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SMM report No. 4/2003

Health technology assessment based on a literature review

Therapeutic use of haematopoietic stem cells from cord blood

SMM 4/2003: Therapeut ic use of haematopoiet ic stem cel ls from cord blood

SINTEF REPORT TITLE


AUTHOR(S)

Lorentz Brinch, Anne Husebekk, Steinar Funderud, Anita LyngstadaasCLIENT(S)

SINTEF Unimed

Address:: P.O Box 124, Blindern 0314 Oslo

Location: Forskningsveien 1 Telephone: 22 06 73 00 Fax: 22 06 79 09

Enterprise No.: NO 948 007 029 MVA

Ministry of Health

REPORT NO. CLASSIFICATION CLIENTS REF.

SFT78A3406 OpenCLASS THIS PAGE ISBN PROJECT NO. NO. OF PAGES

Open 82-14-02971-6 90ELECTRONIC FILE CODE PROJECT MANAGER (NAME, SIGN.) CHECKED BY (NAME, SIGN.)

Document2 Berit Mørland FILE CODE DATE APPROVED BY (NAME, POSITION, SIGN.)

2003-08-20 Berit Mørland

ABSTRACT

The objective of this report has been to evaluate all relevant literature which can elucidate the basis fortherapeutic use of haematopoietic stem cells from cord blood.

STIKKORD NORSK ENGELSK

GRUPPE 1 haematopoietic stem cells GRUPPE 2 cord bloodEGENVALGTE


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Preface

In January 2003, the Norwegian Centre for Health Technology Assessment (SMM) was requested by the Norwegian Ministry of Health to systematically and critically exam-ine the existing documentation of results after transplantations of haematopoietic stem cells from cord blood or placenta. The method involves collecting placental blood after umbilical cord severance of a newborn child, possible cryopreservation (freezing) of isolated stem cells or whole blood, whereupon harvested stem cells are transplanted into the patient. The receiver of the cord blood stem cells may be related, or not related (allogeneic transplantation), or the patients may receive their own stem cells (autologous transplantation). Both cases usually require long-term storage of stem cells cryopre-served in a therapeutic biobank. In addition to assessing clinical effects and side effects/complications when using allogeneic (from other persons) and autologous (own) stem cells from cord blood, the Ministry of Health therefore requested the SMM to elucidate the documented safe storage time for cryopreserved unprocessed cord blood or isolated stem cells as regards clinical effect. This health technology assessment also describes the current practice at Norwegian hospitals, as well as clarifying organisational, economical, ethical and social aspects that affect the decision of whether or not this method should be employed by the Norwegian health service.

The background for the Ministryʼs request to consider therapeutic use of cord blood stem cells, is a specifi c case from the Norwegian regional health authority Helse Vest RHF, where a woman who had just given birth had blood drawn from her placenta after umbilical cord severance, for the purpose of cryopreserving haematopoietic stem cells, in case the child should need treatment with autologous stem cells in the future. A com-mercial fi rm wishes to offer cryopreservation of haematopoietic cord blood stem cells after birth to all pregnant Norwegian women for long-term cryopreservation in a thera-peutic biobank, where the units shall be reserved for the respective clients or their close families (personal or family use). There seems to be uncertainty within the professional environment as to the value of offering storage of cord blood stem cells in a biobank, with regards to both allogeneic and autologous use.

An interdisciplinary review group composed by the following people carried out the health technology assessment:• M.D. Lorentz Brinch, chief physician and Head of Section at Rikshospitalet University

Hospital in Oslo (Professional Leader)• Professor, M.D Anne Husebekk, senior consultant at the University Hospital of North

Norway• Professor Steinar Funderud, the Norwegian Cancer Hospital (Det Norske Radiumhospital)• Doctor of Science Anita Lyngstadaas, The Norwegian Centre for Health Technology

Assessment (Project Manager)

The members of the review group have competence within clinical transfusion medicine (transplantation), diseases in blood-forming tissues, cancers, stem cell biology and meth-odology and are familiar with blood banks and other biobanks. Torbjørn Wisløff, Bach-


elor of Natural Sciences at SMM has evaluated the economical aspects of the method. Bjørn Hofmann, Doctor of Philosophy at the Centre for Medical Ethics, has contributed to parts of the ethics chapter.

All members of the review group have signed a neutrality statement declaring that they do not have any commercial interests or connections that may infl uence their objective evaluation of the material. Economic and professional circumstances have also been accounted for, as well as tasks or duties that are of relevance to this project.

This report is the result of a systematic literature review and a synthesis of available clinical documentation and subsequent appraisal of possible consequences related to the use of the method in the society. The health technology assessment report was then submitted to the parties involved prior to an open discussion seminar arranged by SMM. Commentaries to the report from the Norwegian company BioLante AS, which offers storage of cord blood stem cells, is enclosed (Appendix 1). The Ministry of Health has been continuously informed about the progress of the project.

Oslo, June 2003

Berit Mørland Anita LyngstadaasDirector Senior Researcher


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Content

PREFACE .......................................................................................................................................... .. 3

CONTENT .......................................................................................................................................... . 5

1. MANDATE ......................................................................................................................... ........... 9

2. SUMMARY AND CONCLUSION ................................................................................................ 10

3. INTRODUCTION ........................................................................................................................ 13 Stem cells and stem cell transplantation .............................................................................. 13 Stem cells .................................................................................................................................. 13 Haematopoietic stem cells ........................................................................................... ...... 14 Transplantation of haematopoietic stem cells ....................................................................... 14 Requirements for HLA compatibility for allogeneic transplantations ............................ 15 Searches for suitable donors .............................................................................................. 16 Transplantations of stem cells from cord blood ................................................................... 17 Patient group ........................................................................................................................ 17 Indications ........................................................................................................................ 17 Isolation and cryopreservation ........................................................................................... 18 Harvesting ........................................................................................................................ 18 Quality control ................................................................................................................. 18 Processing ............................................................................................................... ........ 19 Cryopreservation ............................................................................................................ 19 Biobanks ................................................................................................................ .......... 19 Transplantation procedure ................................................................................................. 19 Thawing ............................................................................................................................ 19 Preparing the patient ...................................................................................................... 19 Stem cell transplantation ............................................................................................... 20 Evaluation of clinical effect .................................................................................................. 20 Survival ............................................................................................................................ 20 Engraftment .................................................................................................................... 21 Complications and side effects ...................................................................................... 21 Comparison with other transplantation methods ................................................................. 21

4. SEARCHING FOR AND REVIEWING LITERATURE ................................................................ 24 Inclusion criteria ....................................................................................................................... 24 Search strategy ......................................................................................................................... 25 Searches in databases ........................................................................................................ 25 Systematic reviews ......................................................................................................... 25 Primary literature ................................................................................................... ........ 25 Manual searches.............................................................................................................. .... 26 Literature assessment ............................................................................................................. 26 Sorting .................................................................................................................................. 26


Quality and validity assessment ................................................................................. ....... 27 Evaluation of internal validity (elements of systematic errors) ............................ ..... 27 Statistical evaluation (elements of random errors) ................................................. ... 28 Study quality ranking ...................................................................................................... 28 Level of evidence ............................................................................................................. 29 Synthesis .................................................................................................................................. 30 Literature basis ................................................................................................................... 30 Documentation basis ........................................................................................................... 30 Synthesis of collected documentation ............................................................................... 30 Strength of evidence ....................................................................................................... 30 Methodical and statistical considerations .............................................................................. 31 Study design and sources of error ......................................................................... ........... 31 Cohort studies ................................................................................................................. 31 Case series ....................................................................................................................... 31 Statistical considerations ................................................................................................... 31 Power considerations ..................................................................................................... 31 Statistical analysis methods .......................................................................................... 32

5. ASSESSMENT OF EFFECT – CLINICAL DOCUMENTATION ................................................. 33 Autologous transplantation of stem cells from cord blood ................................................. 33 Allogeneic transplantation of stem cells from cord blood .................................................. 33 Literature basis .................................................................................................................. ...... 34 Documentation basis ................................................................................................................ 38 Results ....................................................................................................................................... 38 Transplantations in children with related donors ................................................... ......... 39 Transplantations in children with unrelated donors ........................................................ 39 Transplantations in adults with unrelated donors ................................................. .......... 40 Evidence tables ...................................................................................................... .............. 40 Quality of cryopreserved stem cells ....................................................................................... 49 Summary and synthesis .................................................................................................... ..... 50

6. ASSESSMENT OF EFFECT - DISCUSSION ............................................................................. 51 Autologous cord blood transplantations ................................................................................ 51 Allogeneic cord blood transplantations .................................................................................. 51

7. RELEVANT ELEMENTS FOR CONSIDERATION ...................................................................... 55 Current practice at Norwegian hospitals .............................................................................. 55 Organisation .............................................................................................................................. 56 Recruitment .......................................................................................................................... 56 Collection ......................................................................................................................... ..... 57 Use of cord blood stem cells ............................................................................................. . 57 Economical aspects .................................................................................................................. 57 Use of biobanks – different costs ....................................................................................... 58 The situation in Norway ....................................................................................................... 63 Patient basis ......................................................................................................................... 63 Summary and commentary .............................................................................................. . 64 Ethical and social considerations ....................................................................................... 64


Donor and related family ......................................................................................................... 65 Informed consent ................................................................................................................. 65 Harvesting ........................................................................................................................ .... 65 Genetic disease .................................................................................................................... 65 Design babies ....................................................................................................................... 66 Right of disposal ................................................................................................................... 66 Anonymity ............................................................................................................................. 67 Commersialisation ............................................................................................................... 67 The Individual patient (recipient) ............................................................................................. 67 Experimental treatment ...................................................................................................... 67 Donor’s anonymity ............................................................................................................... 68 Social aspects ........................................................................................................................... 68 Socio-economic aspects ................................................................................................... .. 68 Ethics and prioritisation ...................................................................................................... 68 Research aspects ...................................................................................................................... 68 Legal aspects............................................................................................................................. 69 Normative ethical theories ....................................................................................................... 70 Duty ethics ............................................................................................................................ 70 Consequence ethics .......................................................................................................... .. 70 Principle-based ethics ...................................................................................................... .. 71

8. DISCUSSION – STATUS, OPPORTUNITIES AND LIMITATIONS ............................................. 72

9. SCIENTIFIC SUMMARY ............................................................................................................. 74

10. REFERENCES ............................................................................................................................ 77

11. APPENDIX - Report commentary from BioLante AS .......................................................... . 85

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The mandate submitted to the review group was prepared by the Norwegian Ministry of Health in co-operation with SMM.

Investigate the documentary basis for therapeutic use of stem cells from cord blood, particularly in consideration of the following questions:

• What is the clinical effect of haematopoietic cord blood stem cell transplantation?• What are the side effects/complications attached to this method?• I s there any difference in clinical effect between the use of allogeneic (from other

persons) and autologous (own) stem cells?• What is the documented safe storage time of cryopreserved blood/cells as regards

clinical effect?• What are the differences in clinical effect in procedures where stem cells from cord

blood, bone marrow and peripheral blood are used?

In addition, the review group shall describe the following elements:

• The extent of the relevant recipient group• Organisational aspects, in particular related to registries/biobanks• Costs attached to the identifi cation and testing of donors, and to allogeneic and

autologous transplantations;• Ethical and social aspects.

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1. Mandate


Transplantation of allogeneic haematopoietic stem cells is an established treatment for some relatively rare malignant blood diseases, congenital or acquired diseases with severe bone marrow failure, and certain metabolic diseases. The best documentation is found for treatment using bone marrow or stem cells mobilized to peripheral blood from HLA-compatible donors, both related and unrelated. Since 1990, cord blood from related or unrelated donors has been used as an alternative to stem cells from bone marrow or blood.

Cord blood can relatively easily be harvested and cryopreserved at any birth. Biobanks cryopreserving cord blood and performing tissue typing have been established, and an international co-operation on guidelines for cryopreservation and storage as well as quality control of cord blood has been initiated. In addition, routines for ordering and transporting cord blood to potential recipients have been established.

The therapeutic use of haematopoietic stem cells from cord blood has been assessed based on publications in medical periodicals. Studies with more than 20 treated patients or 10 patients per disease category have been critically assessed, and data concerning therapeutic effect and side effects are extracted and compared with results from trans-plantations using more conventional stem cell sources.

As of today's date, no prospective studies have been published comparing the results of the use of allogeneic haematopoietic stem cells from cord blood with stem cells harvest-ed from bone marrow or mobilized to blood in directly comparable patient groups.

No case series using autologous stem cells from cord blood have been published.

This literature review has led to the following summary as a reply to the mandate sub-mitted to the review group:

• The clinical effect regarding survival and possible cure of serious diseases by using cord blood transplantations can only be evaluated for allogeneic transplantations, because only data with allogeneic stem cells have been published. The effect has primarily been evaluated in children. Experiences with adults are for the time being relatively limited. There is limited data on long-term follow-up for both patient groups. More specifi cally, the following conclusions can be drawn regarding the clinical effect of allogeneic transplantation:

• Results from transplantations with cord blood from HLA-compatible brothers and sisters of children with known malignant blood diseases or severe bone marrow failure, show that stem cell transplantation with related cord blood donors may be equivalent to transplantation with stem cells from blood or bone marrow with the same HLA- compatibility.

• Stem cell transplantation with unrelated cord blood donor can be a potential cura-tive alternative to transplantation with stem cells from blood or bone marrow in patients, especially children, with certain rare bone marrow diseases without good

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2. Summary and Conclusions


alternative treatment methods, and in leukaemia with high risks of relapse and death without transplantation treatment, where the identifi cation and preparation of a suitable adult donor cannot be done soon enough.

• Compared with bone marrow or peripheral blood, children may achieve accept-able results by transplanting HLA-incompatible stem cells from cord blood.

• In adults, transplantation of cord blood stem cells can only be considered in rare cases depending on whether the number of stem cells in the cord blood graft is suffi cient. Based on existing data, the results of these transplantations used for adults with malignant blood diseases at an advanced stage are not good (less than 10% long-term cured survival).

• Cord blood transplantations are burdened with side effects and complications, which in principle are identical with those of stem cell transplantations with cells from other sources. The conclusion regarding side effects/complications of alloge-neic transplantation is as follows:

• The risk of long-term bone marrow aplasia or engraftment failure after bone mar-

row replacement using allogeneic stem cells from cord blood is higher than in ordinary stem cell transplantation due to the low number of cells in cord blood in proportion to the recipient's weight. This is particularly a problem in adults. Engraftment failure is a life-threatening complication and increases the risk of life-threatening infections and bleedings compared with ordinary allogeneic stem cell transplantations using stem cells from blood or bone marrow from related or unrelated donors.

• The occurrence of severe acute or chronic graft versus host disease (GvHD) seems to be lower when using cord blood compared with allogeneic stem cells from blood or bone marrow with an equivalent degree of HLA compatibility.

• The clinical effect of transplantation of allogeneic stem cells from cord blood com-pared with autologous cord blood stem cells cannot be evaluated as case series using autologous cord blood stem cells have not been published.

In its comment, BioLante points out that a few individual experiences with autolo-gous cord blood transplantation have been published in the media (please refer to the Appendix).

• As of today, the documented safe storage time with regard to clinical effect for cryopreserved cord blood stem cells is up to 10 years. Available documentation indicates that the quality of the cord blood as regards number of cells, viability and clonogenic capacity in vitro is not substantially reduced when stored up to 15 years, but the results have not been compared with clinical data.

• Differences in clinical effect between procedures using allogeneic stem cells from cord blood, bone marrow and peripheral blood have not been examined directly in prospective studies, and such studies are diffi cult to conduct because fi nding equivalent patient groups is problematic. Cord blood is most often used – at least as regards unrelated donors – in cases where a suitable donor for blood or bone mar-row stem cells has not been found within a reasonable period of time. Published studies indicate that the clinical effect – at least in children – may be approximately

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equivalent, given the treated patient categories. The review group has not discussed explicitly whether there are signifi cant differences in clinical effects when using stem cells from bone marrow as opposed to stem cells from blood, as this is of no signifi cance to the main topic of this HTA-report. Peripheral blood is however, the main source of stem cells for medical use in most countries today.

• For the time being, transplantation of haematopoietic stem cells from cord blood is primarily offered when donors for stem cells from bone marrow or peripheral blood has not been identifi ed among relatives or in registries. Transplantation with stem cells solely from cord blood has yet to be performed in Norway. With current disease indications the relevant recipient group for allogeneic stem cells from cord blood will be maximum 10 Norwegian patients per annum. The potential size of this group can be increased signifi cantly if the clinical documentation shows equiv-alent or better results compared with bone marrow or peripheral blood. The prob-ability of a newborn baby some time in the future being in need of autologous cord blood stem cells for treatment of a disease is considered to be very small, based on relevant indications at present around 1:20,000. BioLante AS refers to other calcu-lations of probability where future needs are estimated as 1:2,700 for personal use and 1:1,400 for related use.

• The medical need for establishing Norwegian biobanks with cord blood for trans-plantations with unrelated donors seems to be non-existent. The reasons for this are as follows:

• Co-operation has been established between the international bone marrow reg-istries and biobanks with cryopreserved cord blood, and Norway has access to cord blood from unrelated donors through this co-operation.

• Routines for cryopreserving cord blood have also been established at the Uni-versity Hospital in Oslo for families with children or parents with known blood diseases which can be treated with allogeneic stem cell transplantation and where cord blood could be an alternative, provided the tissue typing compat-ibility is satisfactory and the number of cells are high enough.

• Commercial actors working for cord blood biobanks use fi gures based on a very optimistic future outlook as regards the need for these products. Clinical use of autologous cord blood stem cells has not yet been documented. If pri-vate actors are to be allowed into the Norwegian market, the information and marketing they provide should be controlled. It should also be mentioned that the aforementioned national routines are meant to cover the need for allogeneic use of cord blood stem cells for the relevant patients.

• Transplantation of stem cells from cord blood - like the more established trans-plantation methods where stem cells are harvested from bone marrow or peripheral blood - is an expensive treatment method. As long as allogeneic stem cells from cord blood have not been documented to have a better effect than allogeneic stem cells from bone marrow or peripheral blood, it does not seem to be cost-effective to establish Norwegian biobanks.

• Diffi cult ethical questions are attached to the storage, use and proprietary rights of cryopreserved cord blood.

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Stem cells and stem cell transplantation

Stem cellsStem cells are cells that can develop into differentiated cells and tissues at the same time as they maintain their ability to renew themselves. Self-renewal implies that when a stem cell renews itself, at least one of the daughter cells retain stem cell identity (mother cell). The function of stem cells is to provide specialized cells in order to maintain all functions throughout life. Cells in the differentiation stage from stem cells to specialised cells are called progenitors. The differentiation of haematopoietic stem cells (from blood) in the bone marrow supplies the body with more than a hundred million new blood cells every day – a production which is necessary due to the short life of some of the blood cells.

Stem cells can be divided into three main groups:• Totipotent stem cells Stem cells that can give rise to all types of cells and tissues, including placenta• Pluripotent stem cells Stem cells that can give rise to all types of cells and tissues, excluding placenta• Multipotent stem cells Stem cells that can give rise to several different types of cells and tissues.

Totipotent, pluripotent and multipotent stem cells have different degrees of “maturity” and differentiation and thus different biological characteristics (see below).

The development of the different groups of stem cells can be described as follows: A fertilised egg will, after the fi rst cell division, develop into a blastocyst (blastula). At the 8-16 cell stage, each cell is still able to give rise to a new individual and is therefore totipotent. The blastocyst will attach to the uterus wall before the outer layer of cells develops into the foetal membranes/placenta and the inner cells develop into an embryo. The inner cells can develop into all the different cell types of the body, but they cannot form the placenta. The pluripotent cells in the embryo will gradually specialise into dif-ferent somatic tissues and give rise to multipotent stem cells which are progenitors for a limited number of different cell types during the development.

There are three main sources of stem cells: • Stem cells isolated from early stages of fertilised eggs (embryonic stem cells): Plu-

ripotent cells from superfl uous eggs after in vitro fertilisation (assisted fertilisation) or cells created through therapeutic cloning (where the nucleus in an egg cell has been replaced by a nucleus from a somatic cell)

• Stem cells isolated from aborted embryos (foetal stem cells): Pluripotent cells iso-lated from 5-9 weeks old embryos

• Stem cells isolated from born individuals (adult stem cells): Born individuals include newly-born infants, children and adults. Stem cells can be harvested from different types of tissues and from blood, including cord blood. Different types of stem cells give rise to different types of tissues and cells, as illustrated in Table 3.1

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3. Introduction


Recent research in animal models indicates that stem cells from different tissues can differentiate in different directions and give rise to several types of tissues. If it can be confi rmed that this type of re-differentiation (plasticity) also takes place in humans, it will be possible to manipulate adult stem cells and thus increase their future clinical applicability.

Biologically, embryonic and adult stem cells have different qualities. Embryonic stem cells have great differentiation potential and ability to divide, and are easily cultivated in laboratories. Future therapeutic use could be achieved if universal stem cell lines can be led to the desired cell type, matching the recipient's tissue type, before they are injected into the patient. The advantage with adult stem cells is that they are more differentiated than embryonic stem cells, and are thus less likely to develop cancer once they have been injected into a patient (1). In addition, the patient's own stem cells can be used with the accompanying advantages (please see below). The advantage of using cord blood as an alternative source of stem cells from born individuals, is that the cells have divided fewer times, which theoretically means that they will continue to divide and maintain their biological function longer.

