Hemophagocytic Lymphohistiocytosis: Update of Biology and Treatment Options

Abstract SCI-9

Hemophagocytic lymphohistiocytosis (HLH) is a group of immunodeficiencies characterized by clinical signs and symptoms of extreme inflammation. HLH is now more widely recognized and no longer viewed as a disorder of young children only, as more adults are being diagnosed and treated. HLH is defined by a unique pattern of clinical findings. In addition to fevers, cytopenias, hepatitis, and splenomegaly, markedly increased levels of inflammatory markers in the blood (ferritin and sCD163 reflecting activation of antigen presenting cells; sIL2Ra and neopterin reflecting activation of T cells) constitute the collection of diagnostic criteria. Activation of inflammatory cells within the central nervous system (CNS) is found in approximately 50 percent of children at diagnosis and requires targeted therapy. In many cases immune defects affecting cytotoxicity of T cells and natural killer cells underlie the susceptibility to HLH. Autosomal recessive disorders include perforin deficiency (the major cytotoxin of the immune system), or defects in proteins involved in degranulation and exocytosis of perforin and granzyme B (MUNC 13–4, MUNC18-2, STX11, Rab27a). The latter proteins are involved in degranulation generally within the hematopoietic system, thus impacting the function of neutrophils and platelets as well. A rare defect of granulogenesis, Chediak Higashi syndrome, is also associated with a high incidence of HLH. Two forms of X-linked lymphoproliferative syndrome (XLP1 – SAP deficiency, and XLP2 – XIAP deficiency), as well as the rare autosomal recessive disorder ITK (IL-2 inducible T cell kinase) deficiency, are characterized by a high incidence of Epstein-Barr virus-driven HLH and lymphoproliferation. A common pathogenic mechanism underlying these consequences has not yet been elucidated. Effective initial treatment for HLH consists of cytotoxic and anti-inflammatory agents. The most widely used over the past 20 years has been a combination of CNS-penetrating steroid (Decadron) and etoposide. Another approach has been to use anti-thymocyte globulin (ATG) as induction therapy. Both treatments have resulted in approximately 60 percent responses during the first month of therapy. Supportive care with broad-spectrum antimicrobials is a critical adjunct. More recently, a new induction protocol—hybrid immunotherapy for HLH, combining the features of early ATG followed by etoposide, with steroids—has been opened in the United States (http://clinicaltrials.gov/ct2/show/NCT01104025) and Europe. However, HLH persists or reactivates in nearly half of patients as immune suppression is reduced. While a common approach to reactivation is to reintensify previous therapy, no clear guidelines have been developed for this complication. The use of Campath, a humanized monoclonal anti-CD52 antibody, as salvage therapy prior to hematopoietic cell transplantation (HCT) is being tested, as both activated T cells and activated monocyte/macrophages (histiocytes) are targeted through CD52. Historically, the three-year survival after HCT in patients treated with HLH-94 was 60 percent. More recently, use of Campath-based reduced intensity conditioning protocols have led to improved results after HCT. Campath has the advantage of reducing graft-versus-host disease if properly timed prior to HCT. In a recent contemporaneous series of HCT from unrelated adult donors, three-year posttransplant survival improved from 43 percent to 92 percent with no early transplant-related mortality.