Introduction

In children and adolescents, allogeneic haematopoietic stem cell transplantation (allo-HSCT) not only plays an important role in the treatment of malignant diseases and acquired BM failures, but it is also applied as an effective therapy for a wide range of inborn disorders, including congenital immunodeficiences, some inherited metabolic diseases, hereditary BM failures and haemoglobinopathies.¹

The paediatric population in 19 central and eastern European countries amounts to approximately 80 million children and adolescents 18 years of age. According to western European standards (mean of 19.0 HSCTs/1 million/year), this population requires a yearly total of around 1500–1600 haematopoietic stem cell transplantation (HSCT).² Due to the financial conditions, which were the result of the political situation, the contemporary history of paediatric HSCT in eastern European countries, as compared to Western countries, began more than 10 years later, that is, in the mid-1980s. However, at the end of the 1980s, political and then financial situations started to change. Furthermore, in 2004 and 2007, some eastern European countries became members of the EU. Therefore, it is important to evaluate development, recent achievements and needs of eastern European countries in the field of paediatric HSCT.

The purpose of the study was as follows: (1) to analyse the development of paediatric HSCT activity, that is, in recipients 18 years of age, in eastern European countries up to the end of 2004; (2) to compare paediatric HSCT activity in eastern European countries before and after 31 December 1998; (3) to characterize the recent status of paediatric HSCT activity in eastern European countries and (4) to compare day +100 TRM in recipients 18 years of age in eastern European countries before and after 1 January 1999 according to the type of transplantation and centre category.

Study design and methods

Study design

The following 19 countries are considered eastern European countries: Albania, Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Macedonia, Moldavia, Poland, Romania, Russia, Serbia and Montenegro, Slovakia, Slovenia and Ukraine.

Only patients 18 years of age at the time of autologous or allogeneic HSCT for malignant or non-malignant disease were eligible for this study. Data collection and analysis were based on the EBMT Registry data concerning eligible recipients transplanted till 31 December 2004 by transplant teams from eastern European countries and reported to the EBMT Registry using MED-A forms. Centres were classified as category '1' when they registered only children, category '2' when more than 25% of registered patients were children or category '3' when less than 25% of registered patients were children.

The following variables have been analysed on a yearly basis: (1) number and category of centres performing HSCT in children, (2) total number of HSCTs, (3) type of transplant (autologous or allogeneic), (4) type of donor for allogeneic HSCT (matched sibling donors (MSD), unrelated donors (UD) and mismatched family donors (MMFD)), (5) haematopoietic stem cell (HSC) source (BM, peripheral blood (PB) and cord blood (CB)), (6) indications for HSCT and (7) day +100 TRM.

Activity survey and statistical analysis

The data on transplants were summarized in absolute numbers and calculated as paediatric transplant rates of HSCTs per 10 million of the paediatric population in a given country based on population data obtained from the United States Census Office (www.census.gov). Transplant rates were evaluated according to the total number of HSCTs, autologous HSCT (auto-HSCT) and allo-HSCT. For continuous variables, the median was taken as a cut point. Probability of 100-day TRM was estimated using the product-limit method. Data management and statistical analyses were performed with SPSS (SPSS Inc., Chicago, IL, USA) software packages by Myriam Labopin, EBMT Statistician for the Acute Leukaemia WP Registry.

Results

Participating teams, team densities, centre category and yearly number of allo-HSCT per centre

Between 1985 and 2004, the number of centres performing and reporting HSCT on children increased from 1 in 1985 to 24 in 2003 (Figure 1). However, the total number of centres reporting paediatric HSCT throughout the whole study period was actually 37, although not all of these teams performed paediatric HSCT each year, especially in category 3 centres.

Figure 1.

Number of transplant centres performing HSCT in recipients 18 years of age in eastern European countries. HSCT, haematopoietic stem cell transplantation.

Full figure and legend (72K)

In 2003, among the 24 eastern European transplant centres reporting data to the EBMT, 3 (12.5% ) performed exclusively auto-HSCT, whereas the remaining 21 (87.5% ) carried out auto- and/or allo-HSCT. Fewer than 5 allo-HSCT were performed in 9 (42.8% ) of them, while between 5 and 10 were carried out in 7 centres (33.3% ), between 11 and 20 in 2 (9.5% ) and more than 20 in 3 (14.3% ). Thus, only 5 centres (23.8% ) performed more than 10 allo-HSCTs.

