Activities of blood banks in the Council of Europe Member States related to bone marrow transplantations

Summary

Within the context of intergovernmental co-operation in the field of health, the Council of Europe has consistently selected ethical problems for study. The most important such ethical issue relates to the non-commercialisation of human substances i.e. blood, organs, tissues.

As subject of the 1995/1996 co-ordinated research programme the exploration of the activities of blood banks in relation to bone marrow transplantation was chosen.

This report analyses the situation to 1994 based on three different sources of information; replies from the National Health Authorities to a questionnaire; information gathered by group members on their study visits to certain member states and reports by group members on the situation in their own countries.

The report addresses in different sections specific issues such as activities related to haematopoietic progenitor cell transplantation, quality issues, histocompatibility laboratory data analysis, bone marrow donor registries and cord blood banking and transplantation.

The report concludes with a number of recommendations allowing the development of a future policy in the field of bone marrow transplantion for both the Council of Europe and its member states.

TABLE OF CONTENTS

Page

SECTION 1 - FOREWORD 5

SECTION 2 - INTRODUCTION 7

SECTION 3 - ACTIVITIES RELATED TO BMT IN EUROPE 10

SECTION 4 - QUALITY ISSUES 12

SECTION 5 - HISTOCOMPATIBILITY LABORATORY DATA ANALYSIS 14

SECTION 6 - BONE MARROW DONOR REGISTRIES 15

SECTION 7 - CORD BLOOD BANKING AND TRANSPLANTATION 17

SECTION 8 - CONCLUSIONS 18

SECTION 9 - BIBLIOGRAPHY / REFERENCE MATERIAL 21

APPENDIX 23

SECTION 1

Foreword

The subject of the 1995/1996 co-ordinated medical research programme was chosen by the European Health Committee (CDSP) following the proposal of the Committee of Experts on blood transfusion and immunohaematology (SP-HM). The European Health Committee commissioned a study group to explore the activities of blood banks in relation to bone marrow transplantation.

It comprised the following experts: Dr S Koskimies (Finland), Dr R Kroczek (Germany), Dr M Reti (Hungary), Dr L de Waal (Netherlands), Dr R. Arrieta (Spain), Dr F Carbonell-Uberos (Spain) and Dr I M Franklin (United Kingdom).

At its first meeting 25-27 April 1995 the group drew up a plan of work, assigned the experts' responsibility for visiting specific countries and drew up a questionnaire. This questionnaire was designed to provide information on the points to be dealt with in the study, and included the activities of the blood banks themselves (whether hospital, regional or state), tissue typing laboratories and the bone marrow transplant units. The questionnaire was sent to the national health authorities of all member states, additional information being obtained from the visits. The experts' study visits consisted of the following:

- Denmark, Sweden : Dr Koskimies
- Ireland, France : Dr de Waal
- Switzerland, Belgium, Czech Republic, Poland : Dr Reti
- Italy : Dr Carbonell

The members of the group carried out their study visits prior to December 1995 and their reports were examined by the group at its second meeting (12-14 March 1996), together with the completed questionnaires. At this meeting the key points to be addressed in the final report were determined, and the detailed analysis of the questionnaires allocated according to the personal expertise of the individual.

The group's third meeting (8-9 October 1996) was devoted to finalising the report. It analyses as completely as possible the situation to 1994 based on three different sources of information:

- replies to the questionnaire from the national health authorities;
- information gathered by group members on their study visits to certain member states;
- reports by group members on the situation in their own countries.

SECTION 2

Introduction

Bone marrow transplantation has become an established procedure in the treatment of a variety of haematological malignancies, solid tumours and bone marrow aplasia. In the past few years, the development of, first, haematopoietic growth factors and, more recently, the use of chemotherapy/growth factor primed peripheral blood stem cells, collected through apheresis, has improved the safety and increased the range of applications of bone marrow transplantation. In addition to bone marrow from family and HLA-compatible unrelated donors, peripheral blood stem cells are used for both autologous and allogeneic transplantation. Recently, promising preliminary results have been reported of the use of stem cells from cord blood for transplantation in children.

Whatever source material (bone marrow, peripheral stem cells, cord blood) is used, it is essential in allogeneic transplantation to ensure acceptable tissue compatibility (HLA) between the donor(s) and recipient. In view of the large number of polymorphisms in the population, for those patient with no family donor it is necessary to have access to a large number of potential donors or stored cell-samples to guarantee a satisfactory match between donor(s) and the recipient. Such potential donors are available through donor registries held in many countries world-wide, and collaborating with each other through a hub system co-ordinated by the bone marrow donors worldwide collaboration. The hub is an identified donor registry which acts within a country to identify, advise, test and ultimately arrange the harvesting of a donor when either donor or recipient is outside that country.

The members of the study group perceived that the organisation of bone marrow transplantation in the member states of the Council of Europe varied greatly between countries. In some places hospitals take care of collection, storage, typing and transplantation. In others some of these activities are performed by blood transfusion establishments or tissue transplantation /immunology organisations. Exchange of bone marrow tissues between member states may be affected by these different methods of coordinating these activities. The existence of agreed international standards for the quality of such haematopoietic progenitor cells containing tissues would also assist in facilitating movement of these tissues between countries.

The concept of quality assurance (good manufacturing practice), which already is applied to the manufacturing of pharmaceuticals, is currently also being introduced into other areas including the collection and processing of blood and blood products. For the collection, processing, storage and release/issue of bone marrow and stem cells similar regulations will probably have to be applied. The recent report of the transmission of hepatitis B to patients by the contamination of their peripheral blood stem cell collections within a liquid nitrogen refrigerator emphasises the urgent need to introduce established quality standards universally.

The differences between member states that are commonly found suggest that there is a need for a survey of the current practices in the member countries. The results of such a survey might then be used as the basis for defining a policy for future Council of Europe activities in this area.

This report has been organised in order to meet the following objectives :

- to prepare an overview of the organisations involved in the collection, processing, storage and distribution of bone marrow and haematopoietic stem cells for transplantation,

- to study the quality assurance aspects of bone marrow and stem cells collection, processing, storage and distribution and how the responsibility for this is determined by the various organisations,

- to study histocompatibility aspects of bone marrow transplantation notably with regard to optimising the exchange of volunteer donor bone marrow, peripheral blood stem cells or umbilical cord / placental blood cells between member countries.

On the basis of encouraging improvements in co-operation between bone marrow transplantation units and transfusion services, and stressing the ethical aspects, the study group has drawn up a list of recommendations.

In the course of their work, it became clear that there were significant problems with nomenclature in both the bone marrow transplantation and blood banking fields. It is appropriate at this point to define the terms used in the remainder of this report.

The term bone marrow transplant now embraces peripheral blood stem cells and cord blood as well as marrow derived cells. In order to make clear that an inclusive term is meant the phrase ‘haematopoietic progenitor cell(s)’ will be used to include all sources of such cells and all types of transplant. A bone marrow transplant Unit might perform all or only some such procedures. If the source of haematopoietic progenitor cells is referred to specifically, this will be made clear in the text.

The term ‘blood bank’ is also ambiguous. In some member states this may refer to a centre responsible for collecting, processing testing and manufacturing products, where elsewhere it will refer to a laboratory with cross-matching and issue functions only. Therefore the study group used the following terms to define types of blood transfusion activity. A Transfusion Medicine Unit (TMU) would be equivalent to a collecting, processing and testing blood centre, whereas a hospital blood bank is a laboratory mainly involved in cross-matching and issue. In order to emphasise the similarity between transfusion medicine units and blood centres these are often mentioned together in the text. Because of the involvement of the red cross in many member states, such blood transfusion services were identified separately.

