ASH Position on Cord Blood Banking

In testimony before the Institute of Medicine, ASH stated its support of the establishment of a single, centralized, readily accessible national donor registry that will strengthen the network of cord blood banks to meet the needs of patients in need of cellular and transplantation therapies. The registry must have a centralized Web-based data system accessible to qualified transplant centers with real-time functions for cord blood unit data profiles and unit reservation. Like the current National Bone Marrow Donor Registry Program, the cord blood stem cell bank program should have the following core functions:

• To sponsor research to improve cord blood transplantation outcomes for patients;
• To provide educational programs to increase awareness of clinical applications of cord blood transplantation; and
• To continue to develop and maintain a common set of standards and accreditation among its partners to assure high quality and best clinical practice.

In addition, ASH has been deeply concerned that the controversy over the creation and composition of a national cord blood bank network has stalled reauthorization of the National Bone Marrow Donor Registry (NBMDR) Program. ASH has championed the need to reauthorize this life-saving program. During its spring meeting, the Committee on Practice lobbied Members of Congress about the need to reauthorize the NBMDR while letting the Institute of Medicine develop the optimal structure for a national cord blood banking program. Currently, ASH has posted an advocacy campaign on the ASH Web site that urges the U.S. Senate to take up this important legislation this year.

To participate in ASH's advocacy efforts to reauthorize the NBMDR and to see ASH's testimony regarding cord blood before the Institute of Medicine, please visit the ASH Web site at www.hematology.org

Cord Blood Banking Review

Karen Ballen, M.D.
Massachusetts General Hospital

Introduction:

High dose chemotherapy with or without radiotherapy followed by allogeneic stem cell transplantation is a curative treatment for several cancers. Unfortunately, only 30 percent of patients have a matched sibling donor. It is difficult for many patients, particularly minority patients, to find unrelated bone marrow donors, despite significant efforts by the National Marrow Donor Program (NMDP) and other registries.

Umbilical cord blood has been shown to contain sufficient progenitor cells to provide durable engraftment.¹ Since the first reports of successful unrelated donor cord blood transplants in 1993, approximately 2000 unrelated cord blood transplants have been performed worldwide.² Several questions exist:

1. How successful are cord blood transplants in adults?
2. What is the optimum number and HLA type of cord blood units to be stored?
3. What is the most efficient way to bank and search cord blood units?

Clinical Results:

Results in children who have undergone transplantation with unrelated umbilical cord blood units show a 30-80 percent disease-free survival, depending on disease and age. Unfortunately, the results in adults, who comprise the majority of the stem cell transplants, have been poor. The largest American study of 68 adults reported a 26 percent disease-free survival with three years of follow-up.³ Therefore, many physicians may choose non-cord-blood transplant options, such as mismatched unrelated transplant, haploidentical transplant, autologous transplant, or chemotherapy for their patients. A preliminary study by the International Bone Marrow Transplant Registry (IBMTR) showed comparable results of unrelated cord blood transplant compared to a 5/6 HLA allele matched unrelated bone marrow transplant in adults.⁴ Work at the University of Minnesota, Massachusetts General Hospital, and by others studying sequential (2 cord blood units) cord blood transplant may improve upon these results. New indications for cord blood transplant, such as for gene therapy or for HIV disease, are under investigation. Only approximately 2000 cord blood transplants (of about 350,000 total transplants-less than 1 percent) have been performed worldwide in the last ten years; therefore, the data from a few centers have clearly not altered the management of the majority of transplant physicians. For any cord blood initiative to be successful, adult cord blood transplant must be proven - in large, multicenter initiatives - to be superior, or at least equivalent to mismatched unrelated transplant.

Cord Blood Banking

Banks of cryopreserved umbilical cord blood cells have been established worldwide. Considerable effort has been dedicated to recruitment of minority donors; for example, the American Red Cross Cord Blood Bank recently reported 36 percent non-Caucasian units in inventory.⁵ Cord blood banking is expensive; it costs approximately $1500-$2000 to collect, HLA type, process, and store each cord blood unit. Since the units are "sold" to transplant centers for $15,000-$20,000 per unit, the cord blood bank needs to transplant about 1 in 10 units to be financially viable. Because many fewer than anticipated units have been transplanted, many excellent cord blood banks have been forced to curtail banking activities. Large-scale cord blood banking will only be viable if the usage of cord blood units increases. An estimated 100,000 cord blood units have been banked worldwide. The optimal number of units needed to assure a 4/6 match of sufficient cell dose for 90 percent of the population is not clear. The HLA composition of these frozen units has not been rigorously studied, so it is not known which HLA types are underrepresented in current inventory. A thorough analysis of the stored cord blood inventory is necessary to target specific HLA types that may not be represented, and to avoid unnecessary expense in storing units with HLA types that are already multiply stored.