Number of HSCT and transplant rates

A total of 2342 transplants were reported to the EBMT Registry between 1985 and 2004 (Poland 953, Czech Republic 501, Hungary 269, Russia 217, Croatia 129, Slovakia 71, Bulgaria 45, Serbia and Montenegro 36, Slovenia 35, Belarus 33, Estonia 26, Lithuania 19 and Romania 8) (Table 1). The majority of transplants (1487; 63.5% ) were performed in paediatric centres (category 1), 453 (19.3% ) in centres for adults (category 3) and 402 (17.2% ) in combined centres (category 2). The median of total reported paediatric HSCTs per centre was only 23 (range 1–411).

Table 1 - Number of HSCT in recipients 18 years by individual eastern European country between 1985 and 2004 (N=2342).

Full table

Regarding the type of HSCT, 1053 (45% ) children underwent auto-HSCT, whereas 1289 (55% ) underwent allo-HSCT. The first allo-HSCT was performed in 1985, whereas the first auto-HSCT was performed 3 years later in 1988.

The total yearly number of reported paediatric HSCTs rose from 1 in 1985 to 358 in 2003 and included 197 allo-HSCTs and 161 auto-HSCTs (Figure 2). In countries performing paediatric HSCTs, the median team density (teams/10 million children) was 8 (range 1–28) and the median rate (per 10 million children) of total paediatric, allogeneic and auto-HSCTs was 70 (range 5–410), 35 (range 3–120) and 35 (range 3–290), respectively (Table 2). However, in 2003, no paediatric HSCTs were reported to the EBMT Registry from Albania, Belarus, Bosnia and Herzegovina, Macedonia, Moldavia and Ukraine, that is, from low-income countries as defined by the World Bank (www.worldbank.org).

Figure 2.

Total number of allogeneic and autologous HSCT in 2342 recipients 18 years in eastern European countries between 1985 and 2004. Number of HSCT in 2342 recipients 18 years of age by individual eastern European country between 1985 and 2004. HSCT, haematopoietic stem cell transplantation.

Full figure and legend (75K)

Table 2 - Demographic data and indicators of paediatric HSCT activity in 19 eastern European countries in the year 2003.

Full table (30K)

Donor type for allo-HSCT

Among the 1287 recipients of allogeneic HSCs, 742 (57.6% ) obtained them from MSD, 331 (25.7% ) from UD and 195 (15.2% ) from MMFD (missing data in 19, that is, 1.5% ). The first UD-HSCT was performed in 1993, then the yearly number of UD-HSCT started to gradually increase, and in 2003, UD-HSCT represented 35.6% of all allo-HSCTs (Figure 3). However, out of 68 UD-HSCTs performed in 2003, as many as 59 (86.5% ) were carried out in 3 countries with mid-level incomes, that is, 38 in Poland, 15 in the Czech Republic and 6 in Hungary.

Figure 3.

Allogeneic HSCT in recipients 18 years—number by year and by donor type. HSCT, haematopoietic stem cell transplants.

Full figure and legend (86K)

Stem cell source

Out of 1053 reported auto-transplants, PB was the source of HSC in 751 (71.3% ), BM in 246 (23.4% ) and PB+BM in 52 (4.9% ) (missing data in 4, that is, 0.4% ). The first transplantation of autologous HSC from PB was performed in 1994 and it systematically increased every year since then. It caught up to the number of BM-derived auto-HSCTs in 1995, and reached 144 (89.4% ) of 161 auto-HSCTs performed in 2003.

Of the 1289 reported allogeneic transplants, BM was the source of HSC in 827 (64.3% ), PB in 416 (32.3% ), CB in 23 (1.8% ) and BM+PB in 14 (1.1% ) (missing data in 9, that is, 0.7% ). The first transplantation of PB-derived allogeneic HSC was undertaken in 1994, after which the number very quickly increased, simultaneously with the increase in the number of UD-HSCTs, and in 2003 it surpassed the number of allogeneic BM transplants (101 vs 90). The first CB transplantation was performed in 1994, but there was no significant increase in the number of CB-HSCTs (5 CB transplants in 2003, that is, 2.5% of allo-HSCTs in 2003) over time.

Indications for allo-HSCT

With regard to the indications for allo-HSCT, 945 (73.4% ) children underwent transplantation for malignant diseases, including ALL 376 (29.2% ), AML 234 (18.2% ), CML 177 (13.8% ), MDS 97 (7.5% ), NHL 35 (2.7% ) and other malignancies 31 (2.4% ), while 339 (26.9% ) for non-malignant disorders, including SAA 202 (15.7% ), immunodeficiencies 61 (4.7% ), inborn errors of metabolism 40 (3.1% ), Fanconi anaemia 19 (1.5% ) and others 17 (1.3% ).

