Abstract
Existing literature shows mixed conclusions regarding the impact of ABO incompatibility on outcomes after hematopoietic stem cell transplantation. Because the future for umbilical cord blood (UCB) expansion technologies is bright, we assessed whether this typically overlooked graft characteristic impacted various outcomes after UCB transplantation (UCBT) for nonmalignant disorders (NMDs). A prospectively maintained institutional blood and marrow transplant program database was queried for all patients undergoing first UCBT for NMDs. UCB and recipient ABO compatibility was considered as matched, major mismatched, minor mismatched, or bidirectional mismatched. The impact of ABO incompatibility was assessed on overall survival, graft failure, acute and chronic graft-versus-host disease (GVHD), time to neutrophil and platelet recovery, day 0 to day 100 RBC transfusion burden, and donor hematopoietic chimerism. Through December 2014, 270 patients have undergone first UCBT for various NMDs. In both univariable and multivariable analyses, ABO compatibility status did not appear to impact any outcomes assessed, although a trend toward increased grades III to IV acute GVHD was seen in recipients of major mismatched units. When considering UCBT for treatment of NMDs, ABO compatibility between the donor unit and intended recipient does not appear to be an important consideration in the UCB unit choice.
Keywords: Umbilical cord blood, transplant, Nonmalignant disorders, Alternative donor transplant, Graft–recipient ABO, compatibility
Introduction
Since first described nearly 25 years ago [1], umbilical cord blood (UCB) has become an often used and effective alternative donor graft source for allogeneic hematopoietic stem cells (HSCs) [2,3]. Current UCB unit selection algorithms incorporate major parameters (including total nucleated cell dose and donor–recipient HLA disparity) known to significantly impact survival, relapse, and/or morbidity after UCB transplantation (UCBT). Because ex vivo UCB expansion technology [4,5] may overcome the extrinsic limitations of cell dosing and find widespread application in UCBT, previously overlooked secondary UCB unit characteristics could become primary in selection algorithms. One such intrinsic characteristic is ABO compatibility between the UCB unit and the intended recipient.
Reports of the effect of donor–recipient ABO incompatibility on survival, graft failure, graft-versus-host disease (GVHD), and relapse (in malignant disease) after either marrow- or peripheral blood–derived HSC transplantation (HSCT) are mixed [6-16]. Relatively few reports exist on the effects of donor–recipient ABO incompatibility after UCBT [17-22], particularly in cohorts comprised entirely of patients with nonmalignant disease (NMD) [23-25]. Those that do exist have been largely inconclusive without consistent impact on multiple outcomes of interest; further, none appears to have assessed the effect of ABO incompatibility on post-UCBT RBC transfusion dependence. We aimed to retrospectively determine the impact of UCB unit–recipient ABO incompatibility on both RBC transfusion burden and major transplant-related outcomes after UCBT for NMD.
Methods
The study cohort included 270 consecutive patients with NMDs who underwent their first single- or double-unit UCBT at the University of Minnesota from 1993 to 2014. The study was approved by the University of Minnesota Institutional Review Board. Patient demographics and transplant characteristics were determined from the prospectively maintained University of Minnesota Blood and Marrow Transplant Database. RBC transfusion data were obtained from the university's blood bank computer database (Sunquest).
Three categories of ABO mismatch were defined: (1) major mismatch, characterized by the ability of recipient lymphocytes to produce antibodies (isohemagglutinins) against A or B antigens expressed on UCB-derived erythroid cells (eg, an O blood group recipient receiving a UCB unit with blood type A, B, or AB blood group); (2) minor mismatch, characterized by the ability of donor lymphocytes to produce isohemagglutinins against A or B antigens expressed on recipient erythroid cells (eg, an A, B, or AB blood group recipient receiving an O blood type donor graft); and (3) bidirectional mismatch, characterized by having both major and minor mismatches present (eg, an A blood group recipient with a B blood group donor). Table 1 lists UCB unit–recipient ABO type combinations that comprise the mismatch categories considered in this study.