Response to the questionnaire

As mentioned in the foreword, the questionnaires were distributed in the late summer of 1995. Responders were asked specifically to provide transplant activity for 1994. Other aspects were not so specified although the last complete year for which data would be available would be 1994 or financial year 1994 / 1995. Therefore the data, especially for rapidly developing areas such as cord blood transplantation, will be at least one year old at the time of writing.

The questionnaire was sent to 34 countries, and answers were received from 19 of them. The responses are summarised in table 1. In an additional two countries information was obtained during the visit of the expert member of the study group. Bulgaria, Latvia and Malta have no haematopoietic progenitor cell transplant activity, Malta having a contract with a hospital in the UK. Within those countries which responded to the questionnaire, the percentage of responses was slightly higher from bone marrow transplant units (75%) than from transfusion medicine units (69%).

It appears likely that different countries used different systems for gathering information for completion of the national summary questionnaire. Such differences could be responsible for much of the variations seen in the responses. No attempt was made to verify the data obtained from the questionnaires.

SECTION 3

Activities related to haematopoietic progenitor cell transplantation in Europe

Tables 2a and 2b show the haematopoietic progenitor cell transplant activity in the different countries responding to the questionnaire. Table 2a shows these data organised according to the type of procedure and the type of facility in which it is carried out. Each country’s activity has been identified individually in this table. Table 2b shows a summary of these data by country, with an estimate of the participation of BMT units in the total activity relating to the collection, processing and manipulation of haemopoietic progenitor cells.

Several countries did not provide quantitative information about the number of units performing each activity. Such countries are identified in table 2a.

The collection of whole blood, platelets, plasma and autologous blood is normally made in transfusion medicine units/blood centres. However, it is an important role of hospital blood banks and BMT units in the Czech Republic, Germany and Spain. The red cross is in charge of these activities in Finland, Switzerland and most of Germany.

Recruitment of unrelated bone marrow donors for registries is most commonly done through transfusion medicine units/blood centres using data bases of voluntary normal blood donors or selected platelet donors. Local registries are usually linked with a national registry.

BMT units are the usual site for collecting bone marrow. Peripheral blood stem cells are collected in both TMU/blood centres and BMT units.

Cord blood banks are established in the Czech Republic, Germany and Italy. Other countries collect cord blood but did not have special blood banks for this product in the year of interest, 1994. Since that time there has been a great increase in interest in cord/placental blood as a source of haematopoietic progenitor cells.

Mobilisation of PBSC prior to collection is performed most commonly in BMT units, but some activity is developing in TMU/blood centres in several countries. The questionnaire was not sufficiently detailed to determine whether TMU/blood centres are administering chemotherapy or only haematopoietic growth factors for mobilisation.

Bone marrow and PBSC cryopreservation is an activity divided in the majority of countries between BMT units and TMU/blood centres.

Reinfusion of haematopoietic progenitors is almost universally made in BMT units.

Manipulation of bone marrow and PBSC, such as red cell or plasma depletion, CD34 positive cells selection, T-cell depletion, and purging are activities performed in both BMT units and TMU/blood centres.

Culture ex vivo of CD34+ progenitor cells was performed in only 5 countries, and gene transfer into CD34+ cells in 4 countries.

Numbers of haematopoietic stem cell transplants in Europe

These data are presented in Table 3. The results are as returned in the questionnaire. There are major difficulties in determining the level of activity in haematopoietic progenitor cell transplantation. Probably a more reliable guide is the returns made to the european group for blood and marrow transplantation. These are published each year. The returns for 1994 are shown in the appendix. What is clear is that the numbers of procedures performed is increasing annually, and will increase further if solid tumours become an established indication for haematopoietic progenitor cells transplantation.

National bodies and professional associations involved in setting guidelines or standards in bmt

These are shown in table 4. The types of professional association involved in BMT activities are: haematology, immunology, oncology, transfusion, and specifically transplant.

Standards appear to be established by different combinations of organisations both professional and governmental. Guidelines exist only in nine of the 24 evaluated countries. No compulsory guidelines are in force but established standards are normally operating. Accreditation is not a common practice as yet. There is no clear pan-european consensus at present in regard either to the professional monitoring or the need for accreditation.

SECTION 4

Quality issues

Data from 15 countries was available for analysis. The degree of detail provided also differed substantically between countries, and some responses were so generalised as to be impossible to evaluate.

Some countries either did not respond or have no transplant activity. Very different organisational structures seem to exist throughout the member states.

Testing of peripheral blood of donors of bone marrow and peripheral blood stem cells, and the peripheral blood of mothers whose infant's cord blood is obtained

These data are presented in tables 5, 6 and 7. A similar testing policy on the peripheral blood of all donor types is the rule. In general, testing for the number of CD34⁺ cells in the product is performed. There is universal testing for HIV, HCV and HBV. Different policies are in place for HTLV-1 testing. It is not clear whether this relates to the perceived risk in each country. Testing for CMV, EBV, syphilis and toxoplasma is variable between member states, and also within countries. When differences occur within a given country, TMU/blood centres tend to test more for syphilis, BMT units for CMV, EBV and toxoplasma. Clearly these findings reflect the emphasis on the likely transplant related complications in BMT recipients. Testing for parvovirus B19, hepatitis A, varicella-zoster-virus, herpes-simplex-virus and malaria are performed only by a few BMT units.

Testing of the stem cell containing product (Tables 8, 9 and 10).

Testing for CD34⁺ cell numbers is usual before and after cryopreservation. After cryopreservation and when used fresh, the progenitor-cell containing product is often analysed using short-term colony forming assays. Only a few units perform long-term culture of the product. The testing of the progenitor-cell containing product for infectious markers before cryopreservation is clearly less often performed when compared to the testing of the peripheral blood of donors. Testing is almost universal for aerobic and anaerobic bacteria, and in most instances also for fungi. After cryopreservation, in most countries no further testing for infectious markers is performed but testing for bacteria and fungi may be performed or repeated. Non-cryopreserved (fresh) progenitor-cell containing products are used less often. Most would be for allogeneic BMT or in units or protocols in which cryopreservation is either unavailable or not required. Here again testing for bacteria and fungi is usual, with often no tests for infectious disease markers.

Methods for separation of stem-cell containing material (Table 11).

Because there are significant differences both within and between countries as to the activities undertaken by BMT units and TMU/blood centres these are shown separately in table 11. Almost all units use leucapheresis. A variety of commercial methods is used to enrich for CD34⁺ cells. Purging of malignant cells and T cell depletion is performed less frequently.

Cryopreservation and storage of stem-cell containing products (Table 12)

Cells are usually stored in liquid nitrogen with continuous temperature monitoring. Records are kept in most instances 10 years or longer. Only in relatively few units were very clearly defined, written procedures used for the release and the infusion of the stem-cell containing material.

Standard operating procedures / GMP (Table 13)

The practice of establishing stringent standard operating procedures and GMP rules for the manipulation and testing of stem-cell containing material is not yet universal. In particular, the validation of SOPs is only performed rarely. In practically no country has a national quality assurance scheme for the handling of stem-cell containing material been established. Local or regional schemes do exist in some countries but there are substantial difficulties in the organisation of such schemes.

Accreditation or Licensing (Table 14)

Only in few instances is there a requirement for accreditation or a license for establishments preparing stem-cell containing product. If introduced, usually there is only a semi-formal procedure for BMT units, involving professional peer review processes. Despite this, many countries have a governmental body involved in the setting of standards or guidelines for BMT (see table 4).

SECTION 5

Histocompatibility laboratory data analysis.

Organisation of histocompatibility laboratories appears to be at a more uniform level throughout the responding member countries. No specific problematic issues were identified. The existence of long established, well organised international workshops on histocompatibility, the availability of an international quality assurance scheme, and the eurotransplant exercises have all assisted in the development of a standard model for a histocompatibility service and facilitated the introduction of new techniques.

Histocompatibility testing does not appear to represent an obstacle to the free exchange of haemopoietic progenitor cells containing material, rather it can be seen as a model for other disciplines.