Haematopoietic stem cellsOf all adult stem cells, haematopoietic stem cells from bone marrow have been studied the most. This type of stem cell gives rise to all types of blood cells: red blood cells (erythrocytes), white blood cells and platelets. Haematopoietic stem cells are found in peripheral (circulating) blood (<0.1% of mononuclear cells). In addition, the placenta is rich in haematopoietic stem cells. Thus, haematopoietic stem cells for therapeutic use can be harvested from:• Bone marrow• Peripheral blood (after stimulation with granulocyte-colony stimulating factor, GCSF)• Cord blood/placenta immediately after birth.

Transplantation of haematopoietic stem cellsStem cells can be used in two principally different ways:

Autologous use: • Transplantations where the patient receives his own stem cells (donor and recipient

is the same individual).Allogeneic use: • Transplantations where the patient receives stem cells from another individual

(donor and recipient are different individuals).

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Table 3.1 Classification of adult stem cells according to source and what cells they give rise to Type of stem cell Source Gives rise to Haematopoietic Bone marrow Blood cells Mesenchymal Bone marrow Chondrocytes and bone

cells Epithelial Skin, intestines, liver Skin cells, enterocytes and

hepatocytes Neural Brain Neurons Satellite cells Skeleton and muscles Muscle cells


Donors for allogeneic transplantations can be divided into the following groups accord-ing to decreasing HLA- compatibility between donor and recipients:• Related donors • Siblings (brother or sister): identical or almost identical tissue types (approx. 25–

30% chance of fi nding a donor); • Parents (mother or father): very rarely acceptable HLA- compatibility; • Close relatives (e.g. aunts or uncles): very rarely acceptable HLA- compatibility.• Non-related donors • Voluntary donors in donor registries (approx. 60–70% chance of fi nding compatible

donors among the 70% without related donors).

It can therefore be expected that approx. 20% of the patients cannot fi nd suitable donors among relatives or in bone marrow registries.

In most cases, the decision of whether to use autologous or allogeneic stem cells is determined by the underlying disease. It is desirable to use healthy stem cells for all patients. In situations where it is known that the patient's own stem cells are affected by the disease one is trying to cure (e.g. certain inheritable diseases in blood-forming tis-sues and leukaemias), the transplantation should in principle be performed using stem cells from a healthy individual in order to expect a cure.

Transplantation of haematopoietic stem cells from bone marrow or peripheral blood is currently an established part of the treatment for certain malignant and non-malignant diseases in blood-forming tissues. High-dose chemotherapy combined with autologous transplantations (also known as high-dose treatment with autologous stem cell support, HDT/ASCT), preferably with stem cells from peripheral blood, is the most conventional treatment procedure involving stem cells.

Transplantation with stem cells from cord blood is a newer and more controversial method. Since the fi rst successful transplantation was performed in 1988, more than 2,000 patients throughout the world have been treated with stem cells from cord blood (2). Nevertheless, as sources of stem cells, cord blood and placenta still represent a third and fi nal alternative in situations where a suitable, related or unrelated donor cannot be found. Transplantations with stem cells solely from cord blood have yet to be performed in Norway.

Requirements for HLA- compatibility in allogeneic transplantationsTo make sure the transplanted cells become blood-forming cells (achieve engraftment) and are not rejected, the patient's and the donor's human leukocyte antigens (HLA- antigens) must be as identical as possible. Increased difference in tissue types between donor and recipient – means increased risk of rejection (engraftment failure). When the tissue types are non-identical, the risk of the transplant reacting against the recipient – the so-called graft versus host reaction, GvH reaction - is also increased.

Every person has more than 10 important types of HLA- antigens on the leukocytes, of which one half is inherited from each parent, and these antigens exist in several differ-ent combinations. The most important antigens in connection with transplantations are the so-called HLA-A, HLA-B and HLA-DR antigens. These antigens, which are found on nucleated cells and have a central role in rejection and GvH reactions, can be identifi ed

15


with serologic and molecular techniques by means of a blood test. In practice, 5 such anti-gens (HLA A, B, C, DR and DQ) inherited from each parent are taken into consideration.

In all allogeneic transplantations, an HLA- identical sibling donor (having 6/6 match) will be the best alternative. However, good results have been achieved after related transplantations where 5 out of 6 types of the donor's and the recipient's HLA- antigens were identical (5/6 match). Transplantations with stem cells from cord blood appear to involve less risk of GvH reactions than when stem cells from blood or bone marrow are used (up to 4/6 match). On the other hand, promising results of transplantations with up to 3 differences in HLA- antigens with related donors (3/6 match) have recently been reported for acute myelogenous leukemia - after special pre-treatment - particularly in children when using stem cells mobilised to blood (4).

Searches for suitable donorsOnly 25–30% of patients needing allogeneic stem cell transplantations have suitable donors in their close families. For the remaining patients, suitable donors must be found by searching in national or international registries. At present, over 8 million people are registered as voluntary donors of stem cells from bone marrow/peripheral blood. The various registries are interconnected through a world-wide network. The Norwegian regis-try for bone-marrow donors include over 20,000 registered persons and is connected to this network. Despite the fact that a large number of individuals are registered, ethnic minori-ties are under-represented in these registries thus, the registries do not refl ect all groups of the population. Searching in bone-marrow registries to fi nd suitable donors, subsequent testing of patients and donors and harvesting of stem cells for transplantation could take months. Since most candidates for stem cell transplantations are seriously ill, the amount of time passing prior to transplantation could be crucial for the treatment result.

There are common and less common HLA- combinations. It may be diffi cult to fi nd suit-able donors for patients with rare combinations of HLA- antigens, patients belonging to ethnic minorities or children of mixed marriages.

For approximately 20% of the patients who are candidates for allogeneic stem cell transplantation, suitable donors of bone marrow/peripheral blood cannot be found, nei-ther in close family nor in registries of potential donors. In such cases, cord blood from related or unrelated donors can be an alternative source for stem cells. Biobanks where stem cells from cord blood are cryopreserved for potential future therapeutic use, have been established in several countries. Today, cord blood from >100,000 newborn babies is stored in various biobanks. Local and national biobanks with cord blood for allogene-ic transplantations are organised in a world-wide network called NETCORD (5), which is also connected to registries of potential voluntary donors of stem cells from bone mar-row or peripheral blood. Some of the biobanks have systematically harvested and cryo-preserved cord blood from children from families with a history of diseases treatable with haematopoietic stem cells (6). Private biobanks primarily include cord blood from healthy families. In Norway, biobanks with cord blood have not been established, but routines for cryopreserving cord blood for families with children or parents with known blood diseases have been established at the University Hospital in Oslo (see Chapter 7).

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Transplantation of stem cells from cord blood

Patient groupsTransplantation of haematopoietic stem cells from cord blood is currently offered pri-marily in cases where donors of stem cells from bone marrow or peripheral blood cannot be identifi ed among family members or in registries. The potential size of the recipient group will be determined by whether cord blood is used as an equivalent source of stem cells on a level with bone marrow and peripheral blood, or only when suitable donors of stem cells from bone marrow or blood have not been found.

As the amount of cord blood that can be drawn from the placenta is limited, the number of stem cells is a limiting factor for a successful transplantation result. Cord blood usu-ally has a concentration of nucleated cells of 10–15 x 106/ml, and one unit (one umbili-cal cord/placenta) must yield a volume of ≥20 ml to be suitable for cryopreservation. The amount per unit is thus ≥300 x 106 nucleated cells and will in most cases not be suf-fi cient to reconstitute the bone marrow of an adult (2). Therefore, the recipient group is primarily children (<30 kg), even though adult patients have also been transplanted with stem cells from cord blood with good results. Optimisation of the method as regards yield (see below) and a potential expansion of stem cells in laboratories (see Chapter 8), can enlarge the recipient group to include older children and adults.

Systematic cryopreservation of cord blood and the establishment of biobanks without restrictions related to private/family use (see below) can offer increased availability and opportunities for increased use of both autologous and allogeneic transplantations based on cord blood stem cells. Compared with stem cells from bone marrow and peripheral blood, cord blood has certain potential advantages such as a shorter search period for suitable donors and the possibility of transplantations with a higher degree of HLA- incompatibility between donor and recipient (see below). It is therefore possible that the recipient group for stem cells from cord blood will grow in the near future. However, cord blood transplantations will not obtain the status as an equivalent method for trans-plantation of stem cells from bone marrow or peripheral blood until the clinical benefi t has been documented in prospective, controlled studies of acceptable quality.

IndicationsAllogeneic transplantations with haematopoietic stem cells from cord blood have been used for several indications which include malignant and non-malignant diseases, as listed in Table 3.2.

17


Autologous transplantations where the patient is treated with healthy stem cells from his own cord blood, which has been cryopreserved in anticipation of future therapeutic use, are a potential area of use. Clinical studies using autologous cord blood for transplanta-tions has yet to be published.

Isolation and cryopreservationBlood from the placenta and the umbilical cord is harvested immediately after umbilical cord severance of a fully developed and healthy baby.

HarvestingCord blood can be harvested both in vaginal and caesarean section deliveries(2).

Cord blood can be harvested both before and after the placenta has been delivered. Harvesting before the placenta has been delivered has the disadvantage of taking place while the midwife or the obstetrician is busy taking care of mother and child.

There are several procedures for harvesting cord blood – closed, semi-closed and open collection systems are all used (7). The different methods have been developed to opti-mise the harvested volume and reduce the risk of microbial contamination and contami-nation with maternal blood. The cord blood is collected in a bag where an anticoagulant has been added.

Quality controlA few ml are used for blood typing (ABO and Rhesus (D) typing), counting the number of nucleated cells and for tissue typing (determination of HLA- antigens).

Bacteriologic examination and virus serology are carried out simultaneously on the cord blood and the baby. The mother is followed up with a blood test to test for hepatitis (B and C), HTLV, HIV, CMV and syphilis. The baby is observed over the fi rst six months to

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Table 3.2. Diseases attempted treated with haematopoietic stem cells from cord blood Diseases Diagnosis Malignant diseases Malignant blood diseases

Acute leukaemia Chronic myelogenic leukemia Myelodysplastic syndrome Non-Hodgkin lymphoma

Solid cancer tumors Neuroblastoma

Non-malignant heritable blood diseases Hemoglobin diseases Severe sickle-cell anemia Severe thalassemia

Acquired bone marrow failure Severe aplastic anemia Heritable diseases with bone marrow failure

Blood diseases: Fanconi’s anemia Blackfan Diamond anemia Dyskeratosis congenital

Other heritable diseases Immunodeficiency Severe immunodeficiency, e.g. severe combined immunodeficiency (SCID)

Certain rare metabolic diseases


detect any diseases that will make it unsafe to use the cord blood.

Analysis of the number of CD34+ cells and the number of units forming blood-cell colo-nies shall be carried out prior to transplantation.

ProcessingThe product can be cryopreserved as whole blood, mononuclear cells or isolated stem cells. Various procedures to remove erythrocytes from cord blood will result in a higher concentration of haematopoietic stem cells (processing). The disadvantages of process-ing cord blood are a reduction in the yield of stem cells, increased costs and risks related to microbial contamination.

The use of high-concentrated stem cells offers several advantages. Firstly, the units are smaller and thus require less preservation space. Secondly, the risk of intravas-cular hemolysis in transplantations as a result of incompatibility between the donor's and recipient's ABO blood groups is reduced. In addition, the frequency and degree of toxic reactions are reduced, because a smaller amount of DMSO (dimethyl sulfoxide) is required to cryopreserve the stem cells (see below).

CryopreservationFreezing of cells (cryopreservation) is usually done with 10% DMSO in the cell concen-trate. DMSO is cryoprotective at low temperatures. That means the cells can be stored, usually in liquid nitrogen at -176– C, or in electric ultra-freezers.

Biobanks Provided that neither mother nor child show any sign of serious infectious or genetic disease after six months of follow-up, the stem cells will be further stored in a freezer for the purpose of staying viable for many years so that they can be used for transplanta-tions if required.

Any therapeutic use of stem cells from cord blood can be restricted for personal or fam-ily use only, or be used for any patient with the suitable tissue type. For patients who do not have suitable donors of cord blood in their close family, a search in registries or bio-banks for identifi cation of potential donors may be initiated. If a suitable donor is identi-fi ed, the cord blood will be ready for transplantation within two weeks.

Transplantation procedureThawingThere are various procedures to thaw and prepare stem cells for transplantation.

The thawing procedure usually involves a certain loss of viable cells. In practice, the number of leukocytes before cryopreservation is used to assess whether a unit is suitable for any given patient, and this is accepted provided that harvesting, cryopreservation and thawing is performed in accordance with given standards (8).

Preparation of patientsIn cases of malignant diseases, the patient who is to undergo the transplantation is treated with high-dose chemotherapy or total body irradiation. The purpose of the prepa-ration is partly to treat the original disease and partly to prevent rejection reactions in

19


allogeneic transplantations. In transplantations with HLA- incompatibility, the patients may be given mononuclear anti-T-cell antibodies in addition.

Lately, lower doses of preparatory treatment that do not destroy the patientʼs bone mar-row are used. After achieving engraftment, the new preparation regime aims at taking advantage of the anti-leukaemic effect of the donorʼs white blood cells (GvL effect, see below). So far, cord blood has not been an option in such transplantations.

Prophylaxis against the so-called graft-versus-host disease (GvHD), an immunologic reaction (see above and under), is usually cyclosporine A alone or in combination with prednisolone or methotrexate. Prednisolone is used in treatment of GvHD.

Stem cell transplantationThe stem cell transplantation itself is performed in the same manner as a blood transfu-sion. The patients are treated in hospital until adequate bone marrow function has been established. Later, hospitalisation may be necessary to treat e.g. GvHD or other compli-cations.

Evaluation of clinical effectAll transplantations with haematopoietic stem cells, including stem cells from cord blood performed in Europe, shall be reported to the European Blood and Marrow Trans-plantation group (EBMT). EBMT communicates data to Eurocord, an organisation that analyses and compares clinical data after cord blood transplantations and works on standardising procedures. International registries collecting and analysing data from stem cell transplantations include the International Bone Marrow Transplant Registry (IBMTR) and the International Cord Blood Transplant Registry (ICBTR) as well as the National Marrow Donor Program (NMDP).

Documentation for clinical benefi ts of transplantations of cord blood stem cells appear through registration of parameters connected to survival, survival without relapse of the original disease, engraftment, graft-versus-host disease (GvHD) and other complica-tions. As the aim of the treatment is to cure the patient from a mortal disease, the two fi rst parameters are the most important. In order to draw any conclusion with a suffi cient degree of certainty, the patient must be observed for 2–3 years minimum after the trans-plantation has been performed.

SurvivalSurvival, defi ned as the period from transplantation to death, is a “hard” clinical end-point even though survival in itself does not indicate clinical effect. Observed survival can be reported in per cent after, for instance, three years (three-year survival), alterna-tively as median survival. Kaplan-Meier estimates are frequently used.

Disease-free survival and progression-free survival, i.e. the period from transplantation to relapse of the original disease, death or morbidity caused by complications or for other reasons, are less “hard” endpoints.

Event-free survival has no clear defi nition. The term may include several negative events – from less serious complications to relapse or death.

20


EngraftmentThe term engraftment means that the transplanted cells start producing bloodcells. Engraftment is as such a clinically relevant endpoint that indicates the restoration of a normal bone marrow function. Engraftment failure is the most serious outcome for a patient,as the patient will die as a result of prolonged bone marrow failure (infections and/or bleedings).

Commonly used clinical measures indicating engraftment are the period to reach mini-mum 0.5 x 109/l neutrophilic segmented granulocytes and the period to reach minimum 20 x 109/l platelets in absence of platelet transfusions in the past 5–7 days before mea-suring.

A common defi nition of engraftment failure is the absence of measurable engraftment after 42 days. In most cases, no measurable engraftment after 28 days indicates engraft-ment failure.

Complications and side effectsTransplantations of allogeneic stem cells involve a risk of immunological reactions. Rejection is caused by the patientʼs own immune system reacting to the graft (“host-ver-sus-graft reaction”), while the GvHD is caused by the T-cells in the graft attacking the patient (“graft-versus-host reaction”). The latter reaction is far more common than the former in transplantations with allogeneic stem cells from blood and bone marrow.

• RejectionRejection is divided into primary and secondary rejection. Primary rejection is in prac-tice identical to engraftment failure. Secondary rejection reactions can arise weeks or months after the engraftment. Graft loss occurs in less than 5% of the transplantations where allogeneic bone marrow or peripheral blood stem cells have been used in accor-dance with normal criteria for HLA compatibility. For cord blood, rejection is more frequent, approximately 10–20% dependent upon cell dose and probably the degree of HLA compatibility.

• Graft-versus-host disease (GvHD)Both acute and chronic GvHD can hit several organ systems with varying severity. Acute GvHD is defi ned as GvHD occurring within the fi rst 100 days after the transplan-tation. GvHD can result in a rash, liver damage, diarrhoea, increased risk of infections, and at worst - death. Chronic GvHD is defi ned as GvHD occurring more than 100 days after the transplantation, and the disease is described as limited or extensive depending on the number of organs affected.

Both acute and chronic GvHD can result in death because of organ damage, immuno-defi ciency with complicating infections and toxicity of the necessary treatment. On the other hand, GvHD can lead to a favourable immunologic reaction in leukaemia patients called Graft-versus-leukaemia reaction (GvL) where cytotoxic T-cells in the graft con-tribute to eliminating the remaining cancer cells.

Comparison with other transplantation methodsClinically, transplantations with stem cells from cord blood have both advantages and disadvantages or limitations compared with transplantations with stem cells from bone marrow and peripheral blood, as described in Tables 3.3 and 3.4.

21


22

Table 3.3. Advantages of transplantations of stem cells from cord blood* Advantage Commentary CBT Comparison with BMT/PBT Easily available Harvesting cord blood is easy and

does not involve any discomfort for the donor (blood is drawn from umbilical cord/the placenta after umbilical cord severance).

Harvesting of bone marrow is an invasive method that involves discomfort for the donor. Both BMT and PBT are time-consuming for donor and responsible medical personnel.

Short period from identification of suitable donor until transplantation can be performed

Cryopreserved cord blood has already been tissue typed and tested for diseases. Suitable donors are identified through searches in biobank registries, and stem cells can be prepared for transplantation within two weeks.

Searching in registries for suitable donors with subsequent testing and preparation of stem cells for transplantation takes from 1 to 6 months (median 3.5 months).

All newborn babies are potential donors

Cryopreservation of cord blood from all newborn babies and the establishment of large biobanks will increase the availability of donors for all groups of the population, including ethnic minorities.

Registries of potential donors mainly consist of Caucasians and thus do not cover all groups of the population.

“Immature” cells Cord blood cells have advantageous immunologic qualities which render transplantations with a higher degree of HLA incompatibility between donor and recipient possible.

Cells from bone marrow and peripheral blood from children and adults are more “mature”, which requires a higher degree of HLA compatibility in transplantations.

Lower risk of viral contamination.

Stem cells from cord blood come from an environment with little or no infections. Blood from the umbilical cord or the placenta is rarely infected with HIV, hepatitis or CMV, and the risk of infections of EBV is very low.

The frequency of latent and chronic infections is accumulated during a human’s lifetime. E.g. 70--80% of bone marrow donated from adults will be infected with CMV, with the risk of reactivation and contamination.

*Abbreviations: CBT: cord blood transplantation, transplantation of stem cells from cord blood; BMT: bone marrow transplantation – transplantation of stem cells from bone marrow; PBT: peripheral blood cell transplantation – transplantation of stem cells from peripheral blood; HIV: human immunodeficiency virus; CMV: cytomegalo virus; EBV: Epstein-Barr virus.


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Table 3.4. Disadvantages/limitations of allogeneic transplantations of stem cells from cord blood* Disadvantage/limitation Commentary CBT Comparison BMT/PBT Limited amount of stem cells The concentration of stem cells is

higher in cord blood than in bone marrow, but the limited volume involves an upper limitation to the number of harvestable stem cells for transplantation. As a consequence, the best results with CBT are achieved in children.

Bone marrow and peripheral blood contain a smaller amount of stem cells/ml, but harvesting usually yields enough stem cells

Cord blood from a newborn baby can only be harvested once

Each unit only has a relatively low number of stem cells (please see above). Transplantations with units from multiple donors can in certain cases be performed.

Each donor can donate stem cells several times

Risk of transferring genetic diseases

This risk is reduced by observing the newborn baby for six months before cryopreserved stem cells are used.

Persons with diagnosed genetic diseases are excluded from or not included in donor registries

Possibility of contamination with maternal cells

Cells from the mother that can contaminate the cord blood can lead to severe rejection reactions with the patient. However, the frequency of maternal contamination is regarded as very low.

No risk of maternal contamination

Slow restoration of normal blood function (engraftment)

Possible explanation is that stem cells from cord blood are less “mature” than stem cells from bone marrow or peripheral blood, and that the number of transplanted stem cells is low. Involves increased risk of infections and bleedings for a longer period than in BMT/PBT.

BMT and PBT give quicker restoration of bone marrow function

Treatment with white blood cells if patient has a relapse of the cancer

Not possible Possible

*Abbreviations: please refer to Table 3.3.


This chapter describes the systematic and critical identifi cation, assessment and synthe-sis of clinical documentation with the subsequent grading of the scientifi c evidence to express the validity of the documentation. Literature collected in order to shed light on harvesting and cryopreservation of cord blood, storage in biobanks, optimisation of the method as regards the volume of cord blood and the benefi t of stem cells, etc. was not identifi ed by means of a systematic literature search.

Inclusion criteriaThe identifi cation of publications reporting results after transplantations of haematopoi-etic stem cells from cord blood was based on the inclusion criteria listed in Table 4.1. In addition to relevance related to patient groups, intervention and endpoints, certain requirements were set for the study design.

