CBF IX HLA

(Also see: TRANSPLANTATION OF ADULTS)

  1. The impact of HLA antibodies on engraftment of unrelated cord blood transplants. Takanashi M, Fujiwara K,Tanaka H, Satake M, Nakajima K. Transfusion 2008;48:791-792.

[Note: Stephen Spellman will discuss this issue and present data from the National Marrow Donor Program at the 7th Annual International Umbilical Cord Blood Transplantation Symposium in Los Angeles in June, 2009. www.cordbloodsymposium.org ]

The authors received clinical reports and tested a total of 374 CBT recipients for HLA antibodies. The probability of engraftment did not differ significantly with the age of the patient, the intensity of the conditioning regimen or with the number of mismatched HLAs among donor-recipient pairs.

The incidence of HLA antibodies was 16.4% (41/250) for CBT recipients who were 16 to 79 years old and 5.7% (2/35) for recipients younger than 16 years old. There were 8 CBTs in which the specificity of the HLA antibody was directed against an HLA which was present on the transplanted CB. Four of these 8 CBTs engrafted; three required a second transplantation on days 28, 49, and 154; and one recipient died on day 131.

The Kaplan-Meier estimate of engraftment for CBTs in recipients without HLA antibodies (n = 242) was 92.7% and was 93.6% for recipients with an HLA antibody without the corresponding HLA in the transplanted CB (n = 35). In contrast, the rate of engraftment for recipients with HLA antibody and a corresponding HLA in the transplanted CB was only 58.3% (95% CI, 16.6%-89.7%; n = 8; p = 0.017). The median times to engraftment were days 22, 21 and 46, respectively for the three groups.

The authors interpreted these findings to indicate that the presence of an existing HLA antibody is not a reason to avoid CBT unless the corresponding HLA is present in the proposed CB unit.

  1. Indiscernible benefit of high-resolution HLA typing in improving long-term clinical outcome of unrelated umbilical cord blood transplant. Liao C, Wu JY, Xu ZP, Li Y, Yang X, Chen JS, Tang XW, Gu SL, Huang YN, Tang PH, Tsang KS. Bone Marrow Transplant. 2007;40:201-208.

The authors point out that umbilical cord blood (UCB) transplantation has been noted to result in a remarkably low frequency and severity of graft-versus-host disease (GvHD) and graft rejection compared to that in unrelated bone marrow transplant recipients. At present most banks match UCB donors for respective recipients by HLA-A, -B low-resolution typing and -DRB1 high-resolution typing.

The authors retrospectively conducted high-resolution sequence-based HLA typing on DNA samples available from 65 Chinese UCB-recipient pairs typed previously by using low-resolution sequence-specific oligonucleotide probes and sequence-specific primers, and evaluated the clinical outcome. High-resolution typing revealed imperceptible HLA alleles that were hardly identified in low-resolution typing.

Univariate analyses demonstrated no significant correlation between the extents of high-resolution HLA disparity with engraftment, graft failure, acute GvHD, transplant-related mortality and long-term 6-year overall survival. Data from the study suggest that high-resolution typing for HLA-A, -B and -DRB1 contributed no substantial improvement to UCB transplant outcome. Low-resolution typing appears to be amenable to matching UCB-recipient pairs without compromising the quality of transplant.

These data are important because requiring high-resolution HLA matching may raise unnecessary barriers in deciding the best available UCB donor for a recipient.

[Comment: The data in this report agree with those published by two other groups as cited in this segment of the Annotated Bibliography. See Gluckman et al (Semin Hematol - 2005) and Kogler et al (Bone Marrow Transplant - 2005).]

  1. Hematopoietic stem cell donor selection: the Europdonor experience. Oudshoorn M, van Walraven SM, Bakker JN, Lie JL, V D Zanden HG, Heemskerk MB, Claas FH. Hum Immunol. 2006; 67:405-412.

