How To Understand The Science Of Cord Blood

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1 The Future of Unrelated Donor Stem Cell Transplantation in the UK Part 2 Annexes A Report from the UK Stem Cell Strategic Forum July

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3 Table of Contents Abbreviations... 6 Glossary... 7 Annex The Healthcare Benefits of Unrelated Donor Haemopoietic Stem Cell Transplantation in the UK... 8 Summary... 8 Stem Cells from Adult Donors and Cord Blood... 8 Indications for Unrelated Donor HSCT... 9 The Growth in Unrelated Donor HSCT in the UK... 9 Patient Outcomes Following Unrelated Donor HSCT The Role of Cord Blood HSCT in Children and Adults Annex The Provision of Stem Cells for Transplantation in the UK Summary The Supply of Stem Cells for Transplantation in the UK The Growing Importance of Cord Blood Annex Meeting the Demand for Stem Cells in the UK Summary Health Related Risks Associated with Stem Cell Donation Inequalities in the Provision of Stem Cells for HSCT Donor Search to Transplant Time Estimating the Unmet Need for Unrelated Stem Cells in the UK Likely Changes in Clinical Practice Requirement for Donor Stem Cells Following an Irradiation Incident Annex Increasing the Availability of Adult Donor Haemopoietic Stem Cells for Transplantation Summary The Effect of Registry Size on Identifying Matched Donors Increased Resolution of HLA Typing; Creation of a Fit Panel Advanced Matching Algorithms Importation versus Domestic Supply of Donor Stem Cells Annex Increasing the Availability of Cord Blood Units for Transplantation Summary Optimising the Cord Blood Inventory for the UK A Report from the UK Stem Cell Strategic Forum July

4 Annex Supply Chain Options for Improving the Availability of Donor Stem Cells in the UK The Supply of Unrelated Adult Stem Cells The Role of UK Registries The Performance of UK Registries Opportunities to Improve the Supply of Stem Cells from UK Donors The Supply of Cord Blood Donations for Transplantation Increasing the Utilisation of Cord Blood Banked in the UK Increasing the Genetic Diversity of Banked Cord Blood Units; Managing the Expectations of Those Wanting to Donate Annex Financial Appraisal of Options to Reconfigure the Supply Chains Methodology The Current Cost of Providing Unrelated Adult Stem Cells to UK Patients The Current Cost of Providing Cord Blood to UK Patients Supply Chain Options The Cost of Adult Stem Cell Provision The Cost of Cord Blood Provision Annex Health Economic Analysis Summary QALY Life Gains following Unrelated Stem Cell Transplantation The Cost of Stem Cell Transplantation The Current Cost of Providing Stem Cells for Transplantation Cost-Benefit Analysis Establishing a Fit Stem Cell Registry Donor Panel An Expanded UK Cord Blood Inventory Profile of Expansion Cost-benefit Analysis an Expanded Cord Blood Inventory Costs and Cost Savings Health Gains Complete Assumptions Cost per QALY Results Univariate Sensitivity Analysis Monte Carlo Analysis Conclusions Part 2: Annexes

5 Annex The Commissioning of Unrelated Donor Stem Cell Transplantation in the UK Summary HSCT Performance in the UK: Challenges and Opportunities Standardised Contracts Transplant Centre Output Designation of Centres of Excellence Increasing Understanding Among Commissioners Embedding Best Practice in The UK Annex The Value of Research and Development In Unrelated Donor Stem Cell Transplantation and Regenerative Medicine Summary Unrelated Blood Stem Cell Transplantation Cord Blood Stem Cells for Discovery Research Examples of Key Research and Development Opportunities Sale of Cord Blood Stem Cells for Academic and Commercial Research Securing Cord Blood Stem Cell Research and Development Annex Performance Managing the Provision of Unrelated Donor Stem Cells for Transplantation Summary Commissioning and Contract Monitoring Proposed UK Stem Cell Advisory Forum A UK Stem Cell Registry A UK Cord Blood Inventory A UK Database of Patient Outcomes Annex Stakeholder Consultation Summary Recommendations References A Report from the UK Stem Cell Strategic Forum July

6 Abbreviations ANT BCSH Anthony Nolan Trust British Committee for Standards in Haematology JACIE MFF The Joint Accreditation Committee-ISCT & EBMT Market-forces factor BM BMT BSBMT Bone marrow Bone marrow transplant British Society of Blood and Marrow Transplantation MHRA MRC NCRN Medicines and Healthcare products Regulatory Agency Medical Research Council National Cancer Research Network CB Cord blood NHSBT NHS Blood and Transplant CTC Clinical Trials Committee (BSBMT) NHS-CBB NHS Cord Blood Bank CIBMTR Center for International Blood and Marrow Transplant Research NIBTS Northern Ireland Blood Transfusion Service CBT Cord blood transplant NMDP National Marrow Donor Programme cgmp Current good manufacturing practice ONS Office for National Statistics CMV Cytomegalovirus PBSC Peripheral blood stem cells CPA Clinical Pathology Accreditation PCT Primary Care Trust EBMT EMDIS The European Marrow Group for Blood and Marrow Transplantation European Marrow Donor Information System QALY R & D RIC Quality-adjusted life year Research and development Reduced-intensity conditioning FACT GCSF Foundation for the Accreditation of Cellular Therapy Granulocyte colony stimulating factor SCG SGHD Specialised commissioning group Scottish Government Health Department GIAS GvHD GVL Graft identification advisory service Graft versus host disease Graft versus leukaemia effect SCRM SNBTS Scottish Centre for Regenerative Medicine The Scottish National Blood Transfusion Service HDI Human Development Index TNC Total nucleated cell count HLA Human leukocyte antigen WBMDR Welsh Bone Marrow Donor Registry HRSA HSCT Health Resources and Services Administration Haemopoietic stem cell transplantation WMDA ZKRD World Marrow Donor Association German National Bone Marrow Donor Registry HTA Human Tissue Authority 6 Part 2: Annexes