SECTION 6

Bone marrow donor registries

Structure of registries

Information on bone marrow donor registries was obtained from 20 countries. A total of 45 registries exist in 18 different countries, fifteen countries had a ‘hub’ registry. The total number of donors was in 1994 1.138.800.

In 9 countries the registry was located in a TMU/blood centre or hospital blood bank, in 3 countries a bone marrow transplant unit was involved, in one country the registry was run by clinical immunology unit and in 4 countries it was run totally by other organisations. From 2 countries no information was available.

All registries required the donors to give written consent. The criteria for acceptance were the same as for blood donors except the age. In most registries the upper age limit for marrow donation was 55 years but in some registries it was 50 years. Although for inclusion on a registry it is appropriate to use the same criteria for bone marrow as for blood donors, the requirements at the time of marrow donation are more stringent. The number of blood donors among the registered bone marrow donors varied. In Denmark and Poland all registrants were blood donors, in Hungary, Ireland, the Netherlands, and Switzerland 90-95% were blood donors. Half of the donors were also blood donors in Czech republic, Finland, Italy and Sweden whereas only 10-15% were blood donors in Germany and Portugal. From UK, Spain, Slovakia, France and Belgium this information was not obtained.

Activity of registries
Altogether 838 bone marrow donations took place from these registries in 1994. Of these donations 41% (341) was sent out to another country while at the same time 23% (197) were received from another country. This means that 144 (17%) of bone marrow donations were exported outside Europe. The UK donates abroad 31% (132) of its harvested unrelated bone marrows. If the UK is excluded, the rest of the countries donate an average of 10% of their harvested bone marrows to another country, France, Germany and the Netherlands being the most active exporters. All but 2 countries received bone marrow from another country, eight countries imported more than they exported.

The efficiency of a register may be taken to be the number of donations per 10.000 donors per year. In six countries the usage was more than 10 / 10.000 when in all other countries it varied ranging 0.5-8 per 10.000 donors. Three registries were still so small in number that they have not yet been used at all.

The efficiency did not correlate to the pool size, nor did it correlate to the actual number of blood samples taken for further compatibility studies. Of such blood samples, 10% led to identification of a suitable donor in ‘efficient’ registries when only 4% of blood samples led to a donor in other registries. The activity correlated best to the number (proportion) of DR typed donors in the registry. In efficient registries an average of 80% of the donors were DR typed when in the rest of the registries only 29% were DR typed (see figure 1). Despite this, the data suggest that efficiency increases dramatically when as few as 20 % of donors are of known DR type.

Summary

Registries of unrelated bone marrow donors now cover nearly the whole of Europe. These registries seem to be actively growing. Every registry is collaborating in principle at the national and international level, and also with registries outside Europe.

Half of the registries are run by the blood banks or TMU/blood centres but the organisation involved seems not to have any effect on the level of activity or efficiency of the register.

The general efficiency varied between the countries and it seemed to correlate best with the proportion of DR typed donors in the registry. Registries which have a low proportion of the registered donor typed for HLA-DR have a low ‘usage’ in terms of providing donors for BMT. Registries should therefore ensure that as many donors as possible are DR typed to ensure the efficient use of the panel.

SECTION 7

Cord Blood Banking and Transplantation

Distribution of the questionnaire took place just as interest in cord or placental blood (the terms are used to mean the same thing in this section) as a source of haemopoietic progenitor cells was becoming international. As can be seen from table 23, only France had any significant transplant activity in this area using unrelated donors, although directed donation from a sibling was, although infrequent, more widespread. Perhaps reflecting the rarity of directed donation, a relatively large number of units was involved.
Since there was insufficient information on which to base recommendations, the study group relied on its own experience in this area to propose suggestions.

It is the view of the group that it is essential that the current rapid growth in cord / placental blood transplantation and banking is carried out to a high ethical standard, and that cord blood banks must achieve appropriate GMP or other standards from their inception. The study group believes these aspects to be critical to enable a full evaluation of the processing techniques, and of transplant outcomes, so that cord blood products may be issued to an acceptable agreed standard (in terms of haematopoietic progenitor cell number, quality and other aspects yet to be determined). The 1996 update of the Recommendation No. R (95) 15 on the preparation, use and quality assurance of blood components includes a section on cord blood.

SECTION 8

Conclusions

The study group, in its analysis of the responses to the questionnaires and the visits to member states, had to consider the fundamental issue of whether it is desirable, or important, for there to be collaboration between transfusion medicine services and BMT units. In its deliberations of this matter, the group had in mind the interests of the Council of Europe in the area of the non-commercialisation of blood and blood products, and in ethical issues generally. Achieving the objective of unfettered movement of bone marrow and other haematopoietic progenitor cells containing tissues will be enhanced by improved collaboration between BMT units and transfusion medicine units (TMU)/blood centres in such areas as the identification of agreed standards for these tissues, and the requirements for testing of donors (unrelated or family). Harmonisation of standards for laboratory processing techniques and record-keeping would also be necessary.

In considering these and other issues, the group concluded that there were some activities that would be best delivered by a strong collaboration between, mainly, TMU/blood centres and BMT units, or at least the presence of a mechanism for the exchange of information and advice. This view is based on the respective virtues of TMU/blood centres and BMT units.

Firstly, transfusion medicine has a long and strong history of donor care. This experience, together with the increasing demands being made on family and unrelated donors (peripheral blood stem cells donation, donation of lymphocytes for post-BMT immunotherapy) by the BMT units, makes the involvement of transfusion medicine specialists in the care of the donor of significant ethical importance.

Secondly, TMU/blood centres have a tradition of apheresis, mainly for the production of plasma and platelets. Again, this provides great strengths in terms of donor care and practical knowledge of the techniques, and should enable the expertise to be transferred to the care of donors (autologous or allogeneic) of peripheral blood progenitor cells.

Third, TMU/blood centres generally must adhere to the principles of good manufacturing practice (the rules governing medicinal products in the european community. Volume IV - guide to good manufacturing practice for the manufacture of medicinal products) and already have highly protocolised systems (SOPs, etc.) for the preparation, storage, release and issue of blood products. Such a background is not always evident in the BMT units.

Fourth, BMT units themselves have been centres of considerable innovation, with major technical and therapeutic advances in the past ten years. The rapid widespread adoption of once novel techniques such as PBSC mobilisation and transplantation, CD34+ cell selection, post-BMT adoptive immunotherapy and advances in the management of infectious disease are some examples. Collaboration with such a rapidly developing, ‘frontier’ specialty can only be to the benefit of transfusion medicine.

The study group believes, therefore, that there should be collaboration between TMU/blood centres and BMT units in order to implement the improvements identified below, which follow from the observations made above.

To enable staff to concentrate on their own areas of special expertise; e.g. BMT physicians on caring for patients and developing BMT strategies, transfusion medicine physicians and scientists on caring for donors and processing and testing blood/marrow derived, haematopoietic progenitor cell containing, products. Close collaboration will remain essential to ensure that the strengths of both TMU/blood centres and BMT units continue to be expressed either in improved outcome, or greater accessibility of treatment, for patients.

To encourage the universal development and implementation of SOPs and other validated quality measures in the processing, testing, storage, release and issue of haematopoietic progenitor cell containing products. If implemented, such developments should lead to improvements in the reliability of the product specification.

That minimum quality standards for haematopoietic progenitor cell containing products should be determined within Europe which reflect local legislation but do not impede the unfettered movement of these products to, from or between member states to the benefit of patients.

To ensure that all family and unrelated donors are given appropriate information, including known risks, about the methods of donation and receive ethical care from a physician/advocate who is not the BMT physician.

