Prophylaxis and treatment of GVHD after allogeneic ... - Nature

Bone Marrow Transplantation (2012) 47, 1459 - 1464 & 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12 www.nature.com/bmt

ORIGINAL ARTICLE

Prophylaxis and treatment of GVHD after allogeneic haematopoietic SCT: a survey of centre strategies by the European Group for Blood and Marrow Transplantation T Ruutu1, A van Biezen2, B Hertenstein3, A Henseler2, L Garderet4, J Passweg5, M Mohty6,7, A Sureda8, D Niederwieser9, A Gratwohl10 and T de Witte11 Recommendations on indications for allogeneic haematopoietic SCT have been presented, but transplantation techniques remain poorly standardized. Pre-transplant risk factors are well defined, and reported outcomes vary markedly among patients with similar risk characteristics. It would be of importance to know the impact of differences in treatment procedures. To study properly the different components of allogeneic transplantation, standardization of at least some central procedures would be needed. As the first step, the European Group for Blood and Marrow Transplantation (EBMT) performed a survey among all its 372 member centres performing allogeneic transplantations about their strategies in preventing and treating GVHD. Responses from 79 centres (21% return) from 25 countries (60% return) were received. Although some trends toward more uniform policies compared with a survey carried out 15 years earlier were observed, the present survey still showed marked variability in the GVHD prophylaxis and treatment strategies. On the basis of these findings, EBMT is developing a consensus process aiming at a standardized strategy. Bone Marrow Transplantation (2012) 47, 1459 -- 1464; doi:10.1038/bmt.2012.45; published online 12 March 2012 Keywords: allogeneic stem cell transplantation; graft-versus-host disease; prophylaxis; treatment

INTRODUCTION GVHD is the main procedure-related complication in allogeneic haematopoietic SCT, and the successful prevention and management of this complication is crucial for an optimal outcome. GVHD can be quite effectively prevented by potent immunomodulatory methods, particularly in vitro and in vivo T-cell depletion (TCD), but often at the cost of an increased risk of relapse and rejection. Preventing GVHD without interfering with the GVL effect is a major challenge. Correct information about the value of current approaches is essential to advance our knowledge. Our understanding is largely based on retrospective analyses of registries, such as the registries of the European Group for Blood and Marrow Transplantation (EBMT) and the Center for International Bone Marrow Transplant Research. In this context, pre-transplant risk factors (factors related to the patient, disease and donor) have become well defined. The EBMT risk score1 is composed of five key pre-transplant characteristics and it yields a high power of prediction, hence permitting comparisons of heterogeneous groups. Its value is strengthened by the fact that age, disease stage, time interval from diagnosis to transplantation, donor type and donor recipient sex combination have the same characteristics in all centres. In contrast, the techniques used in allo-SCT are poorly standardized and carried out in different ways. There are many

methodological variants, and even when the procedures are superficially similar, the details may differ markedly. This applies particularly to the prophylaxis and treatment of GVHD, as earlier demonstrated by a survey carried out by the EBMT in the 1990s.2 The reported outcomes of allo-SCT have varied markedly, and part of this may be due to differences in the practices of the prophylaxis and treatment of GVHD. It is well established that the methods of GVHD prophylaxis have relevant and discordant effects on two important outcome measures, non-relapse mortality and relapse.3 - 7 Complete abrogation of GVHD can reduce early non-relapse mortality, but it does so at the expense of a higher relapse rate. Vice versa, failure of GVHD prevention is associated with a stronger GVL effect and, hence, a lower relapse rate, but at the expense of higher non-relapse mortality. The combined impact on overall survival may depend on the particular conditions such as the disease, and, in many settings, it remains a matter of debate. Minor differences in the prevention of GVHD might have an impact, but cannot be identified in retrospective registry analyses due to lack of detailed information and the general heterogeneity of the methods applied. Standards and guidelines for the indications of allogeneic and autologous SCT8 and the use of donors9,10 have been presented, but no similar, widely accepted guidelines exist for the methods of transplantation. Some standardization of transplant procedures,

