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Optimal Donor Selection: Beyond HLA
Biology of Blood and Marrow Transplantation 13:83-86 (2007) 䊚 2007 American Society for Blood and Marrow Transplantation 1083-8791/07/1301-0001$32.00/0 doi:10.1016/j.bbmt.2006.10.011
Optimal Donor Selection: Beyond HLA Dennis L. Confer, John P. Miller National Marrow Donor Program, Minneapolis, Minnesota Correspondence and reprint requests: Dennis L. Confer, MD, National Marrow Donor Program, 3001 Broadway Street NE, Suite 500, Minneapolis, MN 55413 (e-mail: [email protected]).
ABSTRACT Worldwide >10 million adults and 250 000 cord blood units are available for unrelated HCT. HLA matching and, in the case of cord blood units, cell dose are critical determinants for selecting among these donors. Once a list of suitable adult donors or cord blood units is established, the transplantation physician must choose the optimal donor. We review factors that go into making that decision. We conclude that for adults the optimal donor is a male who is younger and has a larger body weight. When selecting among female adults, the optimal donor is also younger with a larger body weight and has never been pregnant. Additional factors, which can be considered and are relevant particularly for cord blood units, include family and medical histories, riskexposure history, collection site characteristics, and geographic location. © 2007 American Society for Blood and Marrow Transplantation
KEY WORDS Tissue donors
●
Stem cell transplantation
INTRODUCTION The selection of optimal donors for allogeneic HCT is a topic focused primarily on the adult volunteer, unrelated donor. In the related donor setting, when ⬎1 suitable HLA-matched donor is available, the choice is frequently straightforward, dictated by donor health issues, CMV serostatus, family social dynamics, or practical logistics. Similarly, with unrelated cord blood units (CBUs), cell dose and HLA matching are the over-riding factors, although there may occasionally be selection considerations created by the family and maternal history of the cord blood donor. However, in the unrelated adult donor setting, even among comparably HLA-matched donors there may be multiple choices. A recent analysis by the National Marrow Donor Program (NMDP) showed that 56% of US patients will have ⱖ10 suitably matched adult donors in the current NMDP file (Table 1). What factors, in addition to HLA match, should be used to distinguish and choose between these donors? Optimal donor selection is distinguished from optimal graft selection. The latter concerns comparing the merits of different graft sources and includes, eg, the decision between a related and an unrelated donor, an adult unrelated donor and a public CBU, or single CBU and double CBU transplantation. Optimal graft selection is frequently dictated by insti-
tutional preference, physician experience, or research priorities. Optimal graft selection is beyond the scope of this review. Among adult unrelated donors, the role of HLA matching has been clearly established and continues to be refined [1-8]. Similarly, with CBU the critical role of cell dose is well accepted [9-11]. The interactions between CBU cell dose and HLA matching are complex but have been addressed in recent publications [12,13]. The implications of HLA and cell dose for selecting adult donors and CBUs were reviewed in the 2006 Education Supplement [14].
DONOR CHARACTERISTICS An NMDP analysis of donor characteristics and their effect on the outcome of unrelated donor marrow transplantation was reported by Kollman et al [15]. The study included 6978 unrelated donor BMTs facilitated between December 1987 and July 1999. Donor characteristics analyzed included age, sex and parity, race, CMV serostatus, ABO type, and HLA matching. Although HLA matching could be evaluated only at the serologic level for HLA-A and -B and the allele-potential level for HLA-DRB1, it was found to significantly affect survival, DFS, aGVHD, cGVHD, and neutrophil engraftment. 83
84
D. L. Confer and J. P. Miller
Table 1. Current Number of HLA Matches for 53 226 Patients Who Have Searched the NMDP Registry* HLA-matched Donors†, n n
Minimum
First Quartile
Median
Third Quartile
Maximum
Proportion with >1 Match
Proportion with >10 Matches
53 226
0
2
14
84
10 651
0.86
0.56
*Patients who previously searched the NMDP registry had their search results updated against the donor file as of April 2006. †Matching determined at intermediate resolution for HLA-A and -B and allele level for HLA-DRB1.
