Autografting

Bone Marrow Transplantation (2005) 35, 869–879. doi:10.1038/sj.bmt.1704892 Published online 14 March 2005

Autologous hematopoietic stem cell transplantation for autoimmune diseases

A Gratwohl1, J Passweg1, C Bocelli-Tyndall2, A Fassas3, J M van Laar4, D Farge5, M Andolina6, R Arnold7, E Carreras8, J Finke9, I Kötter10, T Kozak11, I Lisukov12, B Löwenberg13, A Marmont14, J Moore15, R Saccardi16, J A Snowden17, F van den Hoogen18, N M Wulffraat19, X W Zhao20 and A Tyndall2 for the Autoimmune Diseases Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

  1. 1University Hospital, Basel, Switzerland
  2. 2Stem Cell Transplant Team, Department of Rheumatology, University Basel, Felix Platter Spital, Basel, Switzerland
  3. 3George Papanicolaou Hospital, Thessaloniki, Greece
  4. 4Leiden University Medical Center, Leiden, The Netherlands
  5. 5Hôpital St Louis, Paris, France
  6. 6Istituto per l'Infanzia Burlo Garofolo, Trieste, Italy
  7. 7Universitätsklinikum Charité, Berlin, Germany
  8. 8Hospital Clinic, Barcelona, Spain
  9. 9Klinikum der Albert-Ludwigs Universität Freiburg, Freiburg, Germany
  10. 10Medizinische Universitätsklinik, Tübingen, Germany
  11. 11University Hospital Kralovske Vinohrady, Prague, Czech Republic
  12. 12Institute of Clinical Immunology, Novosibirsk, Russia
  13. 13Erasmus University Medical Center, Rotterdam, The Netherlands
  14. 14Ospedale San Martino, Genova, Italy
  15. 15St Vincents Hospital, Sydney, Australia
  16. 16Ospedale di Careggi, Florence, Italy
  17. 17Sheffield Teaching Hospitals NHS Trust, Sheffield, United Kingdom
  18. 18University Medical Center St Radboud, Nijmegen, The Netherlands
  19. 19University Hospital for Children, Utrecht, The Netherlands
  20. 20The Third People Hospital of Zhengzhou, Zhengzhou, China

Correspondence: Professor A Tyndall, Stem Cell Transplant Team, Department of Rheumatology, University Basel, Felix Platter Spital, Basel CH-4012, Switzerland. E-mail: alan.tyndall@fps-basel.ch

Received 19 October 2004; Accepted 14 January 2005; Published online 14 March 2005.

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Abstract

Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86plusminus4% at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7plusminus3% at 3 years) or disease progression (N=22; 9plusminus4% at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71% of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57–6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11–0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96–3.42)); low intensity, RR2.34 (1.074–5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.

Keywords:

autoimmune disease, autologous hematopoietic stem cell transplantation, immunosuppression, survival, therapy

Autoimmune diseases represent a heterogeneous group of disorders with genetic, environmental and individual etiological factors.1 Immunosuppression and immunomodulation are basic therapeutic strategies in all of them and are generally employed with success. Nonetheless, patients who do not respond, who require more toxic drugs to achieve or maintain remissions or who relapse despite continuing therapy present a therapeutic challenge.

Clinical response in some patients with autoimmune diseases who received hematopoietic stem cell transplantation (HSCT) for conventional indications,2, 3 animal models with HSCT for prevention and treatment of severe autoimmune diseases4, 5 and theoretical considerations all suggest that high-dose chemotherapy followed by hematopoietic stem cell rescue could 'reset' altered immunity.6 Autologous HSCT could be a viable option. This led to an international collaboration and to a concept statement of the European Group for Blood and Marrow Transplantation (EBMT) and the European League against Rheumatism (EULAR) in 19957 to coordinate phase I/II trials and to gather collective experience.

Feasibility was soon documented.8 Standard transplantation techniques, for example, stem cell mobilization, harvesting, graft engineering and conditioning proved to be applicable to these new indications. Toxicity of the procedure was shown to be comparable with results achieved in autologous HSCT for advanced malignancies.9 Pilot series have established and defined response criteria.10, 11, 12, 13, 14, 15 Insufficient data were as yet available to assess factors associated with outcome; mechanisms of action remained hypothetical. The present analysis documents the feasibility and efficacy of the procedure, clarifies the role of dose intensification and forms the basis for the ongoing prospective randomized phase III trials.