1 Department of Medicine, Division of Haematology, Helsinki University Central Hospital, Helsinki, Finland; 2Data Office EBMT Chronic Leukaemia Working Party, Department of Medical Statistics and Bioinformatica, Leiden University Medical Centre, Leiden, The Netherlands; 3Klinik fu¨r Innere Medizin, Klinikum Bremen-- Mitte, Bremen, Germany; 4Service d’Hematologie, Hoˆpital Saint Antoine, Paris, France; 5Service d’Hematologie, Departement Medecine Interne, Hopitaux Universitaires de Geneve, Geneva, Switzerland; 6Centre Hospitalier et Universitaire (CHU) de Nantes, He´matologie Clinique, INSERM CRCNA, UMR 892, Universite´ de Nantes, Faculte´ de Me´decine, Nantes, France; 7Centre d’Investigation Clinique en Cance´rologie (CI2C), CHU de Nantes, Nantes, France; 8Department of Haematology, Addenbrookes Hospital, Cambridge, UK; 9Division of Hematology, Oncology and Hemostasiology, University Hospital Leipzig, Leipzig, Germany; 10Center for Stem Cell Transplantation, University Hospital Basel, Basel, Switzerland and 11Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Correspondence: Professor T Ruutu, Department of Medicine, Division of Haematology, Helsinki University Central Hospital, Biomedicum Helsinki 2 C, POB 705, FIN-00029 HUS, Helsinki, Finland. E-mail: tapani.ruutu@hus.fi Received 1 November 2011; revised 11 January 2012; accepted 5 February 2012; published online 12 March 2012

GVHD prophylaxis and treatment T Ruutu et al

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including the prevention and management of GVHD, would be needed to promote systematic studies on the impact of different components of these procedures. To evaluate the present situation at the EBMT centres as well as to form a platform for standardization, EBMT carried out a survey among its member centres about their strategies in the prophylaxis and treatment of GVHD. On the basis of these findings, EBMT is developing a consensus process aiming at a standardized strategy.

MATERIALS AND METHODS The survey was carried out during February -- July 2010. All EBMT centres performing allogeneic transplantations (n ¼ 372) were approached, and 79 centres (21% return) from 25 countries (60% return) agreed to participate. They filled in a form with 72 questions about their policy in the prophylaxis and treatment of acute and chronic GVHD. The reports were analysed at the EBMT Chronic Leukaemia Working Party Data Office in Leiden, The Netherlands. The forms were completed for all items in most cases, but as occasional answers were lacking (five or fewer answers to a given question unless otherwise specified), the results are usually given as percentages of the centres answering the question.

RESULTS Prophylaxis in transplantations with myeloablative conditioning The centres were asked about their main prophylactic regimen(s) in transplantations from a matched sibling or a matched unrelated donor when myeloablative conditioning was used. A large majority (87%) used the combination of CsA and a short course of MTX (Table 1). CsA þ mycophenolate mofetil (MMF; or mycophenolate sodium) was used by 11% of the centres. Some centres reported to use more than one main regimen. The use of anti-T-lymphocyte or anti-thymocyte globulin (ATG) is described below. Cyclosporine. The prophylactic administration of CsA was usually initiated on day 1 in relation to the infusion of the graft (75% of the centres). Other alternatives were days 7 (1%), 6 (1%), 3 (10%), 2 (10%) and day 0 (1%). The initial route of administration was mostly i.v.; in 5% of the centres, CsA was administered orally from the beginning of the treatment. Short i.v. infusions were given in 56% and a continuous infusion in 40% of the centres. In case of short infusions, the number of infusions per day was one (16%) or two (84%). The initial dose of CsA per kg per day varied considerably. The most common dose was 3 mg (49%), the other alternatives were 1 (7%), 1.5 (1%), 2 (8%), 2.5 (7%), 4 (7%), 5 (16%), 6 (4%), 10 (4%) and 12.5 mg (1%). The highest dose was given orally; otherwise, the oral doses were similar to those given i.v. In two cases, a range was given (1 -- 5 and 2 -- 5 mg). The dosing after the initial dose was mainly determined according to the blood or serum concentrations (90% of the centres). Some centres used a fixed dose schedule (4%), others determined the dose mainly by toxicity but with an upper concentration limit (6%). The concentration was measured from whole blood in 80% and from serum in 20% of the centres (71 answers). The most typical duration of the CsA prophylaxis was 6 months (42% of the centres). In 15% of the centres, the general duration was between 56 and 90 days, in 20% 100 -- 120 days, in 12% 130 -- 150 days, in 7% 7 -- 9 months, and in 3% 1 year. A total of 94% of the centres tapered the CsA dose before discontinuing the administration. Fifty-eight per cent of the centres reported that the duration of prophylaxis is affected by the estimated risk of relapse. The practical details were variable. The centres were asked whether an episode of acute GVHD, which had resolved, had an effect on the duration of the CsA Bone Marrow Transplantation (2012) 1459 - 1464