7 Glossary Allogeneic Allomandatory Apheresis Autologous Antigen CD34+ cells Cord blood bank Engraftment GvHD GvL Haplo-identical High resolution typing Matching Intraosseous injection Neutropenia Stem cell T-cell Allogeneic Transplantation using stem cells from a donor other than the patient A patient for whom HSCT using donor stem cells is the only effective therapeutic option A process where the blood of a donor or patient is extracted, a particular constituent filtered out and the remainder returned to the donor or patient s body Transplantation using the patient s own stem cells A molecule capable of eliciting an immune response An undifferentiated form of pluripotential haemopoietic stem cells A facility storing processed umbilical cord blood for clinical transplantation. To be distinguished from stem cell banks which may store embryonic stem cell-derived lines for research purposes. The process by which transplanted cells regenerate normal blood counts Graft versus host disease - a potentially life-threatening complication where engrafted donor stem cells mount an immune response against the host Graft versus Leukaemia Having the same alleles at a set of closely linked genes on one chromosome (i.e. a sibling or parental cells) Allelic or sequence-based typing that provides additional genetic information on the donor. The degree of parity between the HLA type of a donor and a patient Injection directly into the bone of the donor An abnormally low count of neutrophils, a type of white cell A cell type found in cord blood, adult blood and bone marrow capable of repopulating the blood-forming elements of a patient s bone marrow. A type of white blood cell critical to cell-mediated immunity Transplantation using stem cells from a donor other than the patient A Report from the UK Stem Cell Strategic Forum July

8 Annex 1 The Healthcare Benefits of Unrelated Donor Haemopoietic Stem Cell Transplantation in the UK Summary Haemopoietic stem cell transplantation (HSCT) is a life-saving therapy for a range of malignant and non-malignant diseases. Although HSCT can be performed using autologous stem cells, allogeneic stem cell transplantation is now established as the most effective treatment strategy in a wide-range of haematological malignancies and is an increasingly important treatment option in non-malignant bone marrow disorders. Recent advances have shown that stem cells harvested from a matched unrelated donor or cord blood unit allow the extension of the curative effect of HSCT to patients who lack a matched sibling donor. The number of UK patients benefiting from unrelated donor HSCT has grown significantly in recent years, with 749 transplants performed in Patient outcomes following HSCT using unrelated donor stem cells are improving, with 1-year survival rates for transplanted patients at 54% between 2002 and 2006, compared to 42% between 1996 and 2001 and accumulating data confirms long term survival benefit. HSCT is increasingly an option for older patients and outcomes now compare favourably with those achieved using sibling donor stem cells. Furthermore, patient outcomes following cord blood transplantation are now comparable to those achieved with adult stem cells. Stem Cells from Adult Donors and Cord Blood Stem cells are characterised by their ability to differentiate into multiple tissue types and cell lineages; they offer great potential for regenerative medicine. Haemopoietic progenitor cells are multipotent stem cells found in bone marrow and blood (including cord blood) with the ability to differentiate into red cells, platelets and cells of the immune system. This ability is exploited in HSCT. HSCT is either allogeneic or autologous: Allogeneic stem cell transplantation is performed with stem cells that are collected from a related or unrelated donor. Autologous stem cell transplantation is performed with stem cells that are collected from the patient before treatment and are later re-infused An appropriate human leukocyte antigen (HLA) match is important for all types of HSCT using donor cells. Individuals inherit pairs of HLA alleles encoding pairs of antigens (e.g. HLA-A, -B, -C, DR, DQ) and a full tissue match for three antigens pairs is termed a 6/6 match; a full tissue match for five pairs of HLA antigens is termed a 10/10 match. Matching is important: non-matching grafts may be rejected by the immune system of the recipient and can mount an immune response against the recipient resulting in graft versus host disease (GvHD). The inheritance pattern of HLA types means that the chance of finding a related fully matched donor is around 30%; the remaining 70% of patients therefore require an unrelated stem cell donor. Due to the highly polymorphic (meaning highly variable) nature of HLA, very large numbers of registered donors are required in order for there to be a reasonable chance of finding a matching unrelated donor. Stem cells for allogeneic HSCT may be obtained either from bone marrow (BM), peripheral blood (peripheral blood stem cells or PBSC) or cord blood (CB). The advantages and disadvantages of these sources are described later in this Annex. Umbilical cord blood - donation takes place in hospital maternity departments after birth. There is no evidence of risk to mother or child providing the collection of cord blood takes place within the normal medical protocols surrounding birth. Bone marrow - collected from the pelvic bones using a needle and syringe. The procedure lasts around half an hour and is performed under general anaesthetic. The donor is usually recommended to allow a few days rest to recuperate. 8 Part 2: Annexes