To ensure that the current rapid growth in cord/placental blood transplantation and banking is carried out to a high ethical standard, and that such cord blood banks achieve appropriate GMP or other standards from their inception. The study group believes these aspects to be critical to permit the required evaluation of the procedure, and to ensure that cord blood products are issued to an acceptable agreed standard (in terms of haematopoietic progenitor cell number, quality and other aspects yet to be determined). The 1996 update of the Council of Europe Recommendation No. R (95) 15 on the preparation, use and quality assurance of blood components includes a section on cord blood.

That communication at a european level between the competent professional bodies, particularly those representing transfusion medicine and bone marrow transplantation interests, should be encouraged so as to facilitate the developments proposed above.

The study group also considered that some specific recommendations might be made to member states.

- that procedures (testing for blood borne infections, for example) should be standardised between BMT units, TMU/blood centres and other collaborating bodies in each country. At present, there is considerable variation between centres. It is acknowledged that in some cases standardisation may have to be on the basis of consensus rather than evidence.

- that there should be a convergence of BMT practice throughout Europe. Again, it is acknowledged that in most cases standardisation may have to be consensus rather than evidence based, but appropriate recommendations should have the capacity to be tested against prospective data or studies. It may be appropriate to seek the advice of the european group for blood and marrow transplantation with regard to developing guidelines for BMT practice, in collaboration with other competent bodies (TMU/blood centres, infectious diseases services, etc. ). EBMT does produce a list of appropriate indications for types of BMT procedure, and this would appear a good start point for more management related recommendations.

- that BMT Units should work together with TMU/blood centres to implement GMP/accreditation (as appropriate) for all BMT related laboratory activities. A realistic timetable for implementation should be agreed.

- the training, and continuing education, of all staff involved in the relationship between bone marrow transplantation and transfusion medicine should be broadened to ensure an adequate understanding of each discipline. For example, transfusion medicine specialists should undergo a period of training in medical and/or haematological oncology and BMT, and vice versa.

- in order to ensure the widespread awareness and acceptance of its advice, the committee of experts on blood transfusion and immunohaematology (SP-HM) should consider consulting BMT physicians or their professional organisation(s) when preparing the next version of its guide to haematopoietic progenitor cells collection, processing and storage.

SECTION 9

Bibliography / reference material used or available

• Italian Bone Marrow Donor Registry Standards (July 31, 1995). National programme description.

• British Committee for Standards in Haematology; Clinical Haematology Task Force (1995). Guidelines on the provision of facilities for the care of adult patients with haematological malignancies (including leukaemia and lymphoma and sever bone marrow failure). Clinical & Laboratory Haematology, 17, 3 - 10.

• Documento de consenso organizacion nacional trasplantes - asociacion Espanola de hematologia y hematoterapia - sociedad de hematologia y oncologia pediatrica de la A.E.P. (Grupo Espanol para el tmo infantil). Requisitos para iniciar la busqueda de donante no emparentado para trasplante de medula osea. Anexo 1. Ministerio de Sanidad y Consumo. Espana.

• Matesanz R, Naya M^a T. Editorial. Organizacion de la donacion y trasplantes de medula osea en Espana. Rev. Esp. Trasp. 4, 125 - 129.

• Commission Directive (91/356/EEC) laying down the principles and guidelines for Good Manufacturing Practice for medicinal products for human use. Official Journal of the European Communities No. L 193. 30 p83 - 86.

• Requirements for the collection, processing and quality control of blood, blood components and plasma derivatives (Requirements for Biological Substances no. 27, revised 1992). Annex 2, WHO Technical Report Series No. 840, 1994.

APPENDIX

Table 1 : Responses received to the questionnaire

COUNTRY	TMU / Blood centre	Hospital Blood Bank	Red Cross	BMT Unit	Donor Registry
AUSTRIA (A)	ND
BELGIUM (B)	ND
BULGARIA (BG)	ND
CZECH REP. (CZ)	4/4	7/4		6/6	2/2
DENMARK (DK)	4/4			1/0	1/1
ESTONIA (EE)	ND
FINLAND (FIN)			1	11/9	1/1
FRANCE (F)	43/23
GERMANY (D)	22/10		10/10	38/28
HUNGARY (H)	3/2		3/3	1/1
IRELAND (IE)	ND
ITALY (I)	57/49			46/46	1/1
LATVIA (Lv)	ND
LUXEMBOURG (L)	ND
MALTA (MT)	1/1
NETHERLANDS (NL)	22/9			11/6	1/1
NORWAY (N)				1/1	1/1
POLAND (PL)	ND
PORTUGAL (P)				3/3	1/1
SLOVAKIA (SK)	2/2		2/2	1/1
SPAIN (E)	9/8	3/3		30/22	1/1
SWEDEN (S)	8/8	1/0		3/3	1/1
SWITZERLAND (CH)	3/3				1/1
UNITED KINGDOM (UK)	13/13	included in haematology departments		275/196 *)

*) for the UK, distribution and responses relate to all haematology departments;
48 stated they were involved in BMT.

TMU, Blood Centre Sent / Received
HBB, Hospital blood Bank ND, not detailed data
RC, Red Cross
BMT, Bone Marrow Transplant Unit
Donor Registry

Table 2a : Blood establishments involved in haematopoietic progenitors
transplant activities in Europe.

Data are expressed as follows; country/ no. of units. If no quantitative data are available then; country/n.a. is used to signify that the number of units, or volume of activity, was not specified

