Introduction

Over the past decade, cord blood (CB) has been established as an alternative source of donor cells for allogeneic hematopoietic SCT. The outcome of CB transplants, particularly in children, is similar to those unrelated donor transplants using BM cell or mobilized PBPC.^{5, 6, 7, 8} Early experience in adult CB transplantation (CBT) was hampered by poor engraftment and immune recovery.^{9, 10, 11} Recent experience with better risk patients, double CB unit transplants and submyeloablative preparative regimens have been more encouraging.^{12, 13, 14}

There are several important differences between BM or G-CSF-mobilized PBPC and CB when selecting donors/products for transplantation. CB transplants are being performed with approximately a log fewer hematopoietic progenitors than other stem cell sources.⁵ The adult donor grafts are delivering cell numbers well above the engraftment threshold so that a loss of even half of the product would likely not have a major impact on the transplant. CB as a donor source is not as forgiving. In general, clinical series have shown that CBT is associated with a higher incidence of graft failure and delayed count recovery.^{10, 15} However, these risks are offset by a lower risk for acute and chronic GVHD despite major HLA disparity. This is due in part to the lower number of mature T cells in the graft (functionally CB is a partially T-cell depleted graft) and to the nature of the CB T cells' responsiveness to allogenic stimulus.^{16, 17, 18, 19, 20, 21, 22, 23} The question posed to us was how to apply these observations to one's strategy for CB unit selection, especially when there are competing variables. In this review, we summarize the literature on selection strategy, comparing unrelated adult donor to CB searches, and provide our personal preferences on this issue.

Selection of unrelated adult donor HSC for transplantation: general principles

The two critical components in selecting adult donors for transplantation are HLA compatibility and the ability to harvest hematopoietic progenitors (that is, the availability of the donor). By and large, cell dose is not an issue. The number of hematopoietic progenitors delivered in adult donor hematopoietic SCT is well above minimum thresholds for engraftment and the size differential between donor and recipient is rarely greater than twofold. It has been shown that a larger graft improves the outcome of transplants in BMT.^{24, 25} Higher numbers of cells are required, when there is graft manipulation (such as T-cell depletion and CD34 selection) or submyeloablative preparative regimens are planned.

With adult unrelated donors, it is the HLA matching that is generally the most significant challenge. Current search algorithm recommends matching at least seven of eight high resolution at HLA-A, HLA-B, HLA-C and HLA-DRB1 loci.²⁶ Recent data support that allelic (high resolution) mismatches are as significant as broad antigen mismatches. A recent National Marrow Donor Program review of 3857 US transplantations performed from 1988 to 2003 with patient–donor pairs fully typed for HLA-A, B, C, DRB1, DQB1, DQA1, DPB1 and DPA1 alleles demonstrated that high-resolution DNA matching for HLA-A, B, C and DRB1 (8/8 match) was the minimum level of matching associated with the highest survival.²⁷ A single mismatch detected by low- or high-resolution DNA testing at HLA-A, B, C or DRB1 (7/8 match) was associated with higher mortality (relative risk 1.25, 95% CI 1.13–1.38, P<0.0001) and 1-year survival of 43% compared to 52% for 8/8 matched pairs. In this series, single mismatches at HLA-B or HLA-C appear better tolerated than mismatches at HLA-A or HLA-DRB1. Mismatching at two or more loci compounded the risk. Mismatching at HLA-DP or DQ loci and donor factors other than HLA type were not associated with survival.