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Patients and methods

Study design

This retrospective analysis is based on the concept statement of EBMT/EULAR in 1995. The basic principles include disease categories, patient selection, mobilization, in vitro manipulation, conditioning and treatment.8 Briefly, patients should have a prognosis severe enough to justify the risk, but not be in such a condition as to be beyond salvage. Standard techniques, as used in HSCT for hematological malignancies, should be employed.

Data were collected by questionnaire or the electronic EBMT data management system ProMISe and updated annually. Participating centers (listed in Appendix A1) were requested to report all consecutive transplants and are subject to a random audit process (www.ebmt.org). They were requested to have their protocols approved by an ethics committee and to ask for written informed consent from their patients before HSCT.

Patients and disease categories

From 1995 to July 2003, 473 patients, 64% female, between 2 and 69 years of age (median 34 years) were reported (Table 1). In all, 110 institutions from 21 countries participated. Patients with mobilization data only (N=11) were not included. Data on such patients were collected only initially; follow-up is incomplete. Data on potential complications with mobilized patients were published earlier.10 Patients with second transplants (N=4) were also not included. Data were analyzed as of October 31, 2003 with a median follow-up of 20 months (range, 1–81 months).


Rheumatological (60%) and neurological (33%) autoimmune diseases represent the major disease categories. Substantial numbers of patients, allowing meaningful analysis of factors associated with outcome, were available for multiple sclerosis (N=150), systemic sclerosis (N=71), rheumatoid arthritis (N=70), juvenile idiopathic arthritis (N=51), systemic lupus erythematosus (N=62) and immune thrombocytopenia (N=10).

Definitions

Transplantation techniques (Table 2)
 

Stem cell source was categorized into bone marrow (54 patients; 11%) or peripheral blood stem cells (419 patients; 89%), which did include a few patients (N=4) with both stem cell products. Mobilization was subgrouped into mobilization with growth factor (granulocyte colony-stimulating factor, G-CSF, or granulocyte–macrophage colony stimulating factor, GM-CSF) alone (N=89;21%) and growth factor combined with cyclophosphamide or other chemotherapy (N=289; 69%).


Five main different conditioning regimens were employed, of which four were cyclophosphamide based. They were subgrouped arbitrarily but based on experience from HSCT in hematological malignancies, into high-, intermediate- or low-intensity regimens.16 High-intensity regimens (17%) included busulfan plus cyclophosphamideplusminusantithymocyte globulin and any regimen including radiation; low-intensity (31%) was restricted to cyclophosphamide alone, melphalan alone and fludarabine-based regimens. All other conditioning regimens, including BEAM combination chemotherapy (BCNU, etoposide cytosine arabinoside and melphalan)plusminusantithymocyte globulin, were considered as intermediate-intensity (52%) conditioning regimens.

Graft manipulation and T-/B-cell depletion (Table 2)
 

Graft manipulation and T-/B-cell depletion were grouped into four categories: none (14%), in vitro (29%), in vivo (20%) or both (37%). In the 'none' group, patients neither received antibodies during their conditioning nor their graft was manipulated. In the in vivo group, patients received mono- or polyclonal T-/B-cell antibodies during their conditioning. In the in vitro group, patients received CD34 selected grafts, with or without additional T- or B-cell depletion. 'Both' refers to patients with combined in vivo and in vitro manipulation.

Differences between disease categories

Patient characteristics
 

There were major differences in patient characteristics and treatment variables between the disease groups (Tables 1 and 2). Patients with juvenile idiopathic arthritis and autoimmune cytopenias were younger, and patients with systemic sclerosis and rheumatoid arthritis older than the median of 34 years. The proportion of female patients was higher in all but the immune thrombocytopenia group. The first autoimmune diseases to be treated in substantial numbers with HSCT were MS and hematologic diseases. Systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and juvenile idiopathic arthritis were increasingly treated in more recent years. Time intervals from diagnosis to transplant varied between disease groups. Median time from diagnosis to HSCT was 36 months (2–258 months) for systemic sclerosis, 59 months (2–235 months) for systemic lupus erythematosus, 72 months (15–250 months) for juvenile idiopathic arthritis, 81 months (3–344 months) for multiple sclerosis, 107 months (12–276 months) for immune thrombocytopenia and 113 months (24–287 months) for rheumatoid arthritis.