Donor Age
In the study by Kollman et al [15], use of BM donors who were younger had a significant effect on survival and DFS of transplant recipients. In the multivariate analysis, the relative risk for survival per decade of donor age was 1.10 (95% CI, 1.06-1.14, P ⬍ .001). This effect has also been reported by the Spanish Bone Marrow Donor Registry [16]. The effect of younger donor age was seen in all recipient age groups and was also observed when recipients with acute leukemias and CML were analyzed independently. Younger donor age also reduced the risk of severe aGVHD and cGVHD. The analysis by Kollman et al examined only BM transplant recipients who had received myeloablative conditioning. A more recent NMDP analysis (unpublished) evaluated 7043 recipients whose transplantations occurred between January 2000 and December 2004. Included in this analysis were 3022 (43%) recipients of PBSC grafts and 277 (4%) CBU recipients. The effect of younger donor age (restricted to BM and PBSC donors only) on survival at 1 yr remained statistically significant in multivariate analysis (data not shown). Donor age was the only donor characteristic besides HLA match that influenced recipient survival. Donor Sex and Parity
Among the adult donor population, transplantation physicians prefer male donors. Although females comprise 58% of the total registry volunteers, males comprise 58% of the donors actually selected for HCT. In the BM setting, some of this preference is no doubt driven by body size and the belief that male donors can provide a larger donation. According to NMDP data, the median BM donation by male donors is 1.1 L, with 25% of males donating in excess of 1.35 L. The corresponding figures for female donors are 1.0 and 1.2 L, respectively. As a proportion of body weight, however, female donors make larger donations (median, 15 mL/kg; 75th percentile, 19 versus 12 and 14.5 mL/kg, respectively). The analysis by Kollman et al [15] found no effect of donor sex on survival, aGVHD, or engraftment. However, recipients of BM from female donors were more likely to develop cGVHD [15], but this effect was restricted to female donors with prior pregnancies. Compared with males, the relative risk of
cGVHD for never-pregnant females was 1.09 (95% CI, 0.96-1.24, P ⫽ .17). With a single pregnancy the relative risk was 1.19 (95% CI, 1.0-1.43, P ⫽ .05) and with ⱖ2 pregnancies the relative risk was 1.40 (95% CI, 1.25-1.57, P ⬍ .0001). A similar analysis of cGVHD risk versus PBSC donor parity has not been performed. Males who donate PBSCs may provide a higher dose of the CD34⫹ cells than female PBSC donors irrespective of body weight [17]. An analysis of NMDP donors who received a mobilizing filgrastim dose of ⬃10 g/kg subcutaneously for 5 days shows that males demonstrate a consistently higher median preapheresis peripheral blood CD34⫹ cell count (Figure 1). The difference in median CD34⫹ cell content between males and females is as large as 30%-40% for the lighter donor weight ranges. Donor Weight
Larger donors may be preferred for BM donation because of their larger total blood volume. The study by Kollman et al [15] confirmed that larger donors provided significantly higher infused BM cell doses. For donors weighing ⬍70, 70-90, and ⬎90 kg, median cell doses were 2.95, 3.14, and 3.37 ⫻ 108/kg, respectively (P ⬍ .0001). As shown in Figure 1, even among PBSC donors receiving standard 10-g/kg daily filgrastim dosing,
Figure 1. The median preapheresis peripheral blood CD34⫹ cell concentration is displayed for males (solid line) and females (dashed line) within weight ranges of ⬍60-120 kg. All donors received filgrastim at a dose of ⬃10 g/kg daily for 5 days. The median CD34⫹ cell concentrations for male donors are higher, particularly at the lower weight ranges. The medians for males and females increase with increasing donor weight (P ⬍ .001).
