From the Guidelines
Hemophagocytic lymphohistiocytosis (HLH) in children should be managed with the HLH-94 protocol, which includes initial therapy with dexamethasone, etoposide, and cyclosporine A, as it has been shown to drastically improve the nearly uniformly fatal outcome in pediatric HLH to a long-term survival of over 50% 1.
Key Components of HLH Management
- The HLH-94 protocol consists of corticosteroids, typically dexamethasone, cyclosporine A (CSA), intrathecal therapy, and etoposide, to delete activated T cells and suppress inflammatory cytokine production 1.
- Etoposide, a chemotherapeutic agent, has high specificity against T-cell proliferation and cytokine secretion in mice, and its use is recommended in the management of HLH 1.
- The decision to start HLH-directed treatment depends on clinical judgment and assessment of organ function, and pulsed corticosteroids and elements of HLH-94 may be used 1.
Diagnosis and Treatment
- Diagnosis of HLH requires meeting 5 of 8 criteria: fever, splenomegaly, cytopenias affecting at least 2 cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen/lymph nodes, low/absent NK cell activity, ferritin ≥500 μg/L, and soluble CD25 ≥2,400 U/ml.
- Early recognition is crucial as mortality approaches 50% without treatment, and the pathophysiology involves defective cytotoxic function of NK and T cells, leading to uncontrolled immune activation and cytokine storm.
- Supportive care including antimicrobial prophylaxis, transfusion support, and monitoring for organ dysfunction is essential throughout treatment.
Considerations for Treatment
- A reduced etoposide frequency, from twice weekly to once a week, with or without a reduction in dose from 150 mg/m2 to 50-100 mg/m2, should be considered in adult and elderly patients with chronic comorbidities 1.
- The addition of IV immunoglobulin (IVIG) may be considered, as it has anti-inflammatory potential, but its use has been questioned in certain cases 1.
- Anakinra may reduce mortality in sepsis patients with MAS features, and its use may be considered in the management of HLH 1.
From the Research
Overview of Hemophagocytic Lymphohistiocytosis (HLH) in Children
- HLH is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH 2
- The HLH-2004 study confirmed the efficacy of etoposide and dexamethasone in HLH treatment, with a 5-year probability of survival of 61% 2
Diagnosis and Classification of HLH
- HLH can be classified into primary (familial) or secondary types, with the latter being associated with an underlying malignancy 3
- The HLH-2004 criteria are commonly used for diagnosis, and include five of eight diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes 2, 4
Treatment of HLH in Children
- The HLH-2004 protocol includes etoposide, dexamethasone, and cyclosporine A, and is frequently used in pediatric centers 2, 5
- Hematopoietic stem cell transplantation (HSCT) is the only accepted curative therapy for primary HLH, although cord blood transplantation with a reduced-conditioning regimen has been used with superior outcomes 6
- Immunochemotherapy based on the HLH-2004 protocol has been used for secondary HLH, including EBV-HLH 6
Outcome and Prognosis of HLH in Children
- The 5-year probability of survival for children with HLH is 61%, with a higher survival rate for those with verified FHL (70%) 2
- Pre-HSCT mortality was reduced from 27% to 19% in the HLH-2004 study compared to historical data, although this reduction was not significant 2
- Time from start of therapy to HSCT was shorter in the HLH-2004 study, and reported neurological alterations at HSCT were reduced from 22% to 17% 2