Table 1. Main prophylactic regimen(s) in transplantations from a matched sibling or a matched unrelated donor using myeloablative conditioning Regimen

Proportion of centres (%) using the regimen

CsA+MTX CsA+MMF CsA alone Tacrolimus+MTX Tacrolimus+MMF Tacrolimus alone CsA+alemtuzumab Alemtuzumab alone Ex vivo TCD (solely or in combination with drugs)

87 11 7 5 1 1 1 1 1

Abbreviations: MMF ¼ mycophenolate mofetil; TCD ¼ T-cell depletion.

administration. In 68% of the centres, such an episode modified the duration, and often also the dosing. A number of different policies were reported, affected by the timing and severity of the GVHD episode, as well as the use and effect of additional drugs. In 32% of the centres, such an acute GVHD episode did not affect the length of CsA administration. The policy had no correlation with the duration of the routine prophylaxis. Tacrolimus. Tacrolimus was used for prophylaxis in a way similar to that described above for CsA. Also, similar variation in the policies and practical details was observed. However, due to the small number of centres using tacrolimus, no further analysis was feasible. Methotrexate. The dosage of MTX, used in combination with CsA or tacrolimus, was 15 mg/m2 on day þ 1 and 10 mg/m2 on days þ 3, þ 6 and þ 11 in 61%, and the same dosage, but without the last dose, in 24% of the centres. There were six other variants in the remaining centres (15%), usually with slightly lower doses and slightly differing timing (e.g., days þ 2, þ 4, þ 8). Leucovorin rescue after MTX administration was given in 49% of the centres (66 answers). The schemes as to the timing, dose and route of administration were highly variable. Mycophenolate mofetil. MMF or mycophenolate sodium was used at least for some group(s) of patients given myeloablative conditioning in one third of the centres. The administration started between days 1 and þ 1, and the duration was in most cases (78%) between 4 weeks and 2 months. Three centres used a short treatment of 1 -- 2 days, one centre gave the drug for 3 months, and one centre for 1 year. The MMF dose was calculated in different ways, but the total dose was mainly between 1 and 3 g per day. Two centres measured mycophenolate concentrations to determine the dose. Anti-thymocyte globulin. A total of 20% of the centres did not use ATG for GVHD prophylaxis in any group of patients given myeloablative conditioning. One centre (1%) reported to include ATG in the prophylaxis for all patients. Fifty-seven per cent of the centres included ATG in the routine prophylaxis for recipients of a graft from an unrelated donor. In all, 16 centres (20%) reported another policy with the following indications for ATG prophylaxis: mismatched donor (4 centres), mismatched unrelated donor (3), transplantation from an unrelated donor except for SCID (1), aplastic anaemia (6), non-malignant disease (1), thalassaemia major (1), PBSC transplantation (2) and multitransfused patient (1). A total of 45% of the centres used Thymoglobulin (Genzyme, Cambridge, MA, USA), 39% ATG-F & 2012 Macmillan Publishers Limited


(Fresenius Biotech, Graefelfing, Germany), 15% used both, and 2% another product (62 answers). The median total dose of Thymoglobulin was 7.5 mg/kg (range 4 -- 32 mg/kg), given usually in 3 (43%), 2 (25%) or 4 days (21%), variably between days 8 and 1. The most commonly used total doses of ATG-F were 30 (30%) and 60 mg/kg (19%) with a range of 1.5 -- 75 mg/kg. The infusions were mostly given on 3 days (68%, range 1 -- 5 days), between days 5 and 1. Corticosteroid. A total of 7% of the centres included corticosteroid in their prophylaxis regimen for most (1%) or some groups (5%) of patients. Alemtuzumab. Alemtuzumab was given for GVHD prophylaxis to patients with myeloablative conditioning in 17% of the centres, for most patients (4%) or to specific groups (13%). The specific indications (10 centres) were an unrelated donor (4 centres), and a mismatched donor, high-risk mismatched transplantation, reduced-intensity conditioning (RIC) transplantation, acute leukaemia, blast crisis and CLL (one centre each).