Table 1. Donor–Recipient ABO Combinations and Associated Mismatch Types.
| Mismatch Type | Blood Type | |
|---|---|---|
|
| ||
| Recipient | Donor | |
| Major | O | A, B, AB |
| A | AB | |
| B | AB | |
| Minor | A | O |
| B | O | |
| AB | O, A, B | |
| Bidirectional | A | B |
| B | A | |
HLA-matching status was based on antigen level for HLA-A and -B and allele level at -DRB1. In patients who received double-unit UCBT (n = 45), the HLA and ABO types of the engrafting UCB unit were considered for the analysis. An UCB unit was considered engrafted if >70% donor chimerism was achieved at day 100. If chimerism data for day 100 was unavailable, day 21 data was used instead. In instances where chimerism was <70% in both units (n = 9), the unit with a greater chimerism percentage was then considered in the analysis. For those where chimerism data were unavailable or near zero in both units (n = 6), the unit with more significant mismatch (bidirectional > major > minor > matched) was considered in the analysis.
Conditioning regimens varied by disease and were subject to available institutional protocols at the time of transplantation. Regimens varied in intensity and in their use of serotherapy (antithymocyte globulin or alemtuzamab).
Study Outcomes
The primary study outcome was the cumulative number of RBC transfusions a patient received between transplant days 0 and 100. Patients were generally administered 10 mL/kg of irradiated RBC per transfusion. Indications for transfusion were asymptomatic severe anemia, with hemoglobin < 8 g/dL (<9 g/dL for patients with sickle cell disease), or any symptomatic anemia. For patients who experienced graft failure or who underwent repeat HSCT before day 100, the total number of RBC transfusions was tallied through the day of this event and was normalized to 100 days. Patients who had insufficient RBC transfusion data (UCBT before 2001) were excluded from RBC transfusion burden analysis.
Secondary outcomes included overall survival, the cumulative incidences of graft failure (competing risk, death before day 21), neutrophil recovery by day 42 (competing risks, death or second HSCT), platelet recovery by 1 year (competing risks, death or second HSCT), acute GVHD (aGVHD; competing risk, death), and chronic GVHD (cGVHD; competing risk, death). Additionally, we assessed the incidence of ≥80% donor myeloid chimerism at day 100 and at most recent follow-up, as well as the incidence of severe cord blood unit infusional toxicities. Neutrophil recovery was defined as 3 consecutive days of an absolute neutrophil count ≥ 500/μL before day 42 post-transplant. Platelet recovery was defined as the time to platelet count greater than 50,000/μL before 1 year post-transplant, if preceded by 7 days without platelet transfusion. Graft failure was defined as either failure to achieve absolute neutrophil count ≥ 500/μL by day 42, the demonstration of <5% donor myeloid chimerism at any time, or aplasia after initial engraftment that was not attributable to other causes (such as infection or medication). Both aGVHD and cGVHD were graded according to consensus criteria [26,27]. Donor chimerism was assessed on the myeloid fraction of peripheral blood (or on whole blood if fractionated data were not available). All patients were prospectively assigned a cord blood unit infusional toxicity score according to Common Terminology Criteria for Adverse Events (CTCAE). Severe infusional toxicity was defined as grade 3 or higher by CTCAE version 4 criteria. For UCBTs that were performed before the release of CTCAE version 4, this same definition of severe infusional toxicity was retrospectively applied to ensure consistency through our analysis.
UCB Unit Preparation
Patients in this analysis received UCB units originating from various banks, most achieving pre-cryopreservation RBC reduction using approaches aligned to the original description by Rubinstein et al. [28]. After thaw, UCB units were washed before being administered to transplant recipients in this analyzed cohort. Briefly, on the day of transplant, the UCB unit is removed from its liquid nitrogen storage container and immersed into a 37°C normal saline bath. Ten percent Dextran 40 is slowly added, followed by 5% human serum albumin to the UCB unit, and is then left to equilibrate for 5 minutes. The product is then moved to a transfer bag and centrifuged at 400 × g for 15 minutes at 4°C. Three-fourths of the wash supernatant is transferred into a second transfer bag and is centrifuged at 800×g for 15 minutes at 4°C. Three-fourths of the wash supernatant from the second centrifugation is discarded, and the cell pellets obtained from the 2 centrifugation steps are combined and suspended in 10% Dextran 40 and 5% human serum albumin. Finally, the product is passed through a standard blood filter (170 to 260 μm) before being delivered to the patient care unit.