9 Peripheral blood stem cells - collection is less invasive than for bone marrow. The donor receives four or five daily injections of GCSF (granulocyte colony stimulating factor) which causes stem cells to move from the bone marrow to the circulating blood stream. These injections are usually administered in the donor s home by a visiting nurse. Collecting the stem cells from peripheral blood is an outpatient procedure. The donor s blood is removed and, in a continuous process using an apheresis device, the stem cells are isolated and the remaining blood is returned to the donor. This process lasts 4 to 5 hours and a second session on the next day may be needed. The donor may suffer flu-like symptoms as well as minor discomfort during the collection process (OHE 2010). Umbilical cord blood is rich in haemopoietic stem cells, which are biologically similar to stem cells from adults. However, stem cells and immune system cells in cord blood are relatively biologically naive and have a greater potential to proliferate. In addition, cord blood carries a low potential for infectious disease transmission. Cord blood-derived stem cells have been subject to less genotoxic damage and epigenetic modification than their adult counterparts. Indications for Unrelated Donor HSCT HSCT is a rapidly developing field of medicine that saves and extends the lives of hundreds of patients in the UK every year. Diseases treated by HSCT include haematological malignancies, bone marrow failure syndromes, metabolic disorders and primary immunodeficiencies. In 2008, the most common indications for allogeneic HSCT are acute myeloid leukaemia (33.4%), acute lymphoblastic leukaemia (13.4%), myelodysplastic syndrome (10.6%), non-hodgkin lymphoma (9.9%) and anaemia (5.7%)(BSBMT, 2009). For the majority of these patients, alternatives to HSCT using donor cells do not exist; such patients are termed allomandatory. Allogeneic transplantation for chronic myeloid leukaemia has declined since 2000 due to the development of effective non-transplant therapies such as Imatinib (Lee et al, 2010). The Growth in Unrelated Donor HSCT in the UK In 2009, 57.6% 1 of HSCTs performed in the UK were autologous (BSBMT, 2010), the remainder being allogeneic, either related or unrelated. Although HLA-matched siblings have historically been the preferred source of donor stem cells, this remains an option for only 30% of patients; around 70% of patients required stem cells from an unrelated donor. As a consequence, the use of stem cells from unrelated donors has increased significantly in recent years (Figure 1). In 2009, 749 unrelated donor HSCT were performed (including 88 using cord blood), up from 301 transplants in 2001 (BSBMT, ). Figure 2 shows that the growth in unrelated donor HSCT in the UK has reflected global trends. In 1997, according to the WMDA, 3,082 BM donations and just 155 PBSC donations were issued for transplantation worldwide. By 2009, the number of bone marrow donations had remained stable (3,445), while the number of PBSC donations had increased to 8,162 (WMDA, 2010). These increases have been driven by improved transplant protocols (Section 1.4) and facilitated by the expansion of donor registries. Figure 1 Unrelated donor HSCT in the UK using stem cells from adult donors and cord blood Transplants Unrelated adult donation Cord Blood (prov.) 1 Provisional data, including non-1st transplants. 2 BSBMT data for UK HSCT activity in 2009 is provisional at time of writing. A Report from the UK Stem Cell Strategic Forum July

10 Figure 2 Unrelated donor HSCT trends worldwide. Patient Outcomes Following Unrelated Donor HSCT Clinical, technological and scientific advances have all contributed to reduced post-transplant morbidity and mortality following unrelated donor HSCT. Management of cytomegalovirus (CMV) infection has improved and the incidence of severe graft-versus-host disease (GvHD) has been reduced by strategies such as T-cell depletion of stem cell donations. The use of reduced-intensity conditioning (RIC) has improved post-transplant morbidity and resulted in unrelated donor HSCT becoming a viable option for a growing proportion of older patients (Figure 3) (NMDP, 2010). Figure 3 3 The increasing use of unrelated donor HSCT in older patients. Patient outcomes have also been improved through the increased availability of donor stem cells and a better understanding of the importance of HLA matching. According to NMDP data, the proportion of well matched transplants increased from 28% between 1987 and 1998, to 51% between 1999 and 2002 and 65% between 2003 and 2006 (NMDP, 2010). The accuracy of donor HLA typing also improved over that time through the introduction of improved techniques and quality assessment exercises. Many factors affect patient outcomes following HSCT including the type and stage of disease, patient age, and the degree of HLA match between donor and patient. The major causes of post-operative mortality continue to be relapse, infection, GvHD, and organ toxicity. Nevertheless, through the advances described above, several different measures of patient outcome have improved consistently over the last 25 years (Karanes et al. 2008; Lee et al. 2010). Transplant-related mortality has reduced from 46% between 1996 and 1998 to 26% between 2003 and 2006 (NMDP, 2010). Non-relapse mortality rates in the year following unrelated donor HSCT reduced from 39% of patients in the 1980s to 22% since 2000 (Lee et al. 2010). Finally, one-year survival rates among 3 Adapted with permission from National Marrow Donor Program (NMDP), 2010, Physicians Resource Center, 10 Part 2: Annexes