The first allo-HSCT performed on a child with a malignant disease (AML) was reported in 1985 (Figure 4). The yearly number of allo-HSCTs for malignant diseases systematically increased until 1989, followed by a marked acceleration of this increase until 1998. Among malignant diseases, ALL was not only the major indication for allo-HSCT, but in addition, the number of children transplanted for ALL was continuously growing. Such an increase, however less pronounced, was also observed in children with AML and MDS. The number of allo-HSCT for CML was stable after 1999, while in children with lymphoma and solid tumours this number was stable and very low.

Figure 4.

Allogeneic HSCT by diagnosis and by year in 950 recipients 18 years of age with malignant diseases between 1988 and 2004. HSCT, haematopoietic stem cell transplants.

Full figure and legend (54K)

In eastern European countries, the first three allo-HSCTs for acquired and congenital non-malignant diseases were performed in children with SAA in 1987 (Figure 5). After that time, but especially after 1998, there was a continuous increase in the yearly number of allo-HSCTs in children with non-malignant diseases, particularly in children with SAA (from 3 to 24 in 2003) and immunodeficiencies (from 1 in 1992 to 14 in 2003), although it was less evident in children with inborn errors of metabolism and with Fanconi anaemia.

Figure 5.

Allogeneic HSCT by diagnosis and by year in 339 recipients 18 years with non-malignant diseases between 1988 and 2004. HSCT, haematopoietic stem cell transplants.

Full figure and legend (62K)

Indications for auto-HSCT

Out of 1053 recipients of auto-HSCT, 168 (16% ) were transplanted for neuroblastoma, 129 (12.2% ). for NHL, 124 (11.7% ) for AML, 114 (10.8% ) for ALL, 109 (10.4% ) for Hodgkin's disease, 62 (5.9% ) for Ewing's sarcoma, 16 (1.5% ) for CNS tumour, 15 (1.4% ) for Wilms tumour and 316 (30% ) for other tumours.

The first auto-HSCT in an eastern European country was performed on a child with NHL in 1988 (Figure 6). The yearly number of reported auto-HSCTs up to 1994 increased slowly, and then started to quickly augment (from 22 in 1994 to 161 in 2003), mostly due to the increasing number of transplants in children with solid tumours (from 9 to 105 in 2003), mainly neuroblastoma (from 2 to 35 in 2003), while the number of auto-HSCTs for lymphoma remained stable, and started to decrease in children with acute leukaemia.

Figure 6.

Autologous HSCT by diagnosis and by year in 1053 recipients 18 years of age between 1988 and 2004. HSCT, haematopoietic stem cell transplants.

Full figure and legend (65K)

Day +100 TRM before and after 31 December 1998

Concerning donor type and time period, the day +100 TRM after MSD-HSCT was 143% 1998 and 71% between 1999 and 2004, while in recipients of MUD-HSCT it was 347 and 152% and after MMFD-HSCT 4512 and 213% , respectively. After allo-HSCT, the early TRM in category 1 centres accounted for 163% before 1999 and 121% between 1999 and 2004, in category 2 centres it was 194 and 133% and in category 3 centres 224 and 154% , respectively, while after auto-HSCT it was 73 and 41% , 124 and 73% , and 62 and 43% according to centre category and time period analysed, respectively.

Discussion and the EBMT/ESH Outreach Programme overview

This is the first report that evaluates and demonstrates the development and recent activity in the field of HSCT in the paediatric population, which is made up of approximately 80 million children in the eastern European countries.

The history of paediatric HSCT in the eastern European countries started in 1985 with an MSD-BMT performed on a child suffering from AML, and hence this report analyses data from 1985 to 2004. However, data concerning 2004 were incomplete; therefore, 2003 data were often considered more representative in this report.

