Abstract
Recent advances in allogeneic hematopoietic cell transplant (HCT) have led to an increasing use of alternative donors, including banked umbilical cord blood (UCB). Despite these advances, acute graft-versus-host disease (aGvHD) and chronic GvHD (cGvHD) continue to be the leading causes of early and late transplant related mortality. ABO-mismatch has been frequently reported as a risk factor for GvHD, however data in the UCB recipients is limited. We hypothesized that since the lymphocytes in the cord blood are thought to be naive, they will therefore be less likely to mediate GvHD. Therefore, we analyzed the impact of ABO-mismatch on aGvHD and cGvHD in recipients of single and double UCB-HCT. In both univariate and multivariate analysis presence of ABO-mismatch did not impact aGvHD or cGvHD. While ABO compatible donors are preferred in recipients of URD-HCT, ABO compatibility generally need not be considered in recipients of UCB-HCT.
Keywords: ABO-mismatch, GvHD, allogeneic hematopoietic cell transplantation, cord blood transplantation
Introduction
The ABO antigens are oligosaccharides that are widely distributed in the body including the vascular endothelium. It has been demonstrated that the ABO glycosyltransferase-derived peptides have the potential to function as minor histocompatibility antigens and elicit an in vitro T cell response1. ABO mismatch is well known to increase the risk of graft failure in solid organ transplantation, although allogeneic hematopoietic cell transplantation (allo-HCT) are successfully performed across the ABO barrier2. Most studies report no adverse effects of ABO disparity on survival post HCT. There is however conflicting data regarding the impact of ABO-mismatch on graft-versus-host disease (GvHD) after allo-HCT with some studies reporting increased risk3–6 while others do not7–12. While a recent report suggested poor disease free survival (DFS) with ABO-mismatch in the recipients of umbilical cord blood transplantation (UCB-HCT), there is limited data on the impact of ABO-mismatch on GvHD in UCB-HCT recipients13, 14. We hypothesized that there would be no increase in risk of GvHD in recipients of UCB grafts based on the naïve nature of the T-cells present in the cord blood1. We hence performed a retrospective analysis in a relatively large cohort of the single (N=208) and double (N=295) UCB-HCT recipients to determine the impact of ABO-mismatches on acute GvHD (aGvHD) and chronic GvHD (cGvHD).
Patients and Methods
The study cohort included 503 consecutive patients who underwent allo-HCT from unrelated UCB at University of Minnesota between year 2000 and 2007. The study was approved by the University of Minnesota Institutional review board (IRB). Patient demographic and transplant characteristics, date of onset of acute GvHD and grade, date of onset of cGvHD and dates of survival and relapse are prospectively entered in the University of Minnesota Blood and Marrow transplant database. HLA matching status was based on antigen level HLA-A and -B, and allele level HLA-DRB1 typing. Three categories of ABO-mismatch were categorized: minor ABO-mismatch characterized by the ability of donor lymphocytes to make anti-A or anti-B iso-hemagglutinins (e.g. a recipient with A, B or AB blood group receiving a graft from a donor with an O blood group), major ABO-mismatch characterized by the ability of recipient lymphocytes to make anti-A or anti-B iso-hemagglutinins (O recipient with A, B or AB donor graft) and bidirectional ABO-mismatch characterized by presence of both minor and major mismatches (e.g. blood group A recipient with blood group B or AB donor)11. In the double cord unit recipients the ABO matching status of only the dominant (engrafting) cord was considered in the analysis.
The primary study endpoint was GvHD. aGvHD was graded according to consensus criteria15. cGvHD was defined as per criteria published by the NIH Consensus Group16. Secondary endpoints were transplant related mortality (TRM), disease free survival (DFS) and overall survival (OS). TRM was defined as death without disease relapse or progression. DFS was defined as survival without disease progression or relapse; patients alive without disease progression or relapse were censored at the time of last follow-up. OS was defined as death from any cause and surviving patients were censored at date of last contact.
For statistical analysis, variables related to patient, disease, and transplant characteristics were compared using the Chi-square test for categorical variables and Kruskal-Wallis test for continuous variables. Cumulative incidence for acute and chronic GvHD was calculated treating death as the competing risk. Similarly, the cumulative incidence of TRM was calculated treating disease progression/relapse as competing risk and cumulative incidence for disease progression/relapse was calculated treating TRM as competing risk17. Disease free survival and overall survival were calculated based on Kaplan-Meier estimates20. We used log-rank test to compare differences between groups in the time-to-event analyses and χ2 or Fisher's exact tests for proportions. Patient- and transplant related variables were included in the multivariate cox-regression21 analyses using a stepwise forward selection technique with P≤.05 as the criterion for inclusion in final models. Variables considered included recipient age, disease, donor-recipient gender mismatch, conditioning regimen (myeloablative versus reduced intensity), GvHD prophylaxis, year of transplantation, total graft nucleated cell dose, number of cord blood units, HLA matching and the presence and type of ABO mismatch. The effect of ABO mismatch on outcomes was included in all models. Patient and transplant characteristics are shown in the table 1.
