Cord Blood Unit Access and Selection: 2010 and Beyond: Best Practices and Emerging Trends in Cord Blood Unit Selection

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1 SECTION VIII: NMDP SESSION Cord Blood Unit Access and Selection: 2010 and Beyond: Best Practices and Emerging Trends in Cord Blood Unit Selection Michael Boo, 1 Karen Ballen, 2 Martin Maiers 1 One-fifth, more than 1000, of all transplants facilitated in 2010 by the National Marrow Donor Program (NMDP) have employed 1 or 2 umbilical cord blood units as the graft source. As the use of umbilical cord blood for unrelated allogeneic hematopoietic cell transplantation increases, several issues emerge that require additional attention and refinement. The U.S. Food and Drug Administration is now far along in its implementation of regulatory controls for umbilical cord blood. After October 20, 2011, every unrelated-donor cord blood unit transplanted in the United States must be either licensed or covered under an FDA-accepted IND. It is incumbent upon transplant physicians to review and understand the implications of the FDA s new regulations. In addition, as more transplant programs adopt umbilical cord blood for transplantation, it is important to stay current with the best practices surrounding identification and selection of the best available units. Cell dose, HLA matching, location of mismatched loci, and the role of noninherited maternal alleles are all important considerations for unit selection. This complexity in selection of appropriate units raises issues about the desired inventory of umbilical cord blood units. How many units are needed to meet the needs of all patients who might benefit from cord blood transplantation? Newly developed simulation models are being utilized by NMDP to answer this question. Biol Blood Marrow Transplant 17: S46-S51 (2011) Ó 2011 American Society for Blood and Marrow Transplantation KEY WORDS: Cord blood, Regulation, Matching algorithm REGULATION OF CORD BLOOD BANKING On October 20, 2009, the Center for Biologics Evaluation and Research (CBER), Food & Drug Administration (FDA), issued its Guidance for Industry (Guidance) [1] addressing the licensing of minimally manipulated, unrelated allogeneic placental/umbilical cord blood intended for hematopoietic reconstitution for specific indications. At the same time it issued a Draft Guidance (Draft Guidance) [2] for cord blood units that would be used for the indications addressed in the Guidance but that would not be licensed or licensable. Together, these documents provide further advice to the community concerning how the FDA intends on regulating these products. This document reviews these guidances. From the 1 National Marrow Donor Program, Minneapolis, Minnesota; and 2 Massachusetts General Hospital, Boston, Massachusetts. Financial disclosure: See Acknowledgments on page S50. Correspondence and reprint requests: Michael Boo, JD, National Marrow Donor Program, 3001 Broadway Street NE, Minneapolis, MN ( mboo@nmdp.org). Ó 2011 American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt History In 1997, the FDA proposed a new regulatory framework for human cellular and tissue-based products, including hematopoietic stem/progenitor cells [3]. The proposed framework provided a tiered approach to the regulation of human cellular and tissue-based products, now referred to as human cells, tissues, and cellular and tissue-based products (HCT/Ps). The FDA implemented this approach by promulgating 3 final rules, which comprise 21 CFR Part 1271 [4]. These final rules required registration and listing [5], established standards for donor eligibility [6], and applied Current Good Tissue Practice to cord blood banking [7]. Licensing of Cord Blood Units for Allogeneic Use This Guidance document provides recommendations for the submission of a biologics license application (BLA) [8] for placental/umbilical cord blood products that are: manipulated minimally; and intended for hematopoietic reconstitution in patients with any of the following diseases; B hematologic malignancies S46

2 Biol Blood Marrow Transplant 17:S46-S51, 2011 NMDP Session S47 B Certain lysosomal storage and paroxysmal enzyme deficiency disorders - Hurler Syndrome (MPS I) - Krabbe Disease (Globoid Leukodystrophy) B X-linked adrenoleukodystropy B primary immunodeficiency diseases B bone marrow failure B beta thalassemia; and intended to be used in recipients unrelated to the donor. For the purpose of this Guidance, these minimally manipulated allogeneic products for the above-stated indications are referred to as hematopoietic progenitor cells, cord (HPC-C). Manipulated minimally HPC-Cs that do not meet this definition are not covered by the Guidance and may require submission of a separate IND or pursuit of other premarketing application approval for that product [9]. The Guidance also does not apply to HPC-Cs that are used for autologous use, or use in first- or seconddegree