24

4. Literature search and assessment

Table 4.1. Inclusion criteria Patient group

• All patients regardless of disease indications for stem cell transplantation Further specifications:

o Children and adults o All weight classes

Intervention • Transplantations of haematopoietic stem cells from cord blood

Further specifications: o Autologous and allogeneic transplantations o Related and non-related donors o All degrees of HLA- compatibility o Cryopreserved and ”fresh” stem cells

Endpoints • Survival

o Observed survival • Relapse/progression

o Disease-free survival/progression-free survival • Engraftment

o Graft failure • Complications/side effects

o Graft-versus-host disease (GvHD): acute GvHD degree 1-4, chronic GvHD o Other complications/side effects

• Event free survival Commentary: The term includes several negative events, ranging from less serious complications to relapse or death.

Study design • Systematic reviews: metaanalyses, Cochrane reviews and HTA reports • Randomised studies • Cohort studies (including registry based cohort studies) • Case-control studies • Case series • Reports/registry data with systematic comparison of results after transplantations of cord blood


Search strategyThe literature search was carried out both in bibliographic databases and manually.

Searches in databasesSystematic reviewsSearches for systematic literature reviews were carried out in the following databases:• Health Technology Assessment Database (HTA)• Cochrane Database of Systematic Reviews (CDSR)

The search strategy was based on various combinations of key words and medical index-ing terms including:• Stem cells, haematopoietic stem cell, hematopoietic stem cell transplantation, cell

transplantation, umbilical cord, placenta, cord blood, cord blood banking

No relevant systematic reviews were identifi ed in the Cochrane database.

The following HTA-reports from centres related to INAHTA (International Network of Agencies for Health Technology Assessment) were identifi ed:• Cord blood transplantation. Alberta Heritage Foundation for Medical Research

(AHFMR) 1996: 6 (9)• Cord blood transplantation. Kwankam MMY, Hailey D, and Jacobs P. Alberta Heri-

tage Foundation for Medical Research (AHFMR) 1998 (HTA 13): 39 (10)• Allogeneic stem cell transplantation methods. Jacobs P, Hailey D, and MacLean N.

Alberta Heritage Foundation for Medical Research (AHFMR) 2000 (HTA 18): 44 (11)• Transplantasjon av stamceller från navelstrengblod. Tidiga bedømningar av nye

medicinske metoder (Alert). Statens beredning for medicinsk utvärdering (SBU) 2001 (12). (Transplantation of stem cells from cord blood. Early evaluation of new medi-cal methods (Alert). The Swedish Council on Technology Assessment in Health Care (SBU) 2001 (12)).

None of the reports were considered to be suffi ciently up-to-date to be included in this report, but they were all used as background information and to identify relevant pri-mary studies (manual search).

Primary literatureA structured literature search for primary studies and any metaanalyses was carried out in:• Medline (Ovid)

25

versus bone marrow and/or peripheral blood cells • Case reports

Commentaries: • Case reports are included to illustrate the development on this field • Descriptive registry data from Eurocord can be used as background information • General outlining articles, guidelines, consensus reports and expert commentaries are

excludedOther inclusion criteria

• Language o Articles in English, articles with English abstracts and scientific literature in Norwegian

meeting the inclusion criteria • Time period

o No restrictions Commentary: The first case where cord blood was used in transplantation of haematopoietic stem cells was reported in 1989


26

The systematic search strategy is shown in Table 4.2.

The Medline search identifi ed 414 references that were imported into a RefMan data-base. No metaanalyses were identifi ed in the literature search.

Manual searchesSupplementary manual searches of reference lists in relevant HTA- reports and clinical studies, recent outlining articles and search in Medline for key authors and key words (free text, subject, various combinations) identifi ed an additional 21 possible relevant references, which were also imported into the RefMan database.

Literature assessmentA total of 435 references were identifi ed in the systematic literature search.

SortingThe assessment of relevance, quality and validity was made according to the following step-by-step sorting process: • Step 1: Abstracts and titles identifi ed through the literature search (a total of 435)

were assessed as regards relevance. Full-text articles were ordered for relevant and possibly relevant publications

• Step 2: Full-text articles (a total of 67) were assessed as regards relevance and study design. All full-text publications met the inclusion criteria and constitute the literature basis for this systematic review (13-79)

• Step 3: Relevant articles underwent critical assessment of study quality and validity (see below). The literature review revealed that 50 articles either were case reports, included overlapping data, represented double publications and/or were of unac-ceptable quality, whereas 17 studies met the required inclusion and quality criteria, thus forming the documentation basis for this report (13-29).

Table 4.2. Search strategy in Medline (Ovid)* 1. fetal blood.sh. 2. ((cord or umbilical or fetal or foetal or placenta$) adj5 blood).mp. [mp=ti, ab, rw, sh] 3. 1 or 2 4. hematopoietic stem cell transplantation.sh. 5. transplant$.mp. or tr.fs. [mp=ti, ab, rw, sh] 6. 4 or 5 7. 3 and 6 8. cord blood stem cell transplantation.sh. 9. 7 or 8 10. (clinical trial or meta-analysis or multicenter study or randomized controlled trial).pt. 11. exp epidemiologic study characteristics/ or exp epidemiologic research design/ or exp evaluation studies/ or exp research design/ or exp registries/ or comparative study.sh. 12. (metaanaly$ or meta-analy$ or meta analy$ or (systematic adj (review or overview)) or (clin$ and trial$)).mp. or 1469-493x.is. [mp=ti, ab, rw, sh] 13. 10 or 11 or 12 14. 9 and 13 * The literature search was carried out on 28 January 2003


A summary of the systematic literature search is provided in Table 4.3.

27

Table 4.3. Identification and sorting according to relevance, quality and validity Literature searches Identified references Full-text articles

evaluated=literature basis

Documentation basis

Medline (Ovid) 414 46 11 Manual searches* 21 21 6 Total 435 67 17

*A majority of the references identified by manual search is indexed in Medline, but not identified through the search strategy shown in Table 4.2.

Quality and validity assessment All di i h li b i d i i f d d i i l

Table 4.4. Study hierarchy ranking Level Study design

1 Metaanalyses or systematic reviews of randomised controlled studies (RTCs), RTC 2 Metaanalyses or systematic reviews of cohort or case-control studies, cohort studies, case-

control studies 3 Non-controlled studies (including an element of comparison): register studies, case series,

cross-section studies 4 Descriptive studies, non-systematic reviews, expert statements, case reports

*A majority of the references identifi ed by manual search is indexed in Medline, but not identifi ed through the search strategy shown in Table 4.2.

Quality and validity assessmentAll studies in the literature basis underwent a registration of data and critical assessment when it comes to the relevance, quality and validity of the study according to interna-tionally accepted criteria. The aim was to exclude studies of unacceptable methodologi-cal quality and inadequate level of evidence from the documentation in the joint synthe-sis. In addition to ascertaining that the studies met the general requirements concerning relevance,quality and internal validity, the assessment also included an element of statis-tical evaluation.

Evaluation of internal validity (elements of systematic errors)The fi rst step in the evaluation of internal validity is the classifi cation of study design. Types of studies ranked high in the study hierarchy are usually less burdened with sys-tematic errors than study types of lower ranking (Table 4.4).

None of the studies included in the literature basis (Step 3) are of experimental design, but are based on observations. The study design includes a limited number of cohort studies, large and small case series of which some are based on registries (registry stud-ies), and some case reports.

Clinical studies of high ranking in the study hierarchy do not necessarily have high internal validity. The quality of the study is not only dependent upon the study design, but also on how the study is carried out and analysed. The evaluation of study quality and the validity of the results are based on replies to general “checklists” adapted to cohort studies and case series, as illustrated in Tables 4.5 and 4.6.


Statistical evaluations (elements of random errors)Since there is a possibility of the observed difference in survival, engraftment and com-plications being caused by random variations in study materials, it is more likely that the observed differences are genuine if the study is extensive than if it is limited. In this HTA-report, case series with less than 20 patients or less than 10 patients per disease indication have been regarded as being statistically insuffi cient to be included in the documentation basis of this report.

Study quality rankingBased on a total evaluation of the study quality and the validity of the results according to the checklist for the employed study design and accompanying statistical consider-ations, the studies were ranked in three quality classes (++, + and -). Principles for rank-ing are listed in Table 4.7.

28

Table 4.5. Checklist for cohort studies 1 Are the compared groups clearly defined and comparable as regards important background factors? 2 Are the persons undergoing treatment/intervention (the exposed individuals) representative for their

patient groups? 3 Is the non-exposed cohort selected from the same population as the exposed? 4 Are outcome and intervention/exposition measured identically and reliably in the two groups? 5 Is the follow-up sufficient (type/extent/time) to reveal all endpoints (including side effects/delayed

injuries)? 6 Are losses-to-follow-up and withdrawals identical in the compared groups? 7 Which factors apart from exposure might affect the endpoints (cf. confounding factors)? 8 Has a dose-response connection between intervention/exposure and endpoint been established? 9 Did the person who evaluated the result (endpoint) know about the intervention/exposure? 10 Have sufficient adjustments been made for confounding variables? 11 Have contemporary controls been made?

Table 4.7. Quality class ranking (compared with studies with equivalent design) Ranking Criteria

++ High quality/validity. Used if all or most of the checklist criteria are met. Even though some of the criteria have not been met, it must be very unlikely that the impact of the study or the review is affected.

+ Medium quality/validity. Used if some of the checklist criteria have not been met and/or in cases where the study/review have not been adequately described. Total evaluation indicates that the impact of the study/review is unlikely to be affected.

- Low quality/validity. Used in cases where few or none of the checklist criteria have been met and/or where the study/review has been insufficiently described. Total evaluation indicates that the impact of the study or the review most likely will be affected.

Table 4.6. Checklist for case series 1 Is the study based on a random selection of a suitable patient group? 2 Is the selection representative for the patient group? 3 Is there any chance of the selection being biased? 4 Are the inclusion criteria for the selection clearly defined? 5 Are all the patients in the selection in the same stage of the disease? 6 Is the follow-up sufficient (type/extent/time) to reveal endpoints? 7 Have objective criteria been used to evaluate the endpoint? 8 When comparing patient series, have the series and the dispersion of prognostic factors been

adequately described? 9 Is the registration of data prospective?


The following general requirements for relevance and quality have been taken into account when the studies were ranked: • Case reports are a part of the literature basis for the purpose of revealing important

milestones on the fi eld. However, case reports have no impact as studies and are for that reason ranked as the lowest quality class (-);

• Some case series are reported in reviews, but with an extended follow-up period and a more extensive patient material compared with the original study. Some studies have overlapping patient materials. In addition there are several double publications. Studies belonging to these categories are ranked as the lowest quality class (-);

Level of evidenceThe impact of the documentation for the individual studies was ranked when establish-ing the level of evidence, see Table 4.8. Compared with quality class, the term level of evidence has the advantage that it ranks the impact of the study in relation to studies of other designs as well.

29

Table 4.8. Level of evidence Level Study types and study quality 1++ Excellent meta-analysis, systematic review of randomised controlled clinical studies (RCTs),

or excellent RCT with very little risk of bias or random errors. 1+ Good meta-analysis, systematic review of RTCs, or RTC with little risk of bias or random

errors. 1- Meta-analysis, systematic review of RTCs, or RTCs with great risk of bias or random errors.

2++ Excellent systematic review of cohort or case-control studies, or excellent cohort or case-control studies with very little risk of confounding, bias, or coincidences and great probability of causal connections.

2+ Good systematic review of cohort or case-control studies, or satisfactory conducted cohort or case-control studies with little risk of confounding, bias, or coincidence and moderate probability of causal connection.

2- Systematic review of cohort or case-control studies, or cohort or case-control study with major risk of confounding, bias, or coincidences and a significant risk for non-causal connection.

3++ Satisfactory conducted register study, case series, cross-section study with little risk of confounding, bias, or coincidences.

3+ Satisfactory conducted register study, case series, cross-section study with moderate risk of confounding, bias, or coincidences.

3- Poorly conducted register study, case series, cross-section study with great risk of confounding, bias, or coincidences.

4 Descriptive study, non-systematic reviews, expert statements, case reports


Synthesis

Literature basisThe studies constituting the literature base were classifi ed according to study type, study quality and level of evidence, as shown in Table 4.9.

30

Table 4.9. Classification of included studies Number of studies

Study design/Number

Quality class*/Number

Level of evidence Reference

High (++) /(0) Average (+) / (3) 2+ 13—15

Cohort studies/ (4)

Low (-) / (1) 2- 30 High (++) / (0) Average (+) / (14) 3+ 16—29

Case series/ (55)

Low (-) / (41) 3- 31-71

67

Case/ (8) Low (-) / (8) 4 72-79

* Case reports, studies with overlapping patient material (except two extensive case series, ref 18 and ref 25) and double publications have been ranked as the lowest quality class.

For further classification of the studies as regards donor and recipient (patient group), see Chapter 5, Table 5.1.

Documentation basis A l f 17 di k d hi h ( ) d di ( ) li l h h

* Case reports, studies with overlapping patient material (except two extensive case series, ref 18 and ref 25) and double publications have been ranked as the lowest quality class.

For further classifi cation of the studies as regards donor and recipient (patient group), see Chapter 5, Table 5.1.

Documentation basisA total of 17 studies ranked as high (++) and medium (+) quality classes have enough impact to elucidate the clinical effect and thus form the documentation basis of this health technology assessment. Studies ranked as low (-) quality class are of unacceptable methodological quality and have too little impact to be included as documentation in the joint synthesis (see below).

Studies of high (++) and medium (+) quality are summarised in separate evidence tables (see Chapter 5).

Synthesis of collected documentationThe results from studies included as scientifi c documentation were combined in a quali-tative joint analysis to reach a fi nal result and a conclusion.

Strength of evidenceThe ranking of the impact of the included documentation was performed by determining the strength of evidence, see Table 4.10.

Table 4.10. Strength of evidence Impact Study type and level of evidence

A Minimum a metaanalysis, systematic review or RCT at level 1++, or a systematic review of

When grading the evidence, the consistency of the results were taken into account.

RCT or studies mainly at level 1+ where results are consistent. B Studies at level 2++ showing consistent results, or extrapolated results/partial results from

studies at level 1++ or 1+. C Studies at level 2+ showing consistent results, or extrapolated results/partial results from

studies at level 2++. D Studies at level 3 or 4, or extrapolated results/partial results from studies at level 2+.


Methodical and statistical considerationsPossible sources of error in the included studies that could cause misinterpretation of the analysis are discussed below.

Study design and sources of errorCohort studiesCohort studies in general have a higher impact than case series (cf. the study hierarchy, Table 4.4). The quality of cohort studies is to a large extent infl uenced by whether the study group has been followed over a period of time (prospective cohort) or whether the study is based on historical collection of data about the study group (retrospective cohort), as well as the quality of the control group. An adequate control group should be relevant (from the same group of the population) and equally well characterised as the comparative patient group. Cohort studies with contemporary controls are generally less exposed to treatment and registration bias than studies with historical controls. In addi-tion, all cohort studies are exposed to selection bias.

While systematic differences in the comparative groups (selection bias) can be coun-teracted by adjusting for prognostic and possible confounding factors in the statistical analysis, the varying registration practices which result in systematic differences in the result evaluation cannot be corrected in the statistical analysis.

Cohort studies have the option of matching the study and control groups prior to the analysis. Studies where each patient in the control group is selected based on similarities with patients in the study group (matched control) are generally of higher quality than studies which are not adjusted for known and possible confounding factors before the analysis. An example of analysis methods that can correct differences between the com-parative groups is multiple regressions.

Case seriesCase series are non-controlled studies and therefore have considerably lower validity than controlled studies. Some studies compare the study group with one or several other case series (“controls”). This type of case series with an element of comparison gener-ally has higher impact than case series without any comparison whatsoever.

Case series are often exposed to selection bias; register-based studies less than studies analysing a selected patient material from specifi c institutions. Systematic differences in the compared case series groups can be counteracted by adjusting for possible confound-ing factors in the statistical analysis.

Statistical considerationsStatistical evaluations have been an element of the literature review. The evaluations are based on general methodological knowledge about statistics without employing experts on statistics.

Power calculations In a systematic review with qualitative synthesis, studies with high internal validity but low statistical strength can be excluded. As the synthesis of the collected documentation

31


in this health technology assessment was planned as a qualitative joint analysis, all stud-ies with low statistical impact were ranked as the lower quality class and thus excluded from the documentation basis.

Statistical analysis methodsIn the literature review, emphasis was put on whether the studies had undergone adequate statistical analyses given the main purpose, study design and the number of patients. The evaluation has taken into account the fact that possibilities and require-ments for analysing may have changed after the study had fi nished.

32


The purpose of summarising the literature has been to examine all published results after transplantations of haematopoietic stem cells from cord blood, to reveal the extent of activities where cord blood has been the stem cell source. The effect of the method, including side effects and complications, is described by means of available documenta-tion of acceptable quality, preferably by comparing the results of cord blood transplanta-tions with transplantation procedures using stem cells from bone marrow and/or periph-eral blood. In addition, current knowledge regarding the viability of cryopreserved stem cells is described, evaluated in relation to the clinical effect in transplanted patients.

Autologous transplantation of stem cells from cord bloodThe literature review did not identify clinical studies or case reports related to autolo-gous transplantations of stem cells from cord blood.

Allogeneic transplantation of stem cells from cord bloodAll published results of therapeutic use of stem cells from cord blood include transplantations where donor and recipient are non-identical individuals, i.e. allogeneic transplantations.

The fi rst published, successful allogeneic cord blood transplantation was performed in 1988 (73). A fi ve-year-old boy with severe Fanconi's anaemia, a rare autosomal reces-sive disease that results in bone marrow failure, was treated with haematopoietic stem cells from cord blood harvested from a younger sister. The boy was diagnosed at the age of two. In the next pregnancy, the parents, both healthy, performed a prenatal tissue typ-ing of the foetus who turned out not to be affected by the disease in question, at the same time as it was HLA- compatible with the patient. A girl was born vaginally, and the cord blood was harvested and cryopreserved. After an 8-month long quarantine during which the cord blood was karyotyped and tested for diseases and the girl was observed, the cells were thawed and infused into the patient who had been pre-treated with chemother-apy and radiation. The transplantation was performed without any complications (minor acute GvHD, no chronic GvHD) and restored the boyʼs bone marrow function (100% of the red blood cells showed donorʼs blood type). After 8 years, the patient was reported to be alive with normal bone marrow function (80).

After this fi rst successful transplantation, haematopoietic stem cells from cord blood have been used in several allogeneic transplantations, mainly in treatment of children. The early cord blood transplantations used donors related to the recipients, primarily younger sib-lings. The establishment of biobanks with stored units of cord blood gradually made it pos-sible to search for suitable donors outside the close family. The fi rst allogeneic transplanta-tion with cord blood from an unrelated donor was performed in 1993 (81), and following this, several transplantations have been performed, also in adult patients.Today, allogeneic transplantations of cord blood stem cells are performed on a range of disease indications on malignant and non-malignant haematopoietic diseases as well as congenital immunodefi ciency and solid malignant tumours (see Chapter 3 Table 1.2 ).

33

5. Assessment of effect – clinical documentation


The number of patients treated with allogeneic cord blood transplantations is estimated to be more than 2,000 (81). Published clinical results are available for most of these patients. A summary of the available documentation of results after allogeneic transplan-tations of stem cells from cord blood is provided below.

Literature basisThe literature review identifi ed a total of 67 publications which meet the required inclu-sion criteria regarding relevance and study design (13 - 79) (see Chapter 4). To illustrate the transplantation activities of stem cells from cord blood, central case reports are a part of the literature basis. Table 5.1 classifi es the studies according to study design, donor, recipient and type of disease.

34

Table 5.1. Alphabetic classification of studies included in the literature basis Reference Study design Donor1 Recipient1 Type of disease Commentary and

sorting2

Badell et all. 2000 (16)

Case series Related: HLA identical (2) HLA mismatch (2) Unrelated: HLA match (3) HLA mismatch (21)

Children (28) Leukaemia (21) Genetic diseases (7)

M

Ballen et al. 2002 (31)

Case series Unrelated (7): HLA identical (1) HLA mismatch (6)

Adults (7) Malignant diseases M

Barker et al. 2001 (13)

Cohort study Unrelated (31) Children (31) Malignant and non-malignant diseases

Matched control: BMT3

MBarker 2001 (72) Case Unrelated: Partly HLA

match (1) Adult: Age: 53 (1)

Chronic myeloid leukaemia

Infusion of two cord blood units

MBuckley et al. 1999 (32)

Case series Unrelated (3) Children (3) Severe combined immunodeficiency disease (SCID)

Reports results from BMT3 also

MChan et al. 2001 (33)

Case series Related: HLA identical (3) Children (3) Severe thalassemia Results from BMT3 also reported

MDiaz et al. 1998 (34)

Case series Related: HLA identical (2) Unrelated (5)

Children (7) Haemoblastosis M

Gluckman et al. 1989 (73)

Case Related: HLA identical (1) Child (1) Fanconi’s anaemia First reported case M


Case series Related (78) Unrelated (65)

Children and adults: median age 6 years, 0.2—45 years (143)

Malignant and non-malignant diseases

Unrelated donor is partly included in Rubinstein et al. 1998 (24). Material included in Gluckman 2000 (18).

MO



Children and adults (143)


Same case series as in Gluckman 1997 (17).

DGluckman et al. 1998 (36)




Same patient material as in Gluckman 1997 (17).