Table 1.
Patient and Transplant Characteristics
| Parameter | Donor: recipient ABO matching | ||||
|---|---|---|---|---|---|
| ABO match | Major ABO mismatch |
Minor ABO mismatch |
Bidirectional ABO mismatch |
P | |
| N (%) | 187 (37) | 113 (22) | 161 (32) | 42 (8) | |
| Age at transplant (years: median, range) | 24 (1–69) | 22 (1–67) | 27 (1–68) | 28 (1–61) | |
| Age group | 0.69 | ||||
| 0–20 | 80 (43%) | 53 (47%) | 72 (45%) | 15 (36%) | |
| 21–40 | 43 (23%) | 20 (18%) | 32 (20%) | 13 (31%) | |
| >40 | 64 (34%) | 40 (35%) | 57 (35%) | 14 (33%) | |
| Diagnosis | 0.22 | ||||
| ALL | 93 (50%) | 49 (43%) | 83 (52%) | 24 (57%) | |
| CML | 7 (4%) | 7 (6%) | 4 (2%) | 5 (12%) | |
| Lymphoma | 31 (17%) | 15 (13%) | 29 (18%) | 5 (12%) | |
| Nonmalignant | 39 (21%) | 26 (23%) | 32 (20%) | 6 (14%) | |
| Other Malignancy | 17 (9%) | 16 (14%) | 13 (8%) | 2 (5%) | |
| GvHD prophylaxis | 0.14 | ||||
| CSA | 4 (2%) | 1 (1%) | 0 (0%) | 0 (0%) | |
| CSA/MMF | 140 (75%) | 80 (71%) | 120 (75%) | 38 (90%) | |
| CSA/MP/T-depleted | 2 (1%) | 1 (1%) | 0 (0%) | 0 (0%) | |
| CSA/MTX/PD | 0 (0%) | 1 (1%) | 0 (0%) | 0 (0%) | |
| CSA/PD | 15 (8%) | 6 (5%) | 10 (6%) | 3 (7%) | |
| CSA/PD/ATG | 22 (12%) | 20 (18%) | 30 (19%) | 1 (2%) | |
| Other | 4 (2%) | 4 (4%) | 1 (1%) | 0 (0%) | |
| Total nucleated cell dose × 108/kg median (range) | 0.40(0.12–3.11) | 0.38(0.14–2.27) | 0.38(0.11–4.89) | 0.38(0.17–2.65) | 0.64 |
| Conditioning | 0.84 | ||||
| Myeloablative | 115 (62%) | 64 (57%) | 97 (60%) | 24 (57%) | |
| Reduced intensity | 72 (39%) | 49 (43%) | 64 (40%) | 18 (43%) | |
| Gender mismatch | 0.47 | ||||
| Female donor to male recipient | 67 (36%) | 49 (44%) | 58 (36%) | 18 (43%) | |
| Others | 120 (64%) | 64 (56%) | 103 (64%) | 24 (57%) | |
| Number of cord units | 0.49 | ||||
| Single | 80 (43%) | 45 (40%) | 70 (43%) | 13 (31%) | |
| Double | 107 (57%) | 68 (60%) | 91 (57%) | 29 (69%) | |
| Transplant year | 0.49 | ||||
| 2000–2002 | 46 (25%) | 35 (31%) | 44 (27%) | 6 (14%) | |
| 2003–2005 | 78 (42%) | 43 (38%) | 63 (39%) | 22 (52%) | |
| 2006–2007 | 63 (34%) | 35 (31%) | 54 (34%) | 14 (33%) | |
| HLA mismatch | 0.58 | ||||
| 6/6 | 74 (40%) | 51 (45%) | 65 (41%) | 19 (45%) | |
| 5/6 | 78 (42%) | 49 (43%) | 74 (47%) | 18 (43%) | |
| 4/6 | 35 (19%) | 13 (12%) | 22 (13%) | 5 (12%) | |
| Median follow-up (months) | 46 (13–93) | 50 (12–110) | 48 (12–102) | 54 (26–76) | |
ATG, anti-thymocyte globulin, CSA, cyclosporine; MMF, mycophenolate mofetil; MTX, methotrexate; PD, prednisone
Results
aGvHD
In univariate analysis there was no significant difference in the cumulative incidence of grade II–IV aGvHD in the ABO match, major mismatch, minor mismatch or bidirectional cohorts. The cumulative incidence of grade II–IV aGvHD was 46% (95%CI:38–54%) in the ABO match, 44% (95%CI:35–54%) in major ABO-mismatch, 48% (95%CI:40–57%) in the minor ABO-mismatch and 43% (95%CI:27–58%) in the bidirectional ABO-mismatch groups (P=0.84). (Figure 1a). In multivariate analysis, the risk of grade II–IV aGvHD was similar for UCB recipients with major ABO-mismatch (RR0.91; 95%CI:0.63–1.31, P=0.61), minor ABO-mismatch (RR1.03; 95%CI:0.76–1.40, P=0.85) and bidirectional ABO-mismatch (RR 0.72, 95%CI:0.43–1.21, P=0.21) compared to recipients of ABO-match grafts.