ACTIVITY	TMU / BLOOD CENTRE	HOSPITAL BLOOD BANK	RED CROSS	BMT UNIT	CORD BLOOD BANK	OTHER
Collection of whole blood	A/n.a. CH/n.a. CZ/4 D/18 E/8 F/23 H/3 NL/22 P/n.a. S/8 UK/13	A/n.a. CH/n.a. E/3 I/n.a. N/n.a. P/n.a.	A/n.a. CH/n.a. D/10 FIN/1	D/10 E/15 IRL/1 SL/2
Collection of platelets	A/n.a. CH/n.a. CZ/4 D/18 E/8 EE/n.a. F/19 H/3 NL/22 P/n.a. S/8 UK/13	A/n.a. CH/n.a. E/3 I/n.a. N/n.a. P/n.a.	A/n.a. CH/n.a. D/10 SF/1	D/8 E/16 EE/n.a. FIN/2 SL/2
Collection of plasma	A/n.a. CH/n.a. CZ/4 D/18 E/8 EE/n.a. F/23 H/3 NL/22 P/n.a. S/8 UK/13	A/n.a. CH/n.a. E/3 I/n.a. N/n.a. P/n.a.	A/n.a. CH/n.a. D/10 FIN/1	D/7 E/14 FIN/1 SL/2
Collection of autologous blood	A/n.a. CH/n.a. CZ/4 D/18 E/5 EE/n.a. F/23 H/3 NL/22 PL/1 S/8 UK/10	A/n.a. CH/n.a. E/3 I/n.a. N/n.a.	CH/n.a. D/10	CZ/3 D/10 E/19 IRL/1 P/n.a. PL/1 FIN/1 SL/2 UK/29	CZ/1
Donor registry	A/n.a. D/n.a. DK/1 E/7 F/23 PL/1 S/5 UK/2	A/n.a. E/3 I/n.a. P/n.a.	CH/n.a. D/n.a. FIN/1	CZ/1 D/1 E/13 NL/1 SL/1	D/n.a. NL/7	B/1 H/1 IRL/1 N/1 P/n.a. UK/1
Recruitment of unrelated BMT donors	A/n.a. CZ/4 D/n.a. DK/4 E/6 F/19 H/4 NL/9 PL/n.a. S/7 UK/13	A/n.a. B/2 CZ/4 I/n.a.	B/6 CH/13 D/n.a. FIN/1	CZ/6 D/n.a. PL/5 S/1	CZ/1	E/1 IRL/1 N/1 P/n.a.
Bone Marrow Collection	CH/n.a. CZ/1 E/2 F/12 S/2	A/2 E/2	D/2	A/3 CH/n.a. CZ/4 D/18 DK/3 E/22 EE/n.a. H/3 I/n.a. IRL/2 N/1 NL/11 P/n.a. FIN/5 SL/2 S/4 UK/43	CZ/1
Cord Blood Collection	CZ/1 DK/1 E/1 F/9 H/1 P/n.a. S/2 NL/3	A/1 I/n.a.	D/2	CZ/1 E/12 EE/n.a. D/4 H/1 I/n.a. P/n.a. FIN/2 UK/5	CZ/1 D/n.a. I/n.a.	CH/1 N/1
PBSC collection	CH/n.a. CZ/1 D/18 DK/2 E/4 F/19 H/1 NL/3 P/n.a. PL/1 S/7 UK/16	A/3 E/3 I/n.a. N/n.a. NL/1	D/7	A/4 CH/n.a. CZ/4 D/18 DK/1 E/22 EE/n.a. I/n.a. IRL/2 NL/10 P/n.a. PL/1 S/2 FIN/6 SL/2 UK/43	CZ/1 D/1
PBSC mobilisation	A/n.a. CH/n.a. CZ/1 D/5 E/3 F/12 NL/3 S/4	E/3 NL/1	D/5	A/1 B/n.a. CH/n.a. CZ/5 D/18 DK/3 E/23 EE/n.a. H/1 I/n.a. IRL/2 N NL/10 P/n.a. PL/1 S/3 FIN//9 SL/2 UK/46	D/1
PBSC & Marrow cryopreserva-tion	CH CZ/1 D/5 DK/1 E/5 F/19 H/1 NL/3 P/n.a. PL/1 S/6 UK/19	A/3 E/2 I/n.a.	D/6	A/4 CH/n.a. CZ/3 D/16 E/22 EE/n.a. H/2 I/n.a. IRL/2 P/n.a. PL/1 S/2 FIN/7 SL/2 UK/36	CZ/1 D/n.a.	N/1
Cord Blood cryopreserva-tion	CZ/1 DK/1 F/16 E/3 H/1 NL/3 P/n.a.	A/1	D/2	CZ/1 D/4 E/12 H/1 P/n.a. FIN/2 UK/6	D/n.a. I/n.a.	CH/n.a. N/1
PBSC & Marrow storage 4�	CH/n.a. D/I F/9 P/n.a. UK/2	E/2 I/n.a.	D/2	CH/n.a. D/6 E/8 IRL/2 P/n.a. NL/2 S/1 SL/2 UK/28
PBSC & Marrow reinfusion	A/n.a. CH/n.a. CZ/1 E/4 F/13 S/5	A/n.a. E/3	D/1	A/n.a. CH/n.a. CZ/5 D/16 DK/3 E/8 EE/n.a. H/3 I/n.a. IRL/2 N/n.a. NL/11 P/n.a. S/2 FIN/7 SL/2 UK/46		N/1
CD34+ selection	A/n.a. CH/n.a. CZ/1 D/3 DK/1 E/3 F/11 NL/1 P/n.a. S/4 UK/2	E/1 I/n.a. N/ NL/1	D/4	CH/n.a. CZ/1 D/13 DK/3 E/17 I/n.a. IRL/2 NL/1 P/n.a. FIN/6 UK/16	CZ/1	N/1
Red cell depletion of marrow	A/n.a. CH/n.a. CZ/1 DK/1 E/4 F/14 H/1 P/n.a. PL/1 S/4 UK/4	A/n.a. E/1 I/n.a. N/n.a.	D/5	A/n.a. CH/n.a. CZ/3 D/13 E/17 EE/n.a. H/2 I/n.a. IRL/1 P/n.a. S/1 FIN/4 SL/2 UK/32	CZ/1
Plasma depletion of marrow	A/n.a. CH/n.a. CZ/1 DK/1 D/1 E/4 F/16 H/1 NL/1 P/n.a. S/4 UK/4	A/n.a. E/1 I/n.a. N/n.a. NL/1	D/6	CH/n.a. CZ/3 D/10 E/14 EE/n.a. H/2 I/n.a. IRL/1 NL/10 P/n.a. S/1 FIN/2 UK/30	CZ/1	N/1
Cord Blood volume reduction	A/n.a. CZ/1 DK/1 E/3 F/6 H/1 NL/1 S/1		D/1	CZ/1 D/3 E/5 H/1 I/n.a. UK/2	CZ/1 I/n.a.	N/1
Purging of PBSC & Marrow	A/n.a. CH/n.a. CZ/1 E/4 F/12 NL/1 P/n.a. PL/1 S/4 UK/1	A/n.a. I/n.a. NL/1	D/2	CH/n.a. CZ/1 D/10 E/8 I/n.a. NL/3 S/2 FIN/2 SL/2 UK/10	CZ/1	N/1
T-cell depletion	DK/1 E/3 F/8 NL/1 S/2 UK/1	I/n.a. NL/1	D/2	CH/n.a. D/10 E/9 I/n.a. IRL/1 NL/10 S/2 FIN/2 SL/2 UK/10		N/1
CD34* in vitro expansion	F/6 UK/1		D/2	D/5 E/3 I/n.a. P/n.a. UK/1
CD34+ gene transfer	F/2 UK/1			I/n.a. S/1 UK/3		NL/1

Table 2b: Percentage of the total activity relating to the collction, processing and manipulation of haematopoietic progenitor cells performed in BMT Units.

Activities tabulated by country.


	Collection of		Processing of		Storage of
Countries	bone marrow	PBSC	bone marrow	PBSC	bone marrow	PBSC	PBSC mobilis.
Andorra	no data
Austria	40 %	57 %	25 %	0 %	40 %	57 %	no data
Belgium	no data
Bulgaria	no HPCT in the country
Cyprus	no data
Czech Rep.	83 %	83 %	80 %	80 %	80 %	80 %	83 %
Denmark	100 %	33 %	67 %	67 %	67 %	67 %	100 %
Estonia	no data
Finland	100 %	100 %	100 %	100 %	100 %	100 %	100 %
France	no data
Germany	93 %	42 %	59 %		no data		64 %
Greece	no data
Hungary	100 %	67 %	67 %	67 %	67 %	67 %	100 %
Iceland	no data
Ireland	67 %	50 %	67 %	50 %	67 %	67 %	no data
Italy	100 %	no data
Latvia	no HPCT in the country
Liechtenstein	no data
Lithuania	no data
Luxembourg	no data
Malta	no HPCT in the country
Netherland	100 %	73 %	no data				71 %
Norway	100 %	0 %	0 %	0 %	0 %	0 %	100 %
Poland	no data
Portugal	100 %	no data					100 %
Romania	no data
San Marino	no data
Error! Bookmark not defined.Slovakia	50 %	50 %	67 %	50 %	50 %	50 %	no data
Error! Bookmark not defined.Slovenia	no data
Spain	100 %	73 %	89 %	77 %	85 %	76 %	79 %
Sweden	100 %	20 %	17 %	0 %	20 %	14 %	43 %
Switzerland	no data
Turkey	no data
Error! Bookmark not defined.UK	100 %	88 %	85 %	85 %	80 %	80 %	100 %


