Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

An alternative regimen for FHL was first described by Stephan et al 245 in 1993 and in an expanded trial described by Mahlaoui et al 246 in 2007 . The development of these regimens was based on the recognition that T-lymphocytes play a role in the pathology of HLH as well as macrophages. This discovery was based on the detection of major histocompatibility complex class II positive T-cells, high levels of soluble serum IL-2, CD8, and IFN-γ in the serum of FHL patients. This regimen featured a combination of ATG with corticosteroids, CSA, and intrathecal methotrexate. The Stephan study evaluated six patients and was successful in achieving remission quickly, although two patients died from CNS disease. In the expanded study, the regimen was used to treat 38 consecutive patients with FHL over the course of 14 years. The patients received 45 courses of ATG, with a total dosage of 50 mg/kg or 25 mg/kg varying by severity of disease over the course of 5 days. Methylprednisolone at 4 mg/kg/day was administered with the ATG for 5 days then tapered. Intrathecal methotrexate and corticosteroids were given at various dosages determined by patient age and at intervals varying according to the severity of CNS involvement. Patients also received supportive care with fibrinogen infusions, irradiated packed red blood cells, and platelets. Broad spectrum antibiotics and intravenous immunoglobulins were also given. CSA was added to reach a plasma concentration of 150 ng/mL prior to HSCT. Immediate adverse effects of ATG were relatively minor and presented as fever and chills during infusion that rapidly resolved and did not preclude further treatment. After approximately 2 weeks of ATG treatment, bacterial, viral, or fungal infections were encountered. Infections were more common in patients receiving ATG as a secondary treatment for relapse than in first-line therapy. Once a complete response was achieved as evidenced by normalization of clinical and biological parameters, HSCT was performed for patients with an available HLA identical donor. Patients without a complete response or without a viable donor were given maintenance therapy. Overall, the efficacy of ATG therapy in achieving complete remission was 73%. Using ATG as a first-line treatment had a higher success rate of 82% of patients achieving complete remission versus only about 50% achieving complete remission with second-line ATG treatment. The best outcomes were seen with patients who received HSCT shortly after starting ATG therapy. 246 Infection-associated HLH While treating the inciting infectious agent is important in the treatment of infection-related HLH, treating the identified organism alone is not enough. Most cases of infection-related HLH should be treated aggressively with standard HLH protocols. The exception to this rule is in Leishmania-related HLH, which has been treated successfully with liposomal amphotericin alone. [129] [130] [131] [132] [133] [134] [135] 140, 247 In particular, the prognosis for EBV-associated cases has improved dramatically with chemotherapy and immune modifying agents. In a multivariate analysis of patients on regimens consisting of corticosteroids alone, intravenous immunoglobulins alone, CSA alone, or a combination of treatments without etoposide versus another group of patients receiving etoposide, early introduction of etoposide was the only significant variable for improved survival. 248 Etoposide appears to interfere with EBV-induced lymphocyte