Thrombotic thrombocytopenic purpura after ... - Wiley Online Library

British Journal of Haematology, 2002, 118, 1112–1119

Thrombotic thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation (EBMT) Tapani Ruutu, 1 Jo Hermans, 2 Dietger Niederwieser, 3 Alois Gratwohl, 4 Michael Kiehl, 5 Liisa Volin, 1 Harmut Bertz, 6 Per Ljungman, 7 David Spence, 8 Leo F. Verdonck, 9 H. Grant Prentice, 10 Alberto Bosi, 11 Cecile E. du Toit, 12 Lorentz Brinch 13 and Jane F. Apperley 14 on behalf of the EBMT Chronic Leukaemia Working Party 1Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland, 2Department of Medical Statistics, University of Leiden, Leiden, The Netherlands, 3 Department of Haematology/Oncology, University of Leipzig, Leipzig, Germany, 4Division of Haematology, Kantonsspital, Basel, Switzerland, 5Klinik fu¨r Knochenmarktransplantation und Ha¨matologie/Onkologie GmbH, IdarOberstein, Germany, 6Department of Medicine, Haematology/Oncology, University of Freiburg, Freiburg, Germany, 7 Department of Haematology, Huddinge University Hospital, Huddinge, Sweden, 8Shaikh Khalifa Medical Centre, Abu Dhabi, United Arab Emirates, 9Department of Haematology, University Medical Centre, Utrecht, The Netherlands, 10 Royal Free and University College Medical School, Royal Free Campus, London, UK, 11BMT Unit, Department of Haematology, Ospedale di Careggi, Firenze, Italy, 12Department of Haematology, UCT Medical School, Cape Town, South Africa, 13Department of Medicine, Rikshospitalet, Oslo, Norway, and 14Department of Haematology, Imperial College School of Medicine, London, UK Received 20 August 2001; accepted for publication 3 April 2002

Summary. A survey was carried out among the European Group for Blood and Marrow Transplantation (EBMT) centres to determine the incidence, risk factors, treatment and outcome of thrombotic thrombocytopenic purpura (TTP) following allogeneic haematopoietic stem cell transplantation. TTP was defined as the simultaneous occurrence of red cell fragmentation, laboratory findings of haemolysis, red cell transfusion requirement and de novo or persistant thrombocytopenia caused by consumption, in the absence of disseminated intravascular coagulation. Forty-five centres reported all patients (n ¼ 406) transplanted between July and December 1996. Twenty-three patients developed TTP; the risk of developing TTP was 6Æ7% at 2 years (95% CI: 4Æ1% to 9Æ3%). The median time of onset was 44 d (range 13–319) post transplantation. Significant risk factors for the development of TTP were female gender (P ¼ 0Æ005) and an unrelated donor (P ¼ 0Æ046). To treat TTP, cyclo-

Correspondence: Tapani Ruutu, M.D., Helsinki University Central Hospital, Department of Medicine, Division of Haematology, POB 340, FIN-00029 HUS, Helsinki, Finland. E-mail: tapani.ruutu@ hus.fi

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sporin administration was discontinued in 10 cases, plasma exchanges were performed in five cases and 12 patients received plasma infusions without plasma exchange. TTP resolved in 13 of the 23 patients (57%). The only factor predictive of resolution of TTP was the absence of nephropathy. Seven patients (30%) were alive at follow-up of 38– 45 months from the onset of TTP. Sixteen patients died; the causes were multiple, only three patients had TTP as a central factor. The median time to death was 41 d (range 1– 762 d) from the onset of TTP. TTP is a relatively frequent complication of allogeneic stem cell transplantation and it is associated with high mortality, though death is usually caused by multiple factors. Keywords: allogeneic stem cell transplantation, thrombotic thrombocytopenic purpura, thrombotic microangiopathy, incidence, risk factors.

