Bone Marrow Transplantation, (1999) 23, 1205–1207  1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Case report Successful treatment of refractory acquired pure red cell aplasia (PRCA) by allogeneic bone marrow transplantation

BU Mu¨ller1, A Tichelli2, JR Passweg1, C Nissen3, A Wodnar-Filipowicz3 and A Gratwohl1

Division of Haematology, 1Department of Medicine, 2Haematology Laboratory and 3Department of Research, Kantonsspital, University of Basel, Switzerland

Summary: mia. The bone marrow was normocellular and demon- strated a maturation arrest in erythropoiesis, hyperplastic This case describes a 16-year-old woman treated suc- myelopoiesis and normal megakaryopoiesis. In vitro stem cessfully by a bone marrow transplant from her HLA- cell cultures revealed a maturation arrest in the colony for- identical brother for refractory acquired pure red cell ming unit-erythroid. The patient’s serum did not specifi- aplasia. Conditioning was as for severe aplastic anaemia cally inhibit growth, and inhibition of growth by T-lympho- .with cyclophosphamide 4 ؋ 50 mg/kg and antithymo- cytes was not tested.8 Cytogenetic analysis was normal cyte globulin. Complete donor type engraftment at 3 Serology for parvovirus B19 revealed no evidence of active months reversed to full autologous reconstitution at 2 infection. However, positive IgG and negative IgM serol- years with normal haemopoiesis. The potential impli- ogy were suggestive of previous exposure. The patient’s cations on pathogenesis of the disease as well as on treat- erythropoietin level was increased to 206.4 mU/ml (norm: ment of autoimmune disorders by stem cell transplan- 4–16.4 mU/ml). She received erythrocyte transfusions and tation are discussed. steroids for 5 weeks (prednisone 75 mg/day for 6 days, then Keywords: acquired pure red cell aplasia; marrow trans- 50 mg/day for 4 weeks) as first-line therapy. However, plantation; autoimmune diseases treatment with steroids did not reverse the need for contin- ual transfusions. Additional treatment included intravenous immunoglobulins (Sandoglobulin 0.5 g/kg body weight, Swiss Central Laboratory of Red Cross, Berne, PRCA is a rare haematological disease characterized by Switzerland) for 3 days,4 and cyclosporin A (CsA) selective marrow erythroid aplasia. The congenital form of 300 mg/day for 6 months and resulted only in a transient 1 this disease is termed Diamond–Blackfan anaemia (DBA). improvement of anaemia. CT scan was suggestive of thy- The acquired form can be transient or sustained. Transient mic enlargement and thus a thymectomy was performed. 2 PRCA is often associated with a parvovirus B19 infection, However, after surgery no haematological improvement but other viral aetiologies are discussed. Patients with was observed and histological examination of the thymus acquired PRCA often establish thyomoma and erythropoie- revealed normal thymic tissue. According to a case report, tin antibodies, thus linking an autoimmune disorder and a trial with buserelin LHRH-Analoga (Suprefact, Hoechst 3–7 contributing to its aetiology. Many cases of acquired Marion Roussel) 900 ␮g/day was undertaken.9 However, PRCA may respond to conventional immunosuppressive the patient remained dependent on erythrocyte transfusions therapies, but novel therapeutic strategies for refractory of which she had received a total of 63. acquired PRCA are warranted. Because of persistent anaemia, bone marrow transplan- tation was considered to treat the refractory acquired PRCA and alleviate the need for continuous transfusion support Case report and iron chelating therapy. After ethics committee approval and informed consent, the patient underwent allogeneic We report a 16-year-old woman with acquired refractory BMT from her HLA-identical brother. In view of her young PRCA treated for the first time by high-dose immunosup- age and the relatively low risk of transplant-related mor- pressive therapy followed by allogeneic BMT after she tality, an allogeneic transplant was considered to be the best failed to respond to conventional treatment. At diagnosis choice of therapy. Conditioning was with cyclophospham- the haemoglobin was 5.3 g% with 0.4% reticulocytes ide 50 mg/kg/day for 4 days and antithymocyte globulin (norm: 0.8–2.5%), platelets and