Countries	Reinf. of HPC	CD34 select. of HPC	Red cell depl. of HPC	Plasma depl. of HPC	Purging of HPC	T cell depl. of HPC	In vitro exp.of CD34+ cells	Gene transf.
Andorra	no data
Austria	no	0 %	no data			0 %	0 %	0 %
Belgium	no data
Bulgaria	no HPCT in the country
Cyprus	no data
Czech Rep.	83 %	50 %	75 %	75 %	50 %	0 %	0 %	0 %
Denmark	100 %	75 %	0 %	0 %	0%	0 %	0 %	0 %
Estonia	no data
Finland	100 %	100 %	100 %	100 %	100 %	100 %	0 %	0 %
France	no data
Germany	94 %	65 %	72 %	59 %	83 %	78 %	71 %	0 %
Greece	no data
Hungary	100 %	0 %	67 %	67 %	0 %	0 %	0 %	0 %
Iceland	no data
Ireland	no data
Error! Bookmark not defined.Italy	100 %	no data					100 %	100 %
Latvia	no HPCT in the country
Liechtenstein	no data
Lithuania	no data
Luxembourg	no data
Malta	no HPCT in the country
Netherland	100 %	60 %	0 %	83 %	60 %	83 %	0 %	0 %
Norway	100 %	0 %	0 %	0 %	0 %	0 %	0 %	0 %
Error! Bookmark not defined.Poland	no data
Portugal	100 %	no data			0 %	0 %	100 %	0 %
Romania	no data
San Marino	no data
Slovakia	no	0 %	no data				0 %	0 %
Slovenia	no data
Spain	76 %	81 %	77 %	70 %	67 %	75 %	100 %	0 %
Sweden	29 %	0 %	20 %	20 %	33 %	50 %	0 %	100 %
Switzerland	no data					100 %	0 %	0 %
Error! Bookmark not defined.Turkey	no data
UK	100 %	100 %	100 %	100 %	100 %	100 %	100 %	100 %

Table 3 : Transplant statistics 1994
Data is as provided from the returned questionnaires.
Data provided to the european group for BMT is shown in table 24.


COUNTRY	Population (where given)	Total BMT in 1994	BMT / million	AUTO-GRAFTS	ALLOGRAFTS		CORD BLOOD
					Familial	Unrelated	Familial	Unrelated
AUSTRIA	-	197		106	54	16	21
BELGIUM	-	45				45
BULGARIA	-			ND
CZECH REPUBLIC	10	154	15.4	109	39	4	2
DENMARK	5	151	30.2	100	35	15	1
ESTONIA	1.5	9	6	8	1
FINLAND	5	164	32.8	115	36	10	3
FRANCE	56	2362	42.2	1.983	302	57	7	13
GERMANY	80	1306	16.3	800	414	87	5
HUNGARY	10	30	3	1	28	1
IRELAND	3.5			ND
ITALY	57	1412	24.8	861	502	47	1	1
LATVIA				ND
LUXEMBOURG				ND
MALTA					9
NETHERLANDS	15			ND
NORWAY	4	35	8.75	5	30
POLAND	39			ND
PORTUGAL	10	113	11.3	65	47		1
SLOVAKIA	5	42	8.4	32	10
SPAIN	39	1209	31	976	218	11	4
SWEDEN	5	320	64	210	82	26	2
SWITZERLAND	7	154	22	101	40	13
UNITED KINGDOM	55	1305	23.7	906	266	133

ND, no data available

Table 4 : National bodies and professional associations involved in setting guidelines or standards in bmt


COUNTRY	PROF. ASSOC.	GUIDELINES	NATIONAL BODIES
Error! Bookmark not defined.			PROF.	GOV.
AUSTRIA	HEM,TRF,ONC	N	Y	Y
BELGIUM	ND	Y	Y	Y
BULGARIA	ND	N	ND	ND
CZECH REPUBLIC	HEM,TRF	N	ND	ND
DENMARK	HEM,IMM,ONC	N	Y	Y
ESTONIA	N	N	N	N
FINLAND	HEM,IMM,TRF	N	Y	Y
FRANCE	TRP	Y	Y	Y
GERMANY	TRP, TRF, ONC, HEM	Y	Y	Y
HUNGARY	HEM,IMM,TRF	Y	Y	Y
IRELAND	HEM,TRF	N	Y
ITALY	IMM,TRF,TRP	Y	Y
LATVIA	N	N	N	N
LUXEMBOURG	ND	ND	ND	ND
MALTA	TRF	N	Y	Y
NETHERLANDS	HEM	Y	Y	Y
NORWAY	ND	Y	Y	Y
POLAND	ND	ND	ND	ND
PORTUGAL	ND	ND	ND	ND
SLOVAKIA	ND	ND	ND	ND
SPAIN	HEM,IMM,TRF,TRP	N	Y	Y
SWEDEN	ND	N	Y	Y
SWITZERLAND	HEM,TRF	Y	Y	Y
UNITED KINGDOM	HEM,IMM,TRP	Y	Y	Y

Professional associations:

HEM, Haematology ND, no data available
IMM, Immunology N, negative answer
ONC, Oncology Y, positive answer
TRF, Transfusion
TRP, Transplant

Table 5 : Testing on the peripheral blood of bone marrow donors

EST

F¹

Differential count

++++

34⁺ cell count

++++

+++

++++

+++

++++

+++

HIV

++++

+++

++++

HCV

++++

+++

++++

HBV

++++

+++

++++

HTLV-1

++++

++^b

++++

CMV

++++

+++^b

++++

EBV

++++

+++^b

+++

++++

+++

++++

+++

++++

Syphilis

++++

+++

++++

+++

++++

Toxoplasma

++++

+++^b

++++

+++

++++

other tests (few units); Hepatitis-A-V., Varicella-Zoster-V., Herpes-Simplex-V., Malaria

+ = up to 25% of all responding units; ++ = up to 50% of all responding units; +++ = up to 75% of all responding units;
++++ = up to 100% of all responding units

* = only autologous donors
b = mostly performed by Bone Marrow Transplant Unit
F¹ = only TMU units responded in France

Table 6 : Testing on the peripheral blood of stem cell donors

F¹

FIN

Differential count

++++

Count of 34⁺ cells

++++

+++

++++

+++

++++

HIV

++++

+++

++++

HCV

++++

+++

++++

HBV

++++

+++

++++

HTLV-1

+++^b

++^b

++++

CMV

++++

++++^b

++++

+++

++++

+++

++++

EBV

+++^b

++^b

+++

++++

+++

++++

+++

Syphilis

++++

+++

++++

+++

++++

Toxoplasma

++++

++^b

+++

++++

other tests (few units); Parvovirus B19, Hepatitis-A-V., Varicella-Zoster-V., Herpes-Simplex-V., Malaria

+ = up to 25% of all responding units; ++ = up to 50% of all responding units; +++ = up to 75% of all responding units;
++++ = up to 100% of all responding units

* = only autologous donors
b = mostly performed by Bone Marrow Transplant Unit
F¹ = only TMU units questioned in France

Table 7 : Testing on the peripheral blood of the infant’s mother whose cord blood is obtained

F¹

FIN

Differential count

++++

+++

++++

n.p.

++++

Count of 34⁺ cells

++++

n.r.p.

n.a.

++++

n.p

+++

++++

n.p.

HIV

++++

n.r.p.

++++

n.a.

++++

n.p

++++

n.p.

++++

HCV

++++

n.r.p.

++++

n.a.

++++

n.p

++++

n.p.

++++

HBV

n.r.p.

++++

n.a.

++++

n.p

++++

n.p.

++++

HTLV-1

n.r.p.

+++^b

n.a.

n.p

++++

n.p.

CMV

++++

n.r.p.

++++

n.a.

++++

n.p

++++

n.p.

++++

EBV

n.r.p.

+++^b

n.a.

++++

n.p

+++

++++

n.p.

+++

Syphilis

++++

n.r.p.

++++

n.a.

++++

n.p

++++

n.p.

+++

Toxoplasma

n.r.p.

++++

+++^b

n.a.

++++

n.p

+++

++++

n.p.

