S Adachi1, M Kubota1, Y Akiyama1, T Kato1, T Kitoh2 and K Furusho1 .... We thank Dr Alice S Cary for her advice on the manuscript. oral penicillin. At present ...
Bone Marrow Transplantation, (1997) 19, 183–185 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Successful bone marrow transplantation from an HLA-identical unrelated donor in a patient with hemophagocytic lymphohistiocytosis S Adachi1 , M Kubota1, Y Akiyama1, T Kato1 , T Kitoh2 and K Furusho1 1
Department of Pediatrics, Kyoto University, Kyoto; 2Department of Pediatrics, Maizuru Municipal Hospital, Maizuru, Japan
Summary: We report a 3-year-old girl with hemophagocytic lymphohistiocytosis (HLH) who received BMT from an HLA-identical unrelated donor when the disease was active. She had entered remission in response to chemotherapy consisting of etoposide and methylprednisolone. After a relapse, her disease became refractory to chemotherapy, and splenectomy was performed with marginal improvement. She underwent BMT from an HLAidentical unrelated donor, conditioned with CY, TBI and anti-thymocyte globulin (ATG). She has been in complete remission for 18 months since the BMT. This result suggests that BMT from an HLA-identical unrelated donor should be considered for HLH even if the disease is active. Keywords: hemophagocytic lymphohistiocytosis; unrelated donor transplant; etoposide
Case report The patient was referred to Kyoto University Hospital at 11 months of age because of fever, diarrhea and generalized edema. She was the second child of unrelated parents and weighed 3112 g at birth. There was no family history of consanguinity, and no family history of HLH. She had measles at the age of 7 months and since then had suffered from watery diarrhea. On admission, her body temperature was 38.5°C and splenomegaly (9 cm) and generalized edema were present. Blood examination revealed an anemia of Hb 6.0 g/dl, WBC count 6.2 3 109/l with 35% segmented cells, 20% bands, 42% lymphocytes, 3% monocytes, and a platelet count of 54 3 109/l. The blood chemistry showed a total protein of 3.9 g/dl, albumin 2.4 g/dl, lactate dehydrogenase 1344 IU/l and a high level of triglycerides, 212 mg/dl. C reactive protein was raised at 2.8 mg/dl. The fibrinogen was low at 61 mg/dl. Bone marrow examination revealed a nucleated cell count of Correspondence: M Kubota, 54 Kawahara-cho, Sakyo-ku, Kyoto, 606 Japan Received 7 May 1996; accepted 16 August 1996
19.3 3 104/mm3 and a mild increase of histiocytes showing phagocytosis of neutrophils and erythroblasts (Figure 1). Although cultures for virus from her urine or throat were negative, her serum anti-CMV titer (IgM) was raised. Serum soluble IL-2 receptor was elevated to 3173 U/ml, but IFN-g, tumor necrosis factor (TNF) and IL-6 were within the normal ranges. Serum ferritin was also normal. With a diagnosis of HLH associated with CMV infection, CMV hyperimmuneg-globulin (400 mg/kg/day for 5 consecutive days), acyclovir (30 mg/kg/day) and prednisolone (1 mg/kg/day) were administered (Figure 2). She became afebrile, but splenomegaly persisted and she required platelets at least twice a week. Since gancyclovir (10 mg/kg/day) did not improve her condition, etoposide (VP16) (100 mg/m2), g-globulin (400 mg/kg) and methylprednisolone (mPSL) (200 mg/m2) were administered for 5 successive days. After three courses of treatment, her splenomegaly reduced to 3 cm and blood transfusion became unnecessary. She was discharged at the age of 18 months. One month later, however, her disease had relapsed. She did not respond to the chemotherapeutic regimen described above and needed platelet transfusions every day. Her abdomen was almost completely occupied by an enlarged spleen and she underwent splenectomy with HLA-matched platelet transfusion. Microscopic examination of the resected spleen showed severe fibrosis with accumulation of hemosiderin and proliferation of histiocytes with phagocytosis. Her bone marrow was replaced by histiocytes and fibrosis with minimum hematopoietic elements. Since splenomegaly caused only marginal clinical improvement, she underwent BMT from an unrelated donor identified by the Japan Marrow Donor Program at the age of 3, ie 16 months after the second admission. The patient and her unrelated donor were HLA identical: HLA A*2402, 3101; B*4601, 5401; CW1; DRB1*0405, 0803; DQB1*0401, 0601; DRB4*0103; DQA1*0103, 0302; DPA1*0202. They were different for DPB1*:0501 (patient) vs 0501, 0201 (donor). The MLC between donor and patient was nonreactive. Conditioning consisted of CY (60 mg/kg) on days 26 and 25, TBI 2 Gy on days 24 to 21, and rabbit ATG (2.5 mg/kg) on days 24, 23, 21 and 0. GVHD prophylaxis consisted of CsA (7 mg/kg continuous infusion) and methotrexate (0.3 mg/kg). Acute grade I GVHD (skin rash) was controlled with oral prednisolone, and chronic GVHD (exanthema and dry skin) was well controlled with oral CsA. There were no major infectious complications.
