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© 2002 American Society for Clinical Oncology
Intravenous Immunoglobulin for Hemophagocytic Lymphohistiocytosis?
University Hospital, Geneva, Switzerland To the Editor:On the basis of a retrospective analysis of 47 children and young adults, Imashuku et al1 conclude that early (< 4 weeks from diagnosis) administration of etoposide, preferably with cyclosporin A, is the treatment of choice for patients with Epstein-Barr virus (EBV)–associated hemophagocytic lymphohistiocytosis (HLH). On the other hand, they show data which "indicate that [intravenous immunoglobulin (IVIG)]–based primary regimens may not be adequate for most patients with EBV-HLH."
Conversely, we and others have evidence that IVIG is effective in the treatment of HLH.2,3 What are the reasons for this opposite conclusion? First, the patients analyzed are not the same, particularly regarding age (children and young adults with a median age around 5 years in Imashuku et al and adults with a median age of 35 and 41 years in Larroche et al3 and our series,2 respectively), selection criteria (based on the diagnostic guidelines of the Histiocytic Society, adapted by Imashuku et al,4 not further specified in Larroche et al, and mainly based on serum hyperferritinemia A key finding of our analysis is the efficacy of IVIG if it is administered at the beginning (within hours) of the macrophage activation process and its failure in later stages of the disease.3 Serum ferritin seems to be a useful emergency marker for monitoring macrophage activation. It is possible that IVIG was administered too late in the patients described by Imashuku et al.1 In addition, the patients who profit most from the administration of IVIG have yet to be defined in more detail. For instance, lymphoma-associated HLH is less responsive to IVIG than some other forms (Larroche et al3 and our own unpublished observations). A prospective, randomized trial that is about to start should clarify these question. Furthermore, the recently described rabbit model of EBV-HLH might allow for the testing of different treatment strategies.6 REFERENCES
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: 2665–2673, 2001 2. Emmenegger U, Frey U, Reimers A, et al: Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 68: 4–10, 2001[CrossRef][Medline] 3. 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: 533–539, 2000[Medline] 4. Imashuku S, Tabata Y, Teramura T, et al: Treatment strategies for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Leuk Lymphoma 39: 37–49, 2000[Medline] 5. Kaito K, Kobayashi M, Katayama T, et al: Prognostic factors of hemophagocytic syndrome in adults: Analysis of 34 cases. Eur J Haematol 59: 247–253, 1997[Medline]
6.
Hayashi K, Ohara N, Teramoto N, et al: An animal model for human EBV-associated hemophagocytic syndrome. Am J Pathol 158: 1533–1542, 2001
Response
Kyoto City Institute of Health and Environmental Sciences, Kyoto, Japan In 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. REFERENCES 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: 2665–2673, 2001 2. 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: 533–539, 2000 3. 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 4. 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: 708–714, 1997[CrossRef][Medline] 5. Imashuku S, Hibi S, Tabata Y, et al: Outcome of clonal hemophagocytic lymphohistiocytosis: Analysis of 32 cases. Leuk Lymphoma 37: 577–584, 2000[Medline] 6. Imashuku S: Differential diagnosis of hemophagocytic syndrome: Underlying disorders and selection of the most effective treatment. Int J Hematol 66: 135–151, 1997[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10,000 µg/L and/or demonstration of hemophagocytosis in our series), and underlying diseases. Second, serum ferritin values tend to be lower in the patients of Imashuku et al, which might point to a lower disease activity
