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JME Online First, published on May 13, 2014 as 10.1136/medethics-2013-101673 Viewpoint
Are hybrid umbilical cord blood banks really the best of both worlds? Gregory M T Guilcher,1 Conrad V Fernandez,2 Steven Joffe3 1
Section of Hematology/ Oncology/Transplant, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada 2 Division of Pediatric Hematology/Oncology, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada 3 Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to Gregory M T Guilcher, Section of Pediatric Hematology/Oncology/ Transplant, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B 6A8; greg.guilcher@ albertahealthservices.ca Received 25 June 2013 Revised 8 April 2014 Accepted 24 April 2014
To cite: Guilcher GMT, Fernandez CV, Joffe S. J Med Ethics Published Online First: [ please include Day Month Year] doi:10.1136/ medethics-2013-101673
ABSTRACT Since the first use of umbilical cord blood (UCB) as a medical therapy, the number of UCB banks worldwide has grown. Public UCB banks offer the option of altruistic donation, whereas private banks allow a product to be stored for the exclusive use of the paying client. With many more UCB products banked privately than publicly in countries such as the USA, hybrid models blending aspects of public and private banking have been proposed. One such bank is in operation in the UK. In this paper we review the hybrid UCB model and conclude that it offers limited benefit to the general public. Furthermore, compared with private banking, this model provides few advantages and potential disadvantages to private clients.
INTRODUCTION Umbilical cord blood (UCB) is a tissue rich in blood stem cells that can be collected from the detached umbilical cord and placenta shortly after birth. The use of UCB as a source of haematopoietic stem cells (HSCs) for allogeneic and, rarely, autologous transplantation has increased dramatically over the last 30 years.1–3 UCB products expand the number of patients who can access allogeneic haematopoietic stem cell transplantation (HSCT) due to advantages such as reduced risk of graft versus host disease, less stringent human leucocyte antigen (HLA) matching requirements, and quicker donor activation as compared with HSCs from unrelated adult donors.4 Many parents have the option of banking their newborn’s UCB in either public or private banks. Public banks store altruistically donated UCB from consenting parents by freezing these products and maintaining a searchable inventory accessible to registries that facilitate stem cell transplantation. A publicly banked product that is identified as suitable for HSCT can be purchased on behalf of a recipient, with the cost of the unit partially offsetting the operating costs of the public bank. Private UCB banks, in contrast, store frozen UCB for the exclusive use of a paying client. Hybrid UCB banks, which combine features of private and public banks, market themselves as offering the potential benefits of both options. Although the hybrid model may appear to be ‘the best of both worlds,’ such banks offer few benefits to the general public and disadvantage the private recipient. In what follows, we briefly situate the role of UCB in stem cell transplantation, examine the potential benefits and limitations of public and private banking models, and articulate why hybrid banks should not be the focus of ongoing efforts to
Guilcher GMT, et al.Article J Med Ethics 2014;0:1–4. Copyright author (or doi:10.1136/medethics-2013-101673 their employer) 2014. Produced
expand the availability of UCB products to the public.
WHAT IS HSCT? HSCT is the procedure of infusing blood stem cells from a donor into a recipient. Autologous HSCT, in which the patient’s own stem cells are collected and then reinfused at a later date, is used to rescue production of blood cells after high dose chemotherapy for aggressive malignancies. In allogeneic HSCT, stem cells from another individual are infused into the recipient after she or he receives preparatory chemotherapy, immunotherapy and/or radiation therapy. Historically, allogeneic HSCs (obtained from either bone marrow or peripheral blood) were collected from a related donor or from an unrelated adult donor. More recently, the use of UCB from related or unrelated newborns has been shown to be an effective alternative source of HSCs for transplantation. Indications for allogeneic HSCT include selected haematological malignancies (such as leukaemia) and non-malignant disorders. Non-malignant indications, such as immune deficiencies, haemoglobinopathies and metabolic disorders, are expanding as the morbidity and mortality associated with the procedure decline.5 The ideal stem cell source depends on many factors including the recipient’s underlying condition, donor availability (a suitable related donor is generally preferred), the urgency with which transplantation must begin and the size of the recipient (many UCB units contain too few stem cells to meet the needs of larger recipients).