Treatment variables
 

Transplant techniques varied between all disease categories (Tables 2 and 3). Peripheral blood was used as the stem cell source in about 90% of all patients and disease groups except for patients with juvenile idiopathic arthritis (45%), immune thrombocytopenia (20%) and systemic lupus erythematosus (18%) (Table 2). In two-thirds, peripheral blood stem cells were mobilized with combined chemotherapy and growth factors. Growth factors alone were preferred primarily for patients with rheumatoid arthritis (60%) and immune thrombocytopenia (50%). Conditioning regimens were correlated with disease, but different conditioning regimens were used in all disease categories. BEAM was preferred for patients with multiple sclerosis (59%), and cyclophosphamide for patients with rheumatological disorders. There was heterogeneity in purging methods. No purging was used in as low as 4% of multiple sclerosis patients. In contrast, 91% of all juvenile idiopathic arthritis patients had combined in vitro and in vivo purging.


Outcome analysis

Outcomes studied were survival, transplant-related mortality, disease response and disease progression as defined previously.8 All 473 patients were included in the survival analysis. Response analysis was restricted to the six major disease categories. Response assessment refers to best response at any time after HSCT and the time of assessment varied for the individual disease categories. Responses were classified as sustained, transient (fulfilled response definition but with a subsequent progression) or no response and defined for the individual disease categories as previously published:

  • for multiple sclerosis, stabilization or improvement of the Extended Disability Scoring System (EDSS) over the observation period,12
  • for systemic sclerosis, an improvement in the modified Rodnan skin score over 25% from base line,10
  • for rheumatoid arthritis, as an ACR (American College of Rheumatology) response of 50 sustained without reintroduction of disease-modifying antirheumatic drugs (DMARDs),17
  • for juvenile idiopathic arthritis, as an increase of at least 30% in three out of six core set variables with a worsening of maximally 30% in no more than one of these parameters,18
  • for systemic lupus erythematosus, as reduction of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) to <3 and a daily prednisone dose of 10 mg or less,19 and
  • for immune thrombocytopenia as normalization of the platelet count (>100 times 109/l)20

Responses were reported by the transplant team as such, based on the above criteria. They could not be controlled by the writing committee and have to be regarded with some limitations.

Disease progression was defined as any worsening of these disease criteria after HSCT and include patients with no response and transient response.

Statistical methods

Groups and numerical variables were compared using the chi2 test. Transplant-related mortality, progression-free survival and overall survival were calculated using the Kaplan–Meier estimator. The 95% confidence interval was approximated using two times the standard error as calculated by the Greenwood formula. Multivariate analysis did focus on survival, response, disease progression and transplant-related mortality. It included age group (<20 y, 20–40 y, >40 y), sex, disease, time from diagnosis to transplant, mobilization, conditioning intensity, year of transplant and purging as variables as described above. Probability of survival, transplant-related mortality and response were calculated using Cox's regression analysis and disease progression by logistic regression models. Results of multivariate analyses are expressed as relative risks (RR).