Statistical Analysis
Statistical tests of equivalence among the 4 ABO compatibility groups were conducted. Distributions of continuous demographic variables were compared using ANOVA and categorical demographic variables with chi-square tests. The number of RBC transfusions was compared using a Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method and compared using a standard log-rank test [29]. If a patient had a second HSCT (n = 32; 12%), follow-up time was censored after that date because ABO compatibility could be different with respect to the new donor. Incidence of donor chimerism ≥ 80% was compared using Fisher's exact test. The remaining secondary outcomes (GVHD, graft failure, neutrophil and platelet recovery) were estimated using the cumulative incidence function with competing risks as defined previously [30]. Groups were compared using Gray's test [31]. All time-to-event outcomes were measured from the date of first UCBT. Although UCB unit–recipient ABO compatibility status was not expected to associate with other known predictive factors, we performed multivariable analyses with patient-, disease-, and transplant-related characteristics for all endpoints assessed.
Results
In this 270 patient cohort, 249 (92%) were under 21 years old at UCBT. UCB unit–recipient ABO compatibility status was as follows: 93 matched (34%), 72 major mismatch (27%), 80 minor mismatch (30%), 23 bidirectional mismatch (9%), and 2 unknown. The 2 patients with unknown ABO compatibility status were excluded from further data analyses. The most prevalent primary disorders were adrenoleukodystrophy with cerebral disease (n = 64; 24%), Hurler syndrome (n = 55; 20%), Fanconi anemia (n = 54; 20%), metachromatic leukodystrophy (n = 17; 6%), and hemophagocytic lymphohistiocytosis (n = 8; 3%). The remainder of the 29 total primary disorders each comprised less than 2% of the cohort. There was no significant difference among the 4 ABO-compatibility groups in age, gender, diagnosis category, conditioning intensity, UCB unit–recipient HLA disparity, cell dose received, number of UCB units received, transplant era, Karnofsky/Lansky score, GVHD prophylaxis strategy, or recipient cytomegalovirus serostatus. Related UCB unit transplants were more likely to be ABO-matched (Table 2). No patients experienced severe cord blood unit infusional toxicities.
Table 2. Patient, Disease, and Transplant Characteristics by UCB Unit–Recipient ABO Compatibility.
| ABO Match (n = 93) | Major Mismatch (n = 72) | Minor Mismatch (n = 80) | Bidirectional Mismatch (n = 23) | P | ||
|---|---|---|---|---|---|---|
| Age, yr | Mean | 8.5 | 6.7 | 9.1 | 4.8 | .11 |
| SD | 10.5 | 7.3 | 11.0 | 4.6 | ||
| Gender | Male | 56 (60%) | 44 (61%) | 50 (63%) | 13 (57%) | .96 |
| Diagnosis category | Bone marrow failure | 33 (35%) | 15 (21%) | 18 (23%) | 4 (17%) | .30 |
| Storage disorder | 51 (55%) | 48 (67%) | 51 (64%) | 15 (65%) | ||
| Other | 9 (10%) | 9 (13%) | 11 (14%) | 4 (17%) | ||
| Karnofsky/Lansky score | 100 | 56 (60%) | 45 (63%) | 43 (54%) | 16 (70%) | .47 |