blood relatives as these are under a different statute within the Public Health Services Act [10]. The Guidance identifies those regulations that are applicable to HPC-Cs and include labeling [11], prescription drug advertising [12], compliance with Current Good Manufacturing Practice Regulations [13], and regulations that apply to biological products generally [14]. The Guidance notes that HPC-C manufacture is covered by 2 sets of somewhat overlapping regulations. The Current Good Tissue Practice (cgtp) requirements govern manufacture specifically to prevent the introduction, transmission, or spread of communicable diseases. In addition, because of the licensure and premarketing approval requirements, cord blood banks are also subject to Current Good Manufacturing Practice (cgmp) requirements that apply to pharmaceutical companies. cgmp requirements are intended to ensure the safety, quality, identity, purity, and potency of the manufactured product. Because of the broad scope of the regulations, cgmp compliance subsumes major portions of the cgtp requirements. That is, compliance with the former is sufficient to ensure compliance with the overlapping portions of cgtp. Issues under the Guidance The Guidance specifies the indications for which a licensed cord blood unit is approved. It is assumed that use of a licensed unit for a nonlicensed indication will fall within the off label use exception, although CBER indicates in its Guidance that an IND or other premarket application review would be appropriate. Regulations applicable to a licensed CBB facility include adherence to good manufacturing processes. The extent to which the application of these regulations will require change to current manufacturing practices is unknown. The Guidance does not specify a date of manufacture for which the license would attach. Banks will have to work with the CBER to determine whether pre BLA inventory will qualify as licensed products. It is expected that this will be addressed in most cases through the BLA process. Accessing Unlicensed Cord Blood Units for Allogeneic Use As a companion to the Guidance for BLA for HPC-Cs, CBER also released a Draft Guidance to cover use of HPC-Cs in instances where a licensed unit is not available. Specifically, the Draft Guidance provides for an IND structure to cover the following circumstances: manufactured in non-united States cord blood establishments, listed in international cord blood registries, and selected for treatment of a patient in the United STates; manufactured in United States cord blood establishments before a biologic s license application has been approved and not shown to meet licensing criteria (eg, not shown to be comparable to other licensed HPC-C in inventories); prospectively manufactured in the United States and do not meet licensing criteria, but for which there is no satisfactory alternative. For example, units from babies whose mothers have positive screening for Hepatitis B cannot be licensed, but may be valuable because of their unique HLA phenotypes. Under the Draft Guidance, units that meet the qualifications listed above and are used for the treatment of diseases identified in the Guidance would fall under this IND structure. There are over 500,000 CBUs in the worldwide inventory available for public use. Most of these units are not expected to be licensed in the near future. Thus, most current units will need to be facilitated under an IND for a number of years. The NMDP is developing an IND protocol that will facilitate access by transplant centers to units that fall under the 3 categories. It is envisioned that the NMDP protocol will be flexible with respect to preparative regimens, GVHD prophylaxis, etc., and focus on collecting outcomes data and significant adverse events. The NMDP protocol would allow patients to co-enroll on other clinical trials. The Draft Guidance responded to comments from industry over the course of the data collection process for the BLA that addressed concerns raised regarding existing inventories and the need to have access to wellmatched units in inventories outside of the United States. The Draft Guidance details a number of other elements of an IND for this purpose. For instance,