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Results

Survival

At the time of the analysis (October 2003), 420 patients (89%) were alive and 53 patients (11%) had died: 31 (58% of deceased patients) of transplant-related causes and 22 (42% of deceased patients) of disease progression (Table 3). Causes of transplanted-related mortality were infections (N=16; 50%), hemorrhage (N=4; 12.5%), cardiac toxicity (N=3), interstitial pneumonitis (N=2), veno-occlusive disease (N=2), suicide (N=1) and liver failure of unknown origin (N=1) or unknown causes (N=1). One patient with systemic lupus erythematosus and pancytopenia developed secondary leukaemia 2 years after HSCT and died. Survival was influenced by disease (P<0.005) (Figure 1a; Table 4). It was highest in patients with rheumatoid arthritis and lower than average in systemic sclerosis, systemic lupus erythematosus and immune cytopenias. We failed to show an effect of purging on survival and mortality.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Outcome of patients with autologous HSCT for severe autoimmune disease depending on disease. (a) Probability of survival (n=414). The 3-year probabilities of survival were 99plusminus3% in 70 patients with RA, 92plusminus5% in 150 patients with MS, 84plusminus11% in 51 patients with JIA, 79plusminus27% in 10 patients with ITP, 72plusminus13% in 71 patients with SSc and 78plusminus13% in 62 patients with SLE. P=0.0004 for a global log-rank test. (b) Probability of treatment related mortality (TRM). The 3-year probabilities of TRM were 2plusminus5% in RA patients, 5plusminus5% in MS patients, 11plusminus10% JIA patients, 20plusminus25% in ITP patients, 9plusminus7% in SSc patients and 14plusminus9% in SLE patients. P=0.24 for a global log-rank test. (c) Probability of death from disease progression. The 3-year probabilities were 20plusminus13% in SSc patients, 0 in RA patients, 7plusminus9 in JIA patients, 16plusminus17 in SLE patients, 2plusminus3 in MS patients and 0 in ITP patients. P=0.005 for a global log-rank test. MS: multiple sclerosis; SSc: systemic sclerosis; RA: rheumatoid arthritis; JIA: juvenile idiopathic arthritis; SLE: systemic lupus erithematosus; ITP: immune thrombocytopenia.

Full figure and legend (38K)


Transplant-related mortality

Transplant-related mortality at 3 years was 7plusminus3%. It was associated with disease (P<0.005), year of transplant (P=0.04) and conditioning intensity (P=0.07) (Tables 3 and 4; Figures 1b and 2a). Transplant-related mortality increased with increasing conditioning intensity stepwise from 3plusminus3% in patients with low-intensity conditioning (RR1) to 14plusminus9% in patients with high-intensity conditioning, RR4.77 (1.02–22.1) (Figure 2a; Table 4). Transplant-related mortality did decrease in all disease categories in more recent years, RR0.56 (0.32–0.97).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Outcome of patients with autologous HSCT for severe autoimmune disease depending on conditioning intensity. (a) Probability of treatment-related mortality (TRM) (n=429).The probability of TRM at 3 years was 3plusminus3% in 133 patients receiving low-intensity conditioning regimens, 6plusminus3% in 224 patients receiving intermediate-intensity conditioning regimens and 14plusminus9% in 72 patients receiving high-intensity conditioning regimens. P<0.04 for a global log-rank test. (b) Probability of disease activity (n=427). The probability of disease progression at 3 years was 70plusminus9% in 133 patients receiving low-intensity conditioning regimens, 43plusminus9% in 222 patients receiving intermediate-intensity conditioning regimens and 31plusminus17% in 72 patients receiving high-intensity conditioning regimens. P=0.0001 for a global log-rank test.

Full figure and legend (24K)

Response

In 299 of 370 evaluable patients (81%), response as defined above was observed. It remained sustained in 213 responders (71% of the responders). Of these, 71 patients (19%) failed to respond. Response and type of response differed between disease categories (P<0.0001) and were associated with age (P=0.06) and priming for stem cell collection (P=0.004). Response was more frequently observed in the young age group (RR1) compared to patients above age 40 years, RR0.29 (0.1–0.82), and more frequently in patients mobilized prior to HSCT with combined cyclophosphamide and growth factors, RR3.28 (1.57–6.83). Failure to respond was highest in patients with immune thrombocytopenia (Tables 4 and 5). Failure to respond might include patients with an aggravation of their disease after HSCT. There was no way to distinguish between these two groups in this retrospective analysis.


Disease progression

Disease progression despite initial response was 49plusminus6% at 3 years. It was associated with disease (P<0.0001) and intensity of the conditioning (Tables 4 and 5). It was 31plusminus17% at 3 years for patients with high-intensity conditioning (RR1) and increased stepwise with decreasing conditioning intensity and inversely to transplant-related mortality, to almost 70plusminus9% in patients with low-intensity conditioning, RR2.37 (1.074–5.11) (Figure 2b; Table 4). There was a difference in disease progression in patients without purging methods in univariate (Table 5) analysis. Multivariate analyses failed to show an effect (Table 4).