This review focuses on the benefit of a joint worldwide donor file called Bone Marrow Donors World-Wide, and the experience of the Europdonor Foundation in selecting strategies to identify the best HLA-matched donor in the shortest time. The comments in the review that are pertinent to cord blood transplantation considering the fact that cord blood units are significantly more rapidly available than BM or PBSC are as follows:

The authors cite a study that analyzed 549 unrelated donor searches for Dutch patients performed between 1987 and 2000 to determine the reasons for failure or success to reach transplantation. Only 11% of patients of northwest European origin lacked a compatible donor, whereas 30% became medically unfit for transplantation. In contrast, for the patients of non-northwest European origin, donor shortage was still the most important impediment because 50% lacked a compatible donor.

To reduce the percentage of patients who become medically unfit to proceed with transplantation the timespan between start of the search and transplantation needs to be reduced. In more recent years (2001-2004), the search time for a patient of European origin has decreased from 2.5 months to 1.5 months, and the time from start search until transplantation from 4.4 months to 3.9 months. This has resulted in a decrease of the percentage of patients for whom the donor search had to be stopped from 30 to 24% because the clinical condition of the patient deteriorated to a point that stem cell transplantation was no longer an option.

The authors comment that by accepting a 4/6 matched cord blood unit, the available 200,000 cord blood units could cover the need of “virtually all patients”. Yet their table 2 indicates that this is infrequently done when a well matched adult donor is not available. They list 75 patients (combined northwest European origin and non-northwest European origin) who did not have a suitable adult matched unrelated hematopoietic stem cell donor during 2001-2004. Only 12 (16%) received a cord blood transplant, 16 (21%) received a haploidentical transplant, 4 (5%) received an autologous transplant and 43 (57%) received “conventional therapy. ”

[Comment: This study documents the under-utilization of cord blood transplantation for patients who do not have an HLA-matched sibling donor or a well matched unrelated donor in the adult registries. A startling 57% of such patients were simply not transplanted, whereas only 16% received a cord blood transplant. The other patients received either a haploidentical transplant or an autologous transplant. Considering the fact that cord blood stem cells may be obtained quickly (See Annotated Bibliography, VI. AVAILABILITY AND TIME REQUIRED TO OBTAIN CORD BLOOD VERSUS BONE MARROW) and transplant outcome results rival those of BMT/PBSCT, this would appear to be unacceptable practice. No patient should be denied a hematopoietic cell transplant for lack of a suitable donor unless a search for an adequately matched cord blood unit with an adequate cell dose has been performed.]

  1. Advances in HLA: practical implications for selecting adult donors and cord blood units. Hurley CK, Wagner JE, Setterholm MI, Confer DL. Biol Blood Marrow Transplant. 2006;12(1 Suppl 1):28-33.

Selecting adult unrelated donors: Studies by the NMDP have led the NMDP Histocompatibility Committee to recommend allele-level typing of the potential recipient at HLA-A, -B, -C, and -DRB1 for the purposes of searching and matching. An ideal donor would clearly be one whose alleles match the recipient at HLA-A, -B, -C, and -DRB1. The NMDP data failed to show any additional benefit for matching at HLA-DQ or HLA-DP, although HLA-DQ linkages are valuable in selecting partially typed donors for more detailed evaluation. In the absence of an 8/8 allele–matched donor, the NMDP recommended minimizing the number of allele-level mismatches in total without preferentially weighing any particular locus, eg, HLA-DRB1 as more important than HLA-A, -B, or -C. If antigen mismatching is unavoidable, then the number of additional allele-level mismatches should still be minimized. What remained unknown, however, was how to balance allele mismatches against antigen mismatches (ie, what number of allele mismatches equals an antigen mismatch).

HLA implications for selecting CBUS: Far less information is available to clarify the precise role of HLA in the setting of umbilical cord blood (UCB) transplantation. Overall, there have been fewer UCB transplantations (approximately 6000 worldwide), most have been children with acute leukemia and nonmalignant disease, data on HLA matching are less complete in terms of the availability of high-resolution typing, and the effect of HLA is confounded by the interaction of nucleated cell dose. Most reports have evaluated the effect of mismatching at the intermediate-resolution antigen level for HLA-A and -B and the allele level for -DRB1. HLA-C data and allele-level class I data are rarely available. Nevertheless, Rubinstein et al, in their 1998 report on 562 CBU transplantations, observed that better matching at HLA-A and -B (antigen level) or -DRB1 (high resolution) predicted improved survival. In this milestone study, recipients with 0 or 1 HLA mismatches had a lower risk of nonrelapse events (death, autologous recovery, or retransplantation) than those with ≥2 mismatches.

