Volume 15, Issue 11 , Pages 1400-1406, November 2009
Minor ABO-Mismatches are Risk Factors for Acute Graft-versus-Host Disease in Hematopoietic Stem Cell Transplant Patients
Article Outline
We investigated the impact of ABO and Rhesus (Rh) blood group matching on the outcome of hematopoietic stem cell transplantation (HSCT) of 154 patients matched at 10/10 HLA loci with unrelated donors. ABO and Rh, as potential risk factors, were modeled with the clinical outcome—acute and chronic graft-versus-host disease (aGVHD, cGVHD), relapse, treatment-related mortality (TRM), and overall survival (OS)—by simple, multiple, and competing risk analyses. We found that minor ABO-mismatches represent a significant risk factor for aGVHD (II-IV) with an estimated risk increase of almost 3-fold (hazard ratio [HR]
=2.92, 95% confidence interval [CI]: 1.43-5.95, P=.003), and even 4-fold for aGVHD (III-IV) (HR=4.24, 95% CI: 1.70-10.56, P=.002), but not for other transplant endpoints. No significant association of the Rh matching status with any of the HSCT endpoints was seen. These results suggest that ABO minor mismatches may play a role in aGvHD pathophysiology, possibly by providing the setting for T cell activation and antibody mediated damage. To decrease the risk of aGVHD, ABO matching should be considered in HSCT.
Key Words: Minor ABO-mismatch, Rh antigen, aGVHD, unrelated HSCT
Introduction
Graft versus host disease (GVHD) is one of the major causes of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The occurrence of acute GVHD (aGVHD) in a substantial number of patients given 10/10 HLA matched unrelated or sibling donor grafts 1, 2 indicates that antigens other than major HLA may be relevant for the disease development.
Minor histocompatibility antigens (mHags) are polymorphic allopeptides capable of eliciting an allogeneic T cell response in HLA-matched individuals [3], and they have been associated with the occurrence and control of GVHD 4, 5. In addition, cytokine gene polymorphisms and killer immunoglobuline-like receptor (KIR) genotypes of patients and donors have been suggested to play a role in the aGVHD, albeit via different mechanisms 6, 7, 8.
ABO antigens are carbohydrates expressed on red blood cells and various epithelial and endothelial cells [9]. Their synthesis depends on ABO glycosyltransferases, coded by more than 160 different alleles described until now [10]. Regarding this polymorphism, Eiz-Vesper and colleagues [11] have recently shown in vitro that different synthetic glycosyltransferase peptides can induce peptide-specific T cell responses. This finding indicates potential mHag properties of glycosyltransferases and supports previous clinical reports, showing a significant association of minor ABO-mismatches with increased risk of aGVHD 12, 13, 14 and shorter overall survival (OS) in transplant patients 14, 15, 16. A recent large, multicenter study of 3103 patients given sibling grafts showed only an association of bidirectional ABO-mismatches with a higher risk of severe aGVHD (III-IV), but not with aGVHD (II-IV) or overall aGVHD [13]. There are, however, several reports that showed no impact of ABO matching status on HSCT outcome 17, 18, 19. Rhesus (Rh) mismatches were also either associated with the shorter OS after HSCT [20], or it lacked this association [21]. However, to our knowledge, the effect of blood group mismatches on the HSCT outcome has not been studied in unrelated, HLA-matched pairs.
We therefore examined the impact of ABO and Rh patient-donor incompatibilities on the HSCT outcome of 154 adult patients receiving 10/10 HLA-matched grafts from unrelated donors at 2 transplant centers in Vienna and Prague. Our aim was to investigate if ABO and Rh matching status could be used for risk estimations of HSCT endpoints in patients with HLA class I and class II matched HSCT donors.
Materials and Methods
Study Population
The study population consisted of 154 consecutive patients from Vienna (n=122) and Prague (n=32), who had undergone HSCT with unrelated donors. Transplantations took place between September 1995 and December 2005. Data were analyzed as of September 20, 2008. Median follow-up time of the patients alive was 74 months (range: 35-158 months). All patients and donors were matched for HLA class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1) alleles, and patients transplanted in the Vienna center were additionally matched for HLA-DRB3/4/5 alleles. Retrospective typing showed that 14% of all pairs were also matched for HLA-DPB1 alleles. HLA typing was performed as previously described 22, 23; ABO and Rh typing was performed by standard blood banking methods [24]. Neither ABO nor Rh matching was paid regard to in the donor selection process.