Thrombotic microangiopathy with its consequent clinical syndromes, thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS), is a well-known complication of haematopoietic stem cell transplantation, especially allogeneic transplantation. The reported incidences have varied, in allogeneic transplantation from 1Æ6% Ó 2002 Blackwell Science Ltd

TTP after Allogeneic Stem Cell Transplantation to 76% and in autologous transplantation from 0% to 27% (Pettitt & Clark, 1994; Zeigler et al, 1995; Iacopino et al, 1999; Fuge et al, 2001). In a review of published reports by Pettitt & Clark (1994), the incidence was 13Æ6% in allogeneic and 7% in autologous transplantation. The broad range in reported incidences reflects, in part, the lack of a uniform definition. A large number of abnormalities in blood parameters and endothelial function have been reported in TTP, but their role in the pathogenesis has remained unclear (Pettitt & Clark, 1994; Moake, 1997; Schriber & Herzig, 1997; Sniecinski & O’Donnell, 1998; Wright et al, 1999; Rock, 2000). Progress has been recently made in the understanding of the pathogenesis of de novo TTP with the demonstration of deficient von Willebrand factor-cleaving protease activity, which may be inherited or caused by an antibody (Furlan et al, 1997; Cines et al, 2000). Such an enzyme defect does not seem to have a role in stem cell transplantation-associated TTP (van der Plas et al, 1999) and endothelial injury is likely to be the primary event (Cohen et al, 1989; Holler et al, 1989; Sarode et al, 1995; Schriber & Herzig, 1997). There is substantial evidence for a role of cyclosporin A (CSA) in the pathogenesis of transplantationassociated TTP (Ruggenenti & Remuzzi, 1991), but the syndrome has been reported before its introduction (Chappell et al, 1988). An unrelated donor has been reported to be a risk factor for the development of TTP (Paquette et al, 1998; Fuge et al, 2001) and corticosteroids given together with CSA may also increase the risk (Kalhs et al, 1995; Paquette et al, 1998). TTP in association with stem cell transplantation is a serious complication. The mortality rate has been reported to vary from 0% to 100%, probably as a result of small numbers of patients and differing diagnostic criteria. In the review by Pettitt & Clark (1994), the overall mortality was 31% and thrombotic microangiopathy-attributable mortality was 23%. In two recent studies, the mortality was 50% and 86% (Iacopino et al, 1999; Fuge et al, 2001). No consistently effective treatment is presently available. In order to obtain more information about stem cell transplantation-associated TTP, the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) undertook a survey among European transplantation centres to determine the incidence, risk factors and outcome of clinically significant TTP syndromes, and to identify the treatments used. PATIENTS AND METHODS Study design. This is a retrospective multicentre cohort analysis. All EBMT centres performing allogeneic transplantations (256 centres) were asked for their willingness to participate in the study, and 45 centres from 17 countries agreed to participate (listed in the Appendix). In a survey carried out in 1998, the centres reported all allogeneic stem cell transplantations done during the period from 1 July to 31 December 1996 and the cases of TTP observed among these patients. The survival of the patients with TTP who were alive at the time of the first survey was updated in July 2000.