Similarly, Wagner et al observed an independent effect of HLA match and cell dose on 2-year survival in 102 UCB recipients who underwent transplantation at a single institution. In contrast, Gluckman et al, who analyzed Eurocord data on 550 UCB recipients who underwent transplantation for hematologic malignancies, reported that increasing degrees of HLA disparity had no effect on transplant-related mortality or overall survival.

Two recent publications reported on adults who underwent UCB transplantation. In both studies, HLA matching was again reported at the serologic level for HLA-A and -B and at the allele level for HLA-DRB1. In the European Group for Blood and Marrow Transplantation/Eurocord study, all 584 bone marrow recipients were HLA matched, and 92 (94%) of 98 UCB recipients were mismatched. Despite this difference, transplant-related mortality, relapse, and overall survival were comparable between the 2 groups.

In the US study, 450 adults received bone marrow, and 150 received UCB (77% were mismatched at 2 HLA loci) In contrast to the Eurocord study, survival after UCB transplantations was inferior to that after marrow transplantation from an HLA-matched adult donor and was comparable to that after a 1 antigen/allele–mismatched adult donor. Taken together, both these studies suggest that with respect to survival, UCB is less HLA restricted than adult bone marrow.

Most recently, the Institute of Medicine commissioned a study of UCB outcomes that pooled data contributed by the New York Blood Center, the NMDP, and the National Heart, Lung and Blood Institute Cord Blood Transplantation study. A total of 755 cases representing transplantations of children and adults in the United States were included. Matching for HLA-A and -B was evaluated at the low to intermediate level, and HLA-DRB1 was evaluated at the allele level. The Institute of Medicine study showed a clear effect of HLA matching on survival, with 6/6 matches faring better than 5/6 or 4/6 matches. The magnitude of this effect, however, was most apparent at lower cell doses (<2.5 x 107 total nucleated cells per kilogram).

The Institute of Medicine report is the first major study to emphasize the effect of cell dose relative to HLA match with substantial numbers of patients. The conclusion is that HLA mismatch cannot be evaluated without concomitant consideration of cell dose. The data suggest that the greater the HLA disparity (0 versus 1 versus 2), the greater the effect of cell dose on survival. A higher cell dose can compensate, at least in part, for the negative effect of HLA disparity.

At this point, the precise role of HLA matching in the setting of UCB transplantation is less clear than that with unrelated bone marrow transplantation. Although some studies have suggested that better matching at the antigen level improves survival or reduces transplant-related mortality, others have not made that association. Cell dose and differences in patient populations and treatments confound these analyses. Still, the overall sense is that when considering intermediate-level HLA-A and -B typing and allele-level HLA-DRB1, a 5/6 or 6/6 match is preferred over a 4/6 match. Higher cell doses (>5 x 107 total nucleated cells per kilogram), however, may overcome the negative effect of HLA mismatches. Finally, few data are available to address the allele-level influences of HLA in UCB transplantation.

The article concludes with information about improving the value of HLA data. New programs and search algorithms are being developed and implemented to facilitate the search for appropriate donors.

  1. Human leukocyte antigen matching in cord blood transplantation. Gluckman E, Koegler G, Rocha V. Semin Hematol. 2005;42:85-90.

This is an important publication and should be read in its entirety. It reviews available data regarding the significance of HLA matching specifically in regard to umbilical cord blood transplantation (UCBT). A point that becomes evident is that knowledge about HLA matching for BMT and PBSC transplants is not necessarily relevant to UCBT.

The authors point out that hematopoietic stem cell transplantation (HSCT) from an unrelated cord blood donor is now standard treatment for malignant and nonmalignant hematologic disorders, and that the number of umbilical cord blood transplants (UCBTs) has increased dramatically with between 4,000 and 6,000 patients now having undergone UCBT from unrelated donors.

The article presents an analysis of the Eurocord Registry data which includes more than 1,000 cases of unrelated UCBT.