When choosing between HLA mismatches with multiple donor options, there is no consensus as to which HLA locus mismatches are better tolerated.^{27, 28, 29} Other factors that impact transplant outcome are CMV-negative recipient receiving cells from a CMV-positive donor, ABO mismatching and parity. Ethnic differences may also be an important factor.³⁰ In general, GVHD risk is reported lower in unrelated adult donor within more homogenous populations. The Japanese National Marrow Donor Program reported, on a very homogenous population, an overall lower rate of GVHD with an increase of GVHD in the HLA-mismatch setting (HLA-A and -C mismatch) and a lower survival with HLA-A disparity.³¹

Selection of unrelated donor CB for transplantation: the product in general

A typical successful CB collection is on average 120 ml (range 60–300 ml) and will contain 0.8–3 10⁹ total nucleated cells (TNC). Processing and testing generally result in a loss of 10–20% of the initially harvested blood. The cell dose that is listed on the registries is the TNC at the time of freezing, after processing and testing has occurred. Historically, that number has been similar between the different banks for similar products. However, recent evolution in banking practices have resulted in different TNC for a given hematopoietic progenitor content (CD34 or CFU) due to greater or lesser removal of neutrophils during processing (some automated processors will remove more neutrophils during processing, while other banks will store CB without red cell/neutrophil depletion). This makes interpretation of hematopoietic potential difficult to compare between banks. In general, since CB is a peripheral blood product, there is a fairly close correlation between TNC and hematopoietic progenitor in the 'conventional' red cell- and plasma-depleted product.^{32, 33, 34, 35} As yet, correlative tools to interpret differences between the TNC reported by different banks have not been developed. Unfortunately, multiple attempts at standardizing CD34 and colony forming unit (CFU) quantitation between the labs have not been successful. Thus, despite the limitations of the TNC, it is the measurement most commonly used in CB unit selection currently.

The transplant program is fully dependent on the bank for the quality of the CB unit. In unrelated adult donor collections, collections are performed at the remote collection site but all subsequent processing and storage is performed at the transplant center. In contrast with CB collection, screening, testing, processing, freezing and storage are all performed at the bank. Additionally, CB units may have been collected years before use so that current bank quality measures may not be applicable to those that were operational at the time of banking. This becomes critically important given that CB transplants are performed with cell doses near the threshold of reliable engraftment; modest loss of potency of a product could have major impact on engraftment. There are many organizations (FDA, NMDP, FACT/Eurocord and other national regulatory bodies) that are working with the CB banking community to ensure the quality of the CB units listed available for transplant. At the time of consideration of a CB unit for transplantation, it is reasonable to ask the bank for details of their processing, storage and transplant outcomes in general and as they apply to the specific CB unit. Requalification testing before the release of a unit utilizing a contiguous segment of the CB unit is being developed to confirm unit identity and growth of hematopoietic progenitors before transplantation.³⁵

There has been no correlation between length of storage and transplant outcome measurements. CB units that have been stored for over 10 years are now being used successfully in transplant. There is no consensus as to the shelf life of CB units that are properly stored in liquid nitrogen.

Selection of unrelated donor CB for transplantation: cell dose

While most CB units are analyzed for TNC, CD34 and CFU content at the time of cryopreservation, the TNC is the most standardized between the CB banks and hence is the hematopoietic measurement that is used for CB unit selection (see caveat above). Table 1 summarizes reported minimum cell-dose thresholds and impact of cell dose on transplant outcomes. In general, more is better. For consistent engraftment, a TNC dose >3.7 10⁷/kg was required. Gluckman et al.³⁶ reported a log-linear relation between cell dose and the probability of engraftment. Rubinstein and Stevens³⁷ also noted a stepwise increase in cell dose correlated with the speed of myeloid recovery. Many pediatric centers accept a minimum cell dose of 2 10⁷ TNC/kg but most will target cell doses above 5 10⁷/kg with no upper cell-dose limit. This approach does not work for adults where the achievable cell doses are rarely above 3 10⁷/kg with single CB units. Only a small fraction of CB inventories have adequate cell numbers to support adult transplants.

Table 1 - Minimum cell doses based on hematopoietic measurement and the effect of higher cell dose on transplant outcomes for unrelated donor CB transplant.

Full table

The institutional cellular therapy laboratory has a critical role in the process of CBT . Approximately 20% of CB cells may be lost in the thaw process—owing to cell death coming out of thaw, institutional testing and loss in manipulation. Laboratories need to develop operating procedures that minimize cell loss on thaw. Convention is to use the precryopreservation cell dose and not post thaw cell dose in reporting transplant outcomes.