11 transplanted patients increased from 42% of patients between 1996 and 2001 to 54% between 2002 and 2006 (NMDP, 2010). Improvements have been particularly pronounced for certain diseases such as severe aplastic anaemia, where survival rates doubled between and (Karanes et al. 2008). The Role of Cord Blood HSCT in Children and Adults As a result of the developments described above, patient outcomes following HSCT using stem cells from unrelated donors are now similar to those achieved using stem cells from matched siblings for diseases such as AML (Appelbaum et al. 2008). Depending on their source, haemopoietic stem cells have distinct qualities that can affect transplant outcomes. For example, PBSCs are usually associated with more rapid engraftment, but also a higher incidence of chronic GvHD than with bone marrow. Cord blood, on the other hand, has a much lower stem cell dose than either source of adult stem cells and is associated with longer periods of post-transplant neutropenia. Unlike adult donations, cord blood units cannot be sourced repeatedly if there are issues with stem cell engraftment or if the patient relapses following transplantation. However, cord blood has several positive characteristics as a source of stem cells. As the T-cells are relatively immunologically naive, the severity and incidence of GvHD is considerably lower compared to transplantation using adult PBSC or bone marrow. This allows transplant physicians to use less rigorously matched cord blood units. An improved understanding of the importance of selecting cord blood units containing a high dose of stem cells has also helped improve cord blood transplant outcomes. Several techniques are being developed to increase the rate of engraftment following cord blood transplantation. These include the ex-vivo expansion of stem cells, the co-infusion of haplo-identical CD34+ cells, intraosseous injection and the combined transplantation of two cord blood units. Of these, double cord blood transplantation is the most important and is becoming a very significant therapeutic modality in adult patients. Cord blood also has the advantage of being readily available and rapidly accessible compared to adult donors (Section 3.2). Historically, cord blood has been used predominantly for transplantation in children due to concerns that the low cell dose might make it less suitable for patients with a larger body mass. For paediatric patients, cord is regarded as a readily accessible stem cell source which may achieve less GvHD, improved T-cell reconstitution (Chiesa et al. In press) and improved graft versus leukaemia (GvL) effect (Eapen et al. 2007; Wagner et al. 2009). A review of clinical outcomes following CBT in children concluded that, in the absence of a matched sibling, transplant outcomes for cord blood were comparable and possibly superior to bone marrow, depending on the circumstances. Though for bone marrow failure, matched bone marrow is still preferable as a source for children with acute leukaemia cord blood may be equivalent or even superior (Hough et al. 2009). A recent study found that 5-year leukaemia-free survival for paediatric patients transplanted with 1 or 2 antigen mismatched cord blood was comparable to using matched bone marrow, while matched cord blood appeared to achieve better results (Eapen et al. 2007). A meta-analysis of recent outcome studies with unrelated bone marrow transplants (BMTs) and cord blood transplants (CBTs) concluded that unrelated CBT in children and adults had consistently equivalent survival outcomes compared with unrelated BMT despite greater donor-recipient HLA disparity with unrelated CBT (Hwang et al. 2007). In the adult setting, it has recently become clear that by selecting cord blood units containing high doses of stem cells and through the use of two units, good outcomes can also be obtained in patients with a higher body mass. In 2004, two major studies, performed by Eurocord and the Center for International Bone Marrow Transplant Research (CIBMTR), reported similar outcomes for CBT when compared to unrelated HSCT using BM or PBSC. These studies concluded that, in the absence of a matched unrelated adult donor, matched or mismatched cord blood was an acceptable alternative stem cell source (Laughlin et al. 2004; Rocha et al. 2004). Subsequently, interest in the therapeutic potential of CBT in adults has intensified as a clearer picture of its clinical potential has developed. A Report from the UK Stem Cell Strategic Forum July

12 Clinical studies such as those described above have led to a consensus in the UK regarding the use of matched and mismatched cord blood and adult stem cells for the treatment of different diseases (Shaw et al. 2009). This algorithm, reproduced at Table 1, is based on the premise that cord blood should be treated as an acceptable source of stem cells for patients lacking a suitably matched adult donor and that such transplants should be regarded as a clinical option, rather than a developmental intervention. Table 1 UK Consensus Algorithm for the Selection of Donor Stem Cells Choice Family Donor Unrelated Adult Donor Malignant disease: paediatrics 1st Matched family donor Matched cord (sibling) 2nd 10/10 9/10 Unrelated Cord Blood 6/6 5/6 ( >3 x 10 7 TNC/kg 3rd 8/10 5/6 ( <3 x 10 7 TNC/kg) 4/6 Malignant disease: adults 1st Matched family donor Matched cord (sibling) 2nd 10/10 9/10 3rd 8/10 6/6 5/6 ( >3 x 10 7 TNC/kg 4th 5/6 ( <3 x 10 7 TNC/kg) 4/6 Immunodeficiency/ Metabolic diseases 1st Matched family donor Matched cord (sibling) 2nd 10/10 6/6 3rd 9/10 5/6 ( >3 x 10 7 TNC/kg 4th 5/6 ( <3 x 10 7 TNC/kg) 4/6 Marrow failure 1st Matched family donor Matched cord (sibling) 2nd 10/10 3rd 9/10 6/6 5/6 ( >3 x 10 7 TNC/kg 4th 5/6 ( <3 x 10 7 TNC/kg 4/6 Reproduced from Shaw et al. (2009). 12 Part 2: Annexes