leucocytes were normal. (ATG) 30 mg/kg/day for 3 days consistent with treatment Physical examination was normal, except for signs of anae- for SAA. A total of 2.6 ϫ 108 unmanipulated nucleated cells (CD34ϩ cells: 2.03 ϫ 106) were infused. CsA was Correspondence: Dr A Gratwohl, Division of Haematology, Department given to prevent GVHD. The patient developed generalized of Medicine, Kantonsspital, CH-4031 Basel, Switzerland erythema and hyperbilirubinaemia with some ascites, which Received 10 November 1998; accepted 6 January 1999 were interpreted as acute GVHD II with additional manifes- BMT for acquired PRCA BU Mu¨ller et al 1206 tations of transient veno-occlusive disease. After an aplastic The observation in our patient of autologous reconsti- period of 19 days, she showed full haematological reconsti- tution after allogeneic BMT is not unique. Complete tution. Cytogenetic studies of the bone marrow at 3 months remissions of severe aplastic anaemia after conditioning revealed a male karyotype (donor), and at 6 months a with cyclophosphamide and rejection of the allogeneic graft female karyotype (recipient), confirmed by DNA polymor- were described more than 20 years ago.16 They form the phism studies. At 12 months, cytogenetic analysis revealed basis of current approaches in the treatment of aplastic ana- a chimeric bone marrow karyotype. Of 29 metaphases emia and other autoimmune disease states with high-dose examined, 10 showed a male and 19 a female karyotype. cyclophosphamide alone.17,18 The role of the allogeneic The 2-year cytogenetic analysis again showed reversal to a graft in this situation of autologous reconstitution and the 100% female karyotype, again confirmed by DNA poly- potential mechanisms of microchimeric status remain open morphism studies. CsA was stopped 10 months after BMT to discussion.19 (CsA 200 mg/day was given until 9 months after BMT and The successful treatment of our patient gives strong sup- after that 100 mg/day). The patient remains in CR with nor- port to the concept that acquired PRCA is also an auto- mal autologous haematopoiesis. Three years after the BMT immune disease. This case adds to the growing number of she is healthy, doing well and working full time. patients with serious autoimmune diseases who are being treated and recorded under a combined European Group for Bone and Marrow Transplantation (EBMT/EULAR Discussion guidelines).20 It further suggests that autoimmune diseases can be modified by intensive immunoablation. Many cases of acquired PRCA may respond to conven- In summary, high-dose immunosuppressive therapy with tional immunosuppressive therapies, but novel therapeutic allogeneic BMT should be considered for patients with strategies for refractory acquired PRCA are warranted.10 refractory acquired PRCA with an HLA-identical donor. This case report shows CR for the first time after allogeneic Our case demonstrates that acquired PRCA can be cured BMT in a patient with refractory acquired PRCA. The res- by this approach. The resulting complete restoration of toration of normal autologous haematopoiesis suggests that recipient haematopoiesis suggests that autologous and allo- PRCA is an autoimmune disease similar to SAA, pure geneic BMT should be investigated as a treatment for the white cell aplasia (PWCA) and certain other bone marrow rare patients with acquired PRCA. diseases. Until recently, bone marrow failure was con- sidered secondary to physical or chemical insults, infections or nutritional deficiencies. New considerations suggest that Acknowledgements PRCA, SAA, PWCA and certain other bone marrow dis- eases are induced by immunological mechanisms that can The authors would like to thank A Maerki for her excellent sec- be triggered by an intrinsic stem cell defect or by cell dam- retarial assistance and J Tenen for revision of the manuscript. The age after an extrinsic insult.11 The association of PRCA work was supported in part by the Swiss National Research Foun- with thymoma or lymphoma further suggests an auto- dation grant No. 32–52756.97. immune aetiology.2,3,6,7,12,13 In contrast to SAA, which involves all three lineages, red cells, white cells and plate- lets, PRCA is limited to the red cell lineage. 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