Other measures of graft progenitor content, such as CD34 and hematopoietic colony-forming cell enumeration are likely to be equal or better predictors of successful engraftment (Table 1). Unique to CB is the frequently high percentage of nucleated RBC in the cell product. The nucleated RBC is included in the TNC. Our experience and that of the National Cord Blood Program support that the increased number of primitive progenitors that accompany higher nucleated RBC offset any difference in cell content (that is, we do not adjust TNC for nucleated RBC content).³⁴ For search situations where there are several CB units with comparable TNC and HLA matching, some authors advocated selecting units of higher CD34 or colony-forming cell.^{32, 38} Given the variability of these results between banks, we use the CD34 or CFU assessments to screen out units that may have poor hematopoietic potential—avoiding selection of units with very low-CFU/CD34 content. Similarly, if available, CB CD3 content may be used as a screen for some of the severe immunodeficiency syndromes.

Selection of untreated donor CB for transplantation: HLA matching

CB inventories are only a small fraction of the nine million HSC donors registered around the world. Convention is to define HLA matching for CBT as low-resolution HLA-A and -B matching and high-resolution HLA-DR matching—a huge difference from the 8/8 high-resolution HLA matching used in adult unrelated donor matching. Multiple HLA mismatches are tolerated with CB grafting. When high resolution matching at 10 alleles is looked at in the units selected for transplant, there are frequently many more mismatches present.¹⁵

Over half of our transplants are performed with 4/6 or less HLA matching. In our practice, there is no difference in survival based on degree of HLA matching. The reason for this is that in a primarily pediatric population, we usually achieve high cell doses and we treat many patients with high-risk leukemia.

A distinction needs to be made between adequate and ideal matching. Higher degrees of HLA matching was associated with improved engraftment and transplant outcome compared to 5/6 or 4/6 matches (Table 2) but the impact is relatively small.^{5, 37, 38} This is because of the confounding impact of cell dose on engraftment and HLA mismatch on GVL effect. As yet, there is no consensus as to which specific HLA mismatches are better tolerated. Given that 90% of transplants are performed with at least one major HLA mismatch, it has not been possible to isolate the impact of HLA-C or -DQ mismatching on CB transplant outcomes. Recipients of two HLA-mismatched grafts have fared surprisingly well and the limited data on 3/6 matches is surprisingly good. In general, 3/6 matching is reserved for small children with no other options.¹⁵

Table 2 - Impact of HLA disparity on outcomes following unrelated donor CB transplant.

Full table

Rubinstein and Stevens³⁷ observed that any HLA disparity adversely affected engraftment rate and increased the risk of acute GVHD; but there was no additive effect with increasing incompatibility.³⁷ There was, however, a stepwise increase in the incidence of transplant-related complications with increasing number of HLA mismatches. Gluckman et al.³⁶ noted that the coexistence of class I and class II disparities was associated with a higher incidence of severe GVHD and failure of platelet engraftment.

The effect of HLA mismatch is most apparent when the cell dose is low.³⁹ An important question is how much of the adverse effect of HLA disparity can be over come by a higher cell dose. In malignant diseases, data from the Eurocord registry have demonstrated that with 2–4 HLA differences, the negative effect of delayed engraftment was abrogated by a higher cell dose.⁴⁰ However, a threshold of cell dose to overcome HLA disparities could not be defined.