BENEFITS AND LIMITATIONS OF PUBLIC UCB BANKS IN MAKING UCB AVAILABLE FOR HSCT Public UCB banks allow for the donation of residual blood in the clamped umbilical cord to a facility that stores these products for patients in need of HSCT. Public banks allow clinicians to search for prospective donors on behalf of an identified recipient.1–3 Costs of collection are typically assumed by the bank and recouped, at least in part, by charges to the HSCT recipient (box 1).3 Standards and accreditations vary across banks, but many public UCB banks in North America, Europe and Australia are accredited and audited by professional bodies.1 3 Accreditation requirements dictate that searchable units must be collected and stored using specific standard operating protocols and must meet certain criteria, including adequate cell count and volume. Public banks have policies regarding the timing of the collection of the UCB product to ensure the safety of the mother and baby are paramount, particularly given the altruistic nature of the donation.6 However, UCB collection
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Viewpoint
Box 1 Advantages and limitations of public UCB banking Benefits of public banks Increased likelihood of finding matching source of HSCs for individuals with rare immune (human leucocyte antigen, HLA) types compared with live donor registries Financial cost not incurred by donor Directed donation options exist Limitations of public banks Operating costs covered by haematopoietic stem cell transplantation (HSCT) recipients, philanthropic groups, governments (ongoing funding may be a challenge) Product may not be available for donor’s family if need for HSCT arises Opportunity to donate not universal
can still be performed even with delayed clamping of the umbilical cord—a practice which might reduce the volume of UCB collected but may have important benefits for the newborn.7 The aforementioned standards are critical for the safety of the prospective recipient and essential to physicians selecting products for use in HSCT.1 Only about 25–40% of collected UCB units satisfy these criteria for storage in a public bank; in contrast, most private banks store the product regardless of cell count.1 6 A minority of UCB products procured by public banks has been used in transplantation; most remain in public inventories (90% of the UCB inventory in the New York Blood Center remains available after 10 years of storage).6 8 Therefore, most of the publicly banked UCB products are theoretically still available to the families who donate in the statistically unlikely event that a family member later needs the UCB for HSCT. Furthermore, some public banks allow for directed donation in the event that a pregnant woman has a prior child or other family member with a disease for which allogeneic HSCT may be an appropriate treatment.6 8 While public banks have allowed many patients to undergo HSCT, not all candidates for HSCT can find suitable donors within existing registries. In particular, the likelihood of finding a donor varies across racial/ethnic groups. The variation in rates of donor identification is due to under-representation of some ethnic groups within adult live donor registries and to increased HLA diversity within some ethnic groups.4 9
BENEFITS AND LIMITATIONS OF PRIVATE UCB BANKS IN MAKING UCB PRODUCTS AVAILABLE FOR HSCT Private UCB banks are for-profit entities that offer fee-for-service collection and cryopreservation (freezing) of UCB products. For an upfront cost (typically US$1000–2000), parents may elect to have the UCB collected and cryopreserved.10 11 Ongoing cryopreservation of the UCB product requires payment of an annual fee (typically about US$125). Such products are stored solely for the use of the donor’s family. The primary benefit of private UCB banking is the family’s exclusive access to the product should the need arise (box 2). Depending on where they live, some families may not have the option of public banking. For families who have an identified family member who might need HSCT, private banking may be the only option to store the UCB product. 2
There are several limitations of private UCB banking. First, the cost of such banking is substantial and may not be justified by the potential benefits. Private UCB banking rarely provides medical benefit to the child or family for whom the product has been cryopreserved: estimates of the probability that the product will be used range between 1 in 2700 and 1 in 250 000.3 8 When privately banked UCB products have been used for HSCT, it was almost always known before the UCB was stored that a family member was in need of a donor or at high risk of later requiring HSCT.12 Many professional organisations and experts have expressed concerns that clients of private UCB banks may have insufficient understanding of current accepted indications for, and the likelihood of, UCB use. Given the substantial cost and low probability of using the product, the American Academy of Pediatrics, the American Society of Blood and Marrow Transplantation and the Society of Canadian Obstetricians and Gynecologists have clear position statements recommending against elective private UCB banking unless a family member is at high risk of needing a transplant in the future.13–15 Furthermore, critics have suggested that private UCB banks may overemphasise unproven possible future indications beyond HSCT.2 14 Another limitation of private UCB banking is the variability in quality standards. Private banks might not be required to adhere to the same rigorous donor screening and infectious disease testing as is necessary for public banks, and have financial incentive to accept units that would be considered substandard by public banks.16–18 Private UCB banks typically store the UCB regardless of its quality and do not provide quality reports on the UCB unit (including such metrics as the cell dose collected and the viability of the cells) to the client. Additionally, private UCB collections may be performed by medical or nursing personnel with limited experience in UCB collection. Experience in collection is an important factor in the collection of a quality unit.1 Concerns have been raised that the collection process might distract from the care of the mother and newborn, and that the diversion of any attention from their care is ethically problematic with such a low probability that the UCB product will ever be used.19 Some private