Unrelated BMT for HLH S Adachi et al
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Figure 1
Histiocytes in the bone marrow showing phagocytosis of neutrophils or erythroblasts.
Fever Diarrhea Splenomegaly
Rash Chronic GVHD Splenectomy
Conditioning regimen CY 60 mg/kg × 2 TBI 2 Gy × 6 ATG 2.5 mg/kg × 4
PRED
BMT PRED
IVIG
MTX VP16 mPSL VBL
ACV
CsA
CsA
GCV G-CSF
1992
1993
1994
1995
1.6 1.2 WBC ×109/1
0.8 0.4 0
160 WBC Plt
120 80 40
Plt ×109/1
0
Figure 2 Schematic representation of clinical course. PRED 5 prednisolone; IVIG 5 intravenous immunoglobulin; VP16 5 etoposide; mPSL 5 methylprednisolone; ACV 5 acyclovir; GCV 5 gancyclovir; VBL 5 vinblastine; ATG 5 anti-thymocyte globulin; MTX 5 methotrexate.
Unrelated BMT for HLH S Adachi et al
Engraftment was achieved 6 months after BMT, and was confirmed by HLA-typing. She is doing well more than 18 months after BMT without any therapy except prophylactic oral penicillin. At present, her complete blood count shows Hb 12.1 g/dl, WBC 12.0 3 109/l with 29% segmented cells, 10% bands, 51% lymphocytes, 7% monocytes, 3% eosinophils, and platelet count of 354 3 109/l.
Acknowledgements We thank Dr Alice S Cary for her advice on the manuscript. Thanks are also due to Dr Y Nakashima for the pathological diagnosis of HLH.
References Discussion We report a patient with active HLH who underwent successful BMT from an HLA-identical unrelated donor. HLH is a rare disease characterized clinically by fever, splenomegaly and cytopenia. 1 The cause of the disease is not fully understood, but it has been proposed that T cells play an important role.2 In our case, however, hypercytokinemia, including elevation of IFN-g, TNF and IL-6, was not present in the active stage. The natural course of HLH and its familial form, familial hemophagocytic lymphohistiocytosis, is considered to be rapidly fatal. 3 Use of topoisomerase II inhibitors such as etoposide or teniposide4 or immunosuppressive agents5 has resulted in sustained remission, but most patients die from refractory disease or secondary infections.6 Recent investigators have reported promising results of allogeneic BMT in children with HLH,6–10 but an HLA-matched sibling is available in only about 30% of cases. The experience of using unrelated donors in HLH is limited, and the results are not promising with mismatched donors8 and active HLH.10 We consider that our case is unique since (1) the patient had active disease with persistent cytopenia and fibrotic bone marrow when BMT was performed; and (2) etoposide was not included in the conditioning regimen. Nonetheless, engraftment was finally achieved 6 months after BMT and she no longer needed blood transfusions. She has been doing well for more than 18 months without any complications. In conclusion, if an HLA-A, -B, -DR, DQ identical unrelated donor is available, BMT should be considered for the treatment of HLH even if the disease is active.
¨ st Å. FHL Study Group of the Histi1 Henter J-I, Elinder G, O ocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 1991; 18: 29–33. 2 Henter JI, Elinder G, So¨der O et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991; 78: 2918–2922. 3 Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983; 140: 221–230. 4 Henter JI, Elinder G, Finkel Y, So¨der O. Successful induction with chemotherapy including teniposide in familial erythrophagocytic lymphohistiocytosis. Lancet 1986; 2: 1402–1403. 5 Ste´phan JL, Donadieu J, Ledeist F et al. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. Blood 1993; 82: 2319–2323. 6 Blanche S, Canglia M, Girault D et al. Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single center study of 22 cases. Blood 1991; 78: 51–54. 7 Fisher A, Cerf-Bensussan N, Blanche S et al. Allogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis. J Pediatr 1986; 108: 267–270. 8 Bolme P, Henter JI, Winiarski J et al. Allogeneic bone marrow transplantation for hemophagocytic lymphohistiocytosis in Sweden. Bone Marrow Transplant 1995; 15: 331–335. 9 Todo S, Fujiwara F, Ikushima S et al. Allogeneic bone marrow transplantation for familial erythrophagocytic lymphohistiocytosis, with high dose VP16-containing conditioning regimen. Leuk Lymphoma 1990; 1: 361–364. 10 Scott Baker K, DeLaat CA, Shapiro RS et al. Successful correction of hemophagocytic lymphohistiocytosis with related and unrelated bone marrow transplantation. Blood 1995; 86 (Suppl. 1): 387a (Abstr. 1536).
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