Strategies for Searching Cord Blood Units:

Transplant teams can locate compatible cord blood units by computerized search systems, analogous to unrelated bone marrow transplants. Cord blood units can be searched via cooperative registries such as the NMDP or Netcord, or via the individual cord blood banks, such as the New York Blood Center. The advantage of the cooperative registries is the simultaneous display of multiple cord blood units, easing the time and effort of the transplant coordinator. The advantage of the individual banks are less cost (because a fee - usually $2000-$4000 - is not paid to the "middle man"), more personalized service, and less paperwork. Competition among individual banks will help to lower costs and improve turnaround time. The situation mirrors the early days of unrelated bone marrow registries, many of whom (but not all) joined the NMDP. In our free market economy, the market - in this case transplant centers, patients, and insurance companies - should and will decide the optimal search strategy.

Conclusion:

Cord blood transplants provide an alternative stem cell source for patients without related or unrelated bone marrow/peripheral blood stem cell donors. Funding for cord blood efforts should focus on three areas:

1. Large, multicenter studies of adult cord blood transplant, emphasizing new transplant tech niques and indications.

2. Catalogue of existing cord blood inventory, to determine needed HLA types and to bank specifically those needed HLA types.

3. Support of search strategies via both individual banks and cooperative registries, allowing the market to choose the optimal system.

REFERENCES:

1. Broxmeyer HE, et al. Proc Natl Acad USA 1989; 86: 3828- 3832.
2. Kurtzberg J, et al. N Engl J Med 1996; 335: 157-166.
3. Laughlin MJ, et al. N Engl J Med 2001; 344: 1815-22.
4. Laughlin MJ, et al. Blood 2003; 102: 857a (abstract).
5. Ballen KK, et al. Biol of Blood and Marrow Transplant 2004; 10: 269-275.

Cord Blood Transplantation: The Complexity of Success

David T. Scadden, M.D.
Massachusetts General Hospital
Harvard Medical School

Medical science is certainly not immune to the forces of supply and demand driving our economic lives. Pressures exerted by these forces change and mature the shape of medical research and practice just as they affect commerce. Umbilical cord blood (UCB) transplantation has gone from laboratory and clinical science to an increasingly used medical practice that now, faced with increasing demand and a complicated, de-centralized source of supply, is at a crossroad of development. Presented here is a brief synopsis of where the field stands medically, what pressures it currently faces, and the positions of two major participants in the ongoing debate.

Umbilical cord blood was identified as a source of hematopoietic stem cells by a member of this society, Dr. Hal Broxmeyer, and his colleagues in 1989. It has since become a model of basic science translated to clinical care with successful use in a range of patients with malignant and non-malignant hematologic disease. Now with over 2000 patients transplanted, the utility of umbilical cord blood is demonstrated, if still evolving. Since approximately 30 percent of allogeneic transplant candidates are unable to find a matched sibling donor, the need is real. Couple that with many parents’ perception that banked cord blood could be a future lifesaver for their child, and an irresistible demand for cord blood banking services has emerged. Institutions with a history of public service in blood products have responded and been joined by many more entrepreneurial private efforts, creating a virtual sea of cord blood banks. This presents a significant challenge for transplant physicians seeking a proper donor for their patients, not just in finding the match, but in having confidence that the processing, storing, and analyzing of samples is of optimal quality. Coordination of this process is perceived by many as in the best interest of patients and the field. In an effort to provide some guidance, the Institute of Medicine has been commissioned to provide a report on the topic. Views of a clinician using cord blood and two institutions providing sources of cord blood for transplantation are presented here as background on some of the issues at hand.

National Cord Blood Program

Jeffrey Chell, M.D., and Dennis Confer, M.D.
National Marrow Donor Program

On behalf of the National Marrow Donor Program® (NMDP), we would like to thank the American Society of Hematology and The Hematologist for the opportunity to present our position on umbilical cord blood and on the federal appropriation to increase the number of cord blood units.

Congress has appropriated $10 million for the purpose of increasing the nation's inventory of umbilical cord blood used for unrelated transplantation and research. The funds will be made available after completion of an Institute of Medicine study requested by Congress. The purpose of the study is to make recommendations on how best to establish and fund a National Cord Blood Program.

The NMDP strongly supports federal assistance to increase the number of available cord blood units. Without this assistance, the public cord blood banks will be unable to collect enough units to meet patient needs for the foreseeable future. To ensure that the federal dollars are used efficiently, the NMDP believes that the funds should be used solely to collect and store cord blood units, not to create an infrastructure that would be duplicative of the NMDP. The NMDP has developed all of the systems necessary to administer a national cord blood program. Duplicating these systems would be costly and wasteful.

More importantly, it is in the patient's interest that cord blood units funded by a federal program should be coordinated through the existing network that already supports search, testing, and procurement of cord blood and adult volunteer donations. Cord blood is part of a continuum of cellular therapy including marrow and peripheral blood stem cells. Therefore, as a source of stem cells, cord blood does not compete with adult donation but is complementary. The best source of stem cells for any particular patient depends on a variety of factors. Having all relevant information available through a single search responds to this need. NMDP offers this opportunity today with the world's largest registry of adult volunteer donors and cord blood. We believe this is a tremendous benefit to transplant physicians as it significantly simplifies their ability to quickly identify all available unrelated-donor options and secure the best-matched source of cord blood, marrow, or blood stem cells for their patients.

