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A 68-year-old man was referred to our hospital due to a high fever and pancytopenia. Neither tumors nor infectious lesions were detected. Hemophagocytosis was observed on the bone marrow (BM) smear, although without abnormal cells. Prednisolone therapy was ineffective for the patient's high fever. Later on, we obtained the results of a BM biopsy indicating the presence of infiltration of atypical Reed-Sternberg cells, leading to a diagnosis of HIV-negative primary bone marrow Hodgkin lymphoma (PBMHL). However, the patient died of multiple organ failure before receiving chemotherapy. As the clinical course of PBMHL is rapid, physicians must keep in mind its possibility in similar cases.

Lenalidomide plays a central role in the treatment of multiple myeloma (MM). Ozaki et al. [1] very recently reported two cases that had developed inflammatory reactions to lenalidomide. We also experienced three similar cases among eight cases treated in our hospital from August 2010 to July 2011 (Table 1). Case 1 received lenalidomide (10 mg/day on days 1–21) plus dexamethasone (20 mg on days 1–4) on a 28-day cycle. On day 7 at cycle 1, the patient developed high fever without apparent infection. After tapering the dose of lenalidomide to 5 mg/day without administration of antibiotics, his fever slowly receded. Case 2 received lenalidomide monotherapy (15 mg/day on days 1–21) on a 28-day cycle. On day 14 at cycle 1, the patient developed mild fever without focus of infection. We reduced the dose to 10 mg/day. The fever subsequently receded. Case 3 received lenalidomide (15 mg/day on days 1–21) plus dexamethasone (8 mg on days 1–4) on a 28-day cycle. On day 6 at cycle 1, the patient developed high fever without focus of infection. Five days after stopping lenalidomide, the fever receded. Cases 4–8 received lenalidomide (15 mg on days 1–21) plus dexamethasone therapy (20 mg/day on days 1, 8, 15, 22) on a 28-day cycle. The patient in Case 4 developed high fever due to the oral cavity infection on day 15, while febrile events were not observed in Cases 5–8. To clarify the mechanism underlying the febrile reactions to lenalidomide, we measured serum cytokine levels in these cases by enzyme-linked immunosorbent assay (ELISA) in SRL, Inc. (Tokyo, Japan) using residual serum samples, after obtaining informed consent. As for Cases 1–3, lenalidomide alone or in combination with dexamethasone drastically reduced serum tumor necrosis factor (TNF)-a levels in spite of the febrile reactions (12.2–1.5 pg/ml in Case 1; 2.9–1.8 pg/ml in Case 2; 71.0 to 4.5 pg/ml in Case 3) (Table 1). Lenalidomide also dramatically decreased serum interleukin (IL)-6 levels in Cases 1 and 2 (200.0–8.0 pg/ml in Case 1; 9.0–4.2 pg/ml in Case 2), but not in Case 3 (2.4–54.7 pg/ml). Levels of other cytokines, including pro-inflammatory cytokine IL-1b and anti-inflammatory cytokine IL-10, were scarcely influenced by lenalidomide in these three cases. These results indicate that, although the cytokine(s) involved in the febrile reactions to lenalidomide remains unknown, it appears that, except for the possible involvement of IL-6 in Case 3, these reactions were caused independently of IL-6 and TNF-a. Similarly, lenalidomide reduced serum levels of TNF-a and IL-6 in Cases 4–8, whereas their degrees were considerably different among the cases. Although we cannot deny the possibility that dexamethasone influences the serum cytokine levels, it is believed that serum IL-6 and TNF-a levels are reduced by the standard combination therapy with lenalidomide and dexamethasone in most MM patients. We also examined whether anti-MM effects of lenalidomide might not be affected by the febrile reactions. However, after one cycle of lenalidomide treatment, the % M-protein Y. Morita (&) T. Shimada T. Yamaguchi S. Rai C. Hirase M. Emoto K. Serizawa Y. Taniguchi M. Ojima Y. Tatsumi T. Ashida I. Matsumura Division of Hematology, Department of Internal Medicine, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan e-mail: moriyasu@med.kindai.ac.jp