13 Annex 2 The Provision of Stem Cells for Transplantation in the UK Summary The UK s three stem cell donor registries now have a combined panel of more than 770,000 adult donors, compared to around 575,000 in Of these, the largest is the Anthony Nolan Trust (ANT) with around 405,000 donors, followed by the British Bone Marrow Registry (BBMR) with 310,000 donors and the Welsh Bone Marrow Registry (WBMDR) with 60,000 donors. This reflects international trends, with 16.4 million donors now listed at 76 registries worldwide. Cord blood banks have also grown considerably in the last decade: the NHS Cord Blood Bank (NHS-CBB) now has over 15,500 cord blood donations stored (and 12,435 available for search), though only around 8,500 of these fall within the revised cell count threshold 4. Globally there are 537,000 cord blood units available for transplant, compared to 44,000 in These increases have been accompanied by a substantial shift in stem cell sourcing patterns. A decade ago, bone marrow provided the majority of stem cells for unrelated donor HSCT in the UK; PBSC donations now account for 85% of the UK s adult stem cell use. However, despite slow uptake by the UK transplant community and uncertainty surrounding its application, cord blood has developed into an important source of stem cells. Its use has now extended to adult patients with growing success. Current trends suggest that it is likely to become increasingly important in the future. The Supply of Stem Cells for Transplantation in the UK Registries of Adult Donor Volunteers Patients lacking a suitably matched family member require a matched unrelated donor. The likelihood of identifying a suitable donor is largely determined by the HLA type of the patient and the size and diversity of adult registries and cord blood banks. The significant expansion of donor registries and cord blood inventories in the UK and internationally has therefore been critical in facilitating the steady rise in the number of unrelated donor transplants. The ANT was the first UK donor registry to be established in 1974 and now lists 404,888 stem cell donors. The BBMR lists 309,258 donors and the WBMDR lists 59,696 donors (WMDA, 2010). This growth reflects global trends: there are now 76 international registries with a total of 16.4 million available donors. Increasingly stem cells are provided across national boundaries (Figure 4). Despite its increasing domestic capacity, in 2009 the UK provided 305 (43%) of BM and PBSC donations nationally while 400 (57%) donations were imported. The majority of these were sourced from the German National Bone Marrow Donor Registry (ZKRD) in Germany and the National Marrow Donor Program (NMDP) in the United States (WMDA, 2010). Figure 4 Worldwide trends in the national and international provision of stem cell donations for HSCT 4 The total nucleated cell (TNC) count of a cord blood unit is an important determinant of its clinical value (Annex 1). In May 2010 NHSBT raised the minimum threshold for storage from 4 x 10 8 TNC to 12 x 10 8 TNC for Caucasian donors and 9 x 10 8 TNC for ethnic minority donors. A Report from the UK Stem Cell Strategic Forum July

14 Cord Blood Banks More recently, cord blood banks have been established in the UK and abroad and are now expanding rapidly. The NHS-CBB was the second CBB to be established worldwide. It has the UK s largest cord inventory with over 15,500 cord blood units banked and 12,675 units listed on the BBMR. It is the only facility in the UK to have issued cord blood units for a domestic transplant and has currently provided over 310 cord blood units for transplantation. Internationally, cord blood banks worldwide now have a combined inventory of over 537,000 cord units. This compares to only 44,000 units in The UK s cord blood resources are still developing and, in common with other countries, it remains reliant on international cord banks, particularly those in the United States. In 2009, 16 (15%) of cord blood units were provided nationally, and 91 (85%) of units were sourced from abroad. The Growing Importance of Cord Blood Two trends can be identified over the last ten years, both globally and in the UK. The first is the diminishing use of bone marrow in favour of PBSC (considered above, Figure 2); the second is the increasing use of cord blood over adult stem cells. Until recently, cord blood made a relatively marginal contribution to HSCT in the UK, especially when compared to other countries such as Spain, France and the USA. This was in part due to the successes being achieved by UK transplant physicians using alternate strategies such as T-cell depletion and haploidentical transplantation when no matched sibling or unrelated donor was available (Technopolis, 2009). The UK use of cord blood is compared with other Countries in Figures 5 and 6 (WMDA, 2009). Figure 5 Types of stem cell donation transplanted by country Figure 6 The use of cord blood in unrelated HSCT 14 Part 2: Annexes

15 The use of cord blood in the UK is now increasing; in 2009, of the 812 stem cell donations supplied for transplantation, 104 (13%) were bone marrow, 601 (74%) were PBSC and 107 (13%) were cord blood units. This reflects the increasing use of cord blood for unrelated donor HSCT in the UK (Figure 7). Figure 7 The increased use of cord blood in the UK for unrelated donor HSCT The recent increase in the use of cord blood in the UK is forecast to continue in light of the developing body of evidence regarding post-transplant outcomes in children and adults and a developing national consensus on its use for a range of diseases. Cord blood transplantation now accounts for around 30% of unrelated donor HSCT for patients under the age of 16). With the development of double cord blood transplants, it is increasingly utilised in adults too. Since 2008, adult transplants using cord blood have exceeded the total number of paediatric cord blood transplants (Figure 8) as the number of unrelated donor HSCT performed in adults is much higher (NMDP, 2010). Figure 8 The growing proportion of cord blood transplants on adult patients, A recent review of the UK s cord blood services, commissioned by the Department of Health, highlighted the absence of a national policy on cord blood and recommended that a framework should be developed in conjunction with a high-level advisory committee (Technopolis, 2009). The report notes that although the use of cord blood in the UK was growing, current usage is lower than countries such as Spain (Figure 9), where the investment in cord blood banking has been much greater: while its registry has only 80,314 registered adult donors, its cord bank has 41,771 available cord units (WMDA, 2010). A Report from the UK Stem Cell Strategic Forum July

16 In summary, cord blood is likely to become an increasingly significant source of unrelated donor stem cells in the coming decade. Great Ormond Street Hospital, the largest paediatric stem cell transplant centre in the UK has, in the last few years, shifted its stem cell use towards cord blood which is now used in more than 50% of the transplants it performs (Figure 9). This trend is likely to be followed by other paediatric centres. A similar pattern of significantly increased cord blood transplant activity is predicted in the adult population. Figure 9 The increasing use of cord blood for transplantation at Great Ormond Street Hospital, Transplants Adult donations Cord blood 16 Part 2: Annexes