+ = up to 25% of all responding units; ++ = up to 50% of all responding units; +++ = up to 75% of all responding units; ++++ = up to 100% of all responding units

n.r.p. = not routinely performed
n.p. = procedure not performed
^b = mostly performed by Bone Marrow Transplant Unit
n.a. = no detailed data available
F¹ = only TMU units responded in France

Table 8 : Testing on the stem-cell containing product (bone marrow, PBSC, cord blood) before cryopreservation

F¹

FIN

Differential count

++++

Count of 34⁺ cells

+++

++++

+++

++++

+++

++++

+++

++++

+++

++++

HIV

++++

n.a.

++++

+++

++++

HCV

++++

n.a.

++++

+++

++++

HBV

++++

n.a.

++++

+++

++++

HTLV-1

+^b

n.a.

++++

CMV

++++

++^b

n.a.

++++

EBV

++^b

n.a.

++++

Syphilis

++++

n.a.

++++

+++

++++

Toxoplasma

++++

++^b

n.a.

++++

Anaerobic bacteria

++++

n.a.

++++

+++

++++

+++

Aerobic bacteria

++++

n.a.

++++

+++

++++

+++

Fungi

++++

+++

n.a.

+++

++++

+++

++++

+ = up to 25% of all responding units; ++ = up to 50% of all responding units; +++ = up to 75% of all responding units;
++++ = up to 100% of all responding units

^b = mostly performed by Bone Marrow Transplant Unit
n.a. = no detailed data available
F¹ = only TMU units responded in France

Table 9 : Testing on the stem-cell containing product (bone marrow, PBSC, cord blood) after cryopreservation

	A	CH	CZ	D	DK	E	EE	F¹	H	I	N	NL	FIN	SK	UK
Differential count	++++	++++	++++	++++	n.a.	++++	++++	++++	+	0	++++	++++	+	++++	+++
Count of 34⁺ cells	+++	++++	0	++++	n.a.	++++	++++	++	+++	0	++++	++++	+	++++	++
Short-term CFU assay	+++	n.a.	++	++++	n.a.	0	++++	n.a.	+	0	0	++++	++++	0	+++
Long-term culture	+	n.a.	0	+	n.a.	0	0	0	0	0	0	0	+	0	+
HIV	0	0	0	+	n.a.	+	++++	0	+	0	0	0	0	0	+
HCV	0	0	0	++	n.a.	+	++++	0	+	0	0	0	0	0	+
HBV	0	0	0	++	n.a.	+	++++	0	+	0	0	0	0	0	+
HTLV-1	0	0	0	+^b	n.a.	0	++++	0	+	0	0	0	0	0	0
CMV	0	0	0	+^b	n.a.	+	++++	0	+	0	0	0	0	0	+
EBV	0	0	0	+^b	n.a.	+	++++	0	+	0	0	0	0	0	+
Syphilis	0	0	0	+	n.a.	+	0	0	+	0	0	0	0	0	+
Toxoplasma	0	0	0	+^b	n.a.	0	0	0	+	0	0	0	0	0	+
Anaerobic bacteria	0	0	++++	++++	n.a.	++	0	+++	+++	0	++++	++++	+	0	++
Aerobic bacteria	0	0	++++	++++	n.a.	++	0	+++	+++	0	++++	++++	+	0	++
Fungi	0	0	0	+++	n.a.	++	0	++	+++	0	0	++++	0	0	++

+ = up to 25% of all responding units; ++ = up to 50% of all responding units; +++ = up to 75% of all responding units; ++++ = up to 100% of all responding units
^b = mostly performed by Bone Marrow Transplant Unit
n.a. = no detailed data available
F¹ = only TMU units responded in France

Table 10 : Testing on the stem-cell containing product (bone marrow, PBSC, cord blood) used without cryopreservation

Error! Bookmark not defined.

F¹

FIN

UK²

Differential count

++++

n.a.

++++

n.a.

++++

n.a.

+++

++++

n.p.

++++

Count of 34⁺ cells

++++

n.a.

+++

++++

n.a.

++++

n.a.

+++

++++

n.p.

Short-term CFU assay

++++

n.a.

+++

n.a.

++++

n.a.

++++

n.p.

Long-term culture

n.a.

++++

n.p.

HIV

++++

n.a.

++++

n.a.

++++

n.p.

HCV

++++

n.a.

++++

n.a.

++++

n.p.

HBV

++++

n.a.

++++

n.a.

++++

n.p.

HTLV-1

n.a.

+^b

n.a.

++++

n.p.

CMV

++++

n.a.

++^b

n.a.

++++

n.a.

++++

n.p.

EBV

n.a.

+^b

n.a.

++++

n.a.

++++

n.p.

Syphilis

++++

n.a.

++++

n.p.

Toxoplasma

n.a.

+^b

n.a.

++++

n.p.

Anaerobic bacteria

++++

n.a.

+++

n.a.

+++

++++

n.a.

+++

++++

n.p.

Aerobic bacteria

++++

n.a.

+++

n.a.

+++

++++

n.a.

+++

++++

n.p.

Fungi

++++

n.a.

+++

n.a.

++++

+++

n.a.

+++

++++

n.p.

+ = up to 25% of all responding units; ++ = up to 50% of all responding units; +++ = up to 75% of all responding units; ++++ = up to 100% of all responding units

^b = mostly performed by Bone Marrow Transplant Unit
n.a. = no detailed data available
n.p. = procedure not performed
F¹ = only TMU units responded in France
UK² = only BMT units use and test such products

Table 11 : Methods for separation of stem-cell containing material

F¹

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

Leucapheresis

++++

n.a.

++++

+++

n.p.

++++

n.a.

Commercial CD34⁺ prep.

n.a.

++++

n.p.

+++

n.a.

Purging of malignant cells

n.a.

++++

+++

n.p.

n.a.

T cell depletion

n.a.

++++

+++

n.p.

n.a.

FIN

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

TMU

BMT

Leucapheresis

n.p.

++++

n.a.

++++

n.p.

++++

n.a.

++++

Commercial CD34⁺ prep.

n.p.

++++

n.a.

n.p.

n.a.

Purging of malignant

n.p

n.a.

n.p.

n.a.

T cell depletion

n.p.

n.a.

n.p.

n.a.

+ = up to 25% of all units; ++ = up to 50% of all units; +++ = up to 75% of all units; ++++ = up to 100% of all units

n.a. = no detailed data available
n.p. = procedure not performed
F¹ = only TMU units responded in France

Table 12 : Cryopreservation and storage of stem-cell containing product

Error! Bookmark not defined.

F¹

FIN

Programmed cell freezer

++++

n.a.

++++

other methods

n.a.

at 4�C

n.a.

++++

at -80�C

n.a.

+
(-140�C)

n.a.

Liquid nitrogen

+++

n.a.

++++

+++

++++

Continuous temp. monitoring

+++

n.a.

+++

n.a.

+++

++++

+++

++++

+++

Storage of records

+++

n.a.

++++

+++

yes

++++

Storage of records (years)

n.a.

ind.

var.

n.d.

var.13-ind. >10

>10

10 4-10

n.a.

ind.

How are records stored

n.a.

P/C

n.a.

P/C

n.d.

P/C

Written procedure release

n.a.

+++

n.a.

+++

++++

Written procedure infusion

n.a.

n.a..

+++

n.a.

++++

n.a.

++++

n.a.

+++

+ = up to 25% of all units; ++ = up to 50% of all units; +++ = up to 75% of all units; ++++ = up to 100% of all units
n.a. = no detailed data available n.p. = procedure not performed
F¹ = only TMU units questioned in France
ind. = indefinite var. = variable n.d. = not defined P = paper C = computer

Table 13 : Standard operating procedures (SOP)

Error! Bookmark not defined.

F¹

FIN

Error! Bookmark not defined.

TMU

BMT

Labeling of products

n.a.

n.a

+++

++++

+++

Laboratory analysis

n.a

+++

++++

+++

++++

+++

CD34⁺ counting

n.a

++++

+++

++++

+++

CD34⁺ separation

n.a

n.p.

