- A clear indication for immediate administration of etoposide is severe HLH presenting with imminent organ failure, and individualized modified HLH-94–like treatment has been suggested in secondary HLH (sHLH) 1.
- The addition of IV immunoglobulin (IVIG) (up to 1.6 g/kg in split doses over 2-3 days) may be considered, as it has anti-inflammatory potential, but its use has been questioned in adult-onset Still’s disease 1.
Treatment Approach
- The recommended first-line therapy for HLH includes dexamethasone (starting at 10 mg/m² daily) and etoposide (150 mg/m² twice weekly for 2 weeks, then weekly), following the HLH-94/2004 protocol 1.
- Cyclosporine (target trough levels 200-300 ng/mL) is typically added once the patient's condition stabilizes, and this regimen should continue for 8 weeks, with gradual tapering if clinical improvement occurs 1.
- For refractory cases, consider adding IVIG (1-2 g/kg), anakinra (2-10 mg/kg/day), or alemtuzumab (1 mg/kg), and patients with genetic or recurrent HLH should be evaluated for hematopoietic stem cell transplantation 1.
Supportive Care
- Supportive care is crucial, including infection management, transfusion support, and seizure prophylaxis, as HLH treatment targets the excessive immune activation and cytokine storm that characterizes the condition 1.
- Early recognition using diagnostic criteria (fever, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis, low NK cell activity, high ferritin, and elevated soluble CD25) and prompt initiation of therapy are essential for improving survival in this often fatal condition 1.
From the Research
Definition and Characteristics of HLH
- Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by cytokine dysregulation and uncontrolled activation of T lymphocytes and macrophages 2.
- HLH is categorized as primary when associated with specific genetic mutations or secondary when associated with infections, malignancies, or autoimmune disorders 2.
- Clinical features of HLH include unexplained fever, hepatosplenomegaly, pancytopenia, and severe hyperferritinemia 2, 3.
Diagnosis and Treatment of HLH
- The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics 4.
- The HLH-2004 protocol is used in the diagnosis of HLH, although its use in adults has not been formally validated yet 4, 5.
- Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities 4, 5.
- Immunotherapy targeting CD52 expressed on immune effector cells of HLH is a rational therapeutic approach in patients too ill for traditional cytotoxic chemotherapy 2.
Prognosis and Management of HLH
- The prognosis of HLH is generally poor, warranting rapid diagnosis and aggressive management 4, 6.
- HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential 3.
- Interdisciplinary patient care with rheumatologists, gastroenterologists, neurologists, pediatricians, the transplant team, and pathologists is a prerequisite to successful treatment 5.
- There remains a pressing need for more sensitive, context-specific diagnostic tools and safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH 3.