DGluckman et al. 1998 (37)

Case series Unrelated (65) Median age 9 years, 0.3—45 years (65).


Partly material from Gluckman 1997 (17)

OD





Material included in Gluckman 2000 (18.39)

O


35

Gluckman 2000 (18)


Children and adults (537) Children (429) Adults (108)


Partly material from Gluckman 1997 (17). Same material as Gluckman 2000 (39)

MO

Gluckman et Locatelli 2000 (39)




Same material as in Gluckman 2000 (18)

OGluckman et al. 2001 (40)

Case series Unrelated (399) Children (291) Adults (108)


Same patient material as Gluckman 2000 (39)

DGross et al. 1996 (41)

Case series Related (1) Child: Age: 5 (1)

X-linked lymphoproliferative disease


MIori et al. 1998 (42) Case series Unrelated: HLA mismatch

(10) Children (10) High-risk

leukaemia M

Issaragrisil et al. 1995 (74)

Case Related (1) Child (1) Thalassemia M

Issaragrisil et al. 1997 (43)

Case series Related (6) Children (6) Thalassemia Reports results from BMT3 also

MKawano et al. 1998 (44)

Case series Related: HLA mismatch (13): 8 parents and 5 siblings

Children: median age 11 years (13)


Very limited clinical information

MKnutsen and Wall 2000 (45)

Case series Unrelated (8) Children (8) Severe primary T-cell immunodeficiency

M

Kogler et al. 1999 (46)

Case series Unrelated: 96% HLA mismatch (50)

Children and adults: median age 5 years, 0.3—44 years (50)


M

Kohli-Kumar 1993 (75)

Case Related: HLA identical (1) Child (1) Fanconi’s anaemia M

Kurtzgerg et al. 1996 (19)

Case series Unrelated: 0-3 HLA mismatch (25)

Children (25) Malignant and non-malignant diseases

M

Ladenstein et al. 1997 (47)

Case series Related: HLA identical (18)

Children (18) Severe aplastic anaemia


MLaporte et al. 1998 (48)

Case series Unrelated (6) Adults (6) Malignant blood diseases

M

Laughlin et al. 1998 (76)

Case Unrelated (1) Adult (1) Acute leukaemia M


Case series Unrelated (68) Adults (68) Malignant and non-malignant diseases

M

Lazzari et al. 1996 (49)

Case series Related: HLA identical (4) Unrelated: HLA identical (2), HLA mismatch (2)

Children (5) Adults (3)

Not defined M

Locatelli et al. 1998 (50)


Children: median age 5 years, 1.8—14 years (54)

Acute leukaemia Patient material included in Locatelli 1999 (21)

OLocatelli et al. 1999 (21)

Case series Related (42): HLA identical (30), HLA mismatch (12) Unrelated (60)

Children: median age 5.5 years, 0.3—15 years (102)

Acute leukaemia Partly material from Locatelli 1998 (50). Patient material probably included in Gluckman 2000 (18)

MO

Locatelli et al. Case series Related (44): HLA Children and Thalassemia (33) M 2003 (22) identical (41), HLA

mismatch (3) young adults: median age 5 years, 1—20 years (44)

Sickle-cell anaemia

Lönqvist et al. 2001 (51)

Case series Unrelated: mismatch (2) Children (2) Infantile neuronal ceroid lipofuscinosis

M


36

pMacMillan et al. 1998 (52)


Children (3) Juvenile myelomonocytic leukaemia


MMiniero et al. 1998 (53)

Case series Related: HLA identical (10)

Children: 1-8 years (10)

Thalessemia Sickle-cell anaemia

M

Moretta et al. 2001 (30)

Cohort study Related: HLA identical (11) Unrelated (12)



Matched control: BMT3

Limited clinical information

MNiehues et al. 2001 (54)


Children: median age 5 years, 0—15 years (63)

Malignant diseases (33), non-malignant diseases (30)

Analyses risk factors

MNishihira et al. 1998 (55)

Case series Unrelated (7) Children: median age 4.5 years, 0.7—12.8 years (7)


M

Nobili et al. 2002 (77)

Case Related: HLA identical (1) Child: 2 years (1)

Dyskeratosis congenita

M

Ohnuma et al. 1996 (78)

Case Related: HLA identical (1) Child: 3 years 8 months (1)

Acute promyelocytic leukaemia

M

Ohnuma et al. 2000 (56)

Case series Unrelated (27) Children: median age 2.8 years, 0.5—16.2 years (27)


Part-material probably included in Ohnuma 2001 (23)

OOhnuma et al. 2001 (23)

Case series Unrelated: HLA mismatch (39)

Children and adults: median age 3.1 years, 0.5—28 years (39)

Malignant blood diseases

Probably includes part-material from Ohnuma 2000 (56)

M

Ooi et al. 2001 (57)


Adults: median age 38 years, 20—50 years (7)

Myelodysplatic syndrome-related secondary acute myeloid leukaemia

Patient material included in Ooi 2002 (58)

OOoi et al. 2002 (58)


Adults: median age 38.5 years, 21—51 years (8)

Acute leukaemia Reports results from BMT3 alsoPart-material from Ooi 2001 (57)

MO

Prich et al. 1998 (59)

Case series Related: HLA identical (1) Unrelated: HLA identical (1), HLA mismatch (1)

Children (3) Acute lymphocytic leukaemia

M

Rocha et al. 1998 (60)

Case series Related: HLA identical (60), HLA mismatch (18)

Children and young adults: median age 5 years, 0.2—20 years (78)

Malignant diseases (46), Non-malignant diseases (32)

Part-material probably included in Rocha 2000 (14)

O


Cohort study Related: HLA identical (113)

Children: median age 5 years, younger than 15 years (113)

Malignant diseases (61), Non-malignant diseases (52)

Probably includes part-material from Rocha 1998 (60). Comparison against BMT3

MO


Cohort study Unrelated (99): HLA mismatch 92%


Acute leukaemia Comparison against BMT3

M

Rubinstein et al. 1998 (24)

Case series Unrelated (652): HLA identical (40), HLA mismatch (519), unknown (3)



Includes limited part-material from Gluckman 1997 (17). Material included in Rubinstein and Stevens 2000 (25)

MO

Rubinstein and Stevens 2000 (25)

Case series Unrelated (864): HLA identical (44), HLA mismatch (820)



Part-material from Rubinstein 1998 (24)

MO


37





Part-material from Rubinstein 1998 (24)

MO


Case series Unrelated (864) Children and adults (864)


Same patient material as Rubinstein and Stevens 2000 (25)

DSanz et al. 2001 (62)



Chronic myelogenous leukaemia (CML)

Material probably included in Sanz 2001 (26)

OSanz et al. 2001 (26)



Malignant blood diseases

Probably includes material from Sanz 2001 (62)

MO

Sato et al. 2001 (79)

Case Unrelated (1) Child: 9 years (1)

Acute lymfoblast leukaemia

M

Schwinger et al. 1999 (63)

Case series Related: HLA identical (3) Unrelated (3)

Childre: 0.9—6 years (6)


M

Shaw et al. 1999 (64)

Case series Unrelated: HLA identical (1), HLA mismatch (2)

Children: oldest child 6.33 years (3)

Aplastic anemia, Blackfan Diamond anemia, osteoporosis


M

Shen et al. 1994 (65)


Children: 3—15 years (4)

Solid cancer tumours

Infusion of multiple cord blood units

MSuvatte et al. 1998 (66)

Case series Related: HLA identical (6) Children: younger than 14 years (6)


Also reports results from BMT 3 and PBT3

MVermylen et al. 1998 (67)

Case series Related: HLA identical (2) Children: 3.1 and 5.5 years (2)

Sickle-cell anaemia Also reports data from BMT3

MWagner et al. 1993 (68)

Case series Related (15): HLA identical (13), HLA mismatch (2)

Children: median age 4 years, 2—11 years (15)

Malignant (8) and non-malignant (7) diseases

Material probably included in Wagner 1994 (69) and Wagner 1995 (27)

OWagner et al. 1994 (69)

Case series Related (34): HLA identical HLA mismatch



Probably includes material from Wagner 1993 (68). Material included in Wagner 1995 (69).

OWagner et al. 1995 (27)

Case series Related (44): HLA identical (34), HLA mismatch (10)



Probably includes material from Wagner 1993A and Wagner 1994 (69)

MO

Wagner et al. 1996 (28)

Case series Unrelated: HLA identical (7), HLA mismatch (11)

Children and young adults: median age 2.7


Patient material probably included in Wagner 2002

years, 0.1—21.3 years (18)

(29) O

Wagner et al. 2002 (29)


Children and adults: median age 7.4 years, 0.2—56.9 years (102)


Probably includes material from Wagner 1996 (29)

MO

Yu et al. 2001 (29) Case series Unrelated (44): HLA identical (4), HLA mismatch (40)

Children and young adults: median age 5 years, 0.4—20.6 years (44)


M

Zecca et al. 2002 (71)

Case series Related: HLA identical HLA mismatch Unrelated

Children: under 18 years (32)


Also reports results from BMT3

Analyses complications

M


38

1 – Number of patients in parenthesis2 – O - overlapping patient material; D – double publication; M – main publication/original study on which the review is based3 – BMT – bone marrow transplantation; PBT – peripheral blood cell transplantation

None of the included studies are of experimental design, but they are based on observa-tions. Study design includes cohort studies and case series as well as a few case reports. Some of the studies are based on registries, but none of the registry studies are popula-tion based. Only a very limited number of controlled studies were identifi ed. All cohort studies have a retrospective design with historical controls. A majority of the studies are non-controlled, retrospective case series. Some of the case series compare results after cord blood transplantation with results after bone marrow transplantations, but the patient group which underwent the bone marrow transplantation, do not fulfi l the criteria for a control group. Several of the case series are reviews and are characterised as such, however, they report up-to-date results, often from larger patient groups than the origi-nal study. Several studies have overlapping patient material, which creates uncertainty whether patients from one study are also included in other studies. In addition, a number of double publications exist. This is accounted for in Table 5.1.

Documentation basisThe studies in the literature basis were subject to a systematic and critical assessment of relevance, quality and validity as described in Chapter 4. All original studies of accept-able (high/medium) quality were included in the documentation. In addition, two exten-sive case series with longer follow-up periods than the original studies and with supple-menting patients were included (18 and 25). The required inclusion and quality criteria exclude case reports, studies ranked as low quality studies as well as case series with less than 20 patients or less than 10 patients per disease indication. Thus, the documentation for the HTA-report consists of 17 studies (13 - 29), see Table 5.2.

ResultsWhen summarising the available documentation, a distinction has been made between i) transplantations where donor and recipient are related (primarily siblings), where the

Table 5.2. Classification of studies included in the documentation basis Study design Donor Recipient Evidence gradation Reference

Cohort Case series

Related Unrelated Children Adults Number Quality class

Evidence level

Badell et al. 2000 (16) X X X X 28 + 3+ Barker et al. 2001 (13) X X X 31 + 2+ Gluckman et al. 1997 (17) X X X X X 143 + 3+ Gluckman et al. 2000 (18) X X X X X 527 + 3+ Kurtzberg et al. 1996 (19) X X X 25 + 3+ Laughlin et al. 2001 (20) X X X 68 + 3+ Locatelli et al. 1999 (21) X X X X 102 + 3+ Locatelli et al. 2003 (22) X X X X 44 + 3+ Ohnuma et al. 2001 (23) X X X X 39 + 3+ Rocha et al. 2000 (14) X X X 113 + 2+ Rocha et al. 2001 (15) X X X 99 + 2+ Rubinstein et al. 1998 (24) X X X X 562 + 3+ Rubinstein and Stevens 2000 (25)

X X X X 864 + 3+

Sanz et al. 2001 (26) X X X 22 + 3+ Wagner et al. 1995 (27) X X X 44 + 3+ Wagner et al. 2002 (28) X X X X 102 + 3+ Yu et al. 2001 (29) X X X 44 + 3+


39

HLA- compatibility often is good, and ii) transplantations where donor and recipient are unrelated where transplantations are more often performed with higher degrees of HLA incompatibility. In addition, documentation of results after cord blood transplantations of children versus adults is reported.

Of the included studies, only 3 have attempted to compare the results with other trans-plantation alternatives with patients of the same age group and treated over the same time period, but this has taken place retrospectively and without randomising the treat-ment groups (13, 14 and 15).

Estimated survival and event-free survival for cord blood transplantations from the larg-est patient materials (14, 15, 18 and 20) for different diseases and leukaemias in particu-lar are summarised below. Results from transplantation of cord blood stem cells in leu-kaemias have been systematised according to risk of relapse (standard/high).

Transplantation in children with related donorsThe use of family donors for children yields good results, especially in non-malignant blood diseases. A cohort study comparing transplantation of stem cells from cord blood with stem cells from bone marrow from tissue-type identical donors (14), shows a 3-year survival of 86% versus 84% in non-malignant blood diseases and 46% versus 55% in malignant diseases (Table 5.3). Other case series report good transplantation results when using cord blood stem cells from HLA- compatible siblings (16—18, 21, 22 and 28).

Transplantation in children with unrelated donorsResults when using unrelated donors in children are acceptable, but the observation periods in the included studies are relatively short and several have used event-free survival as the endpoint (Table 5.4). A cohort study comparing transplantations of stem cells from cord blood with stem cells from bone marrow from unrelated donors (15) shows a somewhat lower 2-year survival when using cord blood (35% versus 49%) in children with acute leukaemia. An extensive case series (18) reports results in the shape of event-free survival after 2 years for 291 children with non-malignant heritable diseases (EFS= 41%), malig-nant blood diseases (EFS= 36%) and diseases involving bone marrow failure (EFS= 21%). Results in high-risk patients are not particularly good (15, 18).

Other included studies support cord blood transplantation as a potential curative alternative to transplantations with stem cells from blood or bone marrow (13, 16, 17, 19, 21, 23—25,

Table 5.3. Overall survival and event-free survival (EFS) after transplantation of stem cells fromcord blood – HLA identical family donor

CHILDRENDiagnose group Number Survival EFS Follow-

upReference

Malignant diseaseLeukaemia- low risk- intermediate risk- high risk

Other malignant disease

Non-malignant disease

In total 1136147- 10 - 28 - 9 14

52

46%86%

-

-

3 years Rocha et al. 2000 (14)


40

27 and 29). One of the case series (25) includes an extensive patient material where as many as 679 of a total of 864 patients are children, but as the patient material is insuffi -ciently described, it is diffi cult to evaluate the results for children separately.

*Patient material from Locatelli et al. 1999 (21) probably included in Gluckman et al. 2000.

Transplantation in adults with unrelated donorsTransplantation with cord blood from unrelated donors in adults is illustrated in two case series of some size (Table 5.5). The most extensive case series (18) shows 27% 1-year sur-vival for malignant blood diseases. However, the study s̓ description of its patient material is somewhat incomplete, which complicates the evaluation of the results. The other case series (20) reports survival and event-free survival for patients with malignant and non-malignant diseases after 22 months as 28% and 26% respectively.

Other case series support cord blood transplantation as an alternative method to transplan-tation with stem cells from blood or bone marrow (17, 26, 28).

Evidence tablesThe following evidence tables (in alphabetical order) summarise the studies included in the documentation.

Table 5.4. Total survival and event-free survival (EFS) after transplantation with stem cells fromcord blood – unrelated donor

CHILDRENDiagnose group Number Survival EFS Follow-

upReference

Acute leukaemia- standard risk- high risk

In total: 99- 67 - 32

35%Notspecified

31%Hazard ratio for death >100 days forhigh risk 3.23

2 years Rocha et al. 2001 (15)

Malignant blood diseasesLeukaemia- standard risk- high risk

Other malignant diseasesNon-malignant diseases

Bone marrowfailureHeritablediseases

In total: 291202102- 66 - 36 10089

28

61

-

36%

- 49% - 89%

21%

51%

2 years Gluckman etal. 2000 (18)*

Table 5.5. Overall survival and event-free survival (EFS) after transplantation with stem cells fromcord blood – unrelated donor

ADULTSDiagnose group Number Survival EFS Follow-

upReference

Malignant blood diseasesAcute leukaemia

- standard risk- high risk

108

--

27%

39%17%

- 1 year Gluckman etal. 2000 (18)

Malignant blood diseasesLeukaemia- standard risk- high risk

Non-malignant diseases

54- 29- 25 14

28% 26% 22months



41

Study (16): Badell S, I, Olive OT, Madero LL, Munoz VA, Martinez RA, Verdeguer MA et al. [Transplantation of umbilical cord blood hematopoietic progenitor cells in children]. [Spanish]. Anales Espanoles de Pediatria 2000; 53 (6): 513—519. Objective: Results of cord blood transplantations in Spain Study design: Case series – retrospective Study characteristics Result and conclusion of article Quality assessment and commentary

Donor Related 4

2 HLA id. fam. donors 2 mismatched fam. donors

Unrelated 24

Recipient 28 children, aged 5—17, average 6.5 yrs

Diagnosis Leukaemia 21 Congenital 7

Control group None

Endpoint GvHD Event-free survival (EFS)

Follow-up Average 16.6 months

Data/materialMaterial reported to the Spanish group for bone marrow transplantations in children

Statistical analysisKaplan-Meier

Observed survival In total 34.4% EFS Acute leukaemia 23% EFS Chronic leukaemia 0% EFS

Engraftment 19 out of 28

Complications/side effects29% severe GvHD (8 out of 28)

Authors’ conclusion Best results in patients with congenital diseases. Relatively high level of GvHD.

Quality and validity assessed according to check list Quality class + (medium quality)

Statistical evaluation Few patients, somewhat heterogeneous as regards stage of leukaemia

Other commentariesNo control group Few patients Relatively short observation period

Evidence gradation: Evidence level 3+

Study (13): Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leucocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Blood 2001; 91(10): 2957—2961. Objective: Result of cord blood transplantation at the University of Minnesota Study design: Cohort study – matched-pair analysis Study characteristics

Donor Unrelated 31

Recipient 31 children aged 0.2—17.9 years. Median 4.5 years

Diagnosis Leukaemia 17 Congenital 9 Others 5

Control group Patients transplantation. with unrelated BM from NMDP, T-cell purified or not T-cell purified.

Endpoint Engraftment GvHD Survival Cause of death

Follow-up 2 years

Data/materialRetrospective, single-centre analysis

Statistical analysisMatched-pair analysis

Result and conclusion of article

Observed survival 2 years No significant difference between groups

Engraftment Differences between groups, but not of statistical significance (cord blood 88%, BM not T-cell purified 96%)

Complications/side effectsNo statistical difference in GvHD

Authors’ conclusion UCBT is a cost-effective alternative to HLA matched allogenous BMT in children, particularly if transplantation must be performed quickly with unrelated donor.

Quality assessment and commentary


Statistical evaluation Few patients and probably limited impact as regards proving differences

Other commentariesControl group are patients from same institution, treated in more or less same time period.



42

Study (17): Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. New England Journal of Medicine 1997; 337(6): 373—381. Objective: Analysis of results of allogenous stem cell transplantations with cord blood Study design: Case series – retrospective analysis Study characteristics

Donor Related/family 78, unrelated 65

Recipient Adults 23, children 120

Diagnosis Leukaemia 89 Lymphoma 4 Neuroblastoma 2 Acquired BM failure 7 Congenital BM failure 19 Haemoglobinopathy 8 Congenital metabolism diseases 14

Control group None

Endpoint Engraftment Acute GvHD Chronic GvHD Recidivation Complications


Observed survival One year: 49% Family: 63%, best in HLA matches Unrelated: 29% independent from HLA

Engraftment Family 79% Unrelated 87%

Complications/side effectsAcute GvHD 2: 14/78 family 21/65 unrelated

Authors’ conclusion Cord blood is an alternative source of haematopoietic stem cells for children and some adults with malignant and non-malignant blood diseases. Prospective studies of clinical effect of strategies for donor selection should be conducted.



Other commentariesThe study is retrospective, it is not clear whether all transplantations performed in Europe (and other centres) have been included in this multi-centre study and the patient material is heterogeneous with incomplete information about risk criteria related to the requirements currently being set for a prospective study

Data/materialMulti centre

Statistical analysisKaplan-Meier, Cox Evidence gradation: Evidence level 3+

Study (18): Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Experimental Hematology 2000; 28: 1197—1205. Objective: Evaluate results of cord blood transplantations within Eurocord. Study design: Case series – analysis of reported results from 121 transplantations in 29 countries. Study characteristics


Recipient Children: Family donors 138

Unrelated donors 291 Adults: Unrelated donors 108

Diagnosis Children, family donors a) Malignity 74 (3 non-haematologic), b) other 54 Children, unrelated donors a) malignity 202, b) others 89 Adults, unrelated donors: malignity 108

Control group None for the entire material, but for HLA identical families and for children with leukaemia - both published elsewhere

Endpoint Survival, GvHD

Follow-up Varying periods and accuracy

Data materialPatients reported to Eurocord



Observed survival Children, family donors, 2 year survival 46% in malignancies 76% in aplastic anaemia 79% in metabolic diseases

Children, unrelated donors, 2 year survival EFS malignity 36% Aplastic anaemia 21% Metabolic diseases 51% Adults, unrelated donors, 1 year survival In total 27% Advanced disease 17%

Engraftment Only 50% in aplastic anaemia, unrelated donor Adults 81%

Complications/side effectsChildren, family donors: 20% acute GvHD 2 Children, unrelated donors: 39% acute GvHD 2 Adults, unrelated donors: 38% acute GvHD 2

Authors’ conclusion UCBT is a good alternative (for children?) who need allogenous stem cell transplantation



Statistical evaluation Difficult to evaluate

Other commentariesThis is a review, or a state-of-the-art article on UCBT, with and without controls and data published elsewhere with selection of patients (children with HLA identical family donors, children with acute leukaemia).