Patient and donor characteristics are shown in Table 1. The “acute leukemias” (AL) group consisted of 43 patients with acute myelogenous leukemia (AML) and 21 patients with acute lymphoblastic leukemia (ALL). Thirty-nine patients had chronic myelogenous leukemia (CML). Other diseases included 26 patients with myelodysplastic syndrome (MDS), 13 patients with non-Hodgkin lymphoma (NHL), 1 with Hodgkin disease (HD), 2 with chronic lymphocytic leukemia (CLL), 1 with severe aplastic anemia (SAA), 2 with myeloma, and 6 with chronic myeloproliferative disease. Eighty-three patients had “standard-risk” disease, comprising CML in the first chronic phase, AL and NHL in complete remission (CR), and 71 “high risk” containing all other disease stages. Conditioning therapies applied were either myeloablative (MA; n=109) or reduced intensity (RIC n=45). In vivo T cell depletion (TCD) was performed by antithymocyte globulin (ATG; Fresenius Biotech GmbH, Munich, Germany) administration in 56 patients. Table 1 also gives the types and numbers of transplanted stem cells and types of GVHD prophylaxis. The study has been approved by the Ethic Committees of both participating institutions. Informed consent for hematopoietic stem cell (HSC) donation and transplantation was obtained from all donors and patients.
Table 1. Patient and Donor Characteristics by ABO Matching Status
| ABO Matching Status | ||||||
|---|---|---|---|---|---|---|
| Characteristic | Matched | Major mm | Minor mm | Bidirectional mm | Total | Fischer's Test P-Value |
| Number of patient/donor pairs (%) | 58 (38) | 30 (19) | 44 (29) | 22 (14) | 154 | na |
| Age patients, years, mean [range] | 42 [19-62] | 41 [18-61] | 44 [19-63] | 39 [21-55] | 42 [18-63] | na |
| Age donors, years, mean [range]∗ | 36 [23-57] | 35 [22-52] | 37 [18-52] | 36 [21-51] | 36 [18-57] | na |
| Sex (patient/donor), no.† (%) | ||||||
| F/F | 10 (18) | 6 (22) | 12 (27) | 2 (9) | 30 (20) | .17 |
| F/M | 15 (26) | 7 (25) | 9 (20) | 7 (32) | 38 (25) | |
| M/F | 11 (19) | 4 (14) | 3 (7) | 8 (36) | 26 (17) | |
| M/M | 21 (37) | 11 (39) | 20 (46) | 5 (23) | 57 (38) | |
| CMV status (patient/donor), no. (%) | ||||||
| Pos/Pos | 17 (29) | 5 (16) | 20 (45) | 7 (32) | 49 (32) | .48 |
| Pos/Neg | 19 (33) | 11 (37) | 12 (27) | 7(32) | 49(32) | |
| Neg/Pos | 7 (12) | 6 (20) | 6 (14) | 3 (13) | 22 (14) | |
| Neg/Neg | 15 (26) | 8 (27) | 6 (14) | 5 (23) | 34 (22) | |
| Disease, no. (%) | ||||||
| AL | 26 (45) | 17 (57) | 13 (30) | 8 (36) | 64 (42) | .17 |
| CML | 13 (22) | 3 (10) | 16 (36) | 7 (32) | 39 (25) | |
| “Other” | 19 (33) | 10 (33) | 15 (34) | 7(32) | 51 (33) | |
| Disease stage, no. (%) | ||||||
| Standard risk | 35 (60) | 15 (50) | 21 (48) | 12 (55) | 83 (54) | .61 |
| High risk | 23 (40) | 15 (50) | 23 (52) | 10 (45) | 71 (46) | |
| Conditioning regime, no. (%) | ||||||
| Myeloablative | 41 (71) | 22 (73) | 29 (66) | 17 (77) | 109 (71) | .81 |
| Reduced intensity | 17 (29) | 8 (27) | 15 (34) | 5 (23) | 45 (29) | |
| T cell depletion, no. (%) | ||||||
| T cell depleted | 21 (36) | 10 (33) | 19 (43) | 6 (27) | 56 (36) | .64 |
| Non-T cell depleted | 37 (64) | 20 (67) | 25 (57) | 16 (73) | 98 (64) | |
| HSC source, no. (%) | ||||||
| BM | 27 (47) | 8 (27) | 22 (50) | 9 (41) | 66 (43) | .21 |
| PBSCs | 31 (53) | 22 (73) | 22 (50) | 13 (59) | 88 (57) | |
| Cell dose infused: CD34+ cells ×10−6/kg median [range]‡ | 5.46 [1.24-14.30] | 6.88 [0.99-19.40] | 5.04[1.65-12.00] | 3.68 [1.16-10.90] | 5.4 [0.99-19.4] | na |
| GVHD prophylaxis, no. (%) | ||||||
| CsA+MTX | 34 (59) | 19 (63) | 24 (54) | 12 (55) | 89 (58) | .42 |
| CsA+MMF | 16 (27) | 11 (37) | 14 (32) | 8 (36) | 49 (32) | |
| CsA | 8 (14) | 0 (0) | 6 (14) | 2 (9) | 16 (10) | |
∗Age of 4 donors are missing. |
†Sex of 3 donors are missing. |
‡Thirty-three data points are missing. |
Clinical Endpoints
The endpoints analyzed in this report were aGVHD and chronic GVHD (cGVHD), relapse, treatment-related mortality (TRM), and OS. aGVHD (grades II-IV) and aGVHD (grades III-IV) were separately analyzed in statistical models, as were overall and extensive cGVHD. Assessments of aGVHD and cGVHD and supportive care during HSCT have been previously described [25]. The minimum and maximum times to overall aGVHD (I-IV) were 7 and 75 days, to cGVHD 80 and 107 days. The medical staff performing GVHD assessment was exchanged between the 2 participating centers to ensure consistent evaluation of the disease. Relapse was defined as recurrence of the primary disease after transplantation based on immunohistochemistry criteria. TRM was defined as death because of infections, aGVHD and cGVHD, or organ toxicity without evidence of relapse. OS was measured from the transplantation until death or the last follow-up.
