CBF Cord Blood Forum

i. OVERVIEW

  1. Eleven million donors in Bone Marrow Donors Worldwide! Time for reassessment? van Rood JJ, Oudshoorn M. Bone Marrow Transplant. 2008;41:1-9. Abstract

Data from the World Marrow Donor Association (WMDA) indicates that the number of transplants has tripled between 1997 and 2003 implying that many patients qualifying for a stem cell transplant did not get one in previous years. Between 2000 and 2006, 151,000 patients qualified for an HLA unrelated donor transplant but only 64,720 received one! Overall there is almost a three-fold difference. Clearly we must try to do better.

Why do almost two thirds of patients not reach transplantation? In the first place, the search process is overall much too slow. For 30% of the patients, our search process and work-up for transplantation takes so much time that when finally a donor has been located and found to be fit for donation, the patient has relapsed or is otherwise unfit for transplantation.

The enormous polymorphism of HLA is a second reason why only one out of three patients reaches transplantation. Even with 11 million donors only two out of three Caucasoid patients will find a 10 out of 10 allele-matched donor and for other racial groups, it can be as low as one out of four.

As far as increasing the number of available phenotypes is concerned, increasing the number of (adult) donors is not cost-effective if one recruits donors from a population with a NW European background. “We certainly need more donors, but these can for logistic reasons most efficiently be recruited via cord blood collection.” It is clear that a supply of 40,000 cord blood units could provide grafts to a larger percentage of patients from minority groups than the NMDP with over four million donors.

One can question whether the continuous growth of millions of (adult) donors is really a good thing or are different are additional scenarios preferable? In many registries, the comparison with the “Sorcerer’s Apprentice” is valid.

Looking at the annual WMDA reports, “it is clear that we are witnessing a shift from the use of bone marrow donors to cord blood.”

[Note: At the 7th annual International Cord Blood Transplantation Symposium in Los Angles in June, 2009, Dr. Dennis Confer from the National Marrow Donor Program (NMDP) will discuss “The NMDP goal of facilitating 10,000 HSCTs in the US Annually by 2015.” For further details see www.cordbloodsymposium.org ]

  1. Use of cost-effectiveness analysis to determine inventory size for a national cord blood bank. Howard DH, Meltzer D, Kollman C, Maiers M, Logan B, Gragert L, Setterholm M, Horowitz MM. Med Decis Making. 2008;28:243-253. Abstract

This is a report of a study commissioned by the Institute of Medicine. The authors point out that the NMDP maintains a registry of more than 5 million adults willing to donate bone marrow should they match a transplant candidate (and, in addition, the NMDP has access to a similar number worldwide). Nevertheless locating a matching donor is difficult because there are more than 60 million distinct HLA genotypes. For bone marrow transplants only 6/6 or 5/5 matches are considered but for cord blood, 4/6 matches are also allowed. Survival rates improve with match level, so 6/6 matches are ideal.

The authors supply match probabilities by age group (≥20 and <20 years) and state that results for a 50,000 cord bank inventory most closely approximate the current situation. [Presently, the NMDP is able to provide a 6/6 cord blood unit for 19% of children and 6%% of adults. The matching is an antigen match at HLA-A and –B and allele match at DRB1.]

The following is the projected effect of increasing the inventory from 50,000 to 300,000 for finding a 6/6 matched cord blood unit with a minimum cell dose of 2.5 x 107kg (Note that the following projections regarding the percentage of 6/6 matched units from a bank of 50,000 units correlates closely with the actual percentages released for transplantation by the NMDP as quoted in the previous paragraph):

  50,000 300,000 Increment
Children 23% 42% 19%
Adults 7% 17% 10%

The authors performed a cost effectiveness analysis and concluded that it is cost-effective to increase the cord blood inventory size beyond current levels.

[Note: Increasing the size of the cord blood inventory is cost-effective but increasing the size of the adult registries is not. Hurley et al (Tissue Antigens 2003;61:415-424) estimate that at a registry size of 10 million donors, an additional 7,000,000 donors are needed to increase the chance of matching by 1%. – See below]

  1. Assessment of optimal size and composition of the U.S. National Registry of hematopoietic stem cell donors. Kollman C, Abella E, Baitty RL, Beatty PG, Chakraborty R, Christiansen CL, Hartzman RJ, Hurley CK, Milford E, Nyman JA, Smith TJ, Switzer GE, Wada RK, Setterholm M. Transplantation 2004;78:89-95. Abstract

The authors point out that the number of patients searching the NMDP registry and proceeding to transplant is considerably smaller than what might be expected on the basis of the rate of sibling-donor transplantation. Efforts to find and remove barriers to unrelated stem cell transplantation other than the lack of an HLA-matched donor may prove more cost-effective in increasing the number of transplants.