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Patients. The patient population and the disease characteristics are shown in Table I. There were 406 patients, 233 male (57%) and 173 female (43%), aged between 1 month and 60 years (median 34 years). Two hundred and fifty-six patients (63%) had a human leucocyte antigen (HLA)identical sibling donor, 18 (4%) an other related donor and 132 (33%) an unrelated donor. Of the patients, 75% received a bone marrow graft. A large majority had a malignant haematological disorder. The conditioning regimens and graft-versus-host disease (GVHD) prophylaxis used are shown in Table I. Definitions. For the purposes of the present survey, TTP was defined as the simultaneous occurrence of all of the following: (1) red cell fragmentation on the blood film, (2) laboratory findings of haemolysis, (3) the need for red cell transfusions, (4) de novo or prolonged thrombocytopenia caused by consumption, and (5) negative or, at most, marginally positive laboratory tests for disseminated intravascular coagulation. Parameters recorded. The following parameters were recorded for all patients: age, sex, disease and stage of disease, conditioning, type of donor, source of graft, GVHD prophylaxis, occurrence and grade of acute GVHD, occurrence and severity of chronic GVHD, occurrence of TTP, and follow-up time. Of the patients with TTP, the following additional data were recorded: time from transplantation to the onset of TTP, occurrence of nephropathy, neurological manifestations and veno-occlusive disease (VOD) of the liver, megakaryocytes in the bone marrow, ABO blood groups, treatments given for TTP, outcome of TTP, survival, and, in cases of fatal outcome, whether TTP was a central factor in the death. Statistics. The analysis of risk factors for the development of TTP was based on the Kaplan–Meier survival curves, while the groups were compared by the log-rank test. The patients who developed TTP either died within 25 months or were alive and recovered from TTP with a follow-up of at least 3 years. The predictive value of some factors for survival and recovery from TTP among these patients was determined with Fisher’s exact test. RESULTS Incidence and time of the onset of TTP Of the 406 patients reported, with a median follow-up from transplantation of 415 d (range 4–915 d), 23 had TTP (5Æ7%; 95% CI: 3Æ3–8Æ1%). The actuarial risk of developing TTP was 6Æ7% at 2 years (95% CI: 4Æ1% to 9Æ3%) (Fig 1). The median time of the onset of TTP was d 44 post transplantation, ranging from d 13 to d 319. Risk factors for the development of TTP Two factors significantly predicted the development of TTP; female gender and the use of an unrelated donor (Table I, Figs 2 and 3). These two factors acted independently: similar courses for the two donor groups as shown in Fig 3 were also seen for males and females separately. Age, source of graft, disease or the stage of disease, the type of conditioning, GVHD prophylaxis or the occurrence or grade

Ó 2002 Blackwell Science Ltd, British Journal of Haematology 118: 1112–1119

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T. Ruutu et al Table I. Risk of TTP at 2 years after transplantation.

Total Age (years)

Sex Donor

Source of graft

Disease

Disease Disease Conditioning

TBI GVHD prophylaxis

CSA prophylaxis MTX prophylaxis Acute GVHD grade

< 20 20–40 > 40 Male Female HLA-identical sibling Other related Unrelated Bone marrow Blood stem cells (Bone marrow + blood stem cells 1) AML ALL CML MDS CLL + MM + lymphoma SAA + Fanconi + thalassaemia (Other 22) Acute leukaemia I CR + CML I CP All other leukaemias AML I CR + CML I CP All other indications CyTBI BuCy Other (None 4) No Yes CSA + MTX CSA T-cell depletion only Other (None 8) No Yes No Yes 0+I II + III + IV (Non-evaluable 2)

n

Risk %

406 87 184 135 233 173 256 18 132 303 102

6Æ7 5Æ4 6Æ2 8Æ1 3Æ3 11Æ0 4Æ8 0Æ0 11Æ8 6Æ6 6Æ8

101 86 125 22 35 15

7Æ3 6Æ0 6Æ1 14Æ1 0Æ0 13Æ8

175 137 151 255 233 91 78

6Æ8 6Æ4 7Æ1 6Æ4 6Æ8 4Æ8 7Æ4

144 262 257 49 23 69

5Æ3 7Æ4 5Æ7 7Æ8 4Æ9 10Æ0

31 375 103 303 248 156

4Æ9 6Æ9 8Æ1 6Æ4 6Æ9 6Æ4

log-rank P

0Æ77 0Æ005

0Æ046 0Æ87

0Æ25

0Æ68 0Æ73

0Æ84

0Æ53

0Æ77

0Æ74 0Æ91 0Æ72

ALL, acute lymphatic leukaemia; AML, acute myeloid leukaemia; Bu, busulphan; CLL, chronic lymphatic leukaemia; CML, chronic myeloid leukaemia; CP, chronic phase; CR, complete remission; CSA, cyclosporin A; Cy, cyclophosphamide; MDS, myelodysplastic syndrome; MM, multiple myeloma; MTX, methotrexate; SAA, severe aplastic anaemia; TBI, total body irradiation.