Cause of death Survival

Study (18): Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Experimental Hematology 2000; 28: 1197—1205. Objective: Evaluate results of cord blood transplantations within Eurocord. Study design: Case series – analysis of reported results from 121 transplantations in 29 countries. Study characteristics


Recipient Children: Family donors 138

Unrelated donors 291 Adults: Unrelated donors 108

Diagnosis Children, family donors a) Malignity 74 (3 non-haematologic), b) other 54 Children, unrelated donors a) malignity 202, b) others 89 Adults, unrelated donors: malignity 108

Control group None for the entire material, but for HLA identical families and for children with leukaemia - both published elsewhere

Endpoint Survival, GvHD

Follow-up Varying periods and accuracy

Data materialPatients reported to Eurocord



Observed survival Children, family donors, 2 year survival 46% in malignancies 76% in aplastic anaemia 79% in metabolic diseases

Children, unrelated donors, 2 year survival EFS malignity 36% Aplastic anaemia 21% Metabolic diseases 51% Adults, unrelated donors, 1 year survival In total 27% Advanced disease 17%

Engraftment Only 50% in aplastic anaemia, unrelated donor Adults 81%

Complications/side effectsChildren, family donors: 20% acute GvHD 2 Children, unrelated donors: 39% acute GvHD 2 Adults, unrelated donors: 38% acute GvHD 2

Authors’ conclusion UCBT is a good alternative (for children?) who need allogenous stem cell transplantation



Statistical evaluation Difficult to evaluate

Other commentariesThis is a review, or a state-of-the-art article on UCBT, with and without controls and data published elsewhere with selection of patients (children with HLA identical family donors, children with acute leukaemia).



43

Study (19): Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. New England Journal of Medicine 1996; 335(3): 157—166. Objective: Describe preliminary results of 25 consecutive allogenous stem cell transplantations from unrelated donors Study design: Case series – phase 1 Study characteristics Result and conclusion of article Quality assessment and commentary

Donor Unrelated 25

Recipient Children 24 Adult 1

Diagnosis Malignancy 19 Others 6

Control group None

Endpoint Engraftment GvHD Event-free survival (EFS)

Follow-up Median 171 days

Data/material Patients transplanted with cord blood from New York Blood Center


Observed survival 12 out of 25 EFS 7 – 32 months after transplantation

Engraftment 23/25

Complications/side effectsAcute GvHD 2 9 out of 21 evaluated

Authors’ conclusion Partial mismatched cord blood from unrelated donor could be an alternative source of haematopoietic reconstitution.


Other commentariesLimited and early study showing that transplantation of cord blood from unrelated donors can be performed also without full HLA compatibility.


Study (20): Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. New England Journal of Medicine 2001; 344(24): 1815—1822. Objective: Evaluate the safety of transplantations with unrelated cord-blood donors for adults Study design: Case series - results with cord-blood transplantations at 5 different American clinics Study characteristics

Donor Unrelated 68

Recipient Adults 68, median age 31.4 years, median weight 69 kg.

Diagnosis Malignant blood diseases 54 BM aplasia 13 Congenital metabolic dis. 1

Control group None

Endpoint Haematologic reconstitution GvHD Time to relapse Survival Event-free survival (EFS)

Follow-up 22 months

Data/materialMulti-centre study – consecutive from 5 institutions

Statistical analysisKaplan-Meier, LogRank or Wilcoxon


Observed survival Survival 19/68 (28%) – 22 months median EFS 18/68 (26%) – 22 months median

Engraftment 90%

Complications/side effectsAcute GvHD 2 33/55 possible to evaluate. 32 died of complications within 3 months after the transplantation.

Authors’ conclusionTransplantation with HLA mismatched cord blood can be performed in adults. May be an alternative if an HLA matched unrelated donor cannot be identified soon enough (within 6—8 weeks).



Statistical evaluation Few patients in each sub-group

Other commentariesApproximately 60% of the patients died of complications related to the treatment. The article however does not specify what happened to the patients in the different risk groups.



44

Study (21): Locatelli F, Rocha V, Chastang C, Arcese W, Michel G, Abecasis M et al. Factors associated with outcome after cord blood transplantation in children with acute leukaemia. Eurocord Cord Blood Transplant Group. Blood 1999; 93(11): 3662—3671. Objective: Describe results of allogeneic stem cell transplantations with cord blood in children with acute leukaemia. Study design: Case series – retrospective analysis of results in patients reported to Eurocord. Study characteristics

Donor Related/family 42 Unrelated 60

Recipient 102 children aged 0.3—15 years. Median 5.5 years

Diagnosis Acute leukaemia Standard risk 66 High risk 36

Control group None

Endpoint Engraftment Acute and chronic GvHD Time to relapse TRM Overall survival (OS) Event-free survival (EFS)

Follow-up Family: 4 months Unrelated: 14 months

Data/material Register data

Statistical analysisKaplan-Meier, Log rank, Cox


Observed survival 2-year survival: a) family 39%, b) unrelated 30%

2-year EFS: a) standard risk 49%, b) high risk 8%

Engraftment Family 84% Unrelated 78%

Complications/side effectsFamily: acute GvHD 2: 41% Unrelated: acute GvHD 2: 37%

Authors’ conclusion Transplantations from related or unrelated cord blood donors can be performed in, and cure, children with acute leukaemia. A final conclusion cannot be drawn until a more extensive study with a relevant control group has been conducted.



Other commentariesVery poor results in patients with advanced leukaemia, but hardly poorer than with other treatment methods.

Patient material is probably included in Gluckman 2000 (18).


Study (22): Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle-cell disease. Blood 2003; 101(6): 2117—2143. Objective: Evaluate whether death rates related to transplantations are lower when using cord blood than when conventional allogeneic stem cell transplantations with HLA identical sibling donors are used in thalassemia and sickle-cell anaemia. Study design: Case series – retrospective analysis of patients reported to Eurocord. Study characteristics

Donor Related 44 - HLA identical siblings

Recipient 44 children, siblings, aged 1—20 years: median 5 years

Diagnosis Thalassemia 33 Sickle-cell anemia 11

Control group None

Endpoint Engraftment Overall survival (OS) Event-free survival (EFS)

Follow-up 24 months Data/materialReports submitted to Eurocord

Statistical analysisKaplan-Meier, LogRank, Cox


Observed survival OS: 100% EFS thalassemia: 79% EFS sickle-cell anaemia: 90%

Engraftment 38 patients

Complications/side effectsAcute GvHD 11%

Authors’ conclusion Cord blood transplantation with HLA identical healthy sibling donors give good results for thalassemia and sickle-cell anaemia in children.



Other commentariesJustifiable conclusion



45

Study (23): Ohnuma K, Isoyama K, Ikuta K, Toyoda Y, Nakamura J, Nakajima F et al. Cord blood transplantation from HLA mismatched unrelated donors as a treatment for children with haematopoietic malignancies. British Journal of Haematology 2001; 112(4): 981—987. Objective: Results of allogeneic stem cell transplantation with HLA mismatched cord blood from unrelated donor. Study design: Case series – retrospective material of patients transplanted with donor blood from Japanese donor bank. Study characteristics Result and conclusion of article Quality assessment and commentaryDonor Unrelated 39 – mismatch

Recipient Mainly children aged 0.5—28 years: median 3.1 years

Diagnosis Malignant blood diseases - ALL 21 - AML 15 - CML 1 - MDS 1 - JMML 1

Control group None

Endpoint Engraftment GvHD Overall survival (OS) Event-free survival (EFS)

Follow-up 23.9 months

Data/materialReports from transplantation centres to the cord blood bank


Observed survival 3 years: 49% EFS, high risk 29%, standard risk 75%


Complications/side effectsAcute GvHD 2: 13 out of 32 Chronic GvHD 4 out of 23 at risk

Authors’ conclusion Cord blood transplantation with mismatched unrelated donors can be performed in, and cure, some children with leukaemia. A more extensive study with an adequate control group should be conducted.



Study (14): Rocha V, Wagner JE Jr, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM et al. Graft-versus-Host-Disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. New England Journal of Medicine 2000; 342(25): 1846—1854. Objective: Studying allogeneic stem cell transplantations with cord blood from sibling donors compared with bone marrow transplantations, HLA identical siblings. Study design: Cohort study - retrospective analysis of data from Eurocord compared with IBMTR data from the same period. Study characteristics

Donor Related 113 - HLA identical siblings

Recipient 113 children aged < 15 years: median 5 years

Diagnosis Malignant 61 (54%) Non-malignant 52 (46%) – majority congenital BM failure

Control group Yes, from 2052 patients IBMTR

Endpoint Engraftment GvHD Overall survival (OS)

Follow-up 3 years

Data/materialData reported to Eurocord and IBMTR



Observed survival Cord blood BM

2-year OS malignant 46% 55% 3-year OS non-mal. 86% 84%

Engraftment Cord blood: 89% Bone marrow: 98%

Complications/side effectsCord blood BM

Acute GvHD 2 14% 24% Chronic GvHD 6% 15%

Authors’ conclusion Children who underwent transplantations with cord blood from HLA identical siblings had lower risk of acute and chronic GvHD than children who received bone marrow from HLA identical siblings. The results justify systematic storage of cord blood for families with children who are affected by diseases treatable with allogeneic stem cell transplantations.



Other commentariesThe results form a solid basis for the authors’ conclusion.



46

Study (15): Rocha V, Cornish J, Sievers EL, Filipovich A, Locatelli F, Peters C et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukaemia. Blood 2001; 97(10): 2962—2971. Objective: Compare results after transplantations with cord blood, unmanipulated bone marrow and T-cell purified bone marrow from unrelated donors in children with acute leukaemia. Study design: Cohort study - retrospective analysis of data reported to Eurocord and others. Study characteristics

Donor


Observed survival


Quality and validity assessed accordingUnrelated 99

Recipient 99 children aged 2.5—10 years: median 6 years

Diagnosis Acute leukaemia

Control group Yes, from Eurocord and other centres, consecutive patients

Endpoint Engraftment GVHD Early TRM Event-free survival (EFS) Overall survival (OS)

Follow-up Cord blood: 19 months Bone marrow: 30—33 months

Data/material

Statistical analysisKaplan-Meier, Cox

2 years: C.blood BM BM, TCD OS 35% 49% 41% EFS 31% 43% 37%

Engraftment Cord blood 80% BM 90—96%

Complications/side effectsAcute GVHD 2: Cord blood: 35% Unmanipulated BM: 58% T-cell purified BM: 20%

Authors’ conclusion Both cord blood and BM from unrelated donors are alternatives for children with acute leukaemia without family donors.

to check list Quality class + (medium quality)

Other commentariesThe article gives reasonable evidence for the authors’ conclusion. The course for patients in the high-risk group is not explicitly defined.


Study (24): Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR et al. Outcomes among 562 recipients of placental blood transplants from unrelated donors. New England Journal of Medicine 1998; 339(22): 1565—1577. Objective: Evaluate results of cord blood transplantations with graft from one biobank. Study design: Case series - retrospective analysis of results (multi centre). Study characteristics

Donor Unrelated 562

Recipient 460 children 102 adults

Diagnosis Leukaemia/lymphoma 378 Heritable diseases 137 Non-malignant diseases 47

Control group None

Endpoint Engraftment Graft failure GvHD Event-free survival (EFS)

Follow-up 1 year

Data/materialCord blood from New York Blood Bank. Transplantations at different centres



Observed survival Difficult to separate the various patients groups


Complications/side effectsAcute GVHD 2: 45% Chronic GVHD: 25% 218 dead before day 100

Authors’ conclusionCord blood from unrelated donors is a useable source of haematopoietic stem cells for patients without family donors.



Other commentariesAn important piece of work due to its size. An important basis for other works looking in more detail at survival and complication data for various patient and disease groups.



47

Study (25): Rubinstein P, Stevens CE. Placental blood for bone marrow replacement: The New York Blood Center’s program and clinical results. Baillieres Clinical Haematology 2000; 13(4): 565—584. Objective: Updating of enlarged patient basis from original article New England Journal of Medicine 1998. Study design: Case series – retrospective analysis of transplantation results with cord blood from one biobank. Study characteristics

Donor Unrelated 854

Recipient Children and adults (185 > 18 years)

Diagnosis Leukaemia/lymphoma 571 Heritable diseases 209 Acquired diseases 74

Control group None

Endpoint Engraftment GvHD Event-free survival (EFS) Overall survival (OS)

Follow-up 3 years

Data/material

Statistical analysisKaplan-Meier, Log Rank, Cox


Observed survival EFS (3 years): - Heritable diseases: 48% - Leukaemia/lymphoma: 27% - Acquired diseases: 29%

Engraftment 92.7% - lower in patients > 18 years

Complications/side effectsAcute GvHD dg 2: 48% Chronic GvHD: 31%

Authors’ conclusion Data for unrelated cord blood transplantations are currently preliminary. HLA influences acute GvHD and other complications, and higher HLA compatibility reduces the probability of EFS.



Other commentariesResults for leukaemia and lymphoma transplantations are not particularly good. The risk of recidivation is estimated at 50% for advanced diseases and approx. 25% for patients with less advanced diseases. This indicates an EFS for patients with advanced disease at max. 10—15%. Over 60% have an event within 6 months.


Study (26): Sanz GF, Saavedra S, Planelles D, Senent L, Cervera J, Barragan E et al. Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood 2001; 98(8): 2332—2338. Objective: Evaluate results from CBT with unrelated donors with a standardised conditioning programme. Study design: Case series Study characteristics

Donor Unrelated 22

Recipient 22 adults

Diagnosis CML: 12 – 6 advanced ALL: 6 – all high-risk AML: 3 – 2 high-risk MDS: 1

Control group None

Endpoint Engraftment Event-free survival (EFS) GvHD

Follow-up 3—45 months, median 8 months

Data/materialSingle study, consecutive patients

Statistical analysisKaplan-Meier, Log Rank


Observed survival EFS 1 year: 53%

Engraftment 20 out of 22, one secondary graft failure

Complications/side effectsAcute GvHD 2: 16 Chronic GvHD: 9 out of 10 possible to evaluate TRM day 100: 43%

Authors’ conclusionPreliminary results which may indicate that CBT with unrelated donors may be an alternative for adult patients with haematologic malignancies without bone marrow/blood stem cell donors.


Quality and validity assessed according to after check list Quality class + (medium quality)

Statistical evaluation Few patients in total, few in each group, short follow-up period, no control group.

Other commentariesThis study is too limited, with too short an observation period and too few patients in each group to be attributed any impact of significance.



48

Study (27): Wagner JE, Kernan NA, Steinbuch M, Broxmeyer HA, Gluckman E. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet 1995; 346: 214—219. Objective: Effect of cord blood as source for allogeneic haematopoietic stem cells for sibling transplantations in children. Study design: Case series – retrospective analysis of data reported to the International Cord Blood Registry. Study characteristics

Donor Related 44 - Sibling donor, up to 3 HLA AGMM

Recipient 44 children aged 0.8—16 years: median 5 years

Diagnosis Malignancy: 25 Non-malignancy: 19

Control group None

Endpoint Engraftment GvHD Event-free survival (EFS)

Follow-up 1.6 year median

Data/materialFrom centres in the US and Europe 1988—94



Observed survival EFS for patients with up to 1 HLA Ag incompatibility: - Malignant: 46% - Non-malignant: 78%

Engraftment 85%

Complications/side effectsAcute GvHD 2: 3% Chronic GvHD: 6%

Authors’ conclusionCord blood is an adequate stem cell source for children with an HLA identical or 1 HLA antigen incompatible sibling donor with low risk of GvHD.



Other commentariesHeterogeneous material with few patients in each group.


Study (28): Wagner JE, Barker JN, DeFor TE, Blazar BR, Eide C et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and non-malignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100(5): 1611—1618. Objective: Analysing the effect of HLA incompatibility and CD34 dose on engraftment, GvHD, TRM, recidivation and survival. Study design: Case series – retrospective analysis from individual centres. Study characteristics

Donor Unrelated 102

Recipient > 18 years: 22 < 18 years: 80

Diagnosis Malignancy: 65 Non-malignancy: 37

Control group None

Endpoint Engraftment GvHD TRM Survival

Follow-up 2.7 years median


Observed survival 2 years: non-malignant: 60% malignant, high-risk: approx. 30%

Engraftment 88% (with 5% secondary graft failure)

Complications/side effectsAcute GvHD 2: 39 out of 102 Chronic GvHD: 9% TRM 2 years: 35% on average, significantly lower than with CD34 dose > 2.7 x 105/kg

Authors’ conclusion Dose of CD34 positive cells in the graft important for the result, and more important than HLA incompatibility



Other commentariesHigher survival rate at high-risk malignancies than in other studies.

Data/materialSingle centre

Statistical analysisKaplan-Meier, Cox Evidence gradation: Evidence level 3+


49

Study (29): Yu LC, Wall DA, Sandler E, Chan KW, Grayson G, Kletzel M. Unrelated cord blood transplant experience by the pediatric blood and marrow transplant consortium. Pediatric Hematology & Oncology 2001; 18(4): 235—245. Objective: Analysis of 44 consecutive transplantations with unrelated cord blood over 2 years. Study design: Case series – retrospective unrelated multi centre. Study characteristics

Donor Unrelated 44

Recipient 44 children

Diagnosis Malignancy 34 Non-malignancy 10

Control group None

Endpoint Overall survival (OS) Engraftment Acute GvHD Time to relapse Death

Follow-up 45 months median



Observed survival OS: Malignant: 42% Non-malignant: 54%


Complications/side effectsAcute GvHD 2: 44% Chronic GvHD: 8/29

Authors’ conclusion Cord blood from unrelated donors is an adequate stem cell source for children who need allogeneic stem cell transplantation for malignant or non-malignant diseases.



Statistical evaluation Limited and heterogeneous material.

Other commentariesNo subdivision into low and high-risk patient groups.


Quality of cryopreserved stem cellsAs therapeutic use of stem cells from cord blood is a relatively new method, experience is limited as regards the validity of cord blood stem cells after cryopreservation. The lit-erature review did not identify publications that have documented the safe storage time for cryopreserved blood/cells as regards clinical effect. This could also not be expected taken into consideration the short time period such transplantations have been performed.

However, one publication examining the quality of cord blood which has been stored between 8 weeks and 15 years as regards cell yield, viability and clonogenic capacity was identifi ed (82). The results indicated a median loss of cells of 20% and that stem cells in material stored for more than 15 years (8 donors) had maintained their clonogen-ic potential measured by using standard growth tests. Clinical data are not available.

Published results from stem cell transplantations of long-term cryopreserved cord blood do nevertheless indicate the same level of survival or complications compared with cord blood used immediately after harvesting or where the period of cryopreservation has been short.

Experience from transplantations with blood stem cells from bone marrow, as well as experience with this type of stem cell in laboratories, indicates that stem cells maintain their quality for at least 8 years (83), but experience with cryopreserved cells in general shows that the cells will lose their viability over time. It is therefore important to mea-sure the cells ̓viability after thawing as a surrogate measure for the quality of cryopre-served stem cells. In addition, it will be increasingly more important to carry out func-tional tests of the quality of the cells before using them for transplantations.


50

Summary and synthesisThe validity of the included studies which investigate the clinical effect of transplanta-tions with stem cells from cord blood, have been ranked at level of evidence 2+ (cohort studies) and 3+ (case series). All cohort studies include cord blood transplantations in children. Thus, the collected documentation of the effect of cord blood transplantations in children has moderate impact (strength of evidence C). As the results from cord blood transplantations in adults are only published as case series, the collected documentation of effect in adults has low impact (strength of evidence D).

Having these reservations as regards the impact of the documentation in mind, the clinical effects of cord blood transplantations can be summarised as follows:

Allogeneic stem cell transplantation with unrelated cord blood can be a potential curative alternative to transplantations with blood or bone marrow stem cells in patients - particu-larly children - with certain rare bone marrow diseases without good alternative treat-ment methods, and in leukaemias with high risk of relapse and death without transplan-tation, where suitable donors of blood or bone marrow stem cells cannot be identifi ed within a reasonable period of time. For adult patients, this treatment method should only be considered in very special cases.

Results after transplantations with cord blood from siblings of children with known malignant blood diseases or severe bone marrow failure appear to be equal to transplan-tations with blood or bone marrow stem cells with the same HLA- compatibility.

The literature review did not identify studies that document the safe storage time for cryopreserved blood/cells as regards clinical effect.


51

6. Assessment of effect – discussionThe discussion about cryopreservation and transplantation of stem cells from cord blood can be divided into two main parts; i) the documentation regarding treatment effect and disease indication area, and ii) the practical execution of harvesting, processing, cryo-preservation, storage and delivering stem cells for transplantation. This chapter discusses the indication position based on the literature review and prevailing indications for cord blood stem cell transplantation are discussed.

Autologous cord blood transplantationsExperience with autologous cord blood transplantation has not been published. So far, there is no scientifi c literature that can provide answers to the questions about therapeu-tic effect and results and future possibilities of manipulation of the product such as gene manipulation. Harvesting and cryopreservation of cord blood from newborn babies is technically a fairly simple procedure and hence, it can theoretically be done routinely. Cryopreservation is practised throughout the western world, but has so far been per-formed only sporadically in Norway.