Box 2 Advantages and limitations of private UCB banking Benefits of private banks Family control over umbilical cord blood (UCB) product If prospective recipient in family is identified, allows for collection even if no public bank with directed donation option is available Limitations of private banks Product unavailable to general public Collection may burden a publicly funded system (eg, physician, nursing and hospital resources) UCB clamping practices may be altered in an effort to procure the UCB product (with data to suggest that early clamping produces higher stem cell volumes but can put some newborns at risk) Consumers often misinformed regarding established indications and likelihood of use Products often stored regardless of cell dose and viability (quality)—typically no quality report provided to client Optional adherence to accreditation standards Substantial financial cost to families Guilcher GMT, et al. J Med Ethics 2014;0:1–4. doi:10.1136/medethics-2013-101673
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Viewpoint banks advise early clamping of the umbilical cord to increase collection cell yields, whereas a public bank will collect UCB after the umbilical cord is cut and the delivery is unaltered due to the altruistic nature of the donation.6 10
HYBRID UCB BANKS A hybrid (or dual) UCB bank is a new model of UCB banking in which elements of private and public banking coexist.2 20 For the purposes of this discussion, a hybrid UCB bank is a private institution in which an UCB product is stored for possible public or private use. Several possible models for hybrid banks have been proposed, and one hybrid bank, the Virgin Health Bank, is currently in operation (figure 1).20 21 Virgin Health Bank offers a Community Banking option, which is a hybrid model in which a small amount of UCB is stored exclusively for the client with the remainder stored in an inventory available for public use. Virgin also offers an exclusively private Family Banking option. Virgin’s Community Banking option costs £1195, whereas Family Banking costs £1695. Some models of hybrid UCB banks require a second consent from the client immediately prior to release of an UCB product to an HSCT centre for allogeneic use.2 In contrast, Virgin Health Bank currently requires consent for the donation of a portion of the product to an unrelated recipient at the time of collection. With this consent in place, distribution of the portion of the unit that is stored for public use is ultimately at the discretion of the bank.21
Proposed advantages of hybrid UCB banks With hybrid banking options, families will have the option of banking a child’s UCB in a facility which will store some of the product for the paying consumer, while giving the family the knowledge that an unrelated person might derive benefit from the donation.21 The ‘public’ portion of the product might be donated to a prospective HSCT centre if the inventory was searched, a match identified and quality parameters shown to be acceptable. Proponents state that, under the hybrid model, at least some units that would be otherwise unavailable for public consideration in an exclusively private model would now be available for unrelated HSCT. Given the higher rate of private UCB banking compared with public banking in countries such
as the USA and the continued inability to find matched UCB units for at least some recipients, supporters argue that making additional units available through hybrid banks can only be beneficial.22 23 In theory, hybrid banks also provide financial advantages by leveraging private banking to subsidise the costs of storing units for unrelated-donor transplantation (ie, families altruistically supporting the cost of public donation). Thus a hybrid model might increase the unrelated donor pool while reducing, or at least not increasing, public subsidies. The appropriateness of transferring cost from such public sources to private clients of hybrid UCB banks might be considered by some ethicists to be suspect if the expected benefits to the public are minimal.
Effectiveness of hybrid UCB banks at enhancing access to allogeneic HSCT Some individuals in need of allogeneic HSCT—particularly those with rare HLA subtypes—remain unable to find suitably matched donors within existing public unrelated bone marrow donor registries and UCB banks. Such individuals are disproportionately members of minority ethnic groups. Simply increasing the number of individuals in the donor pool might seem the obvious solution to this problem. However, statistical modelling suggests that for the rarest HLA haplotypes, the reality is more complicated. For example, using adult unrelated-donor registries as an example, doubling the pool of registered African-American donors in the USA would only increase the likelihood of finding HLA-matched donors for this group from 34% to 37%.24 Though many factors, including donor availability and attrition, influence these statistics, the tremendous HLA diversity among African-Americans is the primary challenge in identifying suitable donors.9 24 25 Some data even suggest that due to the diversity of genetic polymorphisms, African-Americans and Hispanic Americans will have lower probabilities of finding a HLA-matched donor than European-American recipients regardless of registry size.9 Unfortunately, as currently constituted, hybrid UCB banks do not encourage targeted banking by families with rare HLA haplotypes. Furthermore, the costs of hybrid banking may represent a particular barrier for many families with rare HLA haplotypes.
Figure 1 Virgin Health Bank Community Banking Model. HSCT, haematopoietic stem cell transplantation; UCB, umbilical cord blood.