Figure 1. Cumulative incidence of grade II–IV aGvHD and cGvHD in UCB recipients.
A) Cumulative incidence of grade II–IV aGvHD in UCB recipients
B) Cumulative incidence of cGvHD in UCB recipients
cGvHD
The cumulative incidence of cGvHD for patients receiving an ABO-matched graft was 19% (95%CI:13–25%), with major ABO-mismatch was 19% (95%CI:11–26%), with minor ABO-mismatch was 24% (95%CI:17–31%) and with bidirectional ABO-mismatch was 17% (95%CI:5–28%), (P=0.59). In multivariate analysis, presence of major ABO-mismatch [RR:1.03 (95%CI:0.60–1.79, P=0.90)], minor ABO-mismatch [(RR1.35; 95%CI:0.85–2.13, P=0.20)] and bidirectional ABO-mismatch [(RR 0.79; 95%CI:0.34–1.83, P=0.59)] was not associated with higher risk of cGvHD compared to the ABO-match group.
Survival
The probability of overall survival (OS) at three years in the ABO-match, major mismatch, minor mismatch and bidirectional mismatch groups was not significantly different significantly in the UCB recipients. The probability of overall survival was 55% (95%CI:46–62%) in the ABO match, 46% (95%CI:38–53%) in the major ABO-mismatch, 47% (95%CI:32–61%) in the minor ABO-mismatch, and 53% (95%CI:43–62%) in the bidirectional ABO-mismatch groups (P=0.68) at three years after transplant. The probability of DFS was 49% (95%CI:41–56%) in the ABO-match, 43% (95%CI:35–50%) in the major ABO-mismatch, 40% (95%CI:25–54%) in the minor ABO-mismatch and 49% (95%CI:39–58%) in the bidirectional ABO-mismatch groups (P=0.78) at three years after transplant. Cumulative incidence of TRM was 24% (95%CI:17–31%) in the ABO-match, 24% (95%CI:18–31%) in the major ABO-mismatch, 22% (95%CI:9–35%) in the minor ABO-mismatch and 23% (95%CI:15–31%) in the bidirectional ABO-mismatched cohorts (P=0.97) at one year after transplant.
Discussion
We hence demonstrate no impact of ABO-mismatch on acute and chronic GvHD in a relatively large cohort of UCB recipients. Recent studies show that double UCB transplantation is associated with a higher risk of GvHD18 and perhaps lower risk of relapse18, 19. The biological basis of this apparently increased allo-reactivity remains to be elucidated. The use of double cord blood units also increases the chances of having an ABO mismatch. However, despite this, we saw no significant impact of ABO-mismatch on the incidence of aGvHD or cGvHD in recipients of UCB. A recent study by Berglund et al found increased association of aGvHD with ABO-mismatch in cord blood recipients14. However the number of patients with ABO-mismatch in that study was limited (n=23). In another study by Blin et al, the impact of ABO incompatibility was evaluated in bone marrow, peripheral blood stem cell (PBSC) and UCB recipients11. The impact of ABO-mismatch on aGvHD in the cord blood cohort could not be assessed due to the low number of cord blood recipients in the study (n=49).
Another study reported decreased DFS with major ABO-mismatch (RR: 1.55, p=0.03)13. Major differences in the patient characteristics (inclusion of only hematologic malignancies, myeloablative conditioning regimens, and single cord only) could account for the difference.
In our study, amongst double UCB recipients, the ABO-matching status of the engrafting cord was considered. Twenty two of the double UCB recipients were noted to have mixed chimerism (defined as at least 5% from each donor at day 100 after transplant). We did not find any significant difference in the incidence of mixed chimerism among the different ABO groups; 9 in minor, 3 in mixed, 6 in major and 4 in ABO matched groups (p=0.34). In these 22 recipients, the worse match was considered, favoring a conservative analysis. We speculate that the lack of impact of ABO-mismatch on the risk GvHD after UCB transplant may be due to the relatively naive nature of T cells in the UCB which are therefore less likely to mount an effective immune response against ABO glycosyltransferases. Moreover, the presence of ABO-mismatch did not influence OS, DFS or TRM in this cohort. Our data does not support a need to use ABO compatibility as an UCB graft selection criteria.
Footnotes
AUTHORS’ DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors have no potential conflicts of interest to disclose
References
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