Intravenous Immunoglobulin for Hemophagocytic Lymphohistiocytosis?
Authors: Urban Emmenegger, Peter J. Spaeth, Klaus A. Neftel, Shinsaku Imashuku, Tomoko Teramura, Eiichi Ishii, Naoko Kinugawa, Masahiko Kato, Masahiro Sako, Kikuko Kuriyama, Shigeyoshi Hibi
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.2.599 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11786591 Intravenous Immunoglobulin for Hemophagocytic Lymphohistiocytosis? Urban EmmeneggerxUrban EmmeneggerSearch for articles by this author , Peter J. SpaethxPeter J. SpaethSearch for articles by this author , Klaus A. NeftelxKlaus A. NeftelSearch for articles by this author Shinsaku ImashukuxShinsaku ImashukuSearch for articles by this author , Tomoko TeramuraxTomoko TeramuraSearch for articles by this author , Eiichi IshiixEiichi IshiiSearch for articles by this author , Naoko KinugawaxNaoko KinugawaSearch for articles by this author , Masahiko KatoxMasahiko KatoSearch for articles by this author , Masahiro SakoxMasahiro SakoSearch for articles by this author , Kikuko KuriyamaxKikuko KuriyamaSearch for articles by this author , Shigeyoshi HibixShigeyoshi HibiSearch for articles by this author Show More University Hospital, Geneva, SwitzerlandZLB Bioplasma AG, Bern, SwitzerlandZieglerspital, Bern, SwitzerlandKyoto City Institute of Health and Environmental Sciences, Kyoto, JapanHamanomachi Hospital, Fukuoka, JapanChiba Children's Hospital, Chiba, JapanGunma University School of Medicine, Gunma, JapanOsaka City General Hospital, Osaka, JapanKyoto Prefectural University of Medicine, Kyoto, Japan https://doi.org/10.1200/JCO.2002.20.2.599 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15012002In Reply:We thank Dr Emmenegger and colleagues for their important remarks about our article on Epstein-Barr virus (EBV)–associated hemophagocytic lymphohistiocytosis (HLH).1 Our conclusion that etoposide rather than intravenous immunoglobulin (IVIG) is important in the treatment of EBV-HLH was based on the 10 patients listed in Table 2, who did not respond sufficiently to regimens that included IVIG but did subsequently improve with etoposide-based regimens. Similar observations are available in previously published Japanese articles, although mostly as case reports. In addition, our analysis clearly showed that therapeutic results were better for patients who received etoposide early (< 4 week from diagnosis) in their treatment course.As we cited in our article, reports on the beneficial effect of IVIG in patients with hemophagocytic syndrome have been accumulated. In article by Larroche et al2 reporting IVIG effectiveness, all 17 cases were non–EBV infection–associated HLH (non–EBV-HLH) or were triggered by other causes. We agree that IVIG is effective for patients with non–EBV-HLH. The reason why EBV-HLH did not respond well enough to IVIG in our study remains to be determined. We think that the first and second issues raised by Emmenegger et al are unlikely, as they explain different IVIG effectiveness between their study and ours. In terms of genetic influences, Beutel et al3 very recently compared the EBV-HLH in German children with that reported from Japan. They observed similar biochemical markers, such as hypercytokinemia and high ferritin and lactate dehydrogenase levels; however, they could not find the hypocellularity and increased large granular lymphocytes in the bone marrow described for Japanese patients.4 In addition, they noted a high proportion of mild clinical courses in Germany, which is different from the reports in Asia.We assume that the EBV-HLH or EBV-related macrophage activation syndrome is distinct from non–EBV-HLH, because the majority of EBV-HLH is a clonal disease. In fact, approximately 90% of the EBV-HLH we studied was confirmed to be mono- or oligoclonal (tested by a terminal probe for EBV), and 60% showed T-cell receptor rearrangements.5 These results suggest that EBV-HLH resides in a gray zone between infectious disease and lymphomatous disease.6 Although clonal disease does not necessarily indicate malignant neoplastic disease, our observation could be compatible with Emmenegger et al's comments that lymphoma-associated HLH is less responsive to IVIG. In this setting, we must be careful in using the term "reactive hemophagocytic syndrome." Because hemophagocytosis itself is reactive, the disease may have been triggered by nonclonally or clonally proliferating lymphocytes or true neoplastic cells. It is possible that IVIG modulates hemophagocytosis due to hypercytokinemia, but it may not suppress the growth of the underlying clonally proliferating cells like in EBV-HLH. We agree that further studies are necessary to find out the most optimal treatment for EBV-HLH, although our study confirmed the superiority of etoposide over IVIG for this often fatal disease. 1. Imashuku S, Kuriyama K, Teramura T, et al: Requirement for etoposide in the treatment of Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis. J Clin Oncol 19:: 2665,2001–2673, Link, Google Scholar2. Larroche C, Bruneel F, André MH, et al: [Intravenously administered gamma-globulins in reactive hemaphagocytic syndrome: Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP]. Ann Med Interne 151:: 533,2000–539, Medline, Google Scholar3. Beutel K, Janka GE, Schneider ME: EBV-associated hemophagocytic lymphohistiocytosis (HLH) in German children. Meeting Program for the XVII Annual Meeting of the Histiocyte Society, 2001, p 40 Google Scholar4. Imashuku S, Hibi S, Morinaga S, et al: Haemophagocytic lymphohistiocytosis in association with granular lymphocyte proliferative disorders in early childhood: Characteristic bone marrow morphology. Br J Haematol 96:: 708,1997–714, Crossref, Medline, Google Scholar5. Imashuku S, Hibi S, Tabata Y, et al: Outcome of clonal hemophagocytic lymphohistiocytosis: Analysis of 32 cases. Leuk Lymphoma 37:: 577,2000–584, Crossref, Medline, Google Scholar6. Imashuku S: Differential diagnosis of hemophagocytic syndrome: Underlying disorders and selection of the most effective treatment. Int J Hematol 66:: 135,1997–151, Crossref, Medline, Google Scholar