Guilcher GMT, et al. J Med Ethics 2014;0:1–4. doi:10.1136/medethics-2013-101673
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Viewpoint Additionally, the differences in quality standards that have been observed between public and private banks may also exist between public and hybrid banks.16–18 As few as one in four publicly donated UCB units meets criteria for storage and availability for allogeneic transplantation; units that do not meet these criteria are excluded from public donor pools. In order to address this concern, hybrid banks would need to ensure quality control during the collection process and to limit searchable inventory to those units that meet current public banking accreditation standards. Another concern is that some models of hybrid banking propose splitting the UCB unit, with a proportion reserved for possible future use by the client. Virgin’s Health Bank’s Community Bank operates under such a model, storing the first 5 mL of the product exclusively for family use, with the remainder available for unrelated donation.21 This splitting is problematic in at least three ways. First, stem cell dose is often a limiting factor in the selection of a suitable UCB unit, in particular when considering larger recipients. Thus, splitting the unit will further reduce the number of products suitable for consideration for unrelated donation. Second, the reserved 5 mL may not be of practical use for autologous HSCT, particularly as the individual grows in size. Although the bank acknowledges that, with current medical technology, the 5 mL volume is insufficient to provide benefit, it also contends that advances in ex vivo stem cell expansion and regenerative medicine techniques are ‘expected,’ and ‘may’ allow for future use.21 Such scientific advances are speculative and may, in fact, obviate the need for private banking. Third, even with ‘full-sized’ cord units, delayed and failed engraftment events are more common with UCB than with marrow and peripheral blood stem cell products. Thus, manipulating an UCB product in any way that may further reduce engraftment without clear medical benefit is ethically problematic for public and private recipients.
‘public’ and ‘private’ components may result in reduced cell doses for each component such that either or both are less likely to be of utility. Clinicians and policy makers who seek to increase the likelihood that individuals with rare immune types will have available donors for HSCT should focus instead on enhancing mechanisms for public donation of high quality UCB products from targeted populations. Contributors All authors contributed to the intellectual content and review of the manuscript. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 2
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5 6 7 8 9 10 11 12
Might the limitations of hybrid UCB banks be overcome? Significant advances in banking technology would be required to swing the balance in favour of a hybrid model. Advances in processing techniques of UCB products to minimise cell loss might eliminate some of the practical limitations of hybrid UCB banks. Ex vivo expansion methods might be developed which could allow for the ‘public’ and ‘private’ aliquots to be of adequate volume and cellular content to be of use. Theoretically, such innovation could expand all UCB bank inventories to the point where additional UCB units on public registries are no longer required—with the exception of rare HLA haplotypes—and make the argument for public benefit from additional units in searchable hybrid banks moot. While searchable public registries will continue to benefit from the addition of rare haplotypes, given the statistical diversity models discussed previously, the challenge of representing all HLA haplotypes in public banks will remain even if large numbers of such units are added. Hybrid UCB banks are unlikely to be the solution to this challenge.
CONCLUSIONS UCB banking has greatly improved access to HSCT for suitable recipients over the last 20 years.1–4 Due to the current limitations associated with the hybrid bank model, such banks are unlikely to contribute measurably to finding HLA-matched donors for patients in need of HSCT. UCB products split into
4
13 14 15 16
17 18
19 20 21 22 23 24
25
Butler MG, Menitove JE. Umbilical cord blood banking: an update. J Assist Reprod Genet 2011;28:669–76. Manegold G, Meyer-Monard S, Tichelli A, et al. Controversies in hybrid banking: attitudes of Swiss public umbilical cord blood donors toward private and public banking. Arch Gynecol Obstet 2011;284:99–104. Smith FO. Why do parents engage in private cord blood banking: fear, realistic hope or a sense of control? Pediatr Blood Cancer 2011;56:1003–4. Barker JN, Byam CE, Kernan NA, et al. Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow Transplant 2010;16:1541–48. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic stem cell transplantation. NEJM 2010;262:2091–101. National Cord Blood Program [Internet]. Long Island City (NY): New York Blood Center, 2010. [cited 9 February 2014]. http://nationalcordbloodprogram.com Tolosa JN, Park DH, Eve DJ, et al. Mankind’s first natural stem cell transplant. J Cell Mol Med 2010;14:488–95. Fox NS, Chervenak FA, McCullough LB. Ethical considerations in umbilical cord blood banking. Obstet Gynecol 2008;111:178–82. Beatty PG, Mori M, Milford E. Impact of racial genetic polymorphism on the probability of finding an HLA-matched donor. Transplantation 1995;60:778–83. Insception Lifebank – Core Blood Program. Mississauga, ON: Lifebank Corp., 2010. http://lifebank.ca (accessed 8 Apr 2014). Viacord. Cambridge, MA: ViaCord Cord Blood Banking and Research, 2013. http:// viacord.com (accessed 6 Jun 2013). Thornley I, Eapen M, Sung L, et al. Private cord blood banking: experiences and views of pediatric hematopoietic cell transplantation physicians. Pediatrics 2009;123:1011–17. ASBMT Board of Directors. ASBMT position statement: collection and preservation of cord blood for personal use. Biol Blood Marrow Transplant 2008;14:364. American Academy of Pediatrics. Cord blood banking for potential future transplantation. Pediatrics 2007;119:165–70. Armson BA. Umbilical cord blood banking: implications for perinatal care providers. J Obstet Gynaecol Can 2005;27:263–90. Sun J, McLaughlin C, Sledge L, et al. Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion 2010;50:1980–7. ACOG Committee Opinion. Umbilical cord blood banking. Obstet Gynecol 2008;111 (2, Pt 1):475–7. Cord Blood Working Group. Combined private and public banking of cord blood and other related products. Leiden, NL: World Marrow Donor Association, 2012. http://www.worldmarrow.org/fileadmin/Committees/Cord_Blood_Working_Group/ 20120328-CBWG-PPR-Hybrid.pdf (accessed 6 Jun 2013). Fisk NM, Roberts IAG, Markwald R, et al. Can routine commercial cord blood banking be scientifically and ethically justified? PLos Med 2005;2:e44. Fisk NM, Atun R. Public-private partnership in cord blood banking. BMJ 2008;336:642–4. Virgin Health Bank. London: Virgin Health Bank; 2011. http://virginhealthbank.com (accessed 6 Jun 2013). Umbilical cord blood banking Richard Branson’s way. Lancet 2007;369:437. Polymenidis Z, Patrinos GP. Towards a hybrid model for the cryopreservation of umbilical cord blood stem cells. Nat Rev Cancer 2008;8:823. Kollman C, Abella E, Baitty RL, et al. Assessment of optimal size and composition of the U.S. national registry of hematopoietic stem cell donors. Transplantation 2004;78:89–95. Switzer GE, Bruce JG, Myaskovsky L, et al. Race and ethnicity in decisions about unrelated hematopoietic stem cell donation. Blood 2013;121:1469–76.
Guilcher GMT, et al. J Med Ethics 2014;0:1–4. doi:10.1136/medethics-2013-101673
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Are hybrid umbilical cord blood banks really the best of both worlds? Gregory M T Guilcher, Conrad V Fernandez and Steven Joffe J Med Ethics published online May 13, 2014
doi: 10.1136/medethics-2013-101673
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References
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JME Online First, published on May 13, 2014 as 10.1136/medethics-2013-101673 Viewpoint
Are hybrid umbilical cord blood banks really the best of both worlds? Gregory M T Guilcher,1 Conrad V Fernandez,2 Steven Joffe3 1
Section of Hematology/ Oncology/Transplant, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada 2 Division of Pediatric Hematology/Oncology, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada 3 Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to Gregory M T Guilcher, Section of Pediatric Hematology/Oncology/ Transplant, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B 6A8; greg.guilcher@ albertahealthservices.ca Received 25 June 2013 Revised 8 April 2014 Accepted 24 April 2014
To cite: Guilcher GMT, Fernandez CV, Joffe S. J Med Ethics Published Online First: [ please include Day Month Year] doi:10.1136/ medethics-2013-101673
ABSTRACT Since the first use of umbilical cord blood (UCB) as a medical therapy, the number of UCB banks worldwide has grown. Public UCB banks offer the option of altruistic donation, whereas private banks allow a product to be stored for the exclusive use of the paying client. With many more UCB products banked privately than publicly in countries such as the USA, hybrid models blending aspects of public and private banking have been proposed. One such bank is in operation in the UK. In this paper we review the hybrid UCB model and conclude that it offers limited benefit to the general public. Furthermore, compared with private banking, this model provides few advantages and potential disadvantages to private clients.
INTRODUCTION Umbilical cord blood (UCB) is a tissue rich in blood stem cells that can be collected from the detached umbilical cord and placenta shortly after birth. The use of UCB as a source of haematopoietic stem cells (HSCs) for allogeneic and, rarely, autologous transplantation has increased dramatically over the last 30 years.1–3 UCB products expand the number of patients who can access allogeneic haematopoietic stem cell transplantation (HSCT) due to advantages such as reduced risk of graft versus host disease, less stringent human leucocyte antigen (HLA) matching requirements, and quicker donor activation as compared with HSCs from unrelated adult donors.4 Many parents have the option of banking their newborn’s UCB in either public or private banks. Public banks store altruistically donated UCB from consenting parents by freezing these products and maintaining a searchable inventory accessible to registries that facilitate stem cell transplantation. A publicly banked product that is identified as suitable for HSCT can be purchased on behalf of a recipient, with the cost of the unit partially offsetting the operating costs of the public bank. Private UCB banks, in contrast, store frozen UCB for the exclusive use of a paying client. Hybrid UCB banks, which combine features of private and public banks, market themselves as offering the potential benefits of both options. Although the hybrid model may appear to be ‘the best of both worlds,’ such banks offer few benefits to the general public and disadvantage the private recipient. In what follows, we briefly situate the role of UCB in stem cell transplantation, examine the potential benefits and limitations of public and private banking models, and articulate why hybrid banks should not be the focus of ongoing efforts to
Guilcher GMT, et al.Article J Med Ethics 2014;0:1–4. Copyright author (or doi:10.1136/medethics-2013-101673 their employer) 2014. Produced
expand the availability of UCB products to the public.