The lack of published results of autologous use can partly be contributed to the fact that cord blood transplantation is a relatively new method. The use of cryopreserved cord blood stem cells from close relatives (related donors), and the establishment of biobanks stor-ing stem cell units where it is possible to search in registries for suitable unrelated donors, have only been possible for transplantations for about 10 years. Eventhough the biobanks include some 100,000 units, and over 2,000 allogeneic transplantations have been reported (2), clinical outcome of autologous cord blood transplantations have yet to be published in the medical literature. Autologous transplantations require stem cells from the patient s̓ cord blood being harvested at birth for cryopreservation, and that the patient has a disease where the treatment with haematopoietic stem cells has been documented effective, or where there is good reason to believe that the treatment will have an effect. Also the stem cells must be unaffected by the disease they are meant to cure. Estimates associated with great uncertainties indicate that a newborn baby who has its cord blood harvested has 0.005% chance of needing (its own) stem cells for future treatment (84).

Allogeneic cord blood transplantationsProspective, randomised studies comparing cord blood transplantations and transplanta-tions of blood or bone marrow cells with corresponding HLA- compatibility have not been published. As of today, it is not realistic to expect the effect of cord blood transplan-tations with unrelated donors to be documented in randomised studies. A placebo-con-trolled study cannot be conducted with this group of patients, who need aggressive treat-ment. It is also unlikely that a randomised study of the use of cord blood with unrelated donors versus related donors with a maximum mismatch of 3 antigens will be conducted. Nor does any cohort study with prospective design and ideal control group exist. On the other hand, some “retrospective” cohort studies with historical controls have been pub-lished, as well as several case series of varying sizes.


52

The documentation for this HTA- report consists of a selection of these studies of an acceptable quality, and includes patients transplanted with cord blood from New York Cord Blood Center, patients who have been transplanted and reported to Eurocord, and experience from single centres. It has been diffi cult to establish to what extent several studies include the same patients.

So far, the closest possible method of reaching a prospective study has been to register patients at the time it has been made clear that indications for allogeneic stem cell trans-plantation are present, and that the patient does not have a sibling donor. The patient is then followed all the way through the transplantation process with either blood or bone marrow cells, cord blood from unrelated donor, or blood or bone marrow cells from related donor with a maximum mismatch of 3 antigens. The purpose is to attempt to reveal which strategy gives the best treatment result. The study planned within EBMT can be illustrated in the following fl ow chart (Figure 6.1):

Figure 6.1

In the included studies, attempts have been made to compare the treatment methods, either through historical controls or by using data from international bone marrow trans-plantation registries with retrospective methodology. A weak point in the majority of the transplantation literature is that it is not population-based and that the selection process prior to the transplantation is vague. In the literature on cord blood transplantation, there is no information about patients where a search was initiated without revealing donors, or about patients where donors were found but the transplantations were not performed. Hence, little knowledge exists on the number of patients where cord blood transplanta-tions were prepared, i.e. the number and type of patients where a search was initiated, and how many eventually received a transplant. Figure 6.2 illustrates the practice regard-ing allogeneic stem cell transplantation with cord blood and reporting of results.

Indication, HLA-identicalsibling

Initiate search

International bonemarrow registries

Haploid (max. 3 HLAmismatch) – family(parents)

Cord blood

Transplanted Transplanted Transplanted

Result Result Result

Indication, HLA-identicalsibling

Initiate search

International bonemarrow registries

Haploid (max. 3 HLAmismatch) – family(parents)

Cord blood

Transplanted Transplanted Transplanted

Result Result t


53

Indications

Search for donor initiated

Donor found

Patient still candidate fortransplantation

Patient transplanted

Diagnosis and prognosis group

Publications about cord bloodtransplantations

Follow-up period

Reported results overall survival

disease- progression free survival

event-free survival- “quality of life”

Indications

Search for donor initiated

Donor found

Patient still candidate for transplantation

Patient transplanted

Diagnosis and prognosis group

Publications about cord bloodtransplantations

Follow-up period

Reported results overall survival

disease- progression free survival

event-free survival - “quality of life”

Figure 6.2

Information about some 2,000 patients who have undergone allogeneic stem cell transplan-tation with cord blood from related or unrelated donors, exists in the included studies. The majority of the transplantations have been performed in children, approximately 1,600. Some 20% of the patients in the included studies are adults. Most of the transplantations were per-formed to treat malignant blood diseases, i.e. leukaemias and above all, acute leukaemias.

In the comparative studies of cord blood transplantations, patients with malignant blood diseases have been divided into two groups: standard and high-risk groups. This division is mainly based on whether the patients are in fi rst or second remissions (standard risk) or later remission or no remis-sion (high risk). This detailed information is important, but has considerable weaknesses. Several variables exist that can distinguish between low, standard and high risk of relapse, especially for patients in the fi rst remission. Clonal chromosome changes in bone marrow cells at the time of diagnosis are one highly important variable. This information is very often missing in literature on cord blood transplantation. It would have been valuable to know how strong the indications for cord blood transplantations really were in the fi rst place. The same argumentation is valid for much of the literature on other types of allogeneic stem cell transplantations. It must be assumed – without knowing for certain – that the patients treated were in fi rst remission with a high risk of relapse.

Furthermore, it is likely that suitable donors, either within the families or in the international registries of bone marrow donors, had not been found within reasonable time for the major-


54

ity of those transplanted with unrelated cord blood donors. In practice, this will be the case for perhaps 20% of patients eligible for transplantation. These would be patients in second or later remission of acute leukaemias, a few patients in later stages than fi rst chronic phase of chronic myelogenous leukaemia - and a few patients with rare, non-malignant bone marrow diseases.

Published case series show that the risk of serious complications in cord blood transplanta-tion is high. How serious they are compared with allogeneic stem cell transplantations with family donors or unrelated donors of bone marrow or peripheral blood should be further investigated. The most important and serious complication is engraftment failure. When transplanting stem cells from bone marrow or peripheral blood from related or unrelated donors, this risk of engraftment failure is lower than 5% following the requirements for HLA- compatibility, whereas the risk in cord blood transplantation is 10—20%. This dif-ference is primarily explained by the low number of cells/stem cells per unit of cord blood. Engraftment failure results in death from bone marrow failure after a few months, and only in exceptional cases can transplanting more stem cells save the patients. The risk of engraft-ment failure is dependent upon the ratio between the number of transplanted stem cells and the patientʼs body weight, and the risk is therefore higher for adults than for children.

For unrelated donors, and comparable A, B and DR incompatibility, the risk of acute GvHD appears to be lower in cord blood transplantation than in transplantations with stem cells from bone marrow or peripheral blood, at least for children. That means that suitable donors could be found more quickly for transplantations of cord blood if the transplantation is urgent. Since the occurrence of early mortality (before day 100) is more frequent in cord blood transplantations than in unrelated blood or bone marrow stem cell transplantations, i.e. fewer patients are at risk, it is more diffi cult to directly compare the risk of chronic GvHD.

Life-quality studies after allogeneic stem cell transplantations with cord blood have not been published.

Results of cord blood transplantations with unrelated donors for so-called high-risk patients show an estimated one-year disease-free survival of approximately 15% for children, and even lower for adults. The prognosis for 5-year survival/5-year disease-free survival has not been disclosed from the available literature.

Certain aspects related to allogeneic stem cell transplantation for malignant diseases compared with other types of treatment must be mentioned. Firstly, allotransplantation could lose some important indications in the future due to medical progress in other treatment modalities. For instance in chronic myelogenous leukaemia, where the thyrosine-kinase inhibitor imatinib mesyl-ate over the past few years, has changed the treatment completely and led to a signifi cant reduc-tion in transplantations . Also in acute leukaemias, the conventional treatment has improved - at least in the early stages of the disease – so that treatment involving transplantation is less frequent . Transplantation in fi rst remission of acute leukaemia with an unrelated donor is only a possibil-ity for high-risk patients, that is around 10 adults in Norway per year. Patients in second or later remission as well as chronic myelogenous leukaemia with lacking response to imatinib, or in late stages of the disease, will be candidates for transplantation with unrelated donors.

Whether or not to accept an estimated risk of engraftment failure in adults of 20% is a contro-versial issue among professionals. It can hardly be accepted for patients with more than 40—50% chance of full recovery with conventional treatment, but for patients in a stage of the dis-ease where the chances of being cured without transplantation and dying within a few months are 0% and 100% respectively, it may be acceptable. This balancing of risk is very diffi cult and should be done in open cooperation between skilled professionals, the patient and relatives.


55

7. Relevant elements forconsiderationCurrent practice at Norwegian hospitalsHigh-dose chemotherapy with autologous stem cell support is currently being performed at all university hospitals in Norway. The most important indications are lymphomas and myelomatosis. This treatment method is rarely used for solid cancer tumours. It has been documented that high-dose chemotherapy with autologous stem cell support for advanced breast cancer could not be recommended based on the results from randomised studies.

Allogeneic stem cell transplantations in Norway are only performed at Rikshospitalet University Hospitalʼs Heamatological section, Medical Department and Paediatric Department. The Norwegian programme for allogeneic stem cell transplantation is drawn up by an advisory committee for allogeneic stem cell transplantations consist-ing of representatives from the university hospital`s sections for blood diseases as well as the oncology departments from all university hospitals and representatives from the laboratories and the clinical staff at Rikshospitalet. Both transplantations with related and unrelated donors where the donors have been identifi ed through international registries of bone marrow donors are being performed at Rikshospitalet. Donor search requests are channelled through the Norwegian Bone Marrow Donor Registryʼs group at the Insti-tute of Immunology, which cooperates with the international network of potential stem cell donors, including NETCORD. As of today, more than 8 million voluntary stem cell donors are registered in international registries.

The stem cell transplantation activities in Norway have from the beginning been performed within internationally accepted indications, and transplantations based on test indications and/or with test methods have only been performed to a low degree because of a lack of resources. In Norway, the need for transplantations on the established indications is today somewhere around 50—60 allogeneic stem cell transplantations per year, of which 15—20 are children. All Norwegian patients who are potential candidates for allogeneic stem cell transplantations are discussed in the advisory committee. The number is not expected to increase. On the contrary, it might decrease for a period due to the adoption of a new drug for chronic myelogenous leukaemia (thyrosin-kinase inhibitor: imatinib mesylate), which gives an excellent response, but to what extent it may prolong the survival or control the disease for several years is currently unknown. Progress in the conventional treatment of acute leukaemias has also been made, which most likely will result in a decrease in trans-plantations in the early stages of the disease in the nearest future.

On the other hand, new transplantation methods (so-called “mini-transplantations”) requir-ing less preparation than routine transplantations, and transplantations with higher degrees of HLA- incompatibility for acute myelogenous leukaemias after special preparation, have yielded promising results. This type of treatment is currently being tested throughout the western world and to some extent also in Norway. This could lead to a considerable increase in the activities, if they prove to be as effective as many people hope.

It has occasionally been necessary to send patients abroad for transplantations due to a lack of capacity in Norway. In recent years, this has mainly been caused by shortages in


56

staff, especially nurses. In 2002, 17 patients (adults and children) were sent to Sweden for treatment. The expenses for these patients while in Sweden were covered by money set aside by the Norwegian government for this specifi c purpose. Since returning to Nor-way, the patients have been treated under the direction of Rikshospitalet, and some have needed hospital treatment due to complications. All these transplantations have been per-formed on established indications and have been within the Norwegian programme for allogeneic transplantations.

The Norwegian National Health Insurance has refunded experimental transplantation treatment abroad for a limited number of patients after applications from individual patients and their treating doctors. These patients have not been referred by the advisory committee for allogeneic stem cell transplantation, which is of the opinion that this type of treatment, for the time being, should still be regarded as experimental. Some of the cases have been discussed by the committee, which has submitted its statements to the National Health Insurance.

Concerning transplantations solely using cord blood, this has - as far as the review group knows – not yet been performed in Norway. The review group is aware of the fact that a related transplantation using bone marrow supplemented with cord blood has been performed in a child. As far as the group knows, no patients have been sent abroad to receive this type of treatment. Except for the fact that a different stem cell source is used, stem cell transplanta-tions with cord blood are performed principally in the same way as ordinary allogeneic stem cell transplantations, having the same potential side effects and complications.

In a few cases, cord blood has been cryopreserved with a view to possible future family transplantations in Norway. Routines have been established at Rikshospitalet for cryopre-serving cord blood for families with children or parents with known blood diseases, which can be treated with allogeneic stem cell transplantation and where cord blood could be used, provided satisfactory HLA- compatibility. If the need for transplantations with unre-lated cord blood donors should arise, Norway can easily buy cord blood abroad. Through the Norwegian registry of bone marrow donors, Norway is cooperating with the interna-tional network of biobanks for cord blood, where NETCORD has a central position.

OrganisationCord blood banks are treatment biobanks with strict requirements for quality inspection and logistics. The banks must be organised according to the Norwegian Acts of Biobanks.

RecruitmentPregnant women should be asked well in advance whether they would be willing to ʻdonate ̓cord blood once the baby is born. The women must be informed about the obliga-tions attached to this donation, especially regarding testing and the 6-month follow-up of the baby. They must also be informed about the chances of having positive test results and the responsibilities related to that. The relevant presumptions regarding private or public use of the cord blood should also be explained. A Danish study shows that 89% of women asked would be willing to donate cord blood (85). It must be made clear that those who choose not to donate cord blood will receive the same kind of treatment during delivery and the same right to stem cell transplantation if this should be necessary. The mother must have given her written, informed consent before the cord blood can be harvested.


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CollectionCord blood is harvested by personnel present in the maternity ward, primarily midwives. The blood is labelled, and the processing should begin within 48 hours after the harvest-ing - which means that the processing does not have to be carried out at the same place as the harvesting (6). The labelling must be person-identifi able for 6 months after the harvesting. At this point, the results from the infection testing of mother and child will be ready, and the childʼs health condition will be evaluated to determine whether the blood can be used. Once this has been done, the blood can be unidentifi ed, but it must be possible to connect the product to the identity of the donor in case the donor at any time should wish to withdraw his consent, or if autologous use of the product should come into question. Cryopreservation of single units for storage in large biobanks can take up a lot of space. For further description of isolation and cryopreservation of haematopoietic stem cells from cord blood, please refer to Chapter 3 (Introduction).

Use of cord blood stem cellsThe biobanks must have an accurate list of all units of cord blood and HLA- types for all units of stem cells. Computer-based searches are conducted in the biobankʼs database, and when compatible cord blood is found, the unit must be identifi ed physically and be sent in liquid nitrogen to the transplantation location. The cells are thawed imme-diately before transplantation. DMSO can be removed by washing the cells or it could be infused along with the cells. Viability testing and microbiologic control of the graft is carried out prior to the infusion. The product should be tested for content of viable CD34+ stem cells and can be tested for the number of colony-forming cells. Regard-ing long-term effects, it is necessary to establish whether the graft contains cells with a long-term ability to reconstitute bone marrow. This type of test can be done in special cell cultures. The requirements for quality controls must apply to both private and pub-lic biobanks, and the documentation of such controls must be available to the regula-tory authority for biobanks. The transplantation in itself is similar to a blood transfusion where the graft is usually infused through a central vein catheter.Experience from the establishment of several biobanks, such as Bristol Cord Blood Bank (86) and the Finnish Red Cross Cord Blood Bank, is that these biobanks are very expen-sive both in establishment and maintenance, and that relatively few units have been used in patient treatment so far.

Economical aspectsAs transplantations of stem cells from cord blood have not yet been performed in Nor-way, there are no defi nite estimates as to how much cord blood transplantations are going to cost at a Norwegian hospital. The costs of cord blood transplantations are dependent on the type of biobank used as stem cell sources:1. Private biobanks with cord blood reserved for private/family use2. National biobank with cord blood for public use3. International biobanks from which cord blood units are bought, just like stem cells

from bone marrow and peripheral blood are bought from donor registries today4. National/regional biobanks with cord blood from a selected group, where the donor

and related family have presumed high risk of disease and where the biobank has been established to increase the supply of possibly HLA-compatible donors


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A summary of the available information about the cost of cord blood for the four alter-native biobanks is provided below. This evaluation does not discuss the effects of the various interventions and possible combinations of these, and is in that respect not an economic evaluation which can be used in connection with prioritising.

Use of biobanks – different costsIndications for use of cord blood require clarifi cation regarding the following questions:• Should transplantation of bone marrow and/or peripheral blood be preferred to stem

cells from cord blood?• Should transplantation of stem cells from cord blood be considered equal to the other

methods?• Should transplantation of stem cells from cord blood be preferred to the other meth-

ods?• Should transplantation of stem cells from cord blood be preferred to the other meth-

ods for certain selected patient groups (such as children versus adults, patients with HLA identical or practically identical donor versus donor with higher degree of HLA incompatibility, patients with specifi c indications, etc.)?

These questions are important because they are of signifi cance as to the number of donors necessary to fi ll the medical need for cord blood transplantations. The potential size of the recipient group is decisive for the costs of establishing a cord blood biobank, in addition to buying and selling from, and searching in, international biobanks and registries.

The choice of strategy is primarily dependent upon the most effective transplantation method. If the effects of the methods are relatively identical, the cost of the different methods will also affect the choice of strategy.

The costs related to transplantations of stem cells from cord blood, bone marrow and peripheral blood differ at very few points. While the transplantations and the post-trans-plantation treatment are more or less identical for all three methods, the procedures prior to the treatment differ. Firstly, cord blood is stored in biobanks while potential donors of bone marrow and peripheral blood are listed in registries. It is signifi cantly more expen-sive to maintain banks with biological material than to maintain registries. On the other hand, it takes considerably less time to collect a unit of cord blood than to identify and prepare a donor of bone marrow or peripheral blood. The cord blood unit is immediately available from the biobank and all that needs to be done is to fi nd a matching unit, carry out confi rming tests, transport it and thaw it. The use of bone marrow and peripheral blood, on the other hand, requires searches for suitable donors, confi rming tests, harvest-ing and transportation. Hence, it is reasonable to assume that the costs related to obtain a unit are lower for cord blood, partly because especially harvesting of bone marrow are associated with high costs not applicable to cord blood.


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1Article in the Norwegian newspaper Dagbladet 31st March 2003.

A simplifi ed overview of the course of events for the different transplantation methods is illustrated below:

Preferring one transplantation method in stead of another will normally be possible only in cases where differences in effect for the different methods have been documented. If the transplantation methods have an approximately identical effect, it is possible to conduct searches in all available registries and biobanks until a suitable donor is found. Once a potential donor has been identifi ed, regardless of the chosen method, this donor is selected. In these cases, the corresponding course of events will be as follows for har-vesting cord blood:

Literature searches for sources describing the four alternative biobanks of cord blood were carried out. A summary of the information is provided below. An attempt has also been made to shed light on specifi c costs associated with the treatments, the current number of patiens and the number of patients that in the near future can benefi t from these methods.

Private biobanks reserved for private/family use (alternative 1)As the background for this report, among other things, is that a commercial company wish-es to offer storage of stem cells from cord blood for private/family use and not for public use, it is natural to use this company as an example. As of 31 March 2003, stem cells from 12 different newborn babies (in Norway) have been sent by this company to Germany for private storage1. Another 10 couples had ordered harvesting of their children s̓ cord blood that spring. Prices offered by this company can be found on their website (87): • Harvesting, transport and processing: NOK 5,500 • Storage and cryopreservation for the fi rst 20 years: NOK 9,900

In total, the company can provide harvesting, transport, processing and preservation for 20 years at a price of NOK 15,400.

Prices of corresponding services have been obtained for 26 different commercial actors in other countries (primarily USA and Europe) and they are all in the region of NOK

HLA typing TransportSearch for unit

Confirming tests

Thawing Transplantation

HLA typing

HLA typing

Search for donor

Search for donor

Confirming tests

Confirming tests

Harvesting

Harvesting

Transport

Transport

Transplantation

Transplantation

Cord blood

Periph. blood Choice of method

Bone marrow


Confirming tests


HLA typing

HLA typing

Search for donor

Search for donor

Confirming tests

Confirming tests

Harvesting

Harvesting

Transport

Transport

Transplantation

Transplantation

Cord blood


Bone marrow


Confirming tests


HLA typing

HLA typing

Search for donor

Search for donor

Confirming tests

Confirming tests

Harvesting

Harvesting

Transport

Transport

Transplantation

Transplantation

Cord blood


Bone marrow


Confirming tests


HLA typing

HLA typing

Search for donor

Search for donor

Confirming tests

Confirming tests

Harvesting

Harvesting

Transport

Transport

Transplantation

Transplantation

Cord blood


Bone marrow


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Alternative scenario: Bone marrow Peripheral blood Cord blood Base case 270,681 273,044 410,130 Only 40% DNA typed 241,785 244,148 410,130 Peripheral blood: Only 25 days in hospital (normally 50)

270,681 203,044 410,130

Cord blood: Only 5-year “shelf life”. Bone marrow and peripheral blood: Some donors lost in the process

349,384 351,747 599,161

100,000 donors needed to cover the Canadian need for stem cells (425,000 in base case)

193,868 196,231 225,640

600,000 donors needed to cover the Canadian need for stem cells (425,000 in base case)

312,041 314,404 509,471

Lower recruitment costs for cord blood 270,681 273,044 406,002 Cord blood: All units assumed to match a donor 270,681 273,044 383,762

12,000–35,000. In the US in particular, advertising for cryopreservation of cord blood stem cells is very popular and the advertisements are often insuffi cient and misleading. The information includes possible effect on conditions which are currently not treated with stem cell transplantations, but where it is assumed that transplantation will be a treatment method in the future (please see Chapter 8)

National biobanks with stem cells from a representative group (alternative 2)Only one publication systematically discusses the costs attached to a national biobank for cord blood (11). This is a Canadian report about the three existing methods for trans-plantation of allogeneic stem cells (bone marrow, peripheral blood and cord blood). This is also the only publication which compares all three methods of stem cell transplanta-tion from an economic point of view. The starting point is that 200 patients need stem cell transplantations in Canada every year. Suitable donors are expected to be found for 120 of these patients. At the same time, it is assumed that 425,000 potential donors are needed to fi ll the annual demand for stem cells in Canada. It is important to note that in this report, the assumed “shelf life” of stem cells from cord blood is 10 years, based on published literature (see Chapter 5). Included in the analysis are costs mainly related to the recruitment of donors, collection, storage, processing and testing of the collected units, as well as the actual transplantation.