| <100 | 34 (37%) | 23 (32%) | 33 (41%) | 6 (26%) | ||
| Data unavailable | 3 (3%) | 4 (6%) | 4 (5%) | 1 (4%) | ||
| Cytomegalovirus serostatus | R+ | 30 (32%) | 28 (39%) | 28 (35%) | 9 (39%) | .84 |
| R−/D− | 62 (67%) | 44 (61%) | 52 (65%) | 14 (61%) | ||
| Data unavailable | 1 (1%) | |||||
| Donor relation | Unrelated | 80 (86%) | 71 (99%) | 79 (99%) | 22 (96%) | .001 |
| Sibling | 13 (14%) | 1 (1%) | 1 (1%) | 1 (4%) | ||
| Donor–recipient HLA match | 6/6 | 33 (35%) | 17 (24%) | 24 (30%) | 4 (17%) | .18 |
| 5/6 | 48 (52%) | 36 (50%) | 38 (48%) | 11 (48%) | ||
| 4/6 | 12 (13%) | 18 (25%) | 18 (23%) | 8 (35%) | ||
| Data unavailable | 1 (1%) | |||||
| GVHD prophylaxis | CSA/MMF | 47 (51%) | 41 (57%) | 47 (59%) | 14 (61%) | .27 |
| CSA/Prednisone | 32 (34%) | 19 (26%) | 29 (36%) | 7 (30%) | ||
| Other | 14 (15%) | 12 (17%) | 4 (5%) | 2 (9%) | ||
| Transplant era | 1993-2004 | 30 (32%) | 25 (35%) | 26 (33%) | 7 (30%) | .73 |
| 2005-2009 | 38 (41%) | 21 (29%) | 25 (31%) | 8 (35%) | ||
| 2010-2014 | 25 (27%) | 26 (36%) | 29 (36%) | 8 (35%) | ||
| TNCdose,×107/kg | Mean | 7 | 8 | 7 | 9 | .27 |
| SD | 5 | 5 | 6 | 8 | ||
| Number of units | Single UCB | 81 (87%) | 60 (83%) | 64 (80%) | 18 (78%) | .57 |
| Double UCB | 12 (13%) | 12 (17%) | 16 (20%) | 5 (22%) | ||
| Conditioning intensity | Myeloablative | 73 (78%) | 52 (72%) | 62 (78%) | 21 (91%) | .29 |
| Nonmyeloablative | 20 (22%) | 20 (28%) | 18 (23%) | 2 (9%) | ||
| Includes Serotherapy | 76 (82%) | 61 (85%) | 66 (83%) | 21 (91%) | .78 |
SD indicates standard deviation; R+, seropositive recipient; R−, seronegative recipient; D−, seronegative donor; CSA, cyclosporine; MMF, mycophenolate; TNC, total nucleated cell.
RBC Transfusion Burden
Thirty-two patients were excluded from the analysis of post-UCBT RBC transfusion burden because of inaccessible data (UCBT pre-2001). Of the remaining cohort (n = 236), the median number of RBC transfusions during transplant days 0 and 100 was 10 (interquartile range, 6 to 18). There was no significant difference in the transfusion burden among all ABO blood type mismatch groups (P = .75) (Table 3). A sensitivity analysis was performed to control for events occurring during transplant days 0 and 100 known to increase transfusion burden, such as an intensive care unit stay or a significant hemorrhagic event. This analysis included 102 patients transplanted from 2006 to 2014, the period in which intensive care unit data were available. This analysis demonstrated no significant difference in transfusion burden among ABO blood type mismatch groups (P = .87), validating that these events were not confounding factors in the whole cohort results.
Table 3. Median Number of RBC Transfusions Days 0 to 100 by UCB Unit–Recipient ABO Compatibility.
| All (n = 236) | ABO Match (n = 80) | Major Mismatch (n = 66) | Minor Mismatch (n = 70) | Bidirectional Mismatch (n = 20) | P | |
|---|---|---|---|---|---|---|
| Number of Transfusions (IQR) | 10 (6-18) | 11 (6-16) | 10 (6-19) | 10 (6-20) | 14 (8-21) | .75 |
IQR indicates interquartile range.