WHAT IS HSCT? HSCT is the procedure of infusing blood stem cells from a donor into a recipient. Autologous HSCT, in which the patient’s own stem cells are collected and then reinfused at a later date, is used to rescue production of blood cells after high dose chemotherapy for aggressive malignancies. In allogeneic HSCT, stem cells from another individual are infused into the recipient after she or he receives preparatory chemotherapy, immunotherapy and/or radiation therapy. Historically, allogeneic HSCs (obtained from either bone marrow or peripheral blood) were collected from a related donor or from an unrelated adult donor. More recently, the use of UCB from related or unrelated newborns has been shown to be an effective alternative source of HSCs for transplantation. Indications for allogeneic HSCT include selected haematological malignancies (such as leukaemia) and non-malignant disorders. Non-malignant indications, such as immune deficiencies, haemoglobinopathies and metabolic disorders, are expanding as the morbidity and mortality associated with the procedure decline.5 The ideal stem cell source depends on many factors including the recipient’s underlying condition, donor availability (a suitable related donor is generally preferred), the urgency with which transplantation must begin and the size of the recipient (many UCB units contain too few stem cells to meet the needs of larger recipients).
BENEFITS AND LIMITATIONS OF PUBLIC UCB BANKS IN MAKING UCB AVAILABLE FOR HSCT Public UCB banks allow for the donation of residual blood in the clamped umbilical cord to a facility that stores these products for patients in need of HSCT. Public banks allow clinicians to search for prospective donors on behalf of an identified recipient.1–3 Costs of collection are typically assumed by the bank and recouped, at least in part, by charges to the HSCT recipient (box 1).3 Standards and accreditations vary across banks, but many public UCB banks in North America, Europe and Australia are accredited and audited by professional bodies.1 3 Accreditation requirements dictate that searchable units must be collected and stored using specific standard operating protocols and must meet certain criteria, including adequate cell count and volume. Public banks have policies regarding the timing of the collection of the UCB product to ensure the safety of the mother and baby are paramount, particularly given the altruistic nature of the donation.6 However, UCB collection
by BMJ Publishing Group Ltd under licence.
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Box 1 Advantages and limitations of public UCB banking Benefits of public banks Increased likelihood of finding matching source of HSCs for individuals with rare immune (human leucocyte antigen, HLA) types compared with live donor registries Financial cost not incurred by donor Directed donation options exist Limitations of public banks Operating costs covered by haematopoietic stem cell transplantation (HSCT) recipients, philanthropic groups, governments (ongoing funding may be a challenge) Product may not be available for donor’s family if need for HSCT arises Opportunity to donate not universal
can still be performed even with delayed clamping of the umbilical cord—a practice which might reduce the volume of UCB collected but may have important benefits for the newborn.7 The aforementioned standards are critical for the safety of the prospective recipient and essential to physicians selecting products for use in HSCT.1 Only about 25–40% of collected UCB units satisfy these criteria for storage in a public bank; in contrast, most private banks store the product regardless of cell count.1 6 A minority of UCB products procured by public banks has been used in transplantation; most remain in public inventories (90% of the UCB inventory in the New York Blood Center remains available after 10 years of storage).6 8 Therefore, most of the publicly banked UCB products are theoretically still available to the families who donate in the statistically unlikely event that a family member later needs the UCB for HSCT. Furthermore, some public banks allow for directed donation in the event that a pregnant woman has a prior child or other family member with a disease for which allogeneic HSCT may be an appropriate treatment.6 8 While public banks have allowed many patients to undergo HSCT, not all candidates for HSCT can find suitable donors within existing registries. In particular, the likelihood of finding a donor varies across racial/ethnic groups. The variation in rates of donor identification is due to under-representation of some ethnic groups within adult live donor registries and to increased HLA diversity within some ethnic groups.4 9
BENEFITS AND LIMITATIONS OF PRIVATE UCB BANKS IN MAKING UCB PRODUCTS AVAILABLE FOR HSCT Private UCB banks are for-profit entities that offer fee-for-service collection and cryopreservation (freezing) of UCB products. For an upfront cost (typically US$1000–2000), parents may elect to have the UCB collected and cryopreserved.10 11 Ongoing cryopreservation of the UCB product requires payment of an annual fee (typically about US$125). Such products are stored solely for the use of the donor’s family. The primary benefit of private UCB banking is the family’s exclusive access to the product should the need arise (box 2). Depending on where they live, some families may not have the option of public banking. For families who have an identified family member who might need HSCT, private banking may be the only option to store the UCB product. 2