1461 Table 2.

Prophylactic regimens used in transplantations with RIC

Regimen

Proportion of centres (%) using the regimen

CsA+MMF CsA+MTX CsA only Tacrolimus+MMF Tacrolimus+MTX Tacrolimus only CsA+tacrolimus CsA+alemtuzumab Sirolimus+MMF Sirolimus Alemtuzumab CsA+methylprednisolone In vivo TCDa In vivo TCDa+CsA Ex vivo TCD

69 38 22 10 3 1 1 1 1 1 1 1 18 1 3

Abbreviations: MMF ¼ mycophenolate mofetil; RIC ¼ reduced-intensity conditioning; TCD ¼ T-cell depletion. aAs reported by the centre. It is obvious that the inclusion of ATG in this group varies among centres.

Other drugs for prophylaxis. Everolimus combined with MMF and sirolimus were in use for some patients in two centres each. Ex vivo TCD. Ex vivo TCD was in use for some groups of patients given myeloablative conditioning in 28% of the centres. Negative selection was used in 11 and positive selection in 18 centres. In 2 of the 11 centres using negative selection, the ‘Campath in the bag’ method was applied. Positive selection was performed with anti-CD34 antibodies. In the centres using TCD, the indication was mostly haploidentical transplantation (63%) or transplantation from an unrelated donor (21%). Two thirds of the centres using ex vivo TCD did not add any immunosuppressive drugs to the prophylaxis regimen. A total of 22% gave CsA and 9% gave various combinations of immunosuppressive drugs in addition to TCD. Prophylaxis in transplantations with RIC The prophylactic regimens used in transplantations with RIC, defined according to the policy of the centre, are shown in Table 2. Many centres had several regimens in use. In contrast to transplantations with myeloablative conditioning, the combination of CsA and MMF was the most frequently used regimen. In the majority (55%), the duration of MMF prophylaxis was approximately 1 month (range 1 -- 85 days). Of the centres using MTX, three quarters used the same dosing as in transplantations with myeloablative conditioning. One quarter had a different policy, often with a lower dosage. In all, 74% of the centres included ATG in the GVHD prophylaxis regimens in RICs for at least some patient groups. A total of 12% of the centres used ATG in RICs only. Seventy-five per cent of centres using ATG both in full-intensity transplantations and in RICs applied the same regimen in both; in the remaining centres, various RIC-specific policies were in use. Ex vivo TCD was used only in two centres (3%). Development of chimerism. The centres were asked whether the development of chimerism affected immunosuppressive treatment after the transplantation. A total of 82% answered positively. With delayed development of full donor chimerism, the intensity of immunosuppressive treatment was usually reduced. Prophylaxis in cord blood transplantation Forty-five centres (57%) reported performing cord blood transplantations and described their GVHD prophylaxis policy. Twentysix centres gave prophylaxis with CsA and MMF, and two of them included also ATG. Nine centres used the combination & 2012 Macmillan Publishers Limited