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Discussion

The present data provide clear evidence that high-dose chemotherapy followed by autologous HSCT can arrest disease progression and induce stable remission in selected patients with severe autoimmune diseases. Response and toxicity differ from disease to disease and each disease has to be considered on its own. Data are obtained from a large international database with 110 participating institutions in 21 countries from Europe and Australasia. Teams used different transplant techniques, but did adhere in principle to a broadly stipulated concept statement of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT).8 Data are very heterogeneous in almost all aspects, in part incomplete, collected over a long observation period and have to be regarded with caution. Despite this heterogeneity, impact on outcome is observed in all disease categories and in all patient groups. These data extend preliminary results from early pilot and single disease focused studies.10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 They confirm the concept of dose intensification as a therapeutic strategy. Increasing intensity reduces the risk of disease progression. In addition, interruption of inevitable disease progression has become possible. These data parallel the observations in lymphoid malignancies and multiple myeloma, that is, dose intensification and autologous HSCT reduce relapse and improve survival.39, 40, 41

There is significant toxicity and there are limitations. Stem cell collection and autologous HSCT are associated with morbidity and mortality. Flares of the disease or lethal complications during mobilization have been reported.9 Transplant-related mortality reached 7plusminus3% in this report with a clear improvement over calendar time, presumably due to better patient selection and experience within the teams.42 This overall transplant-related mortality is still high but comparable with that seen in autologous HSCT for hematological malignancies.39, 40, 41

As in conventional indications for HSCT, risk of transplant-related mortality has to be compared with the risk of disease-related morbidity and mortality. Probability of death from disease progression at 3 years (9plusminus4%) despite HSCT did exceed in this report the risk from transplant-related complications and possibly reflects the severity of the disease at the time of patient selection.

Main factors influencing transplant-related mortality in conventional indications are disease, stage of disease, age of patient, time from diagnosis to HSCT and year of transplant. In part, the same risk factors were identified. There was an association with age and disease stage within specified disease categories. A high EDSS score greater than or equal to6 (reflecting advanced disease in multiple sclerosis) or high pulmonary artery pressure (reflecting advanced disease in systemic sclerosis) were associated with poor outcome.12, 35, 43 We did not attempt to define risk factors associated with specific causes of death, for example, hemorrhage, cardiac toxicity or veno-occlusive diseases. The numbers are too small, and the heterogeneity i.d. too large. Disease-specific analyses must provide these clues.

Selection of the conditioning regimen has been a matter of debate from the very beginning.44 Results of this report provide more insight. High-intensity conditioning regimens were associated with higher risk of transplant-related mortality, but lower probability of disease progression. These novel findings indicate that impact of the procedure on disease outcome is not a chance finding. Sustained disease response was directly associated with survival. Patients with sustained response had a 100% survival at 3 years, and patients with no or transient response had a 20% probability to die from progressive disease within the same time interval. We cannot exclude that patients with response represent a selection of patients with inherent better prognosis. The fact that they were progressive before HSCT speaks for an active part of the procedure.

Autoimmune diseases represent a highly heterogeneous group of disorders and some disease-specific comments need to be added. In multiple sclerosis, flares of the disease have been observed during mobilization45 during conditioning12 and at the time of engraftment in the context of engraftment syndromes.43 In systemic sclerosis, mortality appears to be correlated, especially with severe pulmonary artery hypertension.10 However, successfully transplanted patients with moderate pulmonary hypertension may improve. Marked improvement of high skin scores and lung function has been observed.46 Concepts of irreversible tissue damage during the fibrotic process need to be revised. In immune thrombocytopenia, bleeding remains a major concern and was associated with the death of two patients.47 In systemic lupus erythematosus, initial improvement in all laboratory parameters have been observed in the majority of patients not necessarily correlated with autoantibody response; similar observations hold true for systemic sclerosis. In juvenile idiopathic arthritis, initial mortality was linked to a 'macrophage activation syndrome', better known as 'hemophagocytic lymphohistiocytosis'.28 If observed and recognized as such early on, it can be treated with high-dose steroids.