Generally, between 1985 and 2004 in eastern European countries, significant progress was made in the domain of paediatric HSCT. Namely, there was an increase in the number of paediatric transplant centres, with a predominance of category '1' centres, and a growing number of all types of HSCTs performed on patients 18 years for all the malignant and non-malignant diseases that were considered suitable for treatment by HSCT.¹ Similar trends have been observed in eastern European countries with regard to an increasing number of UD-HSCT, predominance of PB as a source of HSC for autologous transplantation and for allo-HSCT from UD, increasing number of auto-HSCT for neuroblastoma and decreasing number of autologous transplants in children with acute leukaemias.^{2, 3, 4, 5} In addition, after 1 January 1999, significant reduction of the day +100 TRM has been achieved in relation to all types of HSCTs (MSD, MMFD and MUD) and all three categories of transplant centres, which become comparable with early TRM observed in western European paediatric transplant centres.⁶ It is of interest that as in analysis concerning Western countries,⁶ it was found that TRM depends also on centre category; however, only one-fifth of centres performed more than 10 paediatric allo-HSCT per year, and around one-fifth of paediatric HSCTs have been undertaken in category '3' transplant centres.

On the other hand, as compared to western European standards, only one-third of all the needs of the paediatric population from eastern European countries are fulfilled in the HSCT domain, and there are significant differences among these countries, including countries that to date have not registered any paediatric HSCTs. These differences are the result of the financial situation in the individual countries, and rely on the Gross National Income per capita (GNI/capita) as was proven by Gratwohl et al.² These latter countries are especially in need of support in the areas of education, building of infrastructures and implementation of standards.

These are among the reasons why, in 2001, the EBMT in collaboration with the European School of Haematology (ESH) developed the Outreach Programme, that is, a programme supporting emerging HSCT projects and transplant centres in countries with limited resources and/or experience.

The aims of the programme are as follows: (1) to promote the accreditation process, (2) to promote closer collaboration with WPs, (3) to support dealing with national authorities, (4) to improve data management, (5) to support closer collaboration in nursing, (6) to facilitate educational opportunities, (7) to support establishment of twin centres and projects and (8) to maintain information about Outreach activities.

To accomplish these aims, support for the following activities is offered: (1) clinical training for physicians and nurses, (2) statistical training and data management support, (3) technical training, (4) help in preparation for accreditation procedures, (5) support for participation in clinical trials, (6) support in preparation of grant applications and (7) development of Twin Centre programmes.

Detailed and updated information about all activities undertaken within the Outreach Programme is available on: www.ebmt.org/1WhatisEBMT/Outreach/whatisebmt11.htm.

Notes

Conflict of interest

None of the authors declared any financial interests.

References

1. Ljungman P, Urbano-Ispizua A, Cavazzana-Calvo M, Demirer T, Dini G, Einsele H et al. Allogeneic and autologous transplantation for haematological diseases, solid tumors send immune disorders: definitions and current practice in Europe. Bone Marrow Transplant 2006; 37: 439–449. | Article | PubMed | ISI | ChemPort |
2. Gratwohl A, Baldomero H, Frauendorfer K, Urbano-Ispizua A, Niederwieser D, Joint Accreditation Committee of the International Society for Cellular Therapy ISCT, European Group for Blood and Marrow Transplantation EBMT. Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: focus on increasing use of unrelated donors. Bone Marrow Transplant 2007; 39: 71–87. | Article | PubMed | ISI | ChemPort |
3. Gratwohl A, Baldomero H, Labar B, Apperley J, Urbano-Ispizua A, Accreditation Committee of the European Group for Blood and Marrow Transplantation (EBMT. Evolution of hematopoietic stem cell transplantation in Eastern and Western Europe from 1990 to 2003. A report from the EBMT activity survey. Croat Med J 2004; 45: 689–694. | PubMed |
4. Miano M, Cancedda R, Hartmann O, Cornish J, Locatelli F, Egeler RM et al. Survey on haematopietic stem cell transplantation for children in Europe. Bone Marrow Transplant 2005; 35: S3–S8. | Article | PubMed |
5. Gratwohl A, Baldomero H, Frauendorfer K, Urbano-Ispizua A, Joint Accreditation Committee, International Society for Cellular Therapy, European Group for Blood and Marrow Transplantation. EBMT activity survey 2004 and changes in disease indication over past 15 years. Bone Marrow Transplant 2006; 37: 1069–1085. | Article | PubMed | ISI | ChemPort |
6. Dini G, Badell-Serra I, Bordigoni P, Egeler RM, Hartmann O, Klingebiel T et al. Risk factors for transplantation-related mortality show that at least 10 paediatric allo-HSCTs must be a requirement even in combined programmes. Bone Marrow Transplant 2006; 37 (suppl. 1): S54.

Appendices

Appendix

List of eastern European transplant centres reporting paediatric HSCTs to the EBMT Registry. The total number of transplantations are listed first, followed by the number of allografts/autografts.