Total costs per recipient per transplantation are estimated at CAD 270,681 for bone mar-row, CAD 273,044 for peripheral blood and CAD 410,130 for cord blood. Various sen-sitivity analyses have been made, but a majority of these conclude that transplantation of stem cells from cord blood is the most expensive alternative. This is primarily because operating a cord blood biobank is much more expensive than maintaining registries of potential donors. However, sensitivity analyses altering this conclusion are worth men-tioning. If it is assumed that only 100,000 donors are necessary to cover the Canadian need for stem cells, the costs are reduced to CAD 193,868, CAD 196,231 and CAD 225,640 respectively. This means that the conclusion about costs is no longer clear, par-ticularly when considering that yet another sensitivity analysis assumes that donors for cord blood can be found for more than 120 of the 200 patients who need stem cell trans-plantation. If donors are found for all 200 patients, the costs can be assumed to decrease by approximately 10%. An overview of the sensitivity analyses included in the report is provided below (all costs are in Canadian dollars, CAD).


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The authors of the aforementioned report have also published an article in connection with their work (88). The fi gures in the article are more or less identical to these, but the authors have included estimates based on a Canadian need of 6,000 donors (instead of 425,000). In that case, the costs per recipient are almost identical for all three methods (CAD 171,214, CAD 173,577 and CAD 172,047 respectively). However, the estimate of 6,000 donors is questionable as it is based on an Italian source (now closed internet site) which estimates that 50 donors are needed per recipient to fi nd a suitable donor (in (11) the estimate is 2,500 donors per recipient in order to fi nd suitable donors for a suffi cient number of patients).

An additional three articles about biobanks with cord blood have been published (85, 86 and 89). Similar to the Canadian report, one of these articles (89), looks at the possibil-ity of cord blood covering the national (in this case – Italian) need for stem cells. The number of potential donors in this case, however, is reduced to 36 per recipient, a fi gure which seems to be unrealistically low compared with other publications (see above). Articles 85 and 88 only discuss the costs attached to harvesting and preservation of stem cells from cord blood, without including it`s use. In this respect, these articles do not aim to determine the strategy, but rather to shed light on the costs of establishing a national biobank with stem cells from cord blood. There is a major discrepancy between the costs estimated in these two articles, and it is uncertain which one gives the best estimate. Discounting has not been taken into account in either of these two articles. Article 85 assumes that the units can be stored for 75 years, despite the fact that it is impossible to determine for the time being whether stem cells from cord blood can be stored for more than 10 years. The most probable estimate (86) was GBP 285 for the fi rst year and GBP 168 for subsequent years.

To summarise; several estimates of the costs for a national biobank exist. However, only one of the analyses describes the costs satisfactory, and only this analysis will be empha-sised in this connection. According to this Canadian analysis (11), running a national biobank with stem cells from cord blood will cost approximately NOK 2 million per transplanted individual. Corresponding fi gures for running a national registry of bone marrow donors or donors of peripheral blood (which already exists in Norway) are just below NOK 1.35 million per transplanted individual.

International biobank (alternative 3)As mentioned under alternative 2, the differences in price between stem cells from cord blood and the two other methods are caused by the costs of running a cord blood bio-bank. However, according to a Swedish alert (12), cord blood will be less expensive if cord blood units are bought from international biobanks. This Swedish publication also refers to NETCORDʼs homepages (90) which are supposed to have information say-ing that it costs SEK 10,000—15,000 to produce one unit of cryopreserved cord blood, whereas the market price for this service is set at some SEK 150,000. According to this alert, the price is equivalent to the production costs for obtaining stem cells from bone marrow or peripheral blood from unrelated donors. The review group tried to search for prices at other places, and discovered that the price given in this alert is representative for the price of one unit of cord blood stem cells.


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By searching for prices of stem cells, the group has found the following actors (price per unit):Cord blood: • New York Blood Center Placental Blood Program: USD 15,300 (1996) • Ende et al. (91): Approx. USD 15,000 • FDA guidelines: USD 15,300 (86)

Bone marrow: • US National Marrow Donor Program: USD 21,500 (1996) • National Marrow Donor Program: CAD 29,835 (1999) • Average of 15 national bone marrow donor registries: USD 14,175 (1996) (89) • European prices: USD 20,000 - 30,000 (11)

Thus, buying stem cells from international biobanks and registries costs in the region of NOK 100,000-160,000 (prices from 1996 - 1998). There are no signifi cant differences in purchase prices of the different unit types.

Rikshospitalet University Hospital in Oslo is the only hospital in Norway to perform allogeneic stem cell transplantations (see previous paragraphs in this chapter). The review group has been informed that the price of one unit of collected stem cells from bone marrow is some NOK 200,000 (150,000-500,000)2. This is, however, the average cost per patient when including the patients where no suitable donor is found and those who are not transplanted after all. The costs include tissue typing, searching, harvesting and collection of stem cells, but not the actual transplantation and the following treat-ment. Thus, this price includes more or less the same as the aforementioned prices (NOK 100,000-160,000).

Regarding the production of one unit of autologous stem cells from peripheral blood, the review group has received an analysis of the cost per patient3. A short summary of the analysis is provided below.

Description Cost (in NOK)Harvesting, cryopreservation 5,934Re-transfusion 757Blood consumption (per patient in 2002) 9,675Per patient (2 harvestings, 2 cryopres., re-trans.) 23,058CD34 + cell selection 66,501 *Per pat. with purif. (2 harv., 2 cryopres., re-trans.) 89,559

* This is done in a limited number of cases

The analysis does not include doctors ̓fees, which means that the total cost will be high-er than NOK 89,559.1. As a total, this is assumed to be slightly lower than the price of bone marrow, as reported in certain studies (6 and 92).

Biobank for patients with assumed future need for transplantation (alternative 4)The fi rst transplantations with stem cells from cord blood were transplantations in sick children who later had healthy siblings. One possible alternative is therefore to establish 2Personally communicated by Lorentz Brinch, Rikshospitalet University Hospital3Personally communicated by Anne Husebekk, University Hospital of Northern Norway


63

a biobank with cord blood from younger siblings, or generally from children born into families with an increased risk of diseases that can be treated with stem cell transplanta-tions. A recently published study discussing this (6), also reports that the costs per family were USD 3,000. These costs are, however, reported without any further explanation.

The situation in NorwayAccording to the Norwegian DRG system - a system of secondary classifi cation of patients based on existing medical and administrative patient data – the estimated average cost of allogeneic bone marrow transplantations in Norway is NOK 773,417 (DRG 481, DRG weight 25.84, average costs). It has not been possible to determine the percentage of the amount being attached to the purchasing of bone marrow. For this reason, a comparison of this cost has been impossible. One paper concludes that an average Norwegian allogeneic bone marrow transplantation costs NOK 901,982 (93). For the time being, transplantations of peripheral blood belong to the same DRG as bone marrow transplantations.

Patient basisTo evaluate the economic consequences, it is important to have an estimate of the patient basis. For the time being, stem cells from cord blood are regarded as a supplement to the current practice.

As previously mentioned, the current need for stem cell transplantations in Norway is 50—60 per annum. For approximately 20% of these patients no suitable donor is found within the family or in registries within reasonable time. With the current situation, between 2 and 4 of these patients will be children. So far, however, donors have been found for all children needing transplantations in Norway. Concerning adult patients, little documentation exists about the effect of transplantations of stem cells from cord blood (see Chapter 5). Even though suitable donors are not found in bone marrow reg-istries for between 5 and 10 patients every year, reservations against transplantations of cord blood in adults still prevail. In Finland, where the Red Cross has its own cord blood biobank, reports that transplantation of stem cells from cord blood is not an option for adults based on the limited number of stem cells obtained by harvesting.

Based on the fact that stem cells from cord blood are for the time being primarily used for children, three different scenarios are possible: prefer cord blood or bone marrow, or consider them equally effective:

• If bone marrow is chosen as the fi rst option (today s̓ practice), it is reasonable to assume that a maximum 2- 4 children will need stem cells from cord blood every year

• If stem cells from cord blood is preferred, it is reasonable to assume that between 15 and 20 children every year will need this type of stem cell

• If the methods are equalised for children, it is reasonable to assume that between 15 and 20 children every year will need stem cells. Some 80% of these will normally fi nd suitable donors in existing registries, ergo - the real need for stem cells from cord blood will be the same as if bone marrow is chosen as the fi rst option

Due to the development of new treatment methods (see Chapter 8), the need for stem cell trans-plantations is expected to decrease in years to come. However, this need is assumed to increase considerably if new transplantation methods currently being tested, continue yielding good results.


64

Summary and commentsThe most thorough and best-documented study drafting a national biobank with cord blood (11), reports that each transplantation in Canada will cost CAD 410,130 on aver-age. This amounts to more than 2 million Norwegian kroner. The current cost for a bone marrow transplantation is less than half of this, so it does not appear to be cost-effective to establish a biobank for stem cells from cord blood in Norway, as long as the docu-mented effect is approximately identical for all three methods (bone marrow, peripheral blood and cord blood).

Whether or not to allow private actors to store childrenʼs cord blood for payment, will depend on how many patients will actually need such stem cells. Based on the existing knowledge about effect, storage time and range of use, the number appears to be very limited. Due to the fact that the commercial actors use fi gures based on highly optimistic prospects for the future, which are not clinically documented, it is reasonable to control the information they provide in order to prevent customers from paying for a product which is not what they think it is. A different aspect is that private storage of stem cells from cord blood, just like any other private health service, will be a benefi t which can only be enjoyed by certain groups of the population.

Transplantation of stem cells from bone marrow or peripheral blood is currently the most common method in Norway, but cord blood may be used as an alternative stem cell source for children. Equalising the methods is not unthinkable in Norway, provided that cord blood is used primarily for children. If searches in biobanks are carried out simul-taneously, there are good chances of fi nding suitable donors for an additional number of those who do not fi nd bone marrow donors today. If a national biobank with stem cells from cord blood is desired as a supplement, this will probably be very expensive compared with the benefi ts. A less expensive alternative could be a biobank which only stores cord blood from certain families particularly predisposed to disease, for example families with a member suffering from or disposed to a disease known to be treatable with stem cells, or ethnic groups which are underrepresented in international biobanks (such as Lapps).

In years to come, some 2 - 4 cases (max. 10) will most likely occur every year where a suitable donor cannot be found with todayʼs strategy (please refer to the paragraph on patient basis). A national biobank with cord blood might fi ll this need, and it is reason-able to assume that a biobank with cord blood will result in additional years of life for the patients in question. How many additional years are hard to estimate, as long-time survival to only a low degree has been reported in the included studies (see Chapters 5 and 6). In addition, it is diffi cult to estimate the costs attached to such a biobank, since costs relevant for Norwegian conditions have not been available for this strategy. An economic evaluation will not be possible until improved data for long-term survival have been published, including estimates regarding the cost attached to running a national bio-bank as a supplement to existing registries.

Ethical and social considerationsOf the three main sources of stem cells (embryonic, foetal and adult, see Introduction), the use of adult stem cells - perhaps particularly stem cells harvested from cord blood - is regarded as the least problematic source, from an ethical point of view. The placenta and


65

the umbilical cord are usually discarded after birth. In light of this, most people can easily accept using blood from the placenta/cord as a part of the treatment for severe diseases.

The collection and any therapeutic use of stem cells from cord blood are nevertheless associated with ethical questions in relation to the donor and his close family, the indi-vidual patient (recipient) and society. The use of stem cells from cord blood can also be discussed based on different normative ethical theories.

Donor and related familyInformed consentAny drawing of cord blood for storage requires informed consent. Since the newborn baby cannot give its consent, its guardian will decide whether harvesting and storage can take place. It is usually suffi cient that the mother gives her consent, but it can be argued that informed consent should be given by both parents. It has been discussed whether the child should give its consent for further storage and use once it has reached the age of majority.

The analysis of the motherʼs blood also requires informed consent. In addition, informa-tion about the familyʼs medical history on both sides is necessary, especially in relation to heritable diseases.

It should be possible to withdraw the consent and demand the cord blood destroyed at any time.

The information given to the parents about cord blood harvesting should be as objective and unambiguous as possible. The diagnostic tests which will be carried out on the blood from mother and child should be clearly listed, as well as the type of information mother and child will receive afterwards, and that a new health examination is required when the baby is 6 months old. Informed consent to harvesting should be given during pregnancy and well in advance of the estimated date of delivery.

HarvestingThe harvesting of cord blood does not involve any risk for neither mother nor child. Nor does the harvesting cause any pain or discomfort for the donor, because it takes place after the umbilical cord severance. The placenta, which is discarded after the drawing, is of no value to the donor, but the cord blood contains viable stem cells of potential clini-cal value. Estimates, which are uncertain in their nature, indicate that a newborn baby from a healthy family has a 0.005% chance of needing its own cord blood to treat a dis-ease in the future (84).

Genetic diseaseCollected cord blood and blood from the mother is not normally screened for genetic diseases. All Norwegian children are checked at birth for phenylketonuria (PKU) and hypothyrosis. Once the cord blood has been harvested, the child is observed for 6 months in order to discover any heritable diseases. In the event of the child suffering from a severe genetic disease, which cannot be treated nor prevented, the cord blood will not be used for later transplantation. Genetic testing of cord blood stem cells can reveal severe disease or disease dispositions, and it will be necessary with a thorough discussion prior to such testing, to decide upon how and whether the donor and the family should be informed in case of unexpected test results .


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The identifi cation of genetic disease also has ethical and legal implications in relation to disease dispositions (e.g. Huntingtonʼs chorea) and to what type of information employ-ers or insurance companies are entitled to as regards the information disclosed as a result of cord blood harvesting. The donation will be stored with hidden identity, but it must be possible to track the donor to enable the destruction of the product in case the consent should be withdrawn.

ʻDesign babiesʼIn vitro fertilisation (IVF) in combination with genetic pre-implantation diagnostics (at embryonic level) makes it possible to design a baby that will be a potential donor of cord blood for an older brother or sister suffering from a disease. By means of foetal diagnos-tics (of placenta or amniotic fl uid) the foetus can be HLA typed, thus making it possible to fi nd out whether or not the foetus is a potential donor. Such in utero tissue typing involves the possibility of the parents choosing to have an abortion if the foetus ̓cord blood cannot be used therapeutically. ʻDesign babies ̓of this kind have already been the basis for successful cord blood transplantations (94).

There is a chance that children who were conceived and born for the purpose of saving sib-lings may feel like “second-rate” children and thus inferior. Besides, the children could be perceived as tools for the treatment of siblings. The acceptance of such design babies is an ethical dilemma and is forbidden according to the Norwegian Act on Biotechnology

Right of useThe early cord blood transplantations used allogeneic stem cells from siblings and other close relatives where the proprietary rights of the donated cord blood were clear.

There are in principle two different types of treatment biobanks with cord blood. One type is banks with material which has hidden identity for public use for compatible patients. These biobanks can be compared with donor registries, but the stem cells have already been collected and are immediately available. From the very beginning, donors desist from their right to use their own stem cells if they should need transplantation themselves.

The other type is private cord blood biobanks storing cord blood for autologous or fam-ily use. The families carry the costs of harvesting and storing the cells. It has been esti-mated that 0.005% could need these cells (84), and it will be an offer for people who can afford to pay for harvesting and storage. Thus, it breaks with the principle of equal health services in a welfare state. A suggestion has actually been made that families who refuse other people access to their cord blood, should be refused access to national and interna-tional registries and use of cord blood from related biobanks (94).

Biobanks with cord blood for public use can be coordinated with private biobanks. If allogeneic use was to be based on informed consent from the donor or his family, situa-tions might arise where a suitable donor has been identifi ed for a patient, but the dona-tion is refused by the owner because the donor or his close family must relate to the spe-cifi c request of ʻconsumption ̓of his own or the familyʼs ʻbiological spare partʼ.

It can also be argued that the person who contributed the cord blood should have special rights (priority) if he or she should need transplantation with allogeneic stem cells.


67

In certain situations, the collection and storage of cord blood should be reserved for pri-vate or family use only. Families burdened with heritable diseases could benefi t from the infusion of healthy, HLA- compatible stem cells from siblings if it can be documented that they do not carry the heritable disease gene in question. In the future, autologous use could be an alternative if the genetic defect can be corrected in a safe way by means of gene therapy.

AnonymityThe identities of donors in biobanks designed for allogeneic stem cell transplantation with unrelated donors, are not known to the recipients. This ensures the anonymity between donor and recipient. The use of the graft requires the donor not to have shown any signs of genetic or infectious disease for 6 months after harvesting the cord blood, and that the blood testing of the mother is negative as regards HIV and other serious infectious diseases. Despite these precautions, it is not yet possible to make 100% cer-tain that rare genetic diseases are not transferred. Any disease transferred from donor to recipient could be the basis for a potential damages claim from the recipient.

The anonymity of donors in biobanks is challenged by the fact that in the future, several DNA-based tests for diagnosing genetic diseases and genes disposing for disease will be used. Systematic use of gene tests will be able to identify donors with diseases or disease dispositions. Since the test is made anonymous, the donor cannot be traced and informed. It is possible that future tests based on molecular-biological principles will reduce the actual anonymity of donors., This must be made clear when the mother gives her consent to harvest the cord blood.

CommercialisationCompanies offering collection and storage of cord blood primarily address families who want this service as a life-long ʻfamily insuranceʼ. Private individuals carrying the costs of such therapeutic biobanks expect their families to be ensured the proprietary rights of healthy stem cells with identical HLA or a high degree of HLA compatibility. The stored units, which primarily are reserved for family use, can be for sale for public use at a price set by the donor family, the biobank, or both.

Harvesting, cryopreservation, storage and quality assurance of cord blood from non-commercial blood banks are not without costs. The price per unit is relatively high. Any potential profi t devolves to the biobank as an organisation, not as private income, and is meant to cover actual expenses attached to harvesting, cryopreservation, quality assur-ance and storage of the cells.

The individual patient (recipient)Experimental treatmentIn most countries, transplantation of stem cells from cord blood is still regarded as exper-imental and not established treatment. This means that these transplantations usually are performed as a part of clinical studies according to a treatment protocol and with the patientʼs or the parents ̓(if the child is a minor) informed consent, and that the treating institutions systematically report data from and outcome of the transplantations to central bodies, such as Eurocord.


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As a result of the fact that transplantations of cord blood in most cases are regarded as experimental, this method is primarily used as an alternative when bone marrow or peripheral blood-cell transplantation cannot be performed because it has been impossible to fi nd a compatible donor. Searches in registries for potential donors of stem cells from bone marrow or peripheral blood and confi rmation of tissue type are time-consuming activities. Situations may arise where the time aspect makes cord blood the best choice as a source of stem cells in preference to bone marrow or peripheral blood cells. One dose of cord blood will in most cases not contain enough stem cells to transplant to a patient weighing more than 30 kg. Until expansion of stem cells ex vivo can be done without reducing the stem cells ̓quality, cord blood stem cells will primarily be an alter-native for the youngest patients.

Donor s̓ anonymityA personʼs right to know his biological origin is laid down in the Norwegian Biotechnol-ogy Act. Stem cell transplantations can be compared with blood transfusions, where the principle has been established that the product has hidden identity and the recipient does not know anything about the donor and vice versa.

Social aspectsSocio-economic aspectsThe literature review did not identify published patient data showing that autologous transplantation of cord blood is benefi cial. This type of treatment has most likely been in question in only 1:20,000 collected units (84). It could lead to an unfair socio-economic difference between social groups if wealthy parents were to be able to buy cryopreserva-tion possibilities for their offspringʼs cord blood. However, it could be discussed whether it ought to be a priority task for the authorities to fi nance such an offer.

It will not be of any practical signifi cance to individual patients in Norway whether donors are identifi ed in biobanks primarily established for autologous or allogeneic transplantations, or whether the biobank is localised in Norway or in any other country.

Ethics and prioritisingMost economical evaluations indicate increased costs when transplanting cord blood compared with bone marrow transplantations and transplantations of allogeneic stem cells from peripheral blood (see above). Whether or not the Norwegian public health ser-vice should offer transplantation with stem cells from cord blood as a method, is thus a matter of priority.

Cord blood for Norwegian patients is provided through the bone marrow donor regis-try which has access to the international network (NETCORD). Cord blood can also be bought from commercial biobanks abroad provided that the quality requirements have been met and documented. The establishment of a national or Nordic biobank for cord blood will require a considerable amount of resources and thus also a deliberate prioritis-ing by the health authorities.

Research aspectsWhen it comes to the quality of the documentation, it is appropriate to point out that ran-domised studies of the treatment effect are lacking. The comparative studies published so far have been designed as cohort studies or case series, but these are not population-based.


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Research-ethical principles of the the Helsinki Declaration state that testing of new treat-ment methods shall be evaluated in relation to what is regarded as the standard treat-ment. Transplantation of stem cells from bone marrow and peripheral blood is today a part of established treatment programmes, and will thus represent the control group in a randomised study. If the results from non-randomised studies should turn out to be very good as regards cord blood transplantation, some will argue that it is unethical to randomise patients for bone marrow or cord blood transplantations respectively. In that case, it might reduce the chances of systematically obtaining knowledge about treatment effects and side effects of the compared transplantation methods.