The authors present models indicating that continuing to add more volunteers to the donor registries will have a limited effect. Much smaller registries of cord-blood units could provide adequate matches for the large majority of patients.

  1. Maximizing optimal hematopoietic stem cell donor selection from registries of unrelated adult volunteers. Hurley CK, Fernandez Vina M, Setterholm M. Tissue Antigens. 2003;61:415-424. Abstract

The authors point out the obvious: “Continued recruitment of random volunteers will increase the match probability but will eventually lead to diminishing returns.” The continued collection of phenotypes already represented in the registry means that the number of individuals needed to increase the probability of matching by a small increment becomes greater as the registry grows larger. At a registry size of 1 million donors, a further 100,000 donors are needed to increase the chance of matching from 85% to 86%. At 10 million donors, approximately 7,000,000 additional donors are needed to increase the chance of matching by 1%. As these estimates are based on matching at the antigen level, allele level matching requirements must be served by much larger registries. Also, attempts to collect very rare donor phenotypes that may never appear in a searching patient can be counterproductive.

  1. Results of the cord blood transplantation (COBLT) study unrelated donor banking program. Kurtzberg J, Cairo MS, Fraser JK, Baxter-Lowe L, Cohen G, Carter SL, Kernan NA. Transfusion. 2005;45:842-55. Abstract

To meet the ongoing needs of patients, particularly ethnic minorities, the Cord Blood Transplantation (COBLT) Study was conceived by the NHLBI. The COBLT Study is a Phase II, multicenter study designed to determine the utility of UCB for transplantation of patients with malignant and nonmalignant diseases. The goals of the program initiated in 1996 were to develop standard operating procedures (SOPs) for cord blood (CB) donor recruitment and banking and to build an ethnically diverse unrelated CB bank to support a transplantation protocol.

The program included collection centers, three banks, a steering committee, and a medical coordinating center (MCC) that developed and validated SOPs and a Web-based data collection system. External oversight was performed by the National Heart, Lung, and Blood Institute and the MCC.

A total of 34,799 potential donors were screened and 20,710 consented. A total of 17,207 ethnically diverse units were collected between 1998 and 2001. A total of 11,077 (64%) units were cryopreserved and quarantined. Of these, 79 percent met eligibility criteria and were HLA-typed and entered into the search registry. Higher CB volumes and cell counts were obtained from cesarean sections compared to vaginal deliveries. Units from African-American persons contained lower cell counts per volume compared to other ethnicities. Birth weight correlated with volume and cell content. External oversight was accomplished through custom reports generated by the data collection system and periodic site visits. During maintenance, a breach in the SOPs was detected during a site visit at one of the banks. These units were designated for future use in nonclinical research.

In conclusion, the COBLT Study demonstrated that SOPs and data collection can be implemented in multiple banks coordinated by one MCC. Relationships between donor demographics and CB content may be useful in the development of other CB banking programs.

  1. Characterization of banked umbilical cord blood hematopoietic progenitor cells and lymphocyte subsets and correlation with ethnicity, birth weight, sex, and type of delivery: a Cord Blood Transplantation (COBLT) Study report. Cairo MS, Wagner EL, Fraser J, Cohen G, van de Ven C, Carter SL, Kernan NA, Kurtzberg J. Transfusion. 2005;45:856-66. Abstract

The goals of the Cord Blood Transplantation (COBLT) Study banking program were to develop standard operating procedures for cord blood (CB) donor recruitment and banking and to build an ethnically diverse unrelated CB bank to support a transplantation protocol.

This report describes the hematopoietic progenitor cell (HPC) and lymphocyte subset (LS) content of approximately 8000 CB units, and these results were correlated with donor ethnicity, birth weight, gestational age, sex, and type of delivery.

There was a significant correlation of CD34+ cell count with colony-forming unit (CFU)-granulocyte-macrophage (r=0.68, p<0.001), CFU-granulocyte-erythroid-macrophage-megakaryocyte (r=0.52, p<0.001), burst-forming unit-erythroid (BFU-E; r=0.61, p<0.001), and total CFUs (r=0.67, p<0.001). Nucleated red blood cell count was significantly correlated with total CD34+ (r=0.56, p<0.001), total CFU (r=0.50, p<0.001), BFU-E (r=0.48, p<0.001), and counts of CD34+ subsets (p<0.001). Caucasian ethnicity was significantly correlated with higher CD3+/CD4+, CD19+, and CD16+/CD56+ LSs.