85
Optimal Donor Selection: Beyond HLA
there appears to be a strong association between preaphersis peripheral blood CD34⫹ cell content and donor weight. However, filgrastim dosing in these donors was based on actual, unadjusted body weight, so it is conceivable that larger donors actually received higher doses based on lean body mass. The relation between donor weight and donor suitability deserves further examination. DONOR TESTING RESULTS Blood from adult donors and mothers of CBU donors is tested during initial evaluation and the results are available to assist with optimal donor selection. Standard infectious disease testing includes HIV, hepatitis C and B viruses, human T lymphotropic viruses I/II, syphilis and CMV. In general, CBUs are not stored whenever screening tests, with the exception of CMV, are positive. Some cord blood banks routinely employ additional testing to confirm that CBUs are not actively infected with CMV. Controversy exists regarding the banking of CBU where the mother tests positive for anti-HBc (antibodies to hepatitis B core antigen). The incidence of positive test results is higher in certain ethnic populations and, if these units are excluded, CBUs with potentially good HLA matches may be precluded for those same populations. Adult donors who test positive with screening tests in the United States are declared ineligible; however, such donors may still donate in urgent circumstances. These donors will undergo additional confirmatory testing that clarifies the exact risk posed to a potential hematopoietic cell transplant recipient. ABO testing is also available on all adult donors and CBUs. ABO matching or mismatching, however, does not affect recipient survival, DFS, or risk of GVHD [15]. When a potential donor-recipient pair is mismatched at the HLA-antigen level, testing should be performed to confirm that the recipient is not alloimmunized against the donor’s HLA type [18,19]. The presence of anti-HLA antibodies in the recipient, which recognize the donor’s HLA antigens, is associated with a high risk for nonengraftment. The role of testing and matching for miHAs, nonHLA genetic loci, such as killer cell Ig-like receptors (KIRs), or cytokine gene polymorphisms remains to be clarified. Currently there are no data to indicate that matching for KIRs, minor antigens, or certain interleukin genes is necessary outside a research protocol. DONOR HISTORY Adult donors and mothers of CBU donors provide a health history and a risk-exposure history. The
health history may reveal inherited conditions within the family, such as RBC abnormalities or systemic enzyme deficiencies that will render the donor unsuitable. For adult donors the health history is more likely to reveal conditions that will affect the safety of the donation. If such is a donor is cleared for donation, the transplantation physician should still review the conditions for their potential to limit the likelihood of a successful BM or PBSC donation. For example, a donor with prior anesthesia difficulties or musculoskeletal problems might have difficulty with BM donation. Similarly a donor with a history of autoimmune disease or poor venous access might be less suitable for PBSC donation, particularly if a large collection is desirable. A donor’s history (or CBU maternal donor history) of risk exposure is very important and should routinely be reviewed by the transplantation physician. In addition to hepatitis and HIV, the risk history reveals information about vaccinations, malaria, West Nile virus, transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob Disease [CJD] and new variant Creutzfeldt-Jakob Disease [nvCJD]), Chagas disease, and other conditions. COLLECTION SITE The location of the collection site for BM, PBSCs, or CBUs may be an issue that requires attention from the transplantation team. Geographic location may affect product transportation and timing of transplantation. Fresh and frozen products should be transported in validated shipping containers according to established operating procedures. Collection sites, including cord blood banks, that are members of the NMDP network must meet initial membership criteria and annual reevaluations. NonNMDP sites should be evaluated for accreditation by a professional organization such as FACT, AABB, or FACT-Netcord. Sites must also meet Food and Drug Administration regulatory requirements where applicable. When receiving products from donors outside the United States, additional precautions are warranted. Products imported must meet US regulatory and customs importation requirements. The World Marrow Donor Association (WMDA) is a voluntary association of international registries and cord blood banks whose members adhere to WMDA standards and policies. A WMDA accreditation program for international donor registries has recently been established, which over time will provide added assurance about international exchange of HCT products. Similarly, Netcord is an international association of cord blood banks that have agreed to pursue common practices and accreditation for compliance with FACT-Netcord Standards.
86
SUMMARY With respect to cord blood, once the cell-dose and HLA-matching requirements have been satisfied, selection of the optimal CBU from a list of candidate units is primarily a matter of reviewing qualifications of the represented cord blood banks and the maternal health history documents of the individual units. In addition to these issues, for the adult unrelated donor, there are donor-related factors that are known or suspected to influence the overall quality of the resulting BM or PBSC donation. In general, it appears that when HLA matching is the same, the preferred donor is younger, male, and good sized, say ⬎80 kg. When choosing among female adults, in addition to age and body size, attention should be given to parity, with no prior pregnancies preferable to a single pregnancy, which is preferable to ⱖ2 prior pregnancies. Unfortunately, there is, as yet, no way to balance HLA matching against donor age, sex, and size. For example, at what age, if any, does a single-allele mismatch in a younger male donor become superior to 0 alleles mismatched in a 50-yr-old female with no prior pregnancies? Similarly, how does one rate the effect of prior pregnancies against differences in age for prospective female donors? The answers to these questions are unknown. Fortunately for the transplantation physician, younger female donors are more likely to be nulliparous than older females. An additional area of uncertainty is how to factor donor characteristics against a proposed recipient’s risk status. Perhaps donor factors become less important as recipient risk increases. If HLA-matching requirements are satisfied, no donor should be disqualified solely on the basis of age, sex, or size, unless a better donor option is readily available.