of acute GVHD did not significantly predict for TTP (Table I). There were only 31 patients who were not given CSA for GVHD prophylaxis and therefore the possible role of CSA in the development of TTP cannot be properly analysed in the present material. One patient who did not receive CSA, and was one of the 23 patients who had T-cell depletion as the only GVHD prophylaxis, developed TTP. Characteristics of TTP patients Seven of the 23 patients with TTP (30%) also had active or preceding VOD of the liver. Nephropathy, defined as serum

creatinine above the reference range, was present at the time of TTP in 17 patients. Neurological manifestations were observed in six patients; five patients had central nervous system manifestations and one patient had peripheral polyneuropathy. There was a major ABO incompatibility between the patient and the donor in five cases and a minor incompatibility in four cases. The number of megakaryocytes in the bone marrow aspirate or biopsy at the time of TTP was recorded in 13 patients, and estimated to be normal or increased in nine patients and reduced in four patients.


TTP after Allogeneic Stem Cell Transplantation

Fig 1. Risk of TTP after allogeneic BMT. The actuarial risk of developing TTP was 6Æ7% at 2 years (95% CI: 4Æ1–9Æ3%).

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Fig 3. Type of donor as a risk factor of transplantation-associated TTP. The risk of developing TTP was 11Æ8% at 2 years among recipients of a graft from an unrelated donor (MUD), significantly higher than among recipients of a graft from a sibling donor (HLA id sib) (4Æ8%).

Risk factors for outcome after the development of TTP Of the 23 patients with TTP, 16 patients died. The median time from the onset of TTP to death was 41 d (range 1–762 d). Fourteen of the 16 deaths occurred within 6 months; one patient died after 14 months and one after 25 months. The seven patients who survived had a followup of 38–45 months after the development of TTP. Among the 16 deaths, TTP was regarded as a central factor in the death only in three cases; the principle cause of death of the other deceased TTP patients was GVHD in four, infection in three, VOD in three and interstitial pneumonitis in two patients, and graft failure in one patient. The survival of the patients with TTP was 30% 3 years after the development of TTP (Fig 4). Fig 2. Gender as a risk factor of transplantation-associated TTP. The risk of developing TTP was 11Æ0% at 2 years among female patients, significantly higher than among male patients (3Æ3%).

Treatment There was no standard treatment policy and treatments varied between centres. They included discontinuation of CSA administration in 10 patients (43%) and reduction of the dose in two patients, plasma exchange in five (22%) and plasma infusions without exchange in 12 patients (52%), corticosteroids in three patients (13%), and prostacyclin infusions and vincristine in one patient each. Among the 10 patients in which CSA was discontinued, TTP resolved in seven patients and four of these had survived to the time of the analysis. Of the five patients who were treated with plasma exchange, TTP resolved in four patients and one of them survived. In four of the 12 patients given plasma infusions without exchange, TTP resolved and they all survived. One of the three patients treated with corticosteroids died.

Fig 4. Survival of patients with transplantation-associated TTP. Calculated from the onset of TTP onwards. The survival was 30% after a follow-up of 38–45 months.


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T. Ruutu et al Table II. Risk factors for death after the onset of TTP.

TTP resolved Nephropathy Neuropathy Sex Donor VOD

Yes No Yes No Yes No Male Female HLA id sib MUD Yes No

n

Death (within 2 years after TTP)

Alive (more than 3 years after TTP)

13 10 17 6 7 16 7 16 11 12 7 16

6 10 14 2 6 10 6 10 8 8 6 10

7 0 3 4 1 6 1 6 3 4 1 6

P (Fisher)

0Æ007 0Æ045 0Æ37 0Æ37 1Æ00 0Æ37

MUD, matched unrelated donor; VOD, veno–occlusive disease of the liver.