On the basis of immunobiologic fundamentals, it seems logical to pick a unit with the most HLA alleles matching with the recipient for transplant. However, data to support this approach is scarce. Using allelic typing for HLA-A, -B, -C, -DR and -DQ loci, Kogler et al.⁴¹ showed retrospectively that three-quarter of CB transplants had three or more mismatches. Surprisingly, there was no improved survival in the subset of children receiving 10/10 allele-matched CB units. In children with leukemia, when an adequate cell dose could be administered, high-resolution HLA-A, -B, and -DRB1 matching was not found to improve survival.¹⁵ There is some evidence that class II mismatching is less well tolerated⁴² However, this has not been a universal finding. In fact, the reviews from the National Cord Blood Bank do not find an impact on the location of mismatch and outcome in single major HLA-mismatched (5/6) transplants.³⁹

Selection of untreated donor CB for transplantation: noninherited maternal allele matching

One area that needs further exploration and unique to CB is the potential exploitation of noninherited maternal (NIMA) and paternal (NIPA) alleles.⁴³ A fetus is a haplotype match with the mother. In utero, the fetal lymphocytes, which are immunocompetent from 18 weeks gestation, are kept in a state of nonresponsiveness to the mismatching maternal antigens. Since most CB transplants are being performed with major HLA mismatches, at question is whether matching the HLA mismatch to the NIMA would result in a transplant with less GVHD. There is evidence in renal transplantation and partially HLA-matched family member marrow transplants that there is less graft rejection or acute GVHD, respectively, if the HLA mismatch is an NIMA.^{44, 45, 46} In fact, in a small series of haploidentical sibling CB transplants, if the haplotype mismatch was disparate at the NIMA, 0/10 recipients developed GVHD. However, grII–IV GVHD was seen in 4/5 transplants with the mismatch was the NIPA.⁴⁷ It is possible that targeting the mismatch in unrelated donor setting to the NIMA may result in less GVHD—admittedly, this will be difficult to test. Following this logic, one would postulate that transplanting CB from the donor infant to its mother should also have a lower risk of GVHD, given that those CB immune cells have been exposed to the mismatching maternal haplotype while in utero. Since most banks store samples of maternal DNA, NIMA testing is feasible.

Selection of unrelated donor CB for transplantation: other factors

Since only a small fraction of CB transplants are performed with fully HLA-matched CB units, it is difficult to tease out the impact of other factors conventionally associated with transplant outcome—gender or ABO mismatch or CMV status. Most CB units are CMV naive due to the placental barrier. There has repeatedly been an association between CMV positivity in the recipient and poorer transplant outcome, which may be due to the lack of prior exposure of CB cells to CMV.^{15, 48, 49}

ABO mismatches have been associated with delays in red cell and platelet transfusion independence. In a study, 95 adults who underwent unrelated CBT (27 ABO-identical, 29 minor, 21 major and 18 bidirectional ABO-incompatible recipients), Tomonari et al.⁵⁰ reported that neutrophil and red cell engraftment did not differ but that the cumulative incidence of platelet engraftment in ABO-identical/minor ABO-incompatible recipients was higher than in major/bidirectional ABO-incompatible recipients (Hazard ratio (HR) 1.88, P=0.013). In addition, fewer platelet and red cell transfusions were required in ABO-identical/minor ABO-incompatible recipients (HR 0.80, P=0.040).

Selection of unrelated donor CB for transplantation: effect of the underlying diagnosis

In analyzing the data from the Eurocord registry, Gluckman and Rocha⁴⁰ and Gluckman⁵¹ showed that underlying disease affects the CB selection criteria. Transplant for malignant diseases can be successfully performed with a lower cell dose (down to 2 10⁷ NC/kg infused) and that with HLA-mismatching relapse was less frequent. Therefore, in the high-risk cases, a larger unit with greater HLA mismatch may actually be the preferred CB graft.

In the setting of unrelated CBT for nonmalignant disorders, the needs are very different. It is in this population, where GVHD is not beneficial, one would expect to see the greatest impact of HLA matching. In a recent analysis of CBT for Fanconi's anemia, Gluckman et al.⁴⁹ retrospectively analyzed results of unrelated CBT in 93 Fanconi anemia patients. In that series, HLA mismatches were associated with poorer survival.