3 S48 M. Boo et al. Biol Blood Marrow Transplant 17:S46-S51, 2011 potential sponsors of IND could include cord blood banks that will create an IND to make their nonlicensed inventory available to transplant centers, registries that list and facilitate access to cord blood units whose registry includes nonlicensed units; and transplant physicians who may seek an IND for purposes of accessing unlicensed cord blood units for treatment of patients. In creating the opportunity for multiple sponsors, it appears that CBER was responding to issues raised regarding convenience as well as current industry practice regarding access to cord blood units. In many instances, for example, cord blood banks do not have separate registries through which they list their own inventory, but do so under registries such as that maintained by the National Marrow Donor Program. Further, by providing for different opportunities for IND sponsorship, CBER makes it possible for banks that distribute units directly to transplant centers as well as transplant centers with active cord blood programs to create their own INDs. Sponsors are required to submit safety reports and annual reports as required by statutes and regulations governing INDs, to ensure that licensed physicians are qualified to administer HPC-Cs, provide licensed physicians with the required information, maintain an effective IND with respect to investigations, and maintain adequate drug disposition records. CBER anticipates that the investigators under the IND will be physicians who administer HPC-Cs. Investigators are required to report adverse drug events to the sponsor, ensure that the informed consent requirements are met, ensure the IRB review of the HPCs accessed under the IND is obtained, and maintain accurate case histories and drug disposition records. Issues under the IND The IND Guidance provides that cord blood banks, registries, or transplant physicians could be sponsors. It is possible that a single unit could fall under a number of different INDs as where a cord blood bank holds an IND that lists that cord blood unit through a registry that has its own IND. Coordination of data collection under 1 or more INDs will need to be addressed. It is not likely that international registries or cord blood banks will pursue either a BLA or an IND. Although there is significant importation of cord blood units into the United States, no single registry or bank provides enough products to the United States to justify the time and expense or compliance requirements. The NMDP anticipates maintaining an IND that will include these banks and registries. International cord blood banks and registries operate under practices specific to the countries in which they are located as well as commonly meet international standards as provided through accrediting bodies such as NetCord/FACT (Foundation for the Accreditation of Cellular Therapy), and AABB. These registries and accrediting bodies provide a mechanism to assure that the cord blood banks meet either national standards or international standards of operations. How these standards may be used to show qualification under the IND is unclear. Under the regulations, CBER seeks to have access to labels used on products that may be imported under the IND. However, labels are typically in the language of the country in which the unit has been collected and stored, and labels have changed over time as the industry has developed standards for labeling. Products distributed under an IND protocol cannot be charged for unless the FDA specifically grants cost recovery approval [15]. Such approval requires documentation of all costs of manufacture and distribution, among other things, and prohibits including certain expenses. Banks may not have the cost records required to establish cost recovery rates, and further, the costs incurred may have changed over time. Summary With the issuance of the Guidance and Draft Guidance, a framework for licensing of publicly available cord blood units for allogeneic use has now emerged. While the Draft Guidance is yet to be issued in final form, the industry can now move forward toward a market with clearer regulation. Although standards and practices in the cord blood industry will continue to evolve, licensing and companion IND guidance will serve to support consistent quality for banking in the United States while allowing for appropriate importation and use of existing inventory. BEST PRACTICES AND EMERGING TRENDS IN CORD BLOOD UNIT SELECTION Introduction Only 30% of patients have a matched sibling donor, and therefore the majority of patients who need an allogeneic transplant will need to find an alternative stem cell source. Umbilical cord blood (UCB) is a viable stem cell source, particularly for racial and ethnic minority patients who may have a more difficult time finding appropriately matched adult unrelated donors. Over 10,000 UCB have been performed worldwide, and over 500,000 UCB units have been donated and are available in public storage banks. We celebrated the 20th anniversary of the first cord blood transplant 2 years ago, but there is still much to learn about the appropriate strategy for cord blood unit selection for unrelated transplants. In this section, we will discuss