TTP resolved in 13 of the 23 patients (57%). All 10 patients whose TTP did not resolve died within 3 months, while seven of the 13 patients whose TTP resolved had survived to the time of the analysis (P ¼ 0Æ007) (Table II). Three of the 17 patients with and four of the six without nephropathy survived (P ¼ 0Æ045). The absence of nephropathy also predicted the resolution of TTP, seven of 17 patients with and all six without nephropathy recovered from this complication (P ¼ 0Æ017). The following factors had no significant prognostic value as to the resolution of TTP or survival from TTP: sex, type of donor, the disease or the stage of disease, type of conditioning, source of graft, GVHD prophylaxis, occurrence or grade of acute GVHD, chronic GVHD, the time of the onset of TTP, presence of neurological manifestations, VOD, and the type of treatment given. DISCUSSION The present survey illustrates the incidence and risk factors of TTP following allogeneic stem cell transplantation in a large cohort study. The reported incidences of TTP after haematopoietic stem cell transplantation have varied greatly, probably as a result of differences in patient materials and non-uniform definitions. There are no pathognomonic findings, and alertness and a high degree of suspicion of this complication may affect the observed incidences. In the present survey, the risk of developing TTP was 6Æ7% at 2 years, somewhat lower than the mean incidence of 13Æ6% in the review by Pettitt & Clark (1994). In two recent reports using similar criteria, the incidence was 0Æ51% (Iacopino et al, 1999) and 6% (Fuge et al, 2001). Changes in red cell morphology indicating microangiopathy are common and can be seen in a majority of allogeneic transplantation patients (Holler et al, 1989; Zeigler et al, 1995). Female gender and the use of an unrelated donor were identified as risk factors for the development of TTP. Transplantation from an unrelated donor has previously

been reported as a risk factor (Paquette et al, 1998; Fuge et al, 2001). In most previous reports, female patients have not been found to be at a greater risk of developing TTP post transplantation than male patients (Pettitt & Clark, 1994; Zeigler et al, 1995; Paquette et al, 1998), but Fuge et al (2001) observed a significantly higher incidence among females. Ha¨gglund et al (1998) reported a significantly higher incidence of VOD, a related disorder, among female patients than among males and the administration of norethisterone to prevent menstrual haemorrhage was the greatest risk factor. Increased risk of VOD after stem cell transplantation among female patients, with a possible relationship to hormonal treatment, has also been reported by three other groups (Ganem et al, 1988; Nevill et al, 1991; Klingemann et al, 1994). Pregnancy and use of oral contraceptives have been reported to increase the risk of non-transplantation-associated TTP (Brown et al, 1973; Ezra et al, 1996; Rock, 2000). It is possible that hormonal treatment given to female patients explains the difference in the risk of developing TTP, but the data to analyse the role of this factor were not available in this retrospective survey. There is substantial evidence that CSA may play a role in the development of transplantation-associated TTP (Ruggenenti & Remuzzi, 1991). CSA has been shown to cause direct endothelial damage (Zoja et al, 1986; Cohen et al, 1989; Schriber & Herzig, 1997). It increases ADP, collagen and adrenaline-induced platelet aggregation (Grace et al, 1987), thromboxane A2 release, thromboplastin generation and factor VII activity (Schriber & Herzig, 1997), decreases prostacyclin production (Brown & Neild, 1987; Voss et al, 1988), and also decreases thrombomodulin and downregulates protein C (Garcia-Maldonado et al, 1991). Patients treated with CSA have been reported to have a higher incidence of TTP than those not receiving CSA (Holler et al, 1989), but unequivocal evidence from comparative clinical studies of the role of CSA in the development of TTP is lacking. Discontinuation of CSA administration in cases of TTP does not usually clearly ameliorate the complication