CsA þ corticosteroid and one of them included ATG. The other alternatives were CsA alone (three centres), CsA þ MTX (two centres), and CsA þ MMF þ corticosteroid, CsA þ ATG, MMF þ corticosteroid, MMF alone, and ATG alone (one centre each). Treatment of acute GVHD All centres used corticosteroids as the first-line treatment of acute GVHD. A total of 87% used methylprednisolone, the rest predniso(lo)ne. Seventeen per cent of the centres started the treatment at the first signs likely to be caused by GVHD, whereas 82% treated only GVHD of grade II or higher. One per cent reported other policy. The decision to treat acute GVHD was based on clinical signs only in 82% of the centres, whereas in 18% histological documentation was needed. The initial dose of corticosteroid is shown in Table 3. The most common dose was 2 mg/kg per day, the range was 0.5 -- 20 mg/kg per day. In 92% of the centres, the drug was given i.v., and in 8%, it was given orally. The number of doses per day was most commonly two (61%). One dose was given in 20% of the centres, three and four doses in 9% each. Fifty-eight per cent of the centres reported that the severity of acute GVHD affected the initial dosing of corticosteroid. The details were quite variable. In one third of the centres, the type of manifestation or organ involvement had an effect on the initial dose. In many cases, gastrointestinal involvement led to an increased dose, but there were also numerous other approaches. In 77% of the centres, non-absorbable steroids were used for gut GVHD. Topical corticosteroids were used in 80% and topical tacrolimus in 22% of the centres. The typical duration of the initial dosage (70 answers) was most often 1 week (33%), 2 weeks (23%) or 5 days (16%). The reported range was from 3 to 42 days. The reduction of the dose was done according to a scheme (30%) or individually depending on the response (70%). The centres were asked to report the dose of corticosteroid and unresponsiveness, which was regarded as indicating corticosteroid-resistant GVHD and to be an indication for second-line treatment. The responses are shown in Table 4 (71 answers). The minimum time needed to confirm corticosteroid resistance (73 answers) was variable: 2 days (2%), 3 days (11%), 4 -- 5 days (27%), 6 -- 7 days (44%), 10 -- 14 days (13%) or 21 days (3%). Neither the initial corticosteroid dose nor the dose needed for the diagnosis of corticosteroid resistance correlated to the time needed to confirm resistance. Bone Marrow Transplantation (2012) 1459 - 1464


1462 Table 3. Initial dose of methylprednisolone (or equivalent) in the treatment of acute GVHD Dose (mg/kg per day)

Proportion of centres (%)

0.5 -- 1.5 2 3 5 10 20

Table 4.

20 69 4 4 2 1

Definition of corticosteroid resistance

Unresponsiveness to the following corticosteroid dose (methylprednisolone or equivalent; mg/kg/day) 1 2 3 4 5 10

Proportion of centres (%) 4 72 1 1 10 10

There was no widely applied consistent policy for the secondline treatment in corticosteroid resistance. The therapy was often individualized. The forms of treatment included in the repertoire were MMF (in 33% of the centres), anti-TNF antibodies (31%), alemtuzumab (7%), other monoclonal antibodies (16%), ATG (24%), extracorporeal photopheresis (17%), MSCs (7%) and pentostatin (5%). In 12% of the centres, the policy was to just continue the treatment with corticosteroids. In 42% of the centres, the organ manifestation of acute GVHD affected the choice of treatment. For example, in many centres, gut involvement indicated the use of anti-TNF antibodies, but also several other approaches were reported. Treatment of chronic GVHD The first-line treatment of newly diagnosed chronic GVHD in patients not on any immunosuppressive drug treatment was corticosteroid alone in 60%, corticosteroid þ calcineurin inhibitor (CNI) in 34%, and CNI alone in 5% of the centres. If the patient was already on corticosteroid treatment (e.g., following acute GVHD) at the onset of chronic GVHD, 41% of the centres added CNI to the treatment, 18% increased the corticosteroid dose, and 36% did both. If the patient was on CNI treatment only at the onset, 71% added corticosteroid, 3% increased the CNI dose, and 25% did both. In these situations, MMF (or mycophenolate sodium) was used regularly or occasionally in 5% of the centres. If the patient was already on corticosteroid and CNI treatment at the time of the diagnosis of chronic GVHD, 73% of the centres added MMF to the treatment. Extracorporeal photopheresis was an option in this situation in 10% of the centres. Thirty per cent of the centres reported that the type of chronic GVHD, de novo, quiescent or progressive, had an effect on the choice of treatment. The practical approaches were variable. The duration of the first-line treatment, which allowed the evaluation of the efficacy of this treatment, was 2 weeks or shorter in 21%, 2 -- 4 weeks in 12%, 1 month in 42%, 1.5 -- 4 months in 21%, and 9 -- 12 months in 4% of the centres. There was no widely applied clear policy in the second-line treatment. The treatment decisions were largely made on an individual basis. The forms of second-line treatment included in the repertoire and used alone or in combinations were Bone Marrow Transplantation (2012) 1459 - 1464