Secondary Outcomes
For the entire cohort, the rate of 5-year overall survival was 69%. Cumulative incidence of grades III to IV aGVHD at day 100 was 11%; cGVHD at 5 years was 7%. There was no significant difference in overall survival (P = .62) or the cumulative incidences of grades III to IV aGVHD (P = .09) or cGVHD (P = .96) among unit–recipient ABO mismatch groups, although a trend toward increased grades III to IV aGVHD was seen in recipients of major mismatched units. In multivariable analysis, major ABO mismatch did not significantly impact the cumulative incidence of grades III to IV aGVHD (hazard ratio, 1.92; 95% confidence interval, .73 to 5.05; reference, ABO matched group). The cumulative incidence of neutrophil recovery at day 42 was 90%; 72% of the cohort had achieved platelet recovery at 1 year post-transplant. No significant difference in neutrophil recovery (P = .96) or platelet recovery (P = .77) was observed among ABO mismatch groups. Table 4 shows a comparison of secondary outcomes stratified by ABO mismatch status. For all study endpoints shown, the results of multivariable analysis were consistent with univariable outcome trends. Figure 1 provides Kaplan-Meier and cumulative incidence curves of selected outcomes.
Table 4. Major Outcomes after UCB Transplant for NMD by Unit–Recipient ABO Compatibility.
| All (n = 268) | ABO Match (n = 93) | Major Mismatch (n = 72) | Minor Mismatch (n = 80) | Bidirectional Mismatch (n = 23) | P | |
|---|---|---|---|---|---|---|
| Five-year overall survival (95% CI) | 69% (62-75) | 65% (53-74) | 68% (54-78) | 72% (59-81) | 76% (51-89) | .62 |
| Grades II-IV aGVHD at day 100 (95% CI) | 24% (19-30) | 20% (12-29) | 27% (16-38) | 25% (15-35) | 28% (8-49) | .75 |
| Grades III-IV aGVHD at day 100 (95% CI) | 11% (7-15) | 8% (2-15) | 20% (10-29) | 8% (2-14) | 5% (1-14) | .09 |
| cGVHD at 5 years (95% CI) | 7% (4-11) | 8% (2-15) | 8% (1-15) | 7% (1-13) | 5% (1-15) | .96 |
| Graft failure at 1 year (95% CI) | 21% (16-26) | 19% (11-28) | 25% (15-35) | 20% (11-29) | 17% (2-34) | .83 |
| Absolute neutrophil count recovery at day 42 (95% CI) | 90% (86-93%) | 91% (85-97) | 86% (78-94) | 91% (85-98) | 87% (72-98) | .96 |
| Platelet recovery at 1 year (95% CI) | 72% (67-78) | 74% (65-83) | 67% (55-78) | 75% (65-85) | 70% (48-91) | .77 |
CI indicates confidence interval.
Figure 1.
Significant study outcomes stratified by UCB unit–recipient ABO-compatibility status. Kaplan-Meier and cumulative incidence curves for significant study outcomes stratified by unit–recipient ABO mismatch groups. Top (left to right): Overall survival, graft failure, and grades III to IV aGVHD. Bottom (left to right): Time to absolute neutrophil count (ANC) recovery, time to platelet transfusion independence, and cumulative proportion of cGVHD.
Chimerism
The proportion of the study cohort with ≥80% donor engraftment at day 100 was 70%. At the date of most recent contact (median, day 391), this proportion was 74%. There was no significant difference across blood type mismatch groups at either day 100 (P = .89) or date of last contact (P = .33) (Table 5).
Table 5. Proportion of Patient Cohort with >80% Donor Myeloid Chimerism by UCB Unit–Recipient ABO Compatibility.
| All (n = 268) | ABO Match (n = 93) | Major Mismatch (n = 72) | Minor Mismatch (n = 80) | Bidirectional Mismatch (n = 23) | P | |
|---|---|---|---|---|---|---|
| At day 100 (95% CI) | 70% (63-75) | 69% (58-79) | 66% (54-78) | 70% (60-81) | 75% (56-94) | .89 |
| At last contact (95% CI) | 74% (69-79) | 79% (71-87) | 66% (55-77) | 75% (65-84) | 74% (56-92) | .33 |
Discussion
This study is unique in that, to our knowledge, it is the first to analyze the effect of UCB unit–recipient ABO blood type mismatch on outcomes in a population receiving cord blood transplant for NMD; it is also the first to evaluate the relationship between unit–recipient ABO mismatch and erythrocyte transfusion burden in UCBT. Our analysis of data from a large, single-center cohort of patients does not demonstrate an impact of UCB unit–recipient ABO mismatch on either the primary or secondary outcomes of this study. This contrasts with specific morbidities that have previously been ascribed to donor–recipient ABO incompatibility in allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) transplant [32].