17 Annex 3 Meeting the Demand for Stem Cells in the UK Summary HSCT is a life-saving therapy. The majority of patients referred for transplant have no acceptable alternative cure. Despite the millions of registered volunteers available globally, many patients fail to locate a suitable donor, particularly among ethnic minorities. This is because the HLA haplotypes found in ethnic minority individuals are poorly represented in donor registries. While around 90% of Caucasians may typically find a match, for ethnic minorities the matching rates may be as low as 10%. Furthermore, many patients who are successful in locating a donor fail to be transplanted due to death or deterioration. For them, an important contributing factor is the several months it may take to confirm the availability and suitability of a stem cell donor and to arrange for stem cell collection. For these patients, the ready availability of a matched cord blood unit may be life-saving. Overall, current levels of unmet need are estimated to be approximately 440 patients in the UK annually. However, an adequately sized cord blood bank would provide 370 of these patients each year with rapid access to suitable stem cells for transplantation. This would cure around 200 patients in the UK each year of an otherwise fatal illness. Health Related Risks Associated with Stem Cell Donation In the overwhelming majority of cases, obtaining stem cells from bone marrow and peripheral blood does not impose long term adverse consequences on the donor. Instances of sepsis, pelvis fractures and splenic rupture have occurred, but only very infrequently (Pamphilon et al. 2009). Nor is there any evidence to support earlier concerns that the use of G-CSF might be associated with the development of myeloid malignancy in healthy allogeneic donors (Pamphilon et al. 2008). However, transient symptoms are common: recent follow up surveys by the NMDP found that 70% of donors experienced headache, myalgia and fatigue and 80% suffered bone pain. In addition, around 0.6% experienced unexpected toxicities, though they all recovered (Pulsipher et al. 2009). Fatalities and life-threatening incidents are rare, but have been reported: a recent review of 51,024 allogeneic transplants performed between 1993 and 2005, primarily in Europe, reported five donor deaths and 37 severe adverse events, including subarachnoid haemorrhage (Halter et al. 2009). Though the long term risks of adult donation are minimal, cord blood poses no risk to the mother if collected without modification at the third stage of labour, in accordance with standard UK birthing protocols. Collection as performed by the NHS-CBB does not interfere with the management of the birth and only occurs after the baby is born. For the baby, the advantages of delayed cord clamping are improved iron stores and a lower risk of an intraventricular haemorrhage, though there is a raised probability of jaundice requiring phototherapy (Downey and Bewley, 2009). Inequalities in the Provision of Stem Cells for HSCT Unrelated donor HSCT is a life-saving therapy, referred to as allomandatory for the patients for whom it is the only treatment with a reasonable chance of cure. Even with the expansion of international registries, many patients in need of unrelated donor HSCT fail to receive a transplant. Of the 151,000 patients qualifying for an unrelated donor transplant between 2000 and 2006, only 64,720 actually received one (Van Rood and Oudshoorn, 2008). Patients from ethnic minorities are particularly disadvantaged. This is because HLA types are related to ethnicity and ethnic minority donors are underrepresented on registries. Of the donors registered on the BBMR, only 5.1% of donors are non-caucasian (including 1.7% Asian, 1.2% Black, 1.2% mixed race and 0.3% Oriental). To remedy this, targeted recruitment drives by major registries have had some success. A review of the ANT registry in 2005 showed its composition to be more closely aligned with that of the UK population (4.3% Asian, 3.7% Black, 0.4% Oriental). A Report from the UK Stem Cell Strategic Forum July

18 This impacts substantially on the prospects of ethnic minorities successfully locating a match. BBMR data on matching rates suggests that Caucasian patients are more than twice as likely (88%) to locate a suitably matched donor than mixed race patients (40.7%)(BBMR, 2004/5), as illustrated in Figure 10. Similarly, Shaw et al, (2009) report that while up to 30% of Caucasian patients in the UK may be unable to find a 9/10 or 10/10 volunteer adult donor match, for ethnic minority patients this figure is as high as 70% (Shaw et al, 2009). This is mirrored in other major international registries, such as the NMDP, where the identification of a 7/8 or 8/8 matched unrelated donor occurs for more than 90% of US patients of European Caucasian ancestry, more than 70% for those of Asian or Hispanic ancestry, and more than 60% for those of African ancestry (B. Shaw, personal communication, cited in OHE, 2010). A recent survey of 398 searches in the United States found that 89% of Caucasians, 77% of Hispanics but only 52% of African Americans were able to find a 7/8 or 8/8 matched (OHE, 2010). Consequently, it cannot be assumed that Black and minority ethnic patients unable to locate a donor with a UK registry will be able to identify a suitable match in an international registry. Figure 10 Patient matching rates by ethnicity (2004/5) The challenge of identifying matched adult donors for Black and ethnic minority patients is further increased by other factors, including: The greater HLA heterogeneity among certain ethnic groups different ethnic groups have differing levels of HLA heterogeneity. The probability that two randomly selected African-Americans will have an HLA match is about a tenth of the equivalent probability of a match between two Caucasians (Bergstrom et al. 2009). A smaller donor pool as ethnic minorities have a smaller population base, even with comparative levels of representation to Caucasians, ethnic minority patients will have a smaller selection of potential matches. The banking of umbilical cord blood offers an opportunity to reduce this inequality. It is difficult to increase the representation of specific ethnic minorities on a volunteer donor panel, but considerably more practicable to focus collection of cord blood at hospital maternity units that serve populations with relatively high levels of ethnic diversity. Through targeted collection in this way, currently underrepresented HLA types can be made much more available. This would benefit not only ethnic minorities in the UK but also the same ethnic groups in other countries around the world. The NHS-CBB currently has 39.5% ethnic minority representation among its stored units (BBMR, 2010). This is similar to the NMDP in the United States: 44% of its listed cord units are sourced from ethnic minority donors (NMDP, 2010). An additional advantage is that, due to its tolerance of higher levels of HLA mismatch between patient and donor, cord blood can be used with greater flexibility for transplantation on patients with rare haplotypes who lack a similarly matched donor. 18 Part 2: Annexes