extracorporeal photopheresis (53%), MMF (36%), rituximab (12%), CNIs (12%), mTOR (mammalian target of rapamycin) inhibitors (9%), corticosteroid (8%) and tyrosine kinase inhibitors (6%). In 29% of the centres, the clinical manifestation was reported to have an effect on the choice of treatment. For example, predominant skin manifestation was an indication for extracorporeal photopheresis in many centres, but there were also many other policies. In more than 90% of the centres, topical corticosteroids were used in the treatment of chronic GVHD. In all, 41% used topical tacrolimus. DISCUSSION The present survey shows great heterogeneity in GVHD prophylaxis and treatment strategies as well as in the practical procedures among EBMT centres. In the light of presentations at meetings and in publications, as well as on the basis of general experience, this was to be expected. A survey carried out 15 years ago showed similar findings,2 and since then, no widely accepted guidelines have been developed. Allogeneic transplantation is the most efficient treatment for many diseases, but its role in the treatment algorithms varies, largely due to variable procedure-related problems and overall outcomes reported by different study groups. There are several reasons for these differences. The choice of patients is an important factor. It is often difficult to know the contribution of differences in transplantation procedures; it is probably dependent on the transplant setting. Some differences may be of importance, others not. Some components of the transplantation procedure, such as the intensity of the conditioning and immunosuppression, have been shown to have a clear effect on short- and long-term outcomes.5,11,12 Marked differences in the results between centres have been seen in similar patient materials.13 This points to an important impact of transplant strategies and procedures. Therefore, it seems plausible that optimizing transplant procedures would improve the outcome. Allogeneic transplantation is a complicated procedure, and many parts of it, as applied in transplant centres, are not based on adequate scientific evidence. Old routine, unconfirmed study results and personal beliefs have an important role. It is not the aim of this survey to try to point out optimal procedures. What most centres do is not necessarily the optimal way; many widespread routines are based on scanty evidence. However, some of the reported policies that deviate markedly from the most widely applied practices, including the dosing of CsA, the initial corticosteroid dose for the treatment for acute GvHD and the doses of ATG, can be regarded as likely to be non-optimal. The need for standardization of policies is obvious. The present survey has its limitations. The centres that participated represent approximately 21% of all EBMT centres performing allogeneic transplantations. Therefore, this study does not give a complete picture of the situation at the European centres. However, a large number of big and active centres participated. The geographical coverage was also good with centres from 25 countries included, which may be of importance, as it is likely that there is some interaction between countries and practices. The central aim of this study, to show the marked variability in allogeneic transplant strategies and procedures, was clearly reached with this group of participants. The findings of the present survey are largely similar to those reported in the previous, more limited survey2 performed in 1994 -- 1995. Some trends can, however, be observed. For example, in the previous survey, the initial methylprednisolone (or equivalent) dose for the treatment of acute GVHD was more than 10 mg/kg per day in 20% of the centres, but now only one centre reported to use such a dose. Similarly, the definitions of steroid resistance in acute GVHD had changed. The corticosteroid doses & 2012 Macmillan Publishers Limited


reported now as indicating resistance were clearly lower and the variation smaller than in the previous survey. Thus, according to some parameters, there seems to be some trend to more homogenous practices, but the variability is still great. As only a minority of the EBMT centres reported their policy and as the centres in the preceding and the present survey were partly different, conclusions about the trends have to be cautious. One important reason to initiate this survey was to document the present routines of centres for the planning of future studies. Such information is useful when estimating the probable interest of centres in a given treatment trial. It is also important to design clinical protocols in such a way that they do not interfere with the routine procedures of centres more than what is necessary for the central aim of the study. This may be crucial for the recruitment of patients. For trial purposes, it was, for example, useful to document the variable definitions of corticosteroid resistance, as well as the time needed to show the failure of the first-line treatment for acute or chronic GVHD. These aspects have a bearing on planning second-line treatment trials. In conclusion, the present survey demonstrates that significant differences exist between centres in the practices of GVHD prophylaxis and treatment, even when superficially similar protocols are used. This has to be taken into account when interpreting the results of published reports of allo-SCT. It is likely that such differences have an impact on the results obtained. When planning trials, these marked differences in practices should be considered. An effort should be made to standardize protocols as far as possible aiming at an optimal outcome of allogenic transplantations. On the basis of the findings of this survey, EBMT is now developing guidelines for the prophylaxis and treatment of GVHD.