Definitions of ABO and Rh Matching Status
ABO matched pairs had identical ABO blood groups. In the major ABO mismatched group patients had isoagglutinins directed against donor A or B antigens, and in the minor ABO mismatch group donors had isoagglutinins directed against patient A or B antigens. In the bidirectional mismatched group, both patients and donors had isoagglutinins directed against each other. The presence of Rh factor in patients and its absence in corresponding donors was defined as a mismatch in graft-versus-host (GVH) direction, and its presence in donors and absence in corresponding patients was defined as a mismatch in host-versus-graft (HVG) direction.
Statistical Analyses
Fisher's exact test was used to test the association between ABO matching status and other patients' characteristics. The effects of ABO and Rh factors on the aGVHD and cGVHD, relapse, TRM, and OS were analyzed in simple and multiple Cox regression models. From the multiple models we obtained the effect of the ABO or Rh factor adjusted by a selected set of significant clinical factors. The selection of significant clinical factors was done as follows: simple log-rank tests were performed for each of the clinical variables, as listed in Table 1. Clinical variables having P values <.20 were included in a subsequent multiple Cox regression model in which the final set of significant clinical factors was selected using a stepwise selection procedure. Age of patients and donors was first dichotomized using the Classification and Regression Trees (CART) 26, 27. CART divides a continuous variable in 2 groups where the selected cutpoint yields the largest differences in their effects on the outcome. Additional competing risk analyses were performed to evaluate the simple effects of the ABO and Rh factors on aGVHD, cGVHD, TRM, and relapse. All the analyses were performed for each of the endpoints independently. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated in each analysis. The significance level was set to .05 without adjustment for multiple testing. All analyses were performed using R software v. 2.7.1.
Results
ABO and Rh Blood Types of Patients and Donors
The frequencies of ABO blood groups in patients were as follows: 56 patients (36%) had O, 59 (38%) had A, 29 (19%) had B, and 10 (7%) had AB blood group. In donors 67 (43%) had O, 63 (41%) had A, 15 (10%) had B, and 9 (6%) had AB blood group, respectively. Blood group B has a higher frequency in donors; however, the general comparison of ABO group frequencies between patients and donors showed no statistically significant difference. Fifty-eight (38%) patients received ABO matched, and 96 (62%) received ABO mismatched transplants. Major ABO-mismatch was detected in 30 (19%), minor ABO-mismatch in 44 (29%), and bidirectional ABO-mismatch in 22 (14%) patients (Table 1). Within the major ABO-mismatched group patients' isoagglutinins were directed against donors' A (n=20), B (n=5), or AB antigens (n=5). In minor ABO-mismatched transplantations donors' isoagglutinins were directed against patients' A (n=29), B (n=12), or AB antigens (n=3). Among 22 bidirectional mismatches, 16 patients had isoagglutinins directed against donors' A antigen, and 6 had isoagglutinins directed against donors' B antigen. No significant associations between ABO matching status and other risk factors were found (Table 1; Fisher's test column), indicating a fair distribution of patients within different subgroups of risk factors. There were 119 patients (78%) and 125 (81%) donors who were Rh positive, whereas 34 (22%) patients and 29 (19%) donors were Rh negative. There were 23 pairs (15%) Rh mismatched in GVH and 28 pairs (18%) mismatched in HVG direction. In 1 patient Rh data were missing.
aGVHD
aGVHD was assessed in 151 of 154 patients