19 Donor Search to Transplant Time The progression of a patient s disease prior to HSCT is an important contributing cause of treatment failure and death. A study of 3857 transplants between 1988 and 2003 found that, compared to patients transplanted at an early stage of their disease, the mortality risk for intermediate-stage patients was 38% higher. For advanced-stage patients, the risk was roughly double (Lee et al. 2007). The duration of a patient s waiting period frequently determines whether he or she is able to receive HSCT. Currently, search-to-transplant time using adult donor stem cells takes a median of four months (Kernan et al. 1993; Barker et al. 2002) and during this period patients may relapse or die (Davies et al. 1996; Dini et al. 2003). A survey of outcomes at King s College Hospital during 2005 found that, while 28% of patients failed to locate a donor, an additional 33% who successfully found a suitable donor were unable to undergo the procedure as a result of deterioration during the donor search. Overall, only 38% of allomandatory patients in the sample study were actually transplanted (Querol et al. 2009a). The problem of extended waiting periods applies particularly to adult donations. Cord blood units, unlike adult volunteers, are stored in situ and therefore readily accessible for confirmatory testing and shipping when a transplant centre makes a request. A survey of referrals reported a median of only 13.5 (range, 2-387) days to search and choose a cord blood unit for transplantation, compared to 49 (range, 32 to 293) days to obtain a suitable unrelated adult donor (Figure 11) (Barker, 2002). This translates into shorter search-to-transplant times for cord blood HSCT. Figure 11 Search times for bone marrow donations and cord blood units BONE MARROW 19 days (1-257) 30 days (10-101) 50 days (32-293) CORD BLOOD 13.5 days (2-387) Donor identified Formal search time Donor available It is also possible to reduce waiting times and raise the certainty of an appropriate and reliable donor being identified through the development of a fit panel of donors. This is discussed in greater depth in Annex 4. Through regular contact with registered volunteers, the high resolution typing of preferentially selected donors and new recruits, and the use of a predictive search algorithm supported by specialist advisory services, searchinitiation-to-transplant times would be reduced by 4 to 6 weeks (D. Marks, personal communication to the review). Estimating the Unmet Need for Unrelated Stem Cells in the UK Unmet need includes the proportion of patients unable to find a match as well as the patients who may currently locate a suitable donor but who fail to be transplanted due to donor-related issues: donors may be difficult to trace, prove medically unfit for donation or withdraw their consent. As discussed above, a significant number of patients die or deteriorate physically while waiting for a transplant. A Report from the UK Stem Cell Strategic Forum July

20 Failure to Find a Match Caucasian Patients During 2009, 661 unrelated adult HSCT were performed in the UK (data from BSBMT, 2010). If it is assumed that these were all Caucasian patients and if 20% of Caucasian patients are unable to identify a suitable match, then the unmet demand from Caucasians can be estimated as: (0.2/0.8) x 661 = 166 patients per annum The unmet demand from failure to find a match for Caucasian patients is therefore circa 170 patients per annum. Failure to Find a Match Ethnic Minority Patients Ethnic minorities make up 10% 5 of the UK population. If it is assumed that 10% of the demand for unrelated donor stem cells comes from ethnic minorities, then the unmet demand can be estimated as: (0.10/0.90) x (661/0.8) = 92 patients per annum The unmet demand from the failure to find a match for Black and ethnic minority patients is therefore circa 90 patients per annum. Demand Currently met by Cord Blood Donations During 2009, 88 transplants were carried out using cord blood; of these, 17% went to ethnic minority patients (Regan et al. 2010). Subtracting these from the above unmet demand estimates yields: Caucasian unmet demand from failure to find a match = 93 patients per annum Ethnic minority unmet demand from failure to find a match = 77 patients per annum Unmet Demand due to Patient Factors 12% to 33% of patients with a matched unrelated adult stem cell donor do not proceed to transplant due to patient factors such as disease progression and toxicity to additional chemotherapy. It is assumed 50% of these patients would benefit from a rapid cord blood transplant. So unmet demand for these patients can be estimated as between: (0.12/0.88) x 661 x 0.5 = 45.1 patients per annum and (0.33/0.67) x 661 x 0.5 = 163 patients per annum. Taking the mid-point, the unmet demand from patient factors is around 110 patient per annum. Further Demand due to Substitution For unrelated adult donations, optimal patient outcomes are achieved using PBSC or bone marrow matched for 9/10 or 10/10 HLA-A, -B, -C, -DR and -DQ alleles (N. Russell and B. Shaw, personal communication to the review). For patients unable to locate a 9/10 or 10/10 matched donor or requiring urgent transplantation, a cord blood unit is an acceptable alternative stem cell source. For a CBT, the current minimum acceptable standard is a 4/6 HLA-A, -B and DR match (Querol et al. 2009a) and so it provides wider access to patients with rarer HLA haplotypes. Moreover, for CBT, acceptable matching at HLA-A and HLA-B loci can be achieved at lower resolution than required for unrelated adult donations. 5 This figure is based on ethnic minority population shares in England and Wales, Northern Ireland and Scotland, weighted by total population population data was used, 2007 experimental data was used for England and Wales ethnic minority shares and 2001 data was used for Scotland and Northern Ireland ethnic minority shares. 20 Part 2: Annexes