CONFLICT OF INTEREST The authors declare no conflict of interest.

APPENDIX Participating centres Austria Medical University Graz, Department of Internal Medicine, Division of Hematology Medizinische Universita¨t Wien, Klinik fu¨r Innere Medizin, Knochenmarktransplantation Belgium Antwerp University Hospital (UZA), Department of Hematology, Antwerp Edegem Cliniques Universitaires St Luc, Department of Haematology, Brussels University Hospital VUB, Department of Medical Oncology/ Hematology, Brussels University Hospital Gasthuisberg, Department of Hematology, Leuven University of Liege, Department of Hematology Brasil Universidade Estadual de Campinas/TMO/UNICAMP, Cidade Universitaria ‘Zeferino Vaz’, Campinas Croatia University Hospital Center Rebro, Zagreb Czech Republic Charles University Hospital, Department of Hematology/Oncology, Pilsen Institute of Hematology and Blood Transfusion, Prague & 2012 Macmillan Publishers Limited

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REFERENCES 1 Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer 2009; 116: 4715 - 4726. 2 Ruutu T, Niederwieser D, Gratwohl A, Apperley JF. A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1997; 19: 759 - 764. 3 Bacigalupo A, van Lint MT, Occhini D, Gualandi F, Lamperelli T, Sogno G et al. Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 1991; 77: 1423 - 1428. 4 Locatelli F, Zecca M, Rondelli R, Bonetti F, Dini G, Prete A et al. Graft versus host disease prophylaxis with low dose cyclosporine reduces the risk of relapse in children with acute leukemia given HLA identical sibling bone marrow transplantation: results of a randomized trial. Blood 2000; 95: 1572 - 1579. 5 Bacigalupo A. Management of acute graft-versus-host disease. Br J Haematol 2007; 137: 87 - 98. 6 Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009; 373: 1550 - 1561. 7 Inamoto Y, Flowers MED, Lee SJ, Carpenter PA, Warren EH, Deeg J et al. Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation. Blood 2011; 118: 456 - 463. 8 Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009. Bone Marrow Transplant 2010; 45: 219 - 234. 9 Goldman J. Special report: bone marrow transplants using volunteer donors, recommendations and requirements for a standardized practice throughout the world-- 1994 update. Blood 1994; 84: 2833 - 2839. 10 World Marrow Donor Association International standards for unrelated hematopoietic stem cell donor registries. www.worldmarrow.org,_Standards_ December_2007.pdf. 11 Clift RA, Buckner CD, Appelbaum FA, Bearman SI, Petersen FE, Fisher LD et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 1990; 76: 1867 - 1871. 12 Pavlu˚ J, Szydlo RM, Goldman JM, Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011; 117: 755 - 763. 13 Frassoni F, Labopin M, Powles R, Mary J-Y, Arcese W, Bacigalupo A et al. Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Lancet 2000; 355: 1393 - 1398.

Denmark Rigshospitalet, BMT Unit, Department of Hematology, Copenhagen Estonia Tartu University Hospital, Clinic of Hematology and Oncology Finland Helsinki University Central Hospital, Department of Medicine, Division of Haematology France CHRU, Service des Maladies du Sang, Angers Hopital E. Herriot, BMT Unit, Lyon Hopital Saint Antoine, Department of Hematology, Paris Hopital Bretonneau, Service d’Oncologie Me´dical, Tours Germany Charite´ Universita¨tsmedizin Berlin, Campus Virchow Klinikum, Medizinische Klinik m.S. Ha¨matologie/Onkologie University Hospital Erlangen, Department of Medicine 5 University of Freiburg, Department of Medicine-Hematology, Oncology Ernst-Moritz-Arndt-Universita¨t Greifswald, Medizinische Universita¨tsklinik C Martin-Luther-Universita¨t Halle-Wittenberg, BMT Section, State Center for Cell and Gene Therapy, Department of Internal Medicine IV, Halle University Hospital Eppendorf, Bone Marrow Transplantation Centre, Hamburg Hannover Medical University, Department of Hematology/ Oncology University of Heidelberg, Medizinische Klinik und Poliklinik V Bone Marrow Transplantation (2012) 1459 - 1464