REFERENCES 1. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004;104:1923-1930. 2. Hurley CK, Lowe LAB, Logan B, et al. National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants. Biol Blood Marrow Transplant. 2003;9:610-615. 3. Morishima Y, Sasazuki T, Inoko H, et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002;99:4200-4206. 4. Petersdorf EW, Gooley T, Malkki M, et al. The biological significance of HLA-DP gene variation in haematopoietic cell transplantation. Br J Haematol. 2001;112:988-994.
D. L. Confer and J. P. Miller
5. Petersdorf EW, Anasetti C, Martin PJ, et al. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood. 2004;104:2976-2980. 6. Petersdorf EW, Hansen JA, Martin PJ, et al. Major-histocompatibility-complex class I alleles and antigens in hematopoieticcell transplantation. N Engl J Med. 2001;345:1794-1800. 7. Petersdorf EW, Kollman C, Hurley CK, et al. Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program experience. Blood. 2001;98:2922-2929. 8. Petersdorf EW, Gooley TA, Anasetti C, et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood. 1998;92:3515-3520. 9. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611-1618. 10. Rubenstein P, Carrierm C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1998;339:1565-1577. 11. Gluckman E, Rocha V, Arcese W, et al. Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Exp Hematol. 2004;32:397-407. 12. Gibbons R. Analysis of the NYBC, NMDP and NHLBI cord blood data. In: Meyer EA, Hanna K, Gebbie K, eds. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program. Washington, DC: National Academies Press; 2005:265-274. 13. Wall DA, Carter SL, Kernan NA, et al. Busulfan/melphalan/ antithymocyte globulin followed by unrelated donor cord blood transplantation for treatment of infant leukemia and leukemia in young children: the Cord Blood Transplantation study (COBLT) experience. Biol Blood Marrow Transplant. 2005;11:637-646. 14. Hurley CK, Wagner JE, Setterholm MI, et al. Advances in HLA: Practical implications for selecting adult donors and cord blood units. Biol Blood Marrow Transplant. 2006;12:23-33. 15. Kollman C, Howe C, Anasetti C, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98: 2043-2051. 16. Carreras E, Jimenez M, Gomez-Garcia V, et al. Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia. Bone Marrow Transplant. 2006;37:33-40. 17. Fischer JC, Frick M, Wassmuth R, et al. Superior mobilisation of haematopoietic progenitor cells with glycosylated G-CSF in male but not female unrelated stem cell donors. Br J Haematol. 2005;130:740-746. 18. Anasetti C, Amos D, Beatty PG, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med. 1989;320:197-204. 19. Ottinger HD, Rebmann V, Pfeiffer KA, et al. Positive serum crossmatch as predictor for graft failure in HLA-mismatched allogeneic blood stem cell transplantation. Transplantation. 2002; 73:1280-1285.
Optimal Donor Selection: Beyond HLA Dennis L. Confer, John P. Miller National Marrow Donor Program, Minneapolis, Minnesota Correspondence and reprint requests: Dennis L. Confer, MD, National Marrow Donor Program, 3001 Broadway Street NE, Suite 500, Minneapolis, MN 55413 (e-mail: [email protected]).