TTP after Allogeneic Stem Cell Transplantation (Holler et al, 1989; Sarode et al, 1995; Paquette et al, 1998). The role of CSA could not be analysed in a meaningful way in the present survey, as a large majority of patients had received CSA and only a small number of patients had not been given this drug. Total body irradiation (TBI) has been suggested to be a risk factor of TTP or HUS after stem cell transplantation (Chappell et al, 1988; Carlson et al, 1993). In the present study, there was no indication of a predictive role of TBI. In two previous studies, grade II or higher acute GVHD predicted significantly the development of TTP (Holler et al, 1989; Fuge et al, 2001), whereas this was not seen in the study of Paquette et al (1998). In the present study, GVHD was not a significant risk factor for TTP. Age, source of graft (marrow or blood) or disease also had no predictive value. The range of the reported times of the onset of TTP or HUS is wide, from 3 days to 29 months after the transplantation (Pettitt & Clark, 1994; Paquette et al, 1998; Fuge et al, 2001). The median times of onset have varied in different studies between 11 d and 6 months (Pettitt & Clark, 1994). The present findings with the median time of the onset at 44 d and a range of 13–319 d post transplantation are in line with previous experience. The patients with increased serum creatinine levels had a significantly poorer outcome than those with normal levels. However, slight nephropathy is a very common phenomenon after allogeneic transplantation, often related to the use of nephrotoxic drugs, including CSA. Therefore the role of TTP in the nephropathy should be interpreted with great caution. The present data does not permit analysis of a causal or temporal relationship between nephropathy, its possible causes and TTP. Neurological problems were observed in a minority of the patients, seven out of 23 patients. There was no significant difference in the outcome between the patients with and without neurological manifestations: six out of seven vs 10 out of 16 patients died. Seven of the 23 patients with TTP also had active or prior VOD. The occurrence of VOD among patients with transplantation-associated TTP has been reported previously: in the studies by Sarode et al (1995) and Zeigler et al (1995), four out of nine and two out of 21 patients with a thrombotic microangiopathy syndrome also had VOD. These two complications may be regarded as related, as small vessel injury is a central feature in both and they may share aetiological and pathogenetic factors. In the review by Pettitt & Clark (1994), the overall mortality after the occurrence of thrombotic microangiopathy was 31% and thrombotic microangiopathy-attributable mortality was 23%, with marked differences between different studies. In the study of Iacopino et al (1999), the mortality was 50%; in the study of Fuge et al (2001), it was 86%. In the present patient material, the overall mortality was relatively high (70%) probably as a result of the type of patients selected by the criteria used. However, TTP was regarded as a central factor in only three of 16 deaths, giving an overall thrombotic microangiopathy-attributable mortality of 13%. TTP was reported to have resolved in 57% of the cases, but the 3 year survival from the onset of TTP was only 30%. This reflects the fact that patients with TTP