+++

++++

Purging

n.a

n.p.

+++

n.a

+++

n.p.

+++

++++

n.p.

++++

n.p.

++++

+++

Short-term CFU

+++

n.a

n.a.

++++

n.p.

+++

Long-term CFU

n.a

n.a.

n.p.

++++

n.p.

++++

n.p.

++++

n.p.

+++

Bact./virol. testing

+++

n.a

++++

n.a.

++++

Cryopreservation

++++

n.a

+++

n.a

++++

+++

++++

Validation of SOP

++++

n.a

++++

National Quality Assurance

n.a

n.a.

Participation in NQA

n.a

n.a.

GMP for stem cell products

n.a

n.a.

++++

+ = up to 25% of all units; ++ = up to 50% of all units; +++ = up to 75% of all units; ++++ = up to 100% of all units

n.a. = no detailed data available
n.p. = procedure not performed
F¹ = only TMU units responded in France

Table 14 : Requirement for accreditation or license for the preparation of stem cell containing product

FIN

Yes¹

Yes

Yes¹

Yes

n.a.

Yes

1 = semi-formal procedure, at present only for BMT units
² = only BMT units

Table 15 : Histocompatibility testing

Countries analysed:

Belgium	Ireland	Spain
Czech	Italy	Sweden
Denmark	Latvia	Switzerland
Estonia	Netherlands	United Kingdom
Finland	Norway
France	Poland
Germany	Portugal
Hungary	Slovakia

Number of questionnaires sent to HLA-labs : 247

Number of questionnaires returned : 181

Response : 73%

Table 16 : Number of histocompatibility testing laboratories associated with
other services*

	Labs. reporting	BMT Unit	TMU	Immunol dept.	other
Belgium	no data
Czech	n=6		4	2
Denmark	n=4		4
Estonia	n=1	1	1	1	1
Finland	n=2		1**	1
France	n=23	7	11	5	2
Germany	n=54	18	32	13	15**
Hungary	n=4	1	4	2
Ireland	no data
Italy	n=88	9	57	14	8
Latvia	no data
Netherlands	n=7	6	5	4	2
Norway	no data
Poland	n=1		1
Portugal	n=3	2		1
Slovakia	n=2	2	5	1
Spain	n=26	18	6	16	5
Sweden	n=5		2	3
Switzerland	n=3	3
United Kingdom	n=19	12	11	6	2

* HLA-labs can have more than one associate service.

** Red Cross associated

Table 17 : Number of histocompatibility testing laboratories for bone
marrow transplantation

	HLA-labs	Number of inhabitants (per million)	HLA-labs (per 10 million inhabitants)
Belgium	no data
Czech	6	10	6
Denmark	4	5	8
Estonia	1	1.5	6.7
Finland	2	5	4
France	18	56	3.2
Germany	54	80	6.7
Hungary	4	10	4
Ireland	1	3.5	2.9
Italy	88	57	15.4
Latvia	no data
Netherlands	7	15	4.7
Norway	1	4	2.5
Poland	10	39	2.6
Portugal	3	10	3
Slovakia	2	5	4
Spain	26	39	6.7
Sweden	5	5	10
Switzerland	3	7	4.2
United Kingdom	19	55	2.9

Table 18 : HLA-typing techniques


		Serology		Molecular
	n	Class I	Class II	Class 1	Class II
Belgium	no data
Czech	n=6	6	5	1	3
Denmark	n=4	4	4		4
Estonia	n-1	1	1
Finland	n=2	2		1	2
France	n=18	18	16	6	18
Germany	n=42	42	35	12	33
Hungary	n=4	4	4	1	2
Ireland	n=1	1			1
Italy	n=49	49	49	5	21
Latvia	no data
Netherlands	n=7	7	6	4	7
Norway	n=1	1	1	1	1
Poland	n=1	1			1
Portugal	n=3	3	3	3	3
Slovakia	n=2	2	2	1	1
Spain	n=25	25	22	7	21
Sweden	n=5	5	5	0	3
Switzerland	n=3	3	3	1	1
United Kingdom	n=19	18	9	15	19

Total	193	192	165	58	141
%		99	85	30	73

Table 19 : Matching techniques used

.		Serologic X-Match	IEF	hetero-duplex	MLC	CTLp	HTLp
Belgium	no data
Czech	n=5	5	2		3	2	1
Denmark	n=1	1
Estonia	n=1	1			1
Finland	n=2	2			2
France	n=17	17	2	3	14	4	4
Germany	n=36	36	1	3	14	1	1
Hungary	n=4	4			2	1
Ireland	n=1				1		1
Italy	n=19	19	1	4	19	2
Latvia	no data
Netherlands	n=17	7	2		4	2	4
Norway	n=1	1
Poland	n=1	1		1
Portugal	n=3	3		1	3
Slovakia	n=2	2	1		1		1
Spain	n=21	21	3	1	18
Sweden	n=5	5			5
Switzerland	n=3	3			3	3	1
United Kingdom	n=11	10	1	5	11	8	2
	n=138	137	13	18	101	23	13
		99%	9%	13%	72%	16%	9%

Table 20 : Accreditation of histocompatibility laboratories

		ASHI	ASHI planned	EFI	EFI planned
Belgium	no data
Czech	no data				2
Denmark		1
Estonia	no data
Finland					1
France		1	3	1	14
Germany			5		20
Hungary					3
Ireland			1		1
Italy		1	6	1	11
Latvia	no data
Netherlands		3		2	4
Norway			1		1
Poland	no data
Portugal			3		3
Slovakia	no data
Spain			3		17
Sweden*
Switzerland					1
United Kingdom**		1	2	1	6
	n=192	7	24	5	84
		3.6%	12.5%	2.6%	44%

* Sweden has a national accreditation system for these laboratories.
** UK has a national accreditation system in addition

Table 21 : External quality control exercises


		Serological typing		Molecular typing		Cellular typing
	n	National	Inter-national	National	Inter-national	National	Inter-national
Belgium	No data
Czech	6	4	1	2	2	-	-
Denmark	No data
Estonia	No data
Finland	2	-	1	-	1	-	-
France	23	18	-	18	-	4	-
Germany	54	38	20	28	22	3	3
Hungary	4	4	1	2	2	1	-
Ireland	1	-	1	-	1	-	-
Italy	88	45	4	-	4	-	-
Latvia	No data
Netherlands	7	3	7	4	7	-	2
Norway	1	-	1	-	1	-	-
Poland	1	1	-	-	1	-	-
Portugal	3	3	-	3	-	-	-
Slovakia	2	1	-	1	-	-	-
Spain	26	22	7	19	5	12	2
Sweden	5	5	1	-	-	-	-
Switzerland	No data
United Kingdom	19	19	4	18	5	-	-
Total	242	163	48	95	49	20	8
%		67	20	39	20	8	3

n : number of laboratories responding.

Table 24 : Transplant statistics 1994

Data is taken from information provided to the european group for BMT as published in "Bone Marrow Transplantation"

COUNTRY

No of BMT
units

ALLOGRAFTS
(donor type not given)

AUTOGRAFTS

AUSTRIA
BELGIUM
BULGARIA
CZECH REPUBLIC
DENMARK
ESTONIA
FINLAND
FRANCE
GERMANY
HUNGARY
IRELAND
ITALY
LATVIA
LUXEMBOURG
MALTA
NETHERLANDS
NORWAY
POLAND
PORTUGAL
SLOVAKIA
SPAIN
SWEDEN
SWITZERLAND
UNITED KINGDOM

9
10
no report

6
3
1
5
45
33
2
2
43
no report
1
no report
11
2
7
3
2
38
9
7

44

68
112

45
51
0
47
530
552
29
32
500

163
36
47
45
10
286
94
53

524

98
168

101
77
8
87
1345
774
1
2
867

201
41
60
56
33
938
209
101

1062