There are several limitations of private UCB banking. First, the cost of such banking is substantial and may not be justified by the potential benefits. Private UCB banking rarely provides medical benefit to the child or family for whom the product has been cryopreserved: estimates of the probability that the product will be used range between 1 in 2700 and 1 in 250 000.3 8 When privately banked UCB products have been used for HSCT, it was almost always known before the UCB was stored that a family member was in need of a donor or at high risk of later requiring HSCT.12 Many professional organisations and experts have expressed concerns that clients of private UCB banks may have insufficient understanding of current accepted indications for, and the likelihood of, UCB use. Given the substantial cost and low probability of using the product, the American Academy of Pediatrics, the American Society of Blood and Marrow Transplantation and the Society of Canadian Obstetricians and Gynecologists have clear position statements recommending against elective private UCB banking unless a family member is at high risk of needing a transplant in the future.13–15 Furthermore, critics have suggested that private UCB banks may overemphasise unproven possible future indications beyond HSCT.2 14 Another limitation of private UCB banking is the variability in quality standards. Private banks might not be required to adhere to the same rigorous donor screening and infectious disease testing as is necessary for public banks, and have financial incentive to accept units that would be considered substandard by public banks.16–18 Private UCB banks typically store the UCB regardless of its quality and do not provide quality reports on the UCB unit (including such metrics as the cell dose collected and the viability of the cells) to the client. Additionally, private UCB collections may be performed by medical or nursing personnel with limited experience in UCB collection. Experience in collection is an important factor in the collection of a quality unit.1 Concerns have been raised that the collection process might distract from the care of the mother and newborn, and that the diversion of any attention from their care is ethically problematic with such a low probability that the UCB product will ever be used.19 Some private
Box 2 Advantages and limitations of private UCB banking Benefits of private banks Family control over umbilical cord blood (UCB) product If prospective recipient in family is identified, allows for collection even if no public bank with directed donation option is available Limitations of private banks Product unavailable to general public Collection may burden a publicly funded system (eg, physician, nursing and hospital resources) UCB clamping practices may be altered in an effort to procure the UCB product (with data to suggest that early clamping produces higher stem cell volumes but can put some newborns at risk) Consumers often misinformed regarding established indications and likelihood of use Products often stored regardless of cell dose and viability (quality)—typically no quality report provided to client Optional adherence to accreditation standards Substantial financial cost to families Guilcher GMT, et al. J Med Ethics 2014;0:1–4. doi:10.1136/medethics-2013-101673
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Viewpoint banks advise early clamping of the umbilical cord to increase collection cell yields, whereas a public bank will collect UCB after the umbilical cord is cut and the delivery is unaltered due to the altruistic nature of the donation.6 10
HYBRID UCB BANKS A hybrid (or dual) UCB bank is a new model of UCB banking in which elements of private and public banking coexist.2 20 For the purposes of this discussion, a hybrid UCB bank is a private institution in which an UCB product is stored for possible public or private use. Several possible models for hybrid banks have been proposed, and one hybrid bank, the Virgin Health Bank, is currently in operation (figure 1).20 21 Virgin Health Bank offers a Community Banking option, which is a hybrid model in which a small amount of UCB is stored exclusively for the client with the remainder stored in an inventory available for public use. Virgin also offers an exclusively private Family Banking option. Virgin’s Community Banking option costs £1195, whereas Family Banking costs £1695. Some models of hybrid UCB banks require a second consent from the client immediately prior to release of an UCB product to an HSCT centre for allogeneic use.2 In contrast, Virgin Health Bank currently requires consent for the donation of a portion of the product to an unrelated recipient at the time of collection. With this consent in place, distribution of the portion of the unit that is stored for public use is ultimately at the discretion of the bank.21
Proposed advantages of hybrid UCB banks With hybrid banking options, families will have the option of banking a child’s UCB in a facility which will store some of the product for the paying consumer, while giving the family the knowledge that an unrelated person might derive benefit from the donation.21 The ‘public’ portion of the product might be donated to a prospective HSCT centre if the inventory was searched, a match identified and quality parameters shown to be acceptable. Proponents state that, under the hybrid model, at least some units that would be otherwise unavailable for public consideration in an exclusively private model would now be available for unrelated HSCT. Given the higher rate of private UCB banking compared with public banking in countries such
as the USA and the continued inability to find matched UCB units for at least some recipients, supporters argue that making additional units available through hybrid banks can only be beneficial.22 23 In theory, hybrid banks also provide financial advantages by leveraging private banking to subsidise the costs of storing units for unrelated-donor transplantation (ie, families altruistically supporting the cost of public donation). Thus a hybrid model might increase the unrelated donor pool while reducing, or at least not increasing, public subsidies. The appropriateness of transferring cost from such public sources to private clients of hybrid UCB banks might be considered by some ethicists to be suspect if the expected benefits to the public are minimal.