ABSTRACT Worldwide >10 million adults and 250 000 cord blood units are available for unrelated HCT. HLA matching and, in the case of cord blood units, cell dose are critical determinants for selecting among these donors. Once a list of suitable adult donors or cord blood units is established, the transplantation physician must choose the optimal donor. We review factors that go into making that decision. We conclude that for adults the optimal donor is a male who is younger and has a larger body weight. When selecting among female adults, the optimal donor is also younger with a larger body weight and has never been pregnant. Additional factors, which can be considered and are relevant particularly for cord blood units, include family and medical histories, riskexposure history, collection site characteristics, and geographic location. © 2007 American Society for Blood and Marrow Transplantation
KEY WORDS Tissue donors
●
Stem cell transplantation
INTRODUCTION The selection of optimal donors for allogeneic HCT is a topic focused primarily on the adult volunteer, unrelated donor. In the related donor setting, when ⬎1 suitable HLA-matched donor is available, the choice is frequently straightforward, dictated by donor health issues, CMV serostatus, family social dynamics, or practical logistics. Similarly, with unrelated cord blood units (CBUs), cell dose and HLA matching are the over-riding factors, although there may occasionally be selection considerations created by the family and maternal history of the cord blood donor. However, in the unrelated adult donor setting, even among comparably HLA-matched donors there may be multiple choices. A recent analysis by the National Marrow Donor Program (NMDP) showed that 56% of US patients will have ⱖ10 suitably matched adult donors in the current NMDP file (Table 1). What factors, in addition to HLA match, should be used to distinguish and choose between these donors? Optimal donor selection is distinguished from optimal graft selection. The latter concerns comparing the merits of different graft sources and includes, eg, the decision between a related and an unrelated donor, an adult unrelated donor and a public CBU, or single CBU and double CBU transplantation. Optimal graft selection is frequently dictated by insti-
tutional preference, physician experience, or research priorities. Optimal graft selection is beyond the scope of this review. Among adult unrelated donors, the role of HLA matching has been clearly established and continues to be refined [1-8]. Similarly, with CBU the critical role of cell dose is well accepted [9-11]. The interactions between CBU cell dose and HLA matching are complex but have been addressed in recent publications [12,13]. The implications of HLA and cell dose for selecting adult donors and CBUs were reviewed in the 2006 Education Supplement [14].
DONOR CHARACTERISTICS An NMDP analysis of donor characteristics and their effect on the outcome of unrelated donor marrow transplantation was reported by Kollman et al [15]. The study included 6978 unrelated donor BMTs facilitated between December 1987 and July 1999. Donor characteristics analyzed included age, sex and parity, race, CMV serostatus, ABO type, and HLA matching. Although HLA matching could be evaluated only at the serologic level for HLA-A and -B and the allele-potential level for HLA-DRB1, it was found to significantly affect survival, DFS, aGVHD, cGVHD, and neutrophil engraftment. 83
84
D. L. Confer and J. P. Miller
Table 1. Current Number of HLA Matches for 53 226 Patients Who Have Searched the NMDP Registry* HLA-matched Donors†, n n
Minimum
First Quartile
Median
Third Quartile
Maximum
Proportion with >1 Match
Proportion with >10 Matches
53 226
0
2
14
84
10 651
0.86
0.56
*Patients who previously searched the NMDP registry had their search results updated against the donor file as of April 2006. †Matching determined at intermediate resolution for HLA-A and -B and allele level for HLA-DRB1.
Donor Age
In the study by Kollman et al [15], use of BM donors who were younger had a significant effect on survival and DFS of transplant recipients. In the multivariate analysis, the relative risk for survival per decade of donor age was 1.10 (95% CI, 1.06-1.14, P ⬍ .001). This effect has also been reported by the Spanish Bone Marrow Donor Registry [16]. The effect of younger donor age was seen in all recipient age groups and was also observed when recipients with acute leukemias and CML were analyzed independently. Younger donor age also reduced the risk of severe aGVHD and cGVHD. The analysis by Kollman et al examined only BM transplant recipients who had received myeloablative conditioning. A more recent NMDP analysis (unpublished) evaluated 7043 recipients whose transplantations occurred between January 2000 and December 2004. Included in this analysis were 3022 (43%) recipients of PBSC grafts and 277 (4%) CBU recipients. The effect of younger donor age (restricted to BM and PBSC donors only) on survival at 1 yr remained statistically significant in multivariate analysis (data not shown). Donor age was the only donor characteristic besides HLA match that influenced recipient survival. Donor Sex and Parity