Furthermore, CD34+/CD38- and CD34+/CD61+ CB units (HPC-C) were significantly lower in African American and Asian persons compared to Caucasian and Hispanic persons. Male sex was associated with significantly fewer CD3+/CD4+, CD19+, and CD16+/CD56+ but increased CD3+/CD8+ LSs (p<0.001). Finally, cesarean section was associated with significantly higher total CFU and CD16+/CD56+ but lower CD3+/CD4+, CD3+/CD8+, and CD19+ LSs.

These results provide a standard and range for uniformly processed HPC-C progenitor cells and LSs. CB progenitor cells and/or LSs may in the future predict for rapidity of engraftment, incidence of graft-versus-host disease, speed and quality of immuno-reconstitution, graft-versus-tumor effects, and/or success of gene transfection after CB transplantation.

  1. Cord blood banking 2002: 112,010 of 7,914,773 chances. Rebulla P. Transfusion 2002; 42:1246-1248.

A summary of cord blood banking in 2002 indicated that 112,010 mothers have consented to donation of their newborns’ cord blood for long-term cryopreservation in 28 banking programs. Eight of these were in the US and 17 in Europe, which globally accounted for 55,560 and 44,693 units, respectively, or 49.6% and 39.9% of the total inventory. Also, there were 6449 units listed from Australia (5.8%) and 5238 from china (4.7%). More than 2300 allogeneic cord blood transplants have already been performed.

  1. Racial and ethnic composition of volunteer cord blood donors: comparison with volunteer unrelated marrow donors. Ballen KK, Hicks J, Dharan B, Ambruso D, Anderson K, Bianco C et al. Transfusion 2002; 42:1279-1284.Abstract

A presumed advantage of cord blood is the ability to increase minority recruitment. However, a review of the racial composition of five member cord blood banks of the NMDP, representing 9020 cord blood donors, indicated that three of the cord blood banks recruited a lower percentage of minorities than the corresponding marrow donor centers. Further, four of the cord blood banks recruited a lower percentage of minorities compared with delivery data than the corresponding marrow donor centers compared with census population. The conclusion reached that the problem of insufficient minority recruitment of cord blood has not yet been solved.

  1. An international survey of unrelated umbilical cord blood banking. Stanworth S, Warwick R, Fehily D, Persaud C, Armitage S, Navarrete C et al. Vox Sang 2001; 80:236-243.Abstract

This report presents the findings of an international survey of technical and operational aspects of cord blood banking. Nineteen cord blood banks were invited to participate in a postal survey regarding their practice in the 12-month period up to August 1998. A standardized questionnaire was designed to collect information about donor selection, collection, processing, testing, and storage of unrelated umbilical cord blood units. The survey revealed marked variations in cord blood banking practice and demonstrated a need for standardization. The authors suggested further similar surveys to ensure that stardards continued to develop to ensure the safety and quality of cord blood for all patients.

  1. Racial diversity with high nucleated cell counts and CD34 counts achieved in a national network of cord blood banks. Ballen KK, Kurtzberg J, Lane TA, Lindgren BR, Miller JP, Nagan D, Newman B, Rupp N, Haley NR. Biol Blood Marrow Transplant. 2004;10:269-75. Abstract

A presumed advantage of cord blood is the ability to increase recruitment of donors of minority ethnic backgrounds. The American Red Cross Cord Blood Program was established in 1999 with 6 banks and 10 collection sites throughout the country. Racial designations were self-reported on questionnaires, and donor race was collected from each site. Postprocessing nucleated cell counts and CD34(+) counts were obtained on the cord blood units, and results from each racial/ethnic group (white, black, Asian, Hispanic, and Native American) were compared in the natural logarithmic scale by using analysis of variance. A total of 18878 donors consented: 64% white, 16% black, 12% Hispanic, 4% Asian, 1% Native American, and 3% other. Seven thousand eight hundred sixty-six cord blood units were banked for transplantation. The mean preprocessing nucleated cell count was 1220 x 10(6) (range, 327-7300 x 10(6)). There was no difference among racial groups when controlled for site. The mean CD34+ count was 3.28 x 10(6). Blacks had a significantly lower CD34+ count than the other racial/ethnic groups in the Midwest, Northwest, and North Carolina collection sites. The authors concluded that a racially diverse cord blood bank can be achieved. Nucleated cell counts were similar among the different racial/ethnic groups, although CD34+ counts were lower for blacks in some collection sites.