To successfully serve the patient, a registry function also needs to be coordinated with other search and support services. The NMDP has created a network linking together other registries across the world with transplant centers, donor centers, apheresis centers, collection centers, laboratories, and, now, cord blood banks. That network is linked together through a sophisticated, innovative, and up-to-date information system that allows for the seamless flow of information and services. The NMDP continually works with its network partners to define and update standards and adapt its systems to incorporate new ways of supporting the search and procurement process. This system is combined with the other services provided by the NMDP such as education, support, case management, and advocacy services for patients. These services are provided in multiple languages through our Web site, printed materials, and toll-free numbers.

The work of the NMDP is overseen by its Board of Directors, which includes leading authorities on cord blood banking and transplantation, and through its Cord Blood Committee, which is comprised of experts in every aspect of cord blood including banking, transplantation, regulatory, quality, accreditation, research, and obstetrics. Representatives from nearly all the non-profit cord blood banks in the United States serve on this committee. This group is moving ahead with recommendations for industry-wide standards, policies, and procedures that will ensure that existing and future inventories of cord blood will be safe and effective.

A National Cord Blood Stem Cell Bank Network

Pablo Rubenstein, M.D., and Cladd E. Stevens, M.D.
New York Blood Center National Cord Blood Program

Background:

Unrelated Cord Blood (CB) is now a recognized (sometimes preferred) source of hematopoietic stem cells that permits performing HLA-mismatched grafts. In our collaborative study with the International Bone Marrow Transplant Registry, the outcomes of children given CB grafts with one HLA mismatch were as good as those of fully matched unrelated bone marrow recipients.¹ Transplants with two mismatches had slightly less good outcomes. Well-matched, large cell dose CB grafts yielded the best outcomes. Recent studies by others using reduced conditioning regimens have shown a better than 49 percent one-year survival in adults given mismatched cord blood.²

Unfortunately, just as CB begins to fulfill its therapeutic promise, some U.S. CB banks face financial failure; several have stopped collections, and patients may not have effective access to available units. For example, the highly successful Japanese National Cord Blood Program provided CB grafts to 381 patients in the first half of 2004, a yearly rate equivalent to almost 2000 CB transplants for a population as large as the U.S. During the same period, our CB Program provided 100 grafts and the National Marrow Donor Program (NMDP) approximately 80.

Recognizing the field's developments, the predicament of U.S. CB banking, and the unmet needs of patients, we proposed legislation, the "Cord Blood Stem Cell Act of 2003," authorizing federal support to build a national inventory of 150,000 new CB units over five years, introduced with bipartisan support in the House (HR2852) and Senate (S1717). This Act envisaged an independent CB Bank Network following the Japanese model. NMDP opposed its independence as leading to presumed infrastructure duplication. The ensuing controversy delayed the disbursement of a $10 million appropriation in the current fiscal year, pending recommendations for the network structure from an Institute of Medicine study.

The main features of the Act are:

• A Bank Network established and supervised by the Health Resources and Services Administration (HRSA).

• Participating banks selected by an impartial panel based on quality of operations, demonstrated compliance with technical standards, and applicable local and Federal regulations, and on the number, characteristics, and ethnicity of units banked per year.

• Federal funding, directly from HRSA, to cover solely the costs of producing the new CB units and their distribution to patients.

• Participating banks expected to become self-supporting after the period of rapid inventory increase. Sponsoring institutions, however, must warrant the continued availability of these units beyond the period of federal funding.

• A Board of Directors, representative of all interested parties, appointed by HRSA, to establish and coordinate policies for the network and monitor continued compliance with quality and regulatory exigencies.

• The Board to establish a mechanism to ensure on-line access to CB units using technology that guarantees access to all available CB units in the search process.

• HRSA to select an informatics provider based on cost, expertise, and ability to provide real-time distributed computing.

Comments:

Transplant physicians desire "one-stop shopping" access to all potential bone marrow donors and CB units. A distributed search mechanism can best satisfy this requirement, bypassing any need for a duplicative centralized database. Modern distributed informatics would use local CB bank-managed databases, coordinate search/reporting, and assure transparency in unit offerings and selection for transplant physicians and CB banks.

CB grafts, unlike bone marrow, are "manufactured" stem cell products, rapidly available "off-the-shelf." CB banking technology requires concepts and skills very different from those needed by bone marrow donor registries: donor recruitment and management are minor issues for CB banks while cGMP collection, processing, and storing CB units demand technical competencies unnecessary to donor registries. CB banking is a competing technology that requires considerable up-front investment but promises eventual self-sufficiency, a future not possible for donor registries. The CB Bank Network, therefore, should be independent. Control by its competitor would help create a stifling monopoly for therapeutic stem cells.

REFERENCES:

1. Rubinstein P, et al. Blood 2001; 98: 3382a (abstract).
2. Barker JN, et al. Blood 2003; 102: 858a (abstract).

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