Among the adult donor population, transplantation physicians prefer male donors. Although females comprise 58% of the total registry volunteers, males comprise 58% of the donors actually selected for HCT. In the BM setting, some of this preference is no doubt driven by body size and the belief that male donors can provide a larger donation. According to NMDP data, the median BM donation by male donors is 1.1 L, with 25% of males donating in excess of 1.35 L. The corresponding figures for female donors are 1.0 and 1.2 L, respectively. As a proportion of body weight, however, female donors make larger donations (median, 15 mL/kg; 75th percentile, 19 versus 12 and 14.5 mL/kg, respectively). The analysis by Kollman et al [15] found no effect of donor sex on survival, aGVHD, or engraftment. However, recipients of BM from female donors were more likely to develop cGVHD [15], but this effect was restricted to female donors with prior pregnancies. Compared with males, the relative risk of
cGVHD for never-pregnant females was 1.09 (95% CI, 0.96-1.24, P ⫽ .17). With a single pregnancy the relative risk was 1.19 (95% CI, 1.0-1.43, P ⫽ .05) and with ⱖ2 pregnancies the relative risk was 1.40 (95% CI, 1.25-1.57, P ⬍ .0001). A similar analysis of cGVHD risk versus PBSC donor parity has not been performed. Males who donate PBSCs may provide a higher dose of the CD34⫹ cells than female PBSC donors irrespective of body weight [17]. An analysis of NMDP donors who received a mobilizing filgrastim dose of ⬃10 g/kg subcutaneously for 5 days shows that males demonstrate a consistently higher median preapheresis peripheral blood CD34⫹ cell count (Figure 1). The difference in median CD34⫹ cell content between males and females is as large as 30%-40% for the lighter donor weight ranges. Donor Weight
Larger donors may be preferred for BM donation because of their larger total blood volume. The study by Kollman et al [15] confirmed that larger donors provided significantly higher infused BM cell doses. For donors weighing ⬍70, 70-90, and ⬎90 kg, median cell doses were 2.95, 3.14, and 3.37 ⫻ 108/kg, respectively (P ⬍ .0001). As shown in Figure 1, even among PBSC donors receiving standard 10-g/kg daily filgrastim dosing,
Figure 1. The median preapheresis peripheral blood CD34⫹ cell concentration is displayed for males (solid line) and females (dashed line) within weight ranges of ⬍60-120 kg. All donors received filgrastim at a dose of ⬃10 g/kg daily for 5 days. The median CD34⫹ cell concentrations for male donors are higher, particularly at the lower weight ranges. The medians for males and females increase with increasing donor weight (P ⬍ .001).
85
Optimal Donor Selection: Beyond HLA
there appears to be a strong association between preaphersis peripheral blood CD34⫹ cell content and donor weight. However, filgrastim dosing in these donors was based on actual, unadjusted body weight, so it is conceivable that larger donors actually received higher doses based on lean body mass. The relation between donor weight and donor suitability deserves further examination. DONOR TESTING RESULTS Blood from adult donors and mothers of CBU donors is tested during initial evaluation and the results are available to assist with optimal donor selection. Standard infectious disease testing includes HIV, hepatitis C and B viruses, human T lymphotropic viruses I/II, syphilis and CMV. In general, CBUs are not stored whenever screening tests, with the exception of CMV, are positive. Some cord blood banks routinely employ additional testing to confirm that CBUs are not actively infected with CMV. Controversy exists regarding the banking of CBU where the mother tests positive for anti-HBc (antibodies to hepatitis B core antigen). The incidence of positive test results is higher in certain ethnic populations and, if these units are excluded, CBUs with potentially good HLA matches may be precluded for those same populations. Adult donors who test positive with screening tests in the United States are declared ineligible; however, such donors may still donate in urgent circumstances. These donors will undergo additional confirmatory testing that clarifies the exact risk posed to a potential hematopoietic cell transplant recipient. ABO testing is also available on all adult donors and CBUs. ABO matching or mismatching, however, does not affect recipient survival, DFS, or risk of GVHD [15]. When a potential donor-recipient pair is mismatched at the HLA-antigen level, testing should be performed to confirm that the recipient is not alloimmunized against the donor’s HLA type [18,19]. The presence of anti-HLA antibodies in the recipient, which recognize the donor’s HLA antigens, is associated with a high risk for nonengraftment. The role of testing and matching for miHAs, nonHLA genetic loci, such as killer cell Ig-like receptors (KIRs), or cytokine gene polymorphisms remains to be clarified. Currently there are no data to indicate that matching for KIRs, minor antigens, or certain interleukin genes is necessary outside a research protocol. DONOR HISTORY Adult donors and mothers of CBU donors provide a health history and a risk-exposure history. The