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often also have other problems and the clinical situation is often complex. The present findings are in agreement with those of Paquette et al (1998). All their seven patients with thrombotic microangiopathy died, but microangiopathy was not the primary cause of death in any of the cases. The treatment of transplantation-associated TTP is problematic and no generally effective therapies are available. There was no uniform treatment policy in the cases reported in this survey. In the light of the suspicion of a role of CSA in the development of TTP, discontinuing CSA treatment is logical, but, unfortunately, it does not usually reverse the complication (Holler et al, 1989; Paquette et al, 1998). Plasma exchange, which is effective in de novo TTP (Rock et al, 1991; Rock, 2000), was used only in five cases whereas plasma infusions without exchange, shown to be inferior to plasma exchange in the de novo syndrome (Rock et al, 1991), were given to half of the patients. No clear benefit was achieved with either of these treatments. The general experience has been that plasmapheresis is not effective in transplantation-associated TTP (Pettit & Clark, 1994; Sarode et al, 1995; Fuge et al, 2001). Although tacrolimus substitution for CSA has been reported to be successful in some cases of solid organ transplantation (Schriber & Herzig, 1997), tacrolimus can apparently cause TTP or HUS in stem cell transplantation patients (Ichihashi et al, 1992; Gharpure et al, 1995). Corticosteroids, antiplatelet agents, antifibrinolytics, prostacyclin infusions, vincristine, heparin or thrombolytic therapy, i.v. immunoglobulins and splenectomy have not been effective in the treatment of transplantation-associated TTP (Pettitt & Clark, 1994). There are early reports of useful effects obtained with defibrotide (Hamblin et al, 1997; Shaw et al, 1999), an agent shown to be effective in VOD (Richardson et al, 1998; Chopra et al, 2000), and this drug should be studied in larger trials. In conclusion, TTP after allogeneic stem cells transplantation is a formidable clinical problem. There are no generally accepted detailed diagnostic criteria and the pathogenesis is poorly understood. The management is unsatisfactory and the mortality is high. Studies to find better treatments are needed and the results of this survey may serve as a basis for the planning of such studies. REFERENCES Brown, C.B., Clarkson, A.R., Robson, J.S., Cameron, J.S., Thomson, D. & Ogg, C.S. (1973) Haemolytic uraemic syndrome in women taking oral contraceptives. Lancet, 1, 1479–1481. Brown, Z. & Neild, G.H. (1987) Cyclosporine inhibits prostacyclin production by cultured human endothelial cells. Transplantation Proceedings, 19, 1178–1180. Carlson, K., Smedmyr, B., Hagberg, H., O¨berg, G. & Simonsson, B. (1993) Haemolytic uraemic syndrome and renal dysfunction following BEAC (BCNU, etoposide, Ara-C, cyclophosphamide) +/) TBI and autologous BMT for malignant lymphomas. Bone Marrow Transplantation, 11, 205–208. Chappell, M.E., Keeling, D.M., Prentice, H.G. & Sweny, P. (1988) Haemolytic uraemic syndrome after bone marrow transplantation: an adverse effect of total body irradiation? Bone Marrow Transplantation, 3, 339–347.


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APPENDIX Participating centres Australia: Melbourne (A. P. Schwarer), Sydney (P. J. Shaw) Austria: Innsbruck (D. Niederwieser), Linz (D. Lutz) Belgium: Antwerp UZA (Z. Berneman), Brugge (D. Selleslag), Brussels St. Luc (A. Ferrant), Liege University, Department of Medicine (Y. Beguin)

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Finland: Helsinki Department of Medicine (T. Ruutu, L. Volin), Turku (K. Remes) Germany: Berlin Charite´ (R. Arnold), Dresden (M. Bornha¨user), Freiburg University, Department of Medicine-Haematology (H. Bertz), Hamburg Eppendorf (A. R. Zander), Idar-Oberstein (M. Kiehl) Hungary: Budapest St. La`szlo´ (T. Masszi) Iran: Teheran (M. R. Mortazavizadeh) Italy: Firenze Ospedale di Careggi (A. Bosi), Genova Gaslini (E. Lanino/M. Miano), Monza San Gerardo (C. Uderzo), Napoli (B. Rotoli), Padova (L. Zanesco, C. Messina, S. Varotto), Pavia Department of Haematology (E. P. Alessandrino), Turin Regina Margherita (R. Miniero), Vicenza Department of Haematology (R. Raimondi) The Netherlands: Utrecht (L. F. Verdonck) New Zealand: Christchurch (D. N. J. Hart) Norway: Oslo Rikshospitalet (L. Brinch) Slovenia: Ljubljana (J. Pretnar) South Africa: Cape Town UCT (C. E. du Toit) Spain: Barcelona Vall d’Hebron (A. Julia) Sweden: Gothenburg Department of Medicine (J. Carneskog), Huddinge (P. Ljungman), Linko¨ping (G. Juliusson), Lund (B. Sallerfors), Uppsala (K. Carlson) Switzerland: Basel (A. Gratwohl) UK: Birmingham Heartlands (D. W. Milligan), Glasgow Royal Infirmary (D. Spence), Clydebank HCI International Medical Centre (D. Spence), Leicester (R. Hutchinson), London King’s College (G. J. Mufti), London Royal Free (R. Pawson, H. G. Prentice), Manchester Children’s Hospital (A. M. Will), Oxford (T. Littlewood)