Department of Children's Hematology and Oncology, CIC 817, Medical Univeristy, Wroclaw, PL (411; 230/181); Department of Paediatric Hematology and Oncology, CIC 656, University Hospital Motol, Prague, CZ (300; 218/82); Department of Paediatric Oncology, CIC 597, University Hospital, Brno, CZ, (191; 1/190); Department of Pediatric Oncology, Hematology and Transplantology, CIC 641, University of Medical Sciences, Poznan, PL, (160; 150/10); Szent Laszlo Hospital, CIC 739,Budapest, H, (156; 112/44); University Hospital Center Rebro, CIC 302, Zagreb, HR, (129; 58/71); Department of Bone Marrow Translant Research Institute for Pediatric Hematology, CIC 694 Russian's Children's Hospital, Moscow, RUS, (108; 77/31); Lower Silesian Centre for Cellular Transplantation with Marrow Donor Registry, CIC 538, Wroclaw, PL (103; 89/14); Department of Hematology and BMT, CIC 677, Silesian Medical Academy, Katowice, PL (99; 51/48); Department of Pediatrics/BMT Unit GYEK, CIC 599, Postgraduate Medical School, Miskolc, H (93; 27/66); Children's University Hospital Hematology/Oncology, CIC 678, Lublin, PL (92; 40/52); Department of BMT Centre of Hematology, CIC 725, Pavlov Medical University, St Petersburg, RUS (78; 36/42); BMT Unit II Children's Clinic, CIC 684, Pediatric University Teaching Hospital, Bratislava, SK (62; 30/32); Specialized Children's Oncohematology Hospital, CIC 346, Sofia, BG (45; 11/34); Department of Hematology, CIC 730, University of Medical Science, Poznan, PL (39; 14/25); Clinic of Haematology, CIC 582, Military Medical Academy, Belgrade, BIH (36; 30/6); Department of Hematology, CIC 640, University Medical Center, Ljubljana, SLO (35; 21/14); Clinic of Hematology/Oncology, CIC 746, Tartu University Hospital, Tartu, EST (26; 4/22); Department Hematology/Stem Cell Transplant, CIC 504, National Medical Centre, Budapest, H (20; 19/1); Oncology/Hematology BMT, CIC 508, Vilnius University Children's Hospital, Vilnius, LT (19; 6/13); Department of Transplantation Jagiellonian University Medical College, CIC 507, Polish-American Institute of Paediatrics, Cracow-PL, (18; 0/18); Bellorussian Centre for Paediatric Hematology/Oncology, CIC 591, Minsk, BY (17; 17/0); Hospital No 9, CIC 801, Minsk, BY (16; 7/9); Institute of Clinical Immunology, CIC 376, Novosibirsk, RUS (15; 1/14); Research Institute of Hematology, CIC 724, St. Petersburg, RUS (15; 6/9); Pediatric Hematology/Oncology, CIC 764, University Hospital Coll. Med. UMK, Bydgoszcz, PL (13; 3/10); Department of Hematology/Oncology, CIC 718, Charles University Hospital, Pilsen, CZ (10; 8/2); Clinic of Hematology/Transplantology, CIC 610, University Hospital, Bratislava, SK (7; 4/3); Department BMT Unit, CIC 816, Military Medical Academy, Warsaw, PL (6; 5/1); Centre of Hematology/BMT, CIC 296, Fundeni University Institute, Bucharest, RO (5; 3/2); Department of Haematology, CIC 799, Medical University, Gdansk, PL (5; 3/2); IIIrd Paediatric Clinic Hematooncology, CIC 174, University of Medicine and Pharmacy, Timisoara, RO (3; 0/3); Department of Hematology/Oncology, CIC 954, Central Clinical Hospital Med. Univ., Warsaw, PL (3; 2/1); Department of Hematology, CIC 333, Roosevelt Hospital, Banskà Bystrica-SK (2; 0/2); Department of Haematology, CIC 553, Jagiellonian University, Krakow, PL (2; 2/0); Department Hematooncology Intensive Care, CIC 800, M Sklodowska-Curie Memorial Cancer Centre Warsaw, PL (2; 2/0); Department BMT, CIC 370, Clinical Center for Advanced Medical Technologies, St Petersburg, RUS (1; 0/1).

Acknowledgements

We acknowledge all the participating teams for data reported to the EBMT Registry, and Myriam Labopin, EBMT Statistician from the Acute Leukaemia WP Registry, for data management and statistical evaluation.