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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-01-0172.
Submitted January 17, 2002
Accepted April 23, 2002
Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immuno-chemotherapy and bone marrow transplantation
Jan-Inge Henter*, AnnaCarin Samuelsson-Horne, Maurizio Arico, R M Egeler, Goran Elinder, Alexandra H Filipovich, Helmut Gadner, Shinsaku Imashuku, Diane Komp, Stephan Ladisch, David Webb, and Gritta Janka
Department of Pediatric Hematology and Oncology, Karolinska Hospital, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden
* Corresponding author; email: Jan-Inge.henter{at}kbh.ki.se.
Background: Hemophagocytic lymphohistiocytosis (HLH) comprises familial (primary) hemophagocytic lymphohistiocytosis (FHL) and secondary HLH (SHLH), both clinically characterized by fever, hepatosplenomegaly, and cytopenia. FHL, an autosomal recessive disease invariably fatal when untreated, is associated with defective triggering of apoptosis and reduced cytotoxic activity, resulting in a widespread accumulation of T-lymphocytes and activated macrophages. Methods: In 1994 the Histiocyte Society initiated a prospective international collaborative therapeutic study (HLH-94), aiming at improved survival. It combined chemotherapy and immunotherapy (etoposide, corticosteroids, cyclosporin A, and, in selected patients, intrathecal methotrexate), followed by bone marrow transplantation (BMT) in persistent, recurring and/or familial disease. Results: 113 eligible patients aged  15 years from 21 countries started HLH-94 between July 1, 1994 and June 30, 1998. They all either had an affected sibling (n=25) or fulfilled the Histiocyte Society diagnostic criteria. At a median follow-up of 3.1 years, the estimated 3-year probability of survival overall was 55% (95% confidence interval +/-9%) and in the familial cases 51%(+/-20%). Twenty enrolled children were alive and off-therapy for >12 months without BMT. For patients who were transplanted (n=65), died prior to BMT (n=25) or were still on therapy (n=3), the 3-year survival was 45%(+/-10%). The 3-year probability of survival after BMT was 62%(+/-12%). Conclusions: HLH-94 is very effective, allowing BMT in most patients. Survival of children with HLH has been greatly improved.
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