21 It is estimated an additional 70 cord blood transplants could be carried out each year to replace 9/10 HLA matched adult donor stem cell transplants. Total Unmet Demand in the UK From the above, it follows that the unmet need for donor stem cells is circa i.e. 440 patients per annum. Meeting Unmet Demand via an Increased Inventory of Cord Blood Units Optimising the cord blood inventory for the UK is discussed below. Querol et al. (2009a) estimated that a UK inventory of 50,000 cord blood units would be able to meet: 85% of the unmet need from Caucasian patients 50% of the unmet need from Black and ethnic minority patients 90% of the unmet need from patients whose conditions deteriorate while waiting for an adult donor 100% of the unmet need from patients who would have received a 9/10 HLA matched bone marrow donation. Thus, the extra number of UK patients who would be treated from a UK cord blood inventory of 50,000 units would be: Caucasian demand met: 150 patients per annum Black and ethnic minority demand met: 50 patients per annum Patient factors: 100 patients per annum Adult donor stem cell recipients: 70 patients per annum In total, the extra number of patients treated in the UK from an increased cord blood inventory would be 370 (out of a potential 440). However, the number of cord blood units issued would be greater than 370, since two thirds of adults will probably receive double cord blood transplants. Assuming that two thirds of adults receive double cord blood transplants, but all children receive single cord, it is estimated that 1.57 cord blood donations are used per transplant (D. Marks, personal communication to the Review). This would amount to 580 cord blood units per annum. Assuming that around 60% of transplants are successful and that patients who do not receive HSCT have little or no life expectancy, this means that 200 patients (1000 life years) would be cured of an otherwise fatal disease annually. 6 Likely Changes in Clinical Practice Changes in practice in the next decade are difficult to predict, but rates of transplantation are likely to increase as HSCT is increasingly applied to older and infirm patients as salvage chemotherapy improves. Increased rates of transplantation are likely in acute myeloid leukaemia, lymphoma, myelodysplastic syndrome, and acute lymphoblastic leukaemia: a significant proportion of these patients will be in an unstable remission and require urgent access to HSCT. 6 Recent studies have shown survival rates of around 50% following cord blood transplantation for ALL (49% 5-year survival, Tomblyn et al. 2009; 50% 3-year survival, Bachanova et al. 2009) and almost 80% for certain conditions such as Hurler s syndrome (77% 3-year survival, Boelens et al. 2009). It is anticipated that outcomes for good risk adults and children will reach 55%-60% during the 4-8 year period of expansion of the cord blood inventory. A Report from the UK Stem Cell Strategic Forum July

22 Requirement for Donor Stem Cells Following an Irradiation Incident Stem cells may have value following an irradiation event. Though unlikely, an event which irradiated a significant number of individuals could affect their haemopoietic, gastrointestinal and neurological systems. Individuals receiving between 4 and 10 Gy of total body radiation may benefit from stem cell transplantation. However, in an emergency context, the established network of registries might be impaired. Furthermore, many donors could be irradiated themselves or unwilling to attend a hospital close to an area affected by radiation. In these circumstances, a cord blood bank could play a critical role in providing patients with a reliable and readily accessible source of stem cells 7. The Department of Health has identified cord blood as a central component of its contingency plan. Cryopreserved cord units could be supplied for transplantation within a matter of days. Due to its capacity to successfully engraft with relatively high levels of HLA mismatch, an adequately sized bank would provide a 4/6- or 5/6-HLA donor match to as much as 90% of affected individuals. 7 It should be noted that the efficacy of cord blood in this setting has not been tested, and its slow engraftment might not be appropriate for patients with prolonged neutropenia. 22 Part 2: Annexes

23 Annex 4 Increasing the Availability of Adult Donor Haemopoietic Stem Cells for Transplantation Summary The UK now has in excess of 770,000 registered adult volunteers, with millions of additional donors available globally. Increasing the number of donors registered would not significantly increase the chances of UK patients identifying a matched unrelated adult donor. Greater impact on patient outcomes would be achieved through measures to decrease the time taken to provide high quality adult donor stem cells. The latter can be achieved through, the creation of a fit panel of available adult donors. This would be achieved by high resolution typing new recruits and selectively targeting registered donors with a favourable demographic profile as potential donors. By providing further samples for typing, these donors would also confirm their continued availability and willingness to donate. Furthermore, registry searches would be enhanced by the use of a predictive search algorithm that would preferentially list the optimal donor profiles for selection by transplant centres. The Effect of Registry Size on Identifying Matched Donors Though adult registries provide a large proportion of patients with a suitably matched donor, it is unlikely that this proportion can be increased significantly by further increasing the size of adult donor registries. The number of UK patients currently unable to find a matched unrelated donor is described in Annex 3. Figure 12 shows that as registries become larger, the gain in improved matching rates with every additional donor becomes increasingly marginal. By extrapolating from German registry data, increasing a European registry size from 500,000 to 1,000,000 donors raises the proportion of patients finding a matched donor by about 5%. Thereafter, for every million new donors added, search success rates rise by around 2% (S. Querol, personal communication to the review). A registry of 10 million donors would require a further 7 million additional donors to increase donor identification rates by 1% (Hurley et al. 2003). Registry expansion has substantial associated costs; significant investment is required to both expand and maintain the donor base against annual donor attrition rates of around 2%. For these reasons, registries focus effort on increasing the genetic diversity of the panel through targeted recruitment of Black and ethnic minority donors. Figure 12 Relationship between matching rate and size for large European donor registers (data provided by C. Muller, personal communication to the review). A Report from the UK Stem Cell Strategic Forum July