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Friedrich-Schiller-Universita¨t Jena, Klinik fu¨r Innere Medizin II Klinikum Karlsruhe gGmbH, II Medizinische Klinik, Ha¨matologie, Onkologie Universita¨t Rostock, Klinik fu¨r Innere Medizin/Ha¨matologie/Onkologie Deutsche Klinik fu¨r Diagnostik, KMT Zentrum, Wiesbaden Greece George Papanicolaou General Hospital, Haematology Department/ BMT Unit, Thessaloniki Ireland St James Hospital Trinity College, Department of Hematology, Dublin Israel Beilinson Hospital, Hematology and BMT Department, PetachTikva Chaim Sheba Medical Center, Tel-Hashomer Italy Azienda Ospedali Riuniti di Ancona, Clinica di Ematologia, AnconaTorrete Bologna University, S.Orsola-Malpighi Hospital, Institute of Hematology and Medical Oncology L and A Sera`gnoli Ospedale Ferrarotto, Divisione Clinicizzata di Ematologia, Catania Ospedale di Careggi, BMT Unit, Department of Hematology, Firenze Ospedale San Gerardo, Clinica Ematologica dell’Universita MilanoBiocca, Monza Humanitas Cancer Center, Transplantation Unit, Department of Oncology-Hematology, Milano Azienda Ospedaliera, Centro Unico Regionale Trapianti, Reggio Calabria Universita Cattolica S Cuore, Istituto di Ematologia, Rome Lebanon American University of Beirut, Department of Internal Medicine The Netherlands University Medical Center Groningen, Department of Hematology University Hospital Maastricht, Department of Internal Medicine, Hematology/Oncology University Medical Centre, Department of Haematology, Utrecht New Zealand Canterbury Health Laboratories, Department of Haematology, Christchurch Wellington Regional Bone Marrow Transplant Unit, Wellington Hospital Norway Haukeland University Hospital, Department of Haematology, Bergen Rikshospitalet, Department of Medicine, Oslo

Bone Marrow Transplantation (2012) 1459 - 1464

Poland University Hospital, Collegium Medicum UMK, Pediatric Hematology and Oncology, Bydgoszcz Lower Silesian Centre for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw Slovenia University Medical Center, Department of Hematology, Ljubljana Spain Hospital Universitari Germans Trias i Pujol, Barcelona Hospital Vall d’Hebron, Unidad de Adultos, Barcelona University Hospital of Asturias, Clinical Hematology Department, Oviedo Hospital de Navarra, Servicio de Hematologia, Pamplona Hospital U Marque´s de Valdecilla, Servicio de HematologiaHemoterapia, Santander Sweden University Hospital, Department of Hematology, Linko¨ping University Hospital, Department of Hematology, Lund Karolinska University Hospital, Centre for Allogeneic Stem Cell Transplantation Huddinge, Stockholm Umeå University Hospital, Hematology University Hospital, Department of Medicine, Uppsala Switzerland University Hospital, Hematology, Basel Hopitaux Universitaires de Geneve, Departement Medecine Interne, Geneva University Hospital, Clinic of Hematology, Zu¨rich Turkey Akdeniz University Medical School, Department of Pediatric Hematology, Antalya Medical Park Hospitals, Stem Cell Transplant Unit, Antalya Ankara University Faculty of Medicine, Department of Hematology, Adult Stem Cell Transplantation Unit Gazi Universitesi Tip Faku¨ltesi Hastanesi, Eriskin Hematoloji Bilim Dali, Ankara United Kingdom Belfast City Hospital, Department of Haematology University of Wales, College of Medicine, Department of Haematology, Cardiff Bone Marrow Transplant Unit, Beatson, West of Scotland Cancer Centre, Glasgow Leicester Royal Infirmary, Department of Haematology Royal Liverpool University Hospital, Department of Haematology Guy’s Hospital, Department of Haematology, London Imperial College, Department of Haematology, Hammersmith Hospital, London Christie NHS Trust Hospital, Adult Leukaemia and Bone Marrow Transplant Unit, Manchester Nottingham City Hospital

& 2012 Macmillan Publishers Limited