Legal aspectsThe collection and therapeutic use of cord blood are regulated by several Norwegian acts and regulations.

The collection, storage, use and destruction of human biological material, as well as the organisation of these activities are regulated by the Norwegian Biobank Act that came into force July 1st 2003. Cord blood in biobanks falls under this Act.

Transfusion of blood cells falls under the directions for the transfusion service in Norway.

Pre-implantation diagnostics (of embryos after IVF as a part of the production of design-er babies) and foetus diagnostics (in utero to establish whether the foetus is a potential donor) in combination with cord blood transplantation are regulated by the Norwegian Biotechnology Act.

The patientʼs right to participation and information about “available equivalent treat-ment” is laid down in the Norwegian Patient Rights Act (latest amendments to the Act came into force January 1st 2004). The doctors ̓duty to inform their patients about potential treatment methods, including those not performed in Norway, and to assist their patients in realising the desired treatment could therefore be questioned.

Another legal question is how society should relate to the patients who request but fall outside the established treatment indications for new, experimental and often expensive treatment, in Norway or abroad. The handling of patients who request referral to institu-tions abroad which have different treatment indications than those offered in Norway is regulated by the following regulation: “Regulations on contribution for treatment abroad and on the complaints board for contribution for treatment abroad”.

According to the prevailing health legislation in Norway for the national insurance and the regional health authorities with the accompanying regulations, there are special rules as to who can be referred for treatment abroad and have their expenses covered. The most important condition is that the necessary competence to treat the condition does not exist in Norway, and contributions are not made for experimental treatment except in very special cases. The decision of whether patients treated abroad can have their expenses refunded is made by the Norwegian National Insurance Administration. Complaints on rejections will be treated by the Norwegian Governmental Appeal Board regarding medical treatment abroad.


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Normative ethical theoriesDifferent positions and theories within normative ethics will have different views on the use of stem cells from cord blood.

Duty ethicsIn a duty ethical (deontological) framework human worth is fundamental. It is crucial to see every human being as an end in itself, and not only as a mean. In cases where children are born simply because its cord blood is desired to save somebody else, for instance a sibling, these children could be perceived as a means and not also as an end in themselves. Most interpretations of duty ethics will reject the use of cord blood when the child could be perceived as a ʻdesign babyʼ. Furthermore, the duty to save lives is signifi cant for health care professionals. This justi-fi es the use of cord blood to the extent that it has therapeutic potential. Correspondingly, the duty to protect the weak part is a long and powerful tradition. The weak part in this case will be the child. In most situations the child will benefi t from the advantages, but it is important to notice that genetic tests can uncover knowledge of diseases and dispositions that will not benefi t the child. However, the duty to save lives and the duty to protect the interests of the weak will therefore justify the drawing, storage and use of cord blood.

In addition to the respect for human worth, the use of stem cells is attached to the respect for life in general. Stem cells are cells that can give rise to other cells and tissues, and they have the ability to renew themselves. For that reason, they represent biologically and symbolically a ʻsprout of lifeʼ. This issue has been less challenging regarding hae-matopoietic stem cells than embryonic sources. Haematopoietic stem cells do not give rise to new life in the sense that questions of moral status and human worth arise in the same way as for embryonic stem cells.

Consequence ethicsConsequentialists will try to use or desist from using a medical possibility depending on its consequences. The conclusion of consequence ethics will depend on how the conse-quences of the action are interpreted.

A traditional interpretation will be that the use of cord blood represents a potentially good treatment method, and its potentially positive consequences for many patients and the relatively few negative consequences will justify an introduction of the method. Besides, the drawing and storage of own cord blood represents security (to the parents and gradually also for the child) supporting this reasoning.

Alternative interpretations will emphasise other consequences, for instance that biobanks based on proprietary rights might increase the difference between rich and poor, or that the use of stem cells from cord blood could result in children being born as a means of saving others, and that it could have negative consequences for the development of society. Several consequentialists will here seek to limit the potentially negative conse-quences, e.g. through restrictive legislation, in order to realise the positive consequences.


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Principle-based ethicsIn principle-based ethics, the consideration for the principle of autonomy in relation to mother and child could be followed by informed consent (from the mother). The review group is not familiar with cases where harvesting and storage of cord blood could injure the baby, and as of today the use of cord blood does not violate the principle of nonma-lefi cence. In relation to the principle of benefi cence the benefi t of using cord blood could be considerable, while the likelihood of the cord blood being used and the risks attached to drawing and storage are minor.

Biobanks emphasising proprietary rights challenge the principle of justice because not everybody is given the access to the same treatment. There is no reason to disregard the principle of justice as there is a morally acceptable alternative: biobanks where the owner has no proprietary rights. A common principle-based interpretation will therefore reject biobanks based on the individuals ̓proprietary rights to their units, but will be positive to biobanks that respect the principle of justice.


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8. Discussion – status, opportunities and limitationsIs it possible to increase the number of stem cells by expansion?As previously discussed in the introduction to this report, stem cells from cord blood are a very good alternative to allogeneic stem cells when transplanting stem cells. Experi-ence gained by using this stem cell source, however, shows that there is a limiting factor with this method - the number of stem cells obtained by cord blood harvesting. As this problem became evident, the harvesting method has been optimised in order to draw out as many stem cells as possible. Even though this method today is optimised, the number of stem cells in the harvested cord blood will still be a limiting factor if the stem cells are intended for an adult. The reason for this is that a certain amount of stem cells per kilo of bodyweight must be infused into the recipient to secure the success of the stem cell transplantation. This applies to all stem cell transplantations, regardless of the transplant-ed stem cells being autologous or allogeneic.

Seeing that the number of stem cells in some cases is a limiting factor, this problem has been attempted to be solved by expanding the number of stem cells in vitro before the cells are transplanted into the patient. So far, this kind of stem cell expansion has proven unviable. There is an expansion of the number of cells carrying the stem cell marker CD34, but as it turned out, the expansion did not take place in the part of the stem cell pool which gives long-term reconstitution of the patientʼs bone marrow. As there is great interest in cultivating and expanding this type of stem cell, a lot of research is being con-ducted in this fi eld, but at present it is impossible to predict whether the researchers will succeed. Indeed, a Canadian company claims to have cracked the code, but results con-fi rming this have yet to be published.

What is the potential of cord blood stem cells?So far, cord blood has only been used to restore the patients ̓bone marrow functions. Over the past fi ve years in particular, several reports have been published which indicate that blood stem cells can differentiate into functions other than blood cells. Data have been published (though only from in vitro experiments or experiments with mice) claim-ing that these stem cells have the potential to become liver tissue, muscle tissue and even brain tissue. This information has created expectations as to what can be done for sev-eral patient groups. After the fi rst wave of sensational observations subsided and these results have been closer examined, it turns out that several of the fi ndings are based on blood stem cells merging with cells in other tissues, and that the stem cells themselves have not differentiated into new cells in totally different tissues. At this point, it is too early to discuss the functional consequences of this.

Are there types of stem cells in cord blood other than blood stem cells?In the same way as in bone marrow and peripheral blood from adult donors, there are progenitors in cord blood, or stem cells for both mesenchymal cells and endothelial cells. Mesenchymal stem cells are progenitors to, for instance, the bone forming cells as well as chondrocytes and fi broblasts, and possibly muscle cells .Some studies indicate that


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these cells can differentiate into cells with neural characteristics, but this is most likely not a process normally taking place in the body.Cord blood contains very few mesenchymal cells, but the ones that are there can easily be cultured in laboratories. The endothelial stem cells, or more correctly the progenitors, also represent a small fraction of the cells in the cord blood. These are cells which can mature into cells forming blood vessels. It is assumed that these cells - in the same way as has been shown in adults - will be a supplement to the local endothelial cells when new vessels are to be formed in tissues. This is a new research fi eld associated with high expectations.


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9. Scientifi c summary

BackgroundOn a global basis, transplantations with haematopoietic stem cells from cord blood have been performed in more than 2,000 patients. The fi rst successful cord blood transplanta-tion was performed in 1988. Only allogeneic transplantations from related or unrelated donors with different degrees of HLA compatibility have been performed. Autologous transplantations with cord blood stem cells have not been described or documented as a treatment option. In Norway, transplantations of stem cells solely from cord blood have not been performed so far.

The use of haematopoietic stem cells from cord blood has the same disease specifi c indi-cations as the use of stem cells from bone marrow and peripheral blood, and includes several malignant and non-malignant diseases in blood-forming tissues. While trans-plantations of stem cells from bone marrow or peripheral blood are established treatment methods, stem cells from cord blood are primarily an alternative in cases where donors of stem cells from bone marrow or peripheral blood cannot be identifi ed among family members or in registries.

ObjectivesThe objective of this report has been to evaluate all relevant literature which can eluci-date the basis for therapeutic use of haematopoietic stem cells from cord blood. Central issues were possible differences in the clinical effect between the use of stem cells from cord blood, bone marrow and peripheral blood, as well as possible differences in the clinical effect between the use of allogeneic and autologous stem cells from cord blood. The review group was also asked to elucidate the documented safe storage time for cryo-preserved stem cells as regards the clinical effect. In addition, the size of the relevant recipient group should be discussed as well as organisational, economical, ethical and social aspects considering the use of the method.

Search strategySystematic literature searches were conducted in the Health technology assessment Data-base (HTA) and in the Cochrane Database of Systematic Reviews (CDSR). A search for primary studies was conducted in Medline. The database searches were supplemented by manual searches.

Selection criteriaAll literature reporting results after transplantations of haematopoietic stem cells from cord blood was relevant. Both controlled and non-controlled studies were included. In addition, case reports were identifi ed in order to illustrate the development of the meth-od. All literature should be in English or have an English abstract. Scandinavian litera-ture that met the inclusion criteria was also included. No restrictions applied to the time period of the studies. A total of 435 abstracts were evaluated, of which 67 were found to be relevant.


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Data collection and analysisThe relevance of the abstracts was evaluated by an expert and the results were submit-ted to the review group. The evaluation of full-text articles as regards relevance and study design was performed independently by two experts. Only studies with more than 20 patients or 10 patients per disease indication were included. Of the 67 articles that formed the basis of the literature evaluation, 17 were found to meet the established inclu-sion and quality criteria and constituted the documentary basis for the health technology assessment.

ResultsThere are no published results of the therapeutic use of autologous stem cells from cord blood.

For allogeneic transplantations, there are some cohort studies as well as several case series of varying sizes. Randomised studies comparing cord blood transplantations with transplantations of bone marrow or peripheral blood have not been published. The exist-ing cohort studies are all of retrospective design with historical controls. The two largest case series are register studies reporting results from an extensive patient material; alto-gether more than 1,400 patients. None of the studies are population-based. Of the 2,000 patients that have been transplanted with cord blood, approximately 1,600 are children and 400 are adults.

Results from transplantations with related (mainly siblings) and unrelated donors where the donors are either HLA-identical (related) or have varying degrees of HLA- mismatches have been reported. While published results for children exist for all the aforementioned categories, reported cord blood transplantations in adults have been per-formed almost exclusively with unrelated donors.

No publications have been designed to elucidate the maximum safe storage time for cryopreserved cord blood stem cells as regards the clinical effect after transplantation. Cord blood transplantations have been in use for more than 10 years, thus, cord blood stem cells have so far been proven effective after being cryopreserved for about 10 years.

Main conclusionsAutologous transplantation of stem cells from cord blood have not been reported or documented.

The clinical benefi t of allogeneic transplantation of stem cells from cord blood has not yet been directly compared with the results of allogeneic stem cells from bone marrow or peripheral blood in prospective studies. Published studies - all with retrospective design - suggest that the clinical effect of cord blood transplantations, at least in children, may be comparable to transplantations with stem cells from bone marrow or peripheral blood.

The number of stem cells in the cord blood graft is often insuffi cient to obtain adequate engraftment in adults, and the risk of non-engraftment is higher for cord blood transplan-tations than for transplantations with stem cells from bone marrow or peripheral blood.


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The risk of graft-versus-host-disease is probably lower in transplantations with cord blood than when allogeneic stem cells from peripheral blood or bone marrow with com-parable HLA compatibility are used.

Other considerationsEstablishment and maintenance of a cord blood bank is expensive. With the present indications for the use of stem cells from cord blood it seems not to be cost-effective to establish Norwegian biobanks. The access to the NETCORD network and established biobanks abroad provide for cord blood for Norwegian patients if needed.

There are diffi cult ethical questions associated with the storage and use of as well as the proprietary rights to cryopreserved cord blood.


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71. Zecca M, Prete A, Rondelli R, Lanino E, Balduzzi A, Messina C et al. Chronic graft-versus-host disease in children: incidence, risk factors and impact on outcome. Blood 2002; 100(4): 1192—1200.


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11. Appendix

Report commentary from BioLante AS

Reply from BioLante AS/Cryo Cell Nordic on:

SMM report No. 4/2003


Health technology assessment based on a literature review carried out by an review group composed by the following persons:

• M.D. Lorentz Brinch, chief physician and Head of Section at Rikshospitalet Univer-sity Hospital in Oslo (Professional Leader)

• Professor Anne Husebekk, senior consultant at the University Hospital of North Norway • Professor Steinar Funderud, The Norwegian Cancer Hospital

(Det Norske Radiumhospital) • Doctor of Science Anita Lyngstadaas, The Norwegian Centre for Health Health

technology assessment (Project Manager)

BioLante AS/Cryo-Cell Nordic received the report on 25 April 2003 and was to reply by 30 April in connection with a specialist seminar/hearing at SMM.

Our fi nal deadline to reply to this report was 1 June 2003.

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1. General evaluation of the reportOur immediate reaction is that this is a very good and thoroughly prepared report.

However, we do feel that too much emphasis has been put on earlier studies and docu-mentation, and that future possibilities have not been considered.

Some individual experiences with autologous cord blood transplantations have been pub-lished in the media, as illustrated by the included article from Toronto, Canada.

Autologous use of stem cells from cord blood was fi rst used in 1988, as a treatment method for Fanconiʼs anaemia, a pre-stage of leukaemia.

We would like to inform the readers that the use of stem cells harvested from own cord blood is in fact an established treatment method in the US and the UK and in several oth-er European countries, provided that the patient had his stem cells cryopreserved at birth.

2. HLA compatibilityCurrent research shows that stem cell transplantation with related cord blood donor, from HLA- compatible siblings, often is equivalent to transplantation with blood or bone marrow stem cells with the same HLA- compatibility. Children can achieve acceptable results with transplantation of HLA- compatible stem cells from cord blood compared with bone marrow or peripheral blood.

However, children who have cryopreserved their own stem cells, will have a greater chance of successful treatment than with cord blood transplantation with unrelated donors. These children will not be burdened with side effects and complications such as prolonged bone marrow aplasia or chronic graft-versus-host disease (GvHD).

The report also states that the occurrence of severe acute or chronic GvHD appears to be lower when using cord blood than when allogeneic stem cells from peripheral blood or bone marrow with the same degree of compatibility is used.

3. Storage timeRegarding the documented safe storage time, we would like to refer to an article pre-sented on 7 September 2002, on cord blood tested after 15 years of cryopreservation. It was fully functional and in competent condition and it is assumed to be effective for therapeutic use. Ref: Hal E. Broxmeyer, Edward F. Srour, Giao Hangoc, Scott Cooper, Stacie A. Anderson and David M. Bovine. Published by Edward A. Boyse, University of Arizona College of Medicine, Tucson, AZ. USA.

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4. Possibilities and limitationsThe report discusses future prospects to some extent, but it is limited in its assumptions about the future benefi t of stem cell treatment.

We have received replies from Dr. Ph.d. Cornelis H. Kleinbloesem, CEO of Cryo-Cell Europe in Holland and Dr. M.J. Waeterschoot, CEO of Cryo-Cell Labs. They were unfortunately unable to evaluate the report at such short notice, as it was available in Norwegian only and waiting for the translation and the following reply would be too time-consuming. The scientifi c documentation which is presented is comprehensive and we see no reason to question it.

Cryo-Cell has all along regarded stem cells from cord blood as a supplement to bone marrow stem cells. In the report, these methods have been treated and compared as two separate methods. Cryo-Cell is currently conducting extensive research within both fi elds, and has initiated a research project in cooperation with the EU using stem cells from bone marrow to treat the myocardium after myocardial infarct.

Naturally, a report of this kind can only be based on what has been done. However, the purpose and the presumptions of cryopreserving cord blood is the belief in progress, the belief that medical research will continue developing in the future.

BioLante/Cryo-Cell is of the opinion that it will be possible – to a greater extent - to cul-tivate harvested stem cells in the future, thus creating larger volumes and making this an alternative method for adult patients as well.

We do absolutely not favour one stem cell source above the other; be it bone marrow or cord blood – the important thing is the result for the individual patient.

5. Experience from establishmentThe report discusses experience from the establishment of several biobanks, e.g. Bristol Cord Blood Bank and Finlandʼs Red Cross Cord Blood Bank. The results are that these biobanks are very expensive to establish and maintain, and that relatively few grafts have been used in patient treatment so far.

Cryo-Cell Europe and Cryo-Cell International confi rm that the costs of establishing and maintaining biobanks are major. That is the reason why Cryo-Cellʼs laboratories in Bel-gium and Frankfurt preserve stem cell blood from all over Europe.

Experience from Europe and the US show that those who primarily seek an extra insur-ance for their children are parents from families with an anamnesic accumulation of cancer diseases. Norwegian authorities have to decide whether this possibility should be available to Norwegian parents in the same way as it is available to parents in other countries in Europe and the US.

However, should pregnant women in Norway be deprived of the right to choose this alternative to potentially secure their children? The need in Norway is not great enough to establish a national cord blood biobank for the cryopreservation of stem cells.

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We would be happy to enter into a co-operation with the Norwegian government, saving a seat on our medical board for a representative from the health authorities.

We are also open for the possibility of the Norwegian government placing their represen-tatives on our administrative board, if desirable.

Oslo, 1 June 2003

For BioLante AS ForCryo-Cell Nordic The Medical Board

Bjarne Nilsen Dr. Harald Hovind

Please see the appendix: The Sunday Times, 2 pages

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CLOSE WINDOW

April 28, 2002

Parents bank baby blood for stem cell cures

Tony Allen-Mills, Washington

WHEN Lisa Farquharson gave birth to her son Jesse in June 2000, she did something most parents never think about: on advice from her mother, a nurse, she saved the cell-rich blood from her babyʼs umbilical cord.

She could never have imagined that in less than two years her decision would help to save the life of the Canadian infant as he battled against eye cancer.

Jesseʼs story is expected to hasten a mini-revolution in medical care, as tens of thousands of parents seek to store powerful regenerative cells from their babies ̓umbilical blood as a biological insurance against future disease.

A new generation of private blood banks is springing up across America to enable par-ents to store umbilical cells for a guaranteed perfect match should their child ever need blood or a bone marrow transplant.

At the Arizona-based Cord Blood Registry (CBR), 30 Britons are among the 38,000 par-ents who are keeping umbilical blood frozen in liquid nitrogen tanks. More than 100,000 parents have gone to other banks.

Umbilical blood is rich in stem cells, the engines of healthy human growth that devel-op in the embryo and multiply rapidly, manufacturing blood and building the bodyʼs immune system. Researchers believe that stem cells may prove effective in the treatment of a wide range of diseases, including Parkinsonʼs, Alzheimerʼs and arthritis.

Controversy over cloning and abortion is stalling the use of cells from embryos, but interest is increasing in umbilical cord blood, which has already been used in more than 2,000 American transplants with a high rate of success. Most of those involved patients using donated blood from family members. Cases of children who are saved by their own blood are still so rare that some doctors worry that parents are being lured into expensive private schemes to store blood that their sons and daughters will never need.

Yet Farquharson, a former shipping clerk from Bolton, Ontario, has no hesitation in urg-ing parents to follow her example.

“If you passed up the chance to save that blood and something happened,” she said, “it would just be an amazing tug on your heartstrings. They gave Jesse a 0% chance of sur-vival. But we had his cord blood and heʼs still alive.”

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Jesse was four months old when his parents were told that he had a brain tumour which would lead to blindness. Then specialists diagnosed bilateral retinoblastoma, a rare eye tumour.

The diseased eye was removed in November 2000 but the cancer was found to have spread to Jesseʼs spinal fl uid. An aggressive chemotherapy programme aimed at both the eye and spinal cancers appeared to have been successful, but Jesseʼs immune system was destroyed. At risk of death from the slightest infection, he underwent a bone marrow transplant last year using the stem cells his parents had saved.

To the familyʼs delight, the transplant was a huge success. The compatibility complica-tions that often arise with donor marrow or blood never occurred. Jesseʼs healthy umbili-cal cells regenerated swiftly, rebuilding his immune system, and although he is now blind he has returned home with his parents.

“Everyone says he is a miracle child,” said Farquharson.

The commercial blood banks specialising in umbilical cells have seized on this and a handful of similar cases to promote a storage service that can cost parents up to £1,000 in initial charges, with additional annual fees of up to £70.

One researcher recently calculated that there was a one in 1,400 chance that a childʼs stored umbilical cord blood might be used to help a sibling or parent who was ill; and a one in 2,700 chance that a baby would need its own blood.

For some parents, as they ponder a blood storage service that costs about the same as a home computer, the odds are not too long.

“If those cells are there when you need them,” said Farquharson, “youʼll never regret your decision.”

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