HLA Matching and Survival: Analysis of results of UCBT in 1,138 recipients shows that survival according to the number of HLA disparities considering HLA-A, -B, and -DRB1 low-resolution and DRB1 allelic typing is dependent on the number of HLA mismatches but without differences between one and two HLA mismatches.

Role of Allelic Typing: The majority of transplant centers/cord blood banks select UCB units for a respective patient based on HLA-A and -B serology/low resolution typing and HLA-DRB1 high resolution typing. An analysis of outcomes after UCBT in 122 patient/cord blood donor combinations indicated that there was no benefit of additional high-resolution typing for HLA-, -B, -C, -DRB1 and -DQB1 loci. This is in contrast to results using unrelated bone marrow or peripheral blood stem cell donors.

Engraftment: In a study of 550 patients, the authors analyzed factors associated with engraftment outcome of unrelated UCBTs. Transplants were classified as HLA-mismatched with 1, 2, 3 or 4 differences if disparities were detected in HLA-A, -B, or –DRB1 loci. The median number of nucleated cells infused was 3.11 x 107/kg and the median number of CD34+ cells was 1.38 x 105/kg. In multivariate analysis the number of HLA mismatches correlated with the speed of engraftment (p<0.001) and with the number of nucleated cells infused (p<0.0007). In regarding to platelet recovery, multivariate analysis indicated that a high number of infused nucleated cells and absence of both class I and class II HLA disparities were jointly predictive of improved platelet recovery in young patients and those in an early stage of disease. The authors state that such results are the basis for recommending a dose of 2 x 107 nucleated cells/kg and 2 x 105 CD34+ cells/kg to be infused.

Graft-Versus-Host Disease: In a cooperative Eurocord-IBMTR study, the incidence of GVHD was compared after HLA-sibling transplants using UCB or BMT. Both aGVHD and cGVHD incidences were significantly reduced after UCBT compared with BMT.

In a recent Eurocord analysis of unrelated UCBTs, neither the number of HLA disparities nor was the number of CD34+ cells infused was associated with a hazard of >grade II aGVHD. By contrast, a high number of CD34+ cells at freezing and the coexistence of class I and II HLA disparities were associated with the occurrence of severe grade III-IV aGVHD. There was no interaction between HLA disparities and cell dose.

None of the variables analyzed was significantly associated with cGVHD.

Other data demonstrated that the incidence of aGVHD and cGVHD after unrelated HLA-mismatched UCBT in children and adults was reduced compared to unrelated unmanipulated HLA-identical BMT and similar to an unrelated HLA-matched T-cell-depleted BMT.

A study of adults with leukemia compared outcomes between patients who had received UCB mismatched for one HLA or two HLA antigens and patients who had received BMT that had one HLA mismatch or was HLA-matched. The rate of aGVHD was similar for mismatched UCBT and matched BMT; however, aGVHD was less likely after transplantation of mismatched cord blood than after that of mismatched bone marrow. The rate of cGVHD was higher among patients than with HLA-matched marrow but similar to the rate among the recipients of mismatched marrow. Among patients with cGVHD, extensive disease was less frequent among UCB recipients than for HLA-matched or mismatched marrow recipients, with rates of 33%, 52%, and 71%, respectively.

Relapse: In most studies comparing unrelated UCBT to unrelated BMT there has been no evidence of an increased relapse rate after UCBT, despite the low number of lymphocytes infused and the decreased incidence of aGVHD and cGVHD.

Summary --- Choosing the Best UCB: The authors recommend simultaneously searching for an unrelated cord blood and an unrelated bone marrow and they present an algorithm for selecting the optimal stem cell product. Important considerations are disease, disease status, urgency of the transplant and doctor/patient choice. The cord blood graft must have no more than two HLA disparities and more than 2 x 107/kg nucleated cells at cryopreservation.

  1. High-resolution HLA typing by sequencing for HLA-A, -B, -C, -DR, -DQ in 122 unrelated cord blood/patient pair transplants hardly improves long-term clinical outcome. Kogler G, Enczmann J, Rocha V, Gluckman E, Wernet P. Bone Marrow Transplant. 2005;36:1033-41.