4 Biol Blood Marrow Transplant 17:S46-S51, 2011 NMDP Session S49 the most recent data for optimal cord blood unit selection for pediatric transplants, and adult single and double UCB transplants. Pediatric Transplants The first successful UCB transplants were performed in children [16-18]. In an early pediatric experience, Locatelli and others [19] recognized that the infused nucleated cell dose correlated with survival. Rubinstein reported that cell dose was directly correlated with the time to myeloid engraftment; therefore, many pediatric centers accept a minimal cell dose of NC/kg but aim for a target dose of NC/kg. There does not appear to be any disadvantage to very high cell doses [20]. The effect of HLA matching has recently been accepted as an important factor in UCB outcomes. Gluckman reported a higher incidence of graft-versus-host disease (GVHD) and longer platelet recovery with both Class I and Class II mismatches [21]. The effect of HLA mismatch is most important when the cell dose is low [22]. Eapen et al. [23] has shown an improved survival for 6/6 matched cord blood units (60% versus 38% for 5/6 or 4/6) for children with acute leukemia. The Duke group has successfully transplanted several hundred patients with inherited metabolic disorders. In 1 study of 159 patients, infused (postthaw) colony-forming units (CFUs) was the graft characteristic that correlated best with neutrophil and platelet engraftment [24]. There was no correlation between storage time and transplant outcomes, to indicate that the freshness of the unit should be considered in cord blood unit selection [25]. UCB unit viability remains an important determinant of UCB quality. A recent study from the St. Louis Cord Blood Bank showed concordance among trypan blue, acridine orange/propidium iodide, and flow cytometric 7-aminoactinomycin D (7-AAD) viability testing [26]. Global viability of all white blood cell count (WBC) exhibited temperature variation, whereas viability of CD34 1 cells correlated best with colony-forming cell recovery. An attached segment to the UCB, which can be thawed at the transplant center without affecting the integrity of the UCB, ensures graft potency and confirmatory HLA testing just prior to transplantation [27]. Adult Single Cord Unit Transplant The issues of cord blood selection in adults are more complex as a higher cell dose per kilogram is more difficult to achieve. Recent analyses have suggested comparable leukemia free survival probabilities in adults receiving UCB, 8/8 or 7/8 allele level matched unrelated PBSC [28]. Barker and colleagues [29] studied the relationship between cell dose and HLA match in 1068 patients undergoing cord blood transplantation. Both cell dose and HLA match were independent predictors of transplant-related mortality. Patients receiving a 6/6 matched CB unit had improved outcomes, regardless of cell dose. A 4/6 matched UCB with cell dose NC/kg was comparable to a 5/6 matched CB unit with cell dose NC/kg. Recently, the presence of HLA antibodies has been investigated for their potential effect on engraftment after UCB transplantation [30]. Several UCB banks have maternal DNA stored for maternal HLA testing [31]. van Rood and colleagues showed an advantage to selection of units matched at the noninherited maternal allele. The analysis included 1121 patients transplanted for hematologic malignancy. A total of 1059 patients received a mismatched UCB graft; of these patients, 79 patients had a mismatched antigen identical to a donor noninherited maternal allele. These patients had comparable results to those patients receiving a fully matched UCB unit. Remaining questions are the importance of allele level matching for Class I and the importance of other alleles, such as HLA C [32]. These are topics of current investigation. Double Cord Unit Transplant UCB unit selection becomes even more complicated for patients undergoing double cord blood transplant. The population in the United States is, on average, 10 to 15 kg heavier than in Europe and Asia; therefore, double UCB is more popular in the United States [33,34]. In addition, preliminary data suggests that the relapse rate may be lower after double UCB transplantation [35]. It is not clear if the same principles of UCB selection for single UCB transplants apply to double UCB transplants. However, 1 strategy would be to optimize the HLA match and use 2 CBU to increase cell dose [29]. Reduced-intensity double UCB transplantation has become more popular because of a median age of 68 years in patients with acute leukemia, and to improvements in supportive care that allow these older patients to be transplanted successfully [36]. The need for a different cell dose or other selection criteria in reduced intensity compared to myeloablative UCB has not been well studied. Many programs have adopted a minimum UCB requirement of a 4/6 or better A, B, DR HLA match between the patient and each UCB unit and between the 2 UCB for both myeloablative and reduced-intensity double UCB transplantation [33,34,36]. Allele level typing at Class I is not routinely used in UCB selection, despite significant data in the unrelated donor transplant literature supporting optimal allele level matching. Delaney and colleagues [37] used allele level typing at Class I and Class II and