health history may reveal inherited conditions within the family, such as RBC abnormalities or systemic enzyme deficiencies that will render the donor unsuitable. For adult donors the health history is more likely to reveal conditions that will affect the safety of the donation. If such is a donor is cleared for donation, the transplantation physician should still review the conditions for their potential to limit the likelihood of a successful BM or PBSC donation. For example, a donor with prior anesthesia difficulties or musculoskeletal problems might have difficulty with BM donation. Similarly a donor with a history of autoimmune disease or poor venous access might be less suitable for PBSC donation, particularly if a large collection is desirable. A donor’s history (or CBU maternal donor history) of risk exposure is very important and should routinely be reviewed by the transplantation physician. In addition to hepatitis and HIV, the risk history reveals information about vaccinations, malaria, West Nile virus, transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob Disease [CJD] and new variant Creutzfeldt-Jakob Disease [nvCJD]), Chagas disease, and other conditions. COLLECTION SITE The location of the collection site for BM, PBSCs, or CBUs may be an issue that requires attention from the transplantation team. Geographic location may affect product transportation and timing of transplantation. Fresh and frozen products should be transported in validated shipping containers according to established operating procedures. Collection sites, including cord blood banks, that are members of the NMDP network must meet initial membership criteria and annual reevaluations. NonNMDP sites should be evaluated for accreditation by a professional organization such as FACT, AABB, or FACT-Netcord. Sites must also meet Food and Drug Administration regulatory requirements where applicable. When receiving products from donors outside the United States, additional precautions are warranted. Products imported must meet US regulatory and customs importation requirements. The World Marrow Donor Association (WMDA) is a voluntary association of international registries and cord blood banks whose members adhere to WMDA standards and policies. A WMDA accreditation program for international donor registries has recently been established, which over time will provide added assurance about international exchange of HCT products. Similarly, Netcord is an international association of cord blood banks that have agreed to pursue common practices and accreditation for compliance with FACT-Netcord Standards.
86
SUMMARY With respect to cord blood, once the cell-dose and HLA-matching requirements have been satisfied, selection of the optimal CBU from a list of candidate units is primarily a matter of reviewing qualifications of the represented cord blood banks and the maternal health history documents of the individual units. In addition to these issues, for the adult unrelated donor, there are donor-related factors that are known or suspected to influence the overall quality of the resulting BM or PBSC donation. In general, it appears that when HLA matching is the same, the preferred donor is younger, male, and good sized, say ⬎80 kg. When choosing among female adults, in addition to age and body size, attention should be given to parity, with no prior pregnancies preferable to a single pregnancy, which is preferable to ⱖ2 prior pregnancies. Unfortunately, there is, as yet, no way to balance HLA matching against donor age, sex, and size. For example, at what age, if any, does a single-allele mismatch in a younger male donor become superior to 0 alleles mismatched in a 50-yr-old female with no prior pregnancies? Similarly, how does one rate the effect of prior pregnancies against differences in age for prospective female donors? The answers to these questions are unknown. Fortunately for the transplantation physician, younger female donors are more likely to be nulliparous than older females. An additional area of uncertainty is how to factor donor characteristics against a proposed recipient’s risk status. Perhaps donor factors become less important as recipient risk increases. If HLA-matching requirements are satisfied, no donor should be disqualified solely on the basis of age, sex, or size, unless a better donor option is readily available.
REFERENCES 1. Flomenberg N, Baxter-Lowe LA, Confer D, et al. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004;104:1923-1930. 2. Hurley CK, Lowe LAB, Logan B, et al. National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants. Biol Blood Marrow Transplant. 2003;9:610-615. 3. Morishima Y, Sasazuki T, Inoko H, et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002;99:4200-4206. 4. Petersdorf EW, Gooley T, Malkki M, et al. The biological significance of HLA-DP gene variation in haematopoietic cell transplantation. Br J Haematol. 2001;112:988-994.
D. L. Confer and J. P. Miller
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