Effectiveness of hybrid UCB banks at enhancing access to allogeneic HSCT Some individuals in need of allogeneic HSCT—particularly those with rare HLA subtypes—remain unable to find suitably matched donors within existing public unrelated bone marrow donor registries and UCB banks. Such individuals are disproportionately members of minority ethnic groups. Simply increasing the number of individuals in the donor pool might seem the obvious solution to this problem. However, statistical modelling suggests that for the rarest HLA haplotypes, the reality is more complicated. For example, using adult unrelated-donor registries as an example, doubling the pool of registered African-American donors in the USA would only increase the likelihood of finding HLA-matched donors for this group from 34% to 37%.24 Though many factors, including donor availability and attrition, influence these statistics, the tremendous HLA diversity among African-Americans is the primary challenge in identifying suitable donors.9 24 25 Some data even suggest that due to the diversity of genetic polymorphisms, African-Americans and Hispanic Americans will have lower probabilities of finding a HLA-matched donor than European-American recipients regardless of registry size.9 Unfortunately, as currently constituted, hybrid UCB banks do not encourage targeted banking by families with rare HLA haplotypes. Furthermore, the costs of hybrid banking may represent a particular barrier for many families with rare HLA haplotypes.
Figure 1 Virgin Health Bank Community Banking Model. HSCT, haematopoietic stem cell transplantation; UCB, umbilical cord blood.
Guilcher GMT, et al. J Med Ethics 2014;0:1–4. doi:10.1136/medethics-2013-101673
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Viewpoint Additionally, the differences in quality standards that have been observed between public and private banks may also exist between public and hybrid banks.16–18 As few as one in four publicly donated UCB units meets criteria for storage and availability for allogeneic transplantation; units that do not meet these criteria are excluded from public donor pools. In order to address this concern, hybrid banks would need to ensure quality control during the collection process and to limit searchable inventory to those units that meet current public banking accreditation standards. Another concern is that some models of hybrid banking propose splitting the UCB unit, with a proportion reserved for possible future use by the client. Virgin’s Health Bank’s Community Bank operates under such a model, storing the first 5 mL of the product exclusively for family use, with the remainder available for unrelated donation.21 This splitting is problematic in at least three ways. First, stem cell dose is often a limiting factor in the selection of a suitable UCB unit, in particular when considering larger recipients. Thus, splitting the unit will further reduce the number of products suitable for consideration for unrelated donation. Second, the reserved 5 mL may not be of practical use for autologous HSCT, particularly as the individual grows in size. Although the bank acknowledges that, with current medical technology, the 5 mL volume is insufficient to provide benefit, it also contends that advances in ex vivo stem cell expansion and regenerative medicine techniques are ‘expected,’ and ‘may’ allow for future use.21 Such scientific advances are speculative and may, in fact, obviate the need for private banking. Third, even with ‘full-sized’ cord units, delayed and failed engraftment events are more common with UCB than with marrow and peripheral blood stem cell products. Thus, manipulating an UCB product in any way that may further reduce engraftment without clear medical benefit is ethically problematic for public and private recipients.
‘public’ and ‘private’ components may result in reduced cell doses for each component such that either or both are less likely to be of utility. Clinicians and policy makers who seek to increase the likelihood that individuals with rare immune types will have available donors for HSCT should focus instead on enhancing mechanisms for public donation of high quality UCB products from targeted populations. Contributors All authors contributed to the intellectual content and review of the manuscript. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Might the limitations of hybrid UCB banks be overcome? Significant advances in banking technology would be required to swing the balance in favour of a hybrid model. Advances in processing techniques of UCB products to minimise cell loss might eliminate some of the practical limitations of hybrid UCB banks. Ex vivo expansion methods might be developed which could allow for the ‘public’ and ‘private’ aliquots to be of adequate volume and cellular content to be of use. Theoretically, such innovation could expand all UCB bank inventories to the point where additional UCB units on public registries are no longer required—with the exception of rare HLA haplotypes—and make the argument for public benefit from additional units in searchable hybrid banks moot. While searchable public registries will continue to benefit from the addition of rare haplotypes, given the statistical diversity models discussed previously, the challenge of representing all HLA haplotypes in public banks will remain even if large numbers of such units are added. Hybrid UCB banks are unlikely to be the solution to this challenge.
CONCLUSIONS UCB banking has greatly improved access to HSCT for suitable recipients over the last 20 years.1–4 Due to the current limitations associated with the hybrid bank model, such banks are unlikely to contribute measurably to finding HLA-matched donors for patients in need of HSCT. UCB products split into
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Guilcher GMT, et al. J Med Ethics 2014;0:1–4. doi:10.1136/medethics-2013-101673
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Are hybrid umbilical cord blood banks really the best of both worlds? Gregory M T Guilcher, Conrad V Fernandez and Steven Joffe J Med Ethics published online May 13, 2014
doi: 10.1136/medethics-2013-101673
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References
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