At present the majority of transplant centers select umbilical cord blood units for a respective patient based on HLA-A, -B, low resolution typing, and –DRB1 high resolution typing. This contrasts with selection of stem cell products from adult donors where HLA class I (A, B, C) and HLA class II (DRB1 and DQB1) high resolution typing have been implemented to minimize the risk of GVHD and graft rejection. There have been no published data on the significance of high resolution HLA typing in cord blood transplantation. In the present study, the authors assess patient/donor combinations in cord blood transplantation using high resolution DNA typing for both HLA class I and class II loci.

To determine the impact of high resolution HLA typing with outcomes after UCBT, DNAs of 122 pairs (91 children, 31 adults) were analyzed for HLA class I and class II mismatches (MM) based on high resolution typing. For HLA-A, -B on low resolution typing and -DRB1 on high resolution typing, the following MM situation resulted: no MM (13%), one MM (40%), two MM (36%), three MM (8%), four MM (3%). For A, B, C, DR and DQ based on high resolution typing the following MM occurred: No MM (4%), one MM (10%), two MM (15%), three MM (22%), four MM (25%), five MM (12%), six MM (6%), seven MM (3%), eight MM (2%).

The analysis revealed that there was a large number of actual HLA disparities in the 122 recipient/cord blood donor pairs analyzed by HLA-A, -B, -C, -DRB1 allelic subtyping. The degree of mismatching in UCBT was even higher than expected. Several cord blood/patient pairs were transplanted with up to eight mismatches, and the majority with 3 to 4 MM on high resolution typing. However, there was no significant association between number of MM (high resolution) for both HLA-A, -B and -DRB1 and HLA-A, -B, -C, -DRB1 and DQB1 and aGvHD grade II-IV. There was a trend that MM in class I high resolution were associated with neutrophil recovery; HLA-A locus typing analyzed in HvG direction was associated with reduced cumulative incidence of engraftment (P=0.04), the same for C-KIR in HvG direction (P=0.01).

No significant correlation was found between numbers of HLA-MM on the high resolution level with 2-year survival. In contrast to transplantation using stem cells from adults, there was no benefit of high resolution typing for HLA-A, -B, -C and DQ-locus on patient outcomes in this limited and heterogeneous group of cord blood transplant patients.

  1. Human leukocyte antigen matching in unrelated donor hematopoietic cell transplantation. Petersdorf EW, Malkki M. Semin Hematol. 2005;42:76-84.

This review provides up to date information on the significance of HLA matching for unrelated HSCT. However, the data are derived from BMT and PBSC transplants. In this setting, the presence of donor-recipient mismatching is associated with increased risk of post-transplant complications including graft rejection, acute and chronic GVHD and mortality; these risks are increased with multiple HLA mismatches. The authors point out that when donor matching for HLA alleles is feasible, overall transplant outcome is superior. For data on HLA matching in umbilical cord blood transplantation, see citation #4 on previous page.

  1. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Grewal SS, Barker JN, Davies SM, Wagner JE. Blood 2003; 101:4233-4244.Full Text

Limited HLA mismatch appears to be better tolerated with cord blood grafts compared to marrow or peripheral blood. However, current opinion is that the single most important factor influencing time to hematopoietic recovery is the nucleated cell content of the graft relative to recipient size. The effect of HLA mismatch on engraftment is less clear. Nevertheless, analysis of HLA mismatch in one study and in a more recent review update with 861 unrelated cord blood transplants, revealed a relationship between HLA match and engraftment. The median time to neutrophil recovery with 6 antigen-matched grafts was 23 days compared with 28 days with mismatched grafts. However, no association between engraftment characteristics and number of HLAs mismatched (one vs more than one HLA mismatch) was observed.

  1. National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants. Hurley CK, Baxter Lowe LA, Logan B, Karanes C, Anasetti C, Weisdorf D, Confer DL. Biol Blood Marrow Transplant. 2003;9:610-5.

This is an authoritative review by sophisticated investigators (three of whom are among the faculty of the Second Annual International Cord Blood Transplantation Symposium). Although the guidelines refer to marrow transplants, some comments are pertinent to cord blood transplants.