Selection of unrelated donor CB for transplantation: double cord blood units

To overcome the cell-dose restriction, infusion of two separate CB units (double CB) have been used with encouraging results.^{12, 13, 52, 53} When two or more CB units are used as the hematopoietic progenitor cell source, in general, within 1 month post transplant, there is only one unit contributing to hematopoiesis. Neither total nucleated CD34 and CD3 cell doses, HLA matching, nucleated cell viability, ABO typing, gender match or order of unit infusion was predictive of which unit eventually dominated.¹³ The potential benefits of the two units are transient hematopoiesis from the second unit ameliorating toxicity during the time of early post transplant period and immunologic synergy between the two units during the early post transplant period, which is known to be important in the development of alloreactivity and possibly speeding hematopoietic recovery. The potential risks with double cord transplant are negative graft–graft interactions and possibly increased risk of chronic GVHD.

Given the difficulty in determining tolerable mismatches in the single cord setting, it is hard to be dogmatic about HLA matching in the double cord setting. As a generalization, higher cell doses in at least one of the CB units is important (ideally >2.5 10⁷/kg) and it is thought that there should be some matching between both patient–cord and cord–cord. A comparison between single vs double CB transplant is being tested in a phase III trial in children with acute leukemia (BMT CTN 0501).

As an extension of this approach, in a small pilot trial, Lister et al.⁵⁴ infused multiple CB units (5–7 U) at the time of transplant and found that in evaluable patients, there was always one unit becoming the sole source for long-term hematopoiesis. In one long-term survivor, the CB source was only a single antigen match with the recipient.

Selection of unrelated donor CB for transplantation: Texas Transplant Institute perspective

The transplant population in South Texas is highly represented by Hispanic recipients and, as such, HLA matching is frequently a challenge. Given the rapid availability of CB and the ability to use partially matched donors, most unrelated donor transplants in the pediatric program utilize CB as the donor source.

The independent influences of HLA matching and cell dose on the outcome of CB transplants have driven our cord selection approach. Over the past 5 years, we have developed an algorithm for selection of CB units for transplant. As outlined in Table 3, we target maximum cell dose, even at the expense of HLA matching. Only 10% of CB transplants at our center are performed with 6/6 antigen-matched units. A single unit CB is used, if there are more than 2 10⁷ TNC/kg precryopreservation with 6/6 antigen-matched CB and a minimum of 3 107 TNC/kg, if there is 4/6 HLA matching. High-resolution HLA-A, -B and -DR typing is obtained on both donor and recipient. While we start with matching at low antigen level for class I and high resolution for class II, if a 4/6 or 3/6 matched unit is being considered, we would like to have the matches be allelic matches. Matching at both HLA-DRB1 alleles is preferred, especially, when there are multiple mismatches (that is, 4/6 match). Mismatches at both class II (either antigen or allele) loci are not accepted.

Table 3 - Texas Transplant Institute algorithm for CB unit selection target cell dose: TNC>5 10⁷ nucleated cells/kg.

Full table

When several large CB units are available, and the cell dose is at least 3–5 10⁷ TNC/kg, we would choose the unit with the best HLA match. In situations of a small well-matched unit and a much larger less well-matched unit, we will utilize the larger unit preferentially, especially, when treating malignancies. In larger patients, when the cell-dose threshold is not met, we use two CB units for transplantation. This functionally includes all adult transplants. In young children with no other options, we will utilize 3/6 HLA-matched units, with at least one match at HLA-A, -B and -DR. We have not noticed a difference in engraftment, GVHD or survival with these less well-matched units, but our numbers are small and these are a selected group of young children for whom we can generally achieve a very large cell dose.

Up to 10% of CB transplants will be complicated by primary graft failure. We monitor engraftment closely in the first few months post transplant and will proceed to an early second transplant utilizing a submyeloablative preparative regimen.⁵⁵ In these situations, we target the largest CB unit(s) with a minimum of 4/6 HLA matches, accepting a DRB1 allele mismatch, if necessary. Given the real risk for graft failure, it is advised to have an alternative stem cell source identified before transplantation. At our center, we have a second CB unit on reserve at the bank.

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