5 S50 M. Boo et al. Biol Blood Marrow Transplant 17:S46-S51, 2011 determined that HLA match did not predict survival or the predominant cord. Allele level matching at HLA B was associated with improved neutrophil engraftment, however. The clinical importance of killer-immunoglobulin receptor-ligand (KIR-L) mismatching is under investigation, with conflicting results. Willemze et al. [36] found a survival advantage to KIR-L mismatching in recipients of myeloablative transplants with acute leukemia. Brunstein and colleagues [38] studied 91 single and 166 double UCB recipients. Brunstein and colleagues [39] studied 91 single and 166 double UCB recipients. KIR-L mismatching had no effect on GVHD or survival after myeloablative conditioning, but after reducedintensity conditioning, KIR-L mismatch between the patient and the dominant unit resulted in a higher rate of GVHD, increased transplant related mortality, and inferior survival. These results suggest that KIR-L mismatching should be avoided in reduced-intensity UCB transplantation. Further investigation will be required, however, to ascertain the impact, particularly on overall survival (OS), of KIR-L mismatching in the different patient populations. Strategy for Cord Blood Unit Selection 1. All patients should receive a cell dose of NC/kg. If double UCB each UCB should have cell dose of NC/kg. 2. All patients should receive a 4/6 or better A, B, DR HLA matched CBU. If double UCB, the units should also be a 4/6 or better HLA match to each other. 3. If units have an adequate cell dose of NC/kg, a 6/6 match is preferable, then a 5/6 matched unit. 4. Avoid HLA mismatches at loci in which patients have preformed HLA antibodies. 5. If maternal typing is available, select mismatch at the noninherited maternal allele. 6. Still under investigation: HLA C and HLA DQ matching, KIR matching, and need for allele level typing at Class I. MODELING THE UTILITY OF A CORD BLOOD UNIT INVENTORY Given the dual requirements for HLA matching and a minimum acceptable cell dose, the challenge of modeling the utility of a cord blood unit inventory becomes quite complex. The model must consider the HLA composition of the inventory, the HLA repertoire of the patient population, the nucleated cell content of stored units and the weight of the searching patients. To address the HLA matching issue, one must know the frequency of various HLA haplotypes (eg, A, B, DR haplotypes for 6 of 6 matching) in the registry and in the searching patient population. Given the haplotype frequencies, phenotype frequencies can be computed from haplotype combinations that yield the given phenotype. Tomi and colleagues [40,41] pioneered methods for estimating haplotype frequencies from HLA phenotype information. The computational technique, termed the Estimation Maximization (EM) Algorithm, essentially says that if a specific set of A, B, and DR types are seen often in a population of phenotypes, they are probably on the same chromosome and thus represent a haplotype. Given the phenotype data from a large population, the EM algorithm makes it possible to calculate thousands of haplotype frequencies. Tomi et al. performed such calculations for adult bone marrow donors typed by low-resolution serologic methods and segmented into 4 racial populations. We have developed methods to extend haplotype frequency calculations to the high-resolution allelelevel within 21 specific racial and ethnic populations. For example, we identified 4 populations of Blacks: African American, African, Caribbean, and South or Central American. Within the population often referred to as Asian/Pacific Islander, we found 8 distinct groups: Chinese, Japanese, Korean, Filipino, Vietnamese, South Asian, Hawaiian/Other Pacific Islander, and Other Southeast Asian. Our methods have allowed us to model an adult donor registry at 7-8 of 8-allele matching stringency and a cord blood unit inventory with intermediate matching at HLA-A and B and allele-level matching at DRB1 within and between each racial/ethnic population. We have also modeled the impact of a minimum cell dose ( NC/kg) in pediatric and adult patient populations. Our analysis shows that Caucasians of European extraction have the highest likelihood of finding a suitable adult donor or a suitable cord blood unit. Matching rates are lowest for the Black populations, but umbilical cord blood is more likely to provide a suitable match than the adult donor registry. Summary The field of umbilical cord blood transplantation continues to change. A regulatory framework for the United States will be implemented during Clinical practices surrounding unit selection have become more robust. As the clinical knowledge increases, it helps to refine and improve computational models that examine the likelihood of a suitable matching unit and the impact of increasing umbilical cord blood unit inventories. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose.

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