Major ABO incompatibility has been associated with increased erythrocyte transfusion burden in patients who have received an allogeneic BM or PBSC transplant [33]. This increased transfusion burden is associated with 2 separate physiologic processes. First, anemia may result from hemolysis of the erythrocyte component of an HSC graft as a result of preformed recipient antibodies cognate for antigens present on donor type A (N-acetylgalactosamine) or type B (galactose) RBCs [32]. Fortunately, clinically significant hemolysis in this setting has been largely eliminated by the practice of RBC depletion of major-mismatched HSC grafts (including cord blood units) before transplant. In our cohort, >95% of UCB units were RBC deplete before transplant. Second, persistent circulation of recipient isohemagglutinins can disrupt normal post-transplant BM maturation, resulting in prolonged suppression of hematopoiesis, delayed RBC engraftment, and longer time to transfusion independence [32]. Theoretically, the risk of this second process should also be present in major-mismatched UCBT, although we have not found clinical evidence to support this. Future research may better elucidate the mechanisms protective against hematopoietic suppression in the major ABO mismatch UCBT population.
Minor ABO incompatibility has been associated with increased incidence of acute GVHD in populations who have received an allogeneic BM or PBSC transplant [34]. This increase in aGVHD is due to donor T cell sensitization against recipient ABO glycosyltransferase-derived peptides [35], which act as minor histocompatibility antigens and trigger an adaptive immune response. Despite this common occurrence in both BM and PBSC transplant settings, Romee et al. [22] found no association between minor ABO mismatch and GVHD in UCBT in a predominantly adult population with malignant disease. We also did not observe association between UCB unit–recipient minor ABO mismatch and aGVHD incidence. Romee et al. [22] speculated that this finding was because of the presence of naive T cells in the UCB that are largely unable to mount an immune response against recipient ABO glycosyltransferase-derived antigens. Others have demonstrated that serotherapy in pretransplant conditioning is associated with a decreased probability of severe aGVHD [36], because of in vivo allograft T cell depletion and delayed immune reconstitution. In our cohort, nearly all patients (84%) received serotherapy in their conditioning regimen with either antithymocyte globulin or alemtuzamab. Consequently, on the basis of our study, a conclusion cannot be made about the capacity of naive T cells in UCB to mount an alloreactive response against ABO glycosyltransferase-derived peptides.
In both univariable and multivariable analyses of our cohort, there was a statistically nonsignificant trend in severe aGVHD among recipients of major ABO mismatched UCB units. Although this is an interesting finding, it is probably neither biologically nor clinically relevant. Instead, it is likely a random byproduct of testing multiple outcomes in conjunction with the relative infrequency of severe aGVHD (11%) in the studied cohort.
Although many transplant centers select an ABO-matched cord blood unit to be given when there is a choice among several units, there is a lack of evidence to support this decision. The data from our study do not support the use of this criterion to guide cord blood unit selection, particularly when another cord blood unit may be deemed a more suitable choice based on other well-established unit selection criteria.
In conclusion, we do not find evidence to suggest that UCB unit–recipient ABO incompatibility affects overall survival, graft failure, time to neutrophil or platelet engraftment, aGVHD or cGVHD incidence, or donor chimerism when the transplant indication is NMD. Furthermore, the unit–recipient incompatibility status does not appear to impact post-UCBT RBC transfusion burden. Therefore, when considering UCBT for the treatment of NMD, the ABO match status of a donor unit and intended recipient does not appear to be a major criterion to guide unit selection.
Acknowledgments
Financial disclosure: Supported by National Institutes of Health grant P30 CA77598 using the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota, and by the National Center for Advancing Translational Sciences of the National Institutes of Health award number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of interest statement: There are no conflicts of interest to report.
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