Multiple mechanisms have been postulated to explain potential effects of autologous HSCT in the treatment of autoimmune diseases.1, 5 Elimination of all autoreactive T or B cells has been advocated. Such considerations would also require elimination of T and B cells in the graft. The observation of similar response with or without graft manipulation and disease stabilization despite persistence of autoantibodies argues against this hypothesis. An association between purging and disease response or disease progression was suggested in univariate analysis, but could not be substantiated in multivariate analysis when other factors were taken into account. In contrast to the situation of tumor therapy, where no conceivable benefit could be derived from reinfusion of tumor cells, there are theoretical arguments against purging in patients with autoimmune diseases. In a rheumatoid arthritis HSCT trial, no clear benefit was demonstrated concerning disease relapse in manipulated vs unmanipulated grafts.25 Any T-cell depletion or CD34 selection could eliminate autoreactive as well as regulatory T cells, and aggravate the autoimmune reaction. The role of graft manipulation remains open and needs to be addressed in controlled, disease-specific settings.

It remains open as to which is the best approach and best technology to be used, but some conclusions are possible. Standard technologies as used in the treatment of hematological malignancies can be applied. Peripheral blood remains the preferred source of stem cells.44 Peripheral blood cells ensure more rapid reconstitution, can be collected easily in higher numbers than bone marrow cells and are easier to manipulate. Peripheral blood cells can be mobilized with or without cyclosphosphamide priming. Cyclophosphamide might provide higher cell numbers, give additional disease control and reduce the incidence of growth factor-induced disease flares. Concerning conditioning, there is no indication that disease-specific regimens are required. Conditioning intensity primarily impacts on outcome. Alternative approaches are being investigated for patients with severe autoimmune diseases, for example, the use of cyclophosphamide alone48 or allogeneic HSCT.49 Both are considered as more toxic approaches by the initial EBMT/EULAR statement. There is a prolonged period of aplasia with high-dose cyclophosphamide dose50 and there is an inherent higher risk of transplant-related mortality with allogeneic HSCT.49 A potential benefit from a graft-versus-autoimmune effect is still hypothetical.3

In summary, the data suggest, despite their limitations, that high-dose chemotherapy and autologous HSCT can modify disease course in a substantial proportion of patients with severe autoimmune disorders. Risk factors for outcome can be defined. Prospective controlled studies are now warranted to define the value of autologous HSCT compared to nontransplant strategies and to establish long-term benefits. They have to be planned for each disease category. Such studies have started for patients with systemic sclerosis (www.astistrial.com), multiple sclerosis and rheumatoid arthritis. They are planned for patients with systemic lupus erythematosus or juvenile idiopathic arthritis and Crohn's disease. These trials are based on current results and should give an answer in the years to come.

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Appendices

Appendix A1

List of participating centers:

Austria: Vienna, Vienna University Hospital; Australia: Brisbane, Mater Hospital; Hobart, Royal Hobart Hospital; Melbourne, Royal Melbourne Hospital; Perth, Sir Charles Gairdner Hospital; Royal Perth Hospital; Sydney, St Vincent's Hospital; Belgium: Brussels, Children University Hospital, Erasmus Hospital, Institut Jules Bordet; Liège, Centre Hospitalier Universitaire; Leuven, University Hospital Gasthuisberg; China: Nanjing, Gu Lou Hospital; Peking, Peking University Medical Center Hospital; Zhengzhou, The Third People Hospital of Zhengzhou; Czech Republic: Pilsen, Charles University Hospital; Prague, University Hospital Kralovske Vinohrady, University Hospital Motol; Finland: Kuopio, Kuopio University Hospital; Turku, Turku University Central Hospital; France: Besançon, Hôpital Jean Minijoz; Brest, Hôpital Morvan; Clermont Ferrant, Centre Hospitalier Universitaire; Lille, Hôpital Claude Huriez; Limoges, Centre Hospitalier Regional Universitaire Limoges; Marseilles, Institut Paoli Calmettes; Paris, Centre Hospitalier Universitaire Cochin, Hôpital Necker, Hôpital St Antoine, Hôpital St Louis, Pitie-Salpetriere; Strassbourg, Hôpital Universitaire de Hautepierre; Toulouse, Hôpital de Purpan; Germany: Berlin, Universitätsklinikum Charité, Charité-Virchow Klinikum; Bochum, University Hospital Knappschfts-Krankenhaus; Dresden, Universitätsklinikum; Düsseldorf, Henrich Heine Universität; Erlangen, University Hospital; Frankfurt, Universitätsklinikum; Freiburg, Klinikum der Albert-Ludwigs Universität Freiburg; Halle, Martin-Luther-Universität; Hannover, Medizinische Hochschule; Heidelberg, University of Heidelberg; Jena, University of Jena; Münster, Universitätsklinik; Tübingen, Medizinische Universitätsklinik; Wiesbaden, Deutsche Zentrum für Krankeitsdiagnostik; Hungary: Miskolc, Postgraduate Medical School; Greece: Thessaloniki, George Papanicolaou Hospital; Israel: Haifa, Rambam Medical Center; Jerusalem, Hadassah University Hospital; Italy: Cagliari, University of Cagliari; Ferrara, Ospedale St Anna; Firenze, Ospedale di Careggi, Ospedale Pediatrico 'A.Meyer'; Genova, Ospedale San Martino; Milano, Ospedale San Raffaele; Modena, University of Modena; Monza, Ospedale San Gerardo; Torino, Ospedale San Luigi Orbassano; Padova, University Hospital; Palermo, Ospedale Oncologico 'La Maddalena'; Pavia, Policlinico San Matteo; Pescara, Ospedale Civile; Pisa, University of Pisa; Reggio Emilia, Arcispedale Santa Maria Nuova; Reggio Calabria, Azienda Ospedaliera Bianchi-Melacrino-Morelli; Roma, Ospedale San Camillo, Università 'La Sapienza', Università Tor Vergata; Trieste, Istituto per l'Infanzia Burlo Garofolo; Udine, University Hospital; Japan: Osaka, Osaka Medical Center; The Netherlands: Leiden, Leiden University Medical Center; Nijmegen, University Medical Center St Radboud; Rotterdam, Erasmus University Medical Center; Utrecht, University Medical Center; Poland: Poznan, K. Marcinkowski University; Russia: Novosibirsk, Institute of Clinical Immunology; St Petersburg, St Petersburg State I. Pavlov Medical University; Slovakia: Bratislava, University Hospital; Spain: Barcelona, Hospital Clinic, Hospital Santa Creu i Sant Pau, Hospital Vall d'Hebron; Cádiz , Hospital del SAS; Lugo, Hospital Xeral-Calde; Madrid, Clinica Puerta de Hierro, Hospital Infantil La Paz, Hospital G.U. Gregorio Maranon, Hospital de la Princesa; Malaga, Hospital Carlos Haya; Palma de Mallorca, Hospital San Dureta; Santander, Hospital Universitario 'Marquéz de Valdecilla'; Sevilla, Hospital Universitario Virgen del Rocio; Valencia, Hospital Clinico Universitario; Sweden: Göteborg, Sahlgrenska University Hospital; Lund, University Hospital; Uppsala, University Hospital; Switzerland: Basel, Kantonsspital; Zürich, University Children Hospital; UK: Birmingham, University of Birmingham; Leeds, University of Leeds; Liverpool, Royal Liverpool University Hospital; London, Great Ormond Street Hospital, Hammersmith Hospital, Royal Free Hospital, St George's Hospital, University College Hospital; Newcastle, Royal Victoria Infirmary; Nottingham, Nottingham City Hospital.

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Acknowledgements

We would like to acknowledge the participating centres, the support of the project by the EBMT corporate members (Amgen Europe, Hoffmann-La Roche Ltd, Gilead Sciences, Baxter Oncology, Pharmacia Corporation, Chugai-Aventis, Fresenius HemoCare, SangStat, Schering AG, Gambro BCT, Elan Pharmaceuticals, Miltenyl Biotec GmbH, Therakos, Wyeth-Lederlé, Astra, Cobe International, Nextar, Liposome Co., Imtix, the Horton Foundation, the Swiss National Research Foundation, the Regional Cancer League Basel and the Délégation Régionale à la Recherche Clinique (DRRC), Assistance Publique-Hôpitaux de Paris (AP-HP), the French Ministry of Health (Programme Hospitalier de Recherche Clinique: PHRC 1997 AOM 97-030) and Professor E Gluckman, Hôpital St Louis, Paris).

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