Under the heading, “How Long Do I Search for Donors?” the authors state the following: If an acceptably matched donor cannot be identified within the current NMDP registry, it is very unlikely that newly recruited donors will match the patient in a useful time frame. The NMDP donor file contains 5 million donors and each NMDP search also evaluates an additional 3.5 million donors listed in Bone Marrow Donors Worldwide, so patients who do not find a match in this pool must have infrequent haplotypes. The likelihood that a recipient’s type will be represented in newly added recruits when it did not appear in the initial file of 5 million is exceedingly low. Therefore, it is recommended that alternative treatment options be reevaluated when the initial search does not reveal a well matched donor. The alternative options recommended are unrelated cord blood transplantation, a partially matched related donor transplantation, or nontransplant therapy. Therefore the clinician must judge whether, for example, an unrelated cord blood transplant or chemotherapy has the best chance of favorable outcome a given patient.

The authors also point out that a prolonged search time may expose patients, such as those with acute leukemia, to additional toxic chemotherapy, an increased risk of infection, and risk of relapse. (See Annotated Bibliography, Topic VI. Availability and time required to obtain cord blood versus bone marrow.)

  1. Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Gluckman E, Rocha V, Arcese W, Michel G, Sanz G, Chan KW, Takahashi TA, Ortega J, Filipovich A, Locatelli F, Asano S, Fagioli F, Vowels M, Sirvent A, Laporte JP, Tiedemann K, Amadori S, Abecassis M, Bordigoni P, Diez B, Shaw PJ, Vora A, Caniglia M, Garnier F, Ionescu I, Garcia J, Koegler G, Rebulla P, Chevret S; Eurocord Group. Exp Hematol. 2004;32:397-407.Abstract

The authors (all 29 of them!) analyzed 550 UCBTs for hematologic malignancies reported to the Eurocord Registry with the goal of determining optimal cord blood donor selection. Their objective was to delineate an algorithm to help clinicians choose the best cord blood unit, with emphasis on the effects of cell dose and HLA disparities. Outcomes analyzed were hematopoietic recovery, GVHD, relapse, 100 day TRM, and overall survival. The results confirmed previous findings on the association of nucleated cell dose with the speed and probability of neutrophil and platelet recovery. A higher CD34 cell dose resulted in a higher probability of aGVHD, although the authors cautioned that this observation must be confirmed in unicentric studies because of interlaboratory variation in measurements of CD34+ cells and grading of GVHD. However, contrary to previous reports, the prognostic influence of cell dose when predicting survival or TRM disappeared when considered in multivariable analyses.

There was an association between the number or type of HLA disparities with engraftment and aGVHD grade III-IV and with relapse, the later suggesting a graft-vs-leukemia effect. However, TRM and survival were not associated with HLA disparities, in agreement with previously reported data. However, these findings appear to contradict a report based on a series of 562 UCBTs in which HLA disparities were not associated with the probability of neutrophil recovery and GVHD, but with 1-year TRM. Thus, there is difficulty in establishing, from the available data, consensual guidelines for donor choice based on HLA incompatibilities.

It has been suggested that cell dose and number of HLA mismatches interact mutually on engraftment and on other outcomes. Thus a higher cell dose in the graft could partially overcome the negative impact of HLA for each level of HLA disparity; however, this hypothesis has not been proved. The authors found no statistical evidence of any interaction between cell dose and HLA disparities (p = 0.81).

Survival was related to the transplant center as well as to the period of transplantation, with a decreased mortality after 1998 compared to before 1998 (p = 0.02).

Would a cord blood unit with 4 x 107/kg nucleated cells (NCs) but no HLA disparities be preferable to a cord blood unit with 6 x 107 NCs but one HLA disparity? The authors state that no accurate answer to this point can be determined from their data.

The authors conclude that their results show that two major factors, cell dose and HLA, can be used to choose a cord blood unit. A higher the number of cells and a lower the number of HLA disparities will increase the probability of engraftment; a higher the number of HLA disparities will increase the incidence of acute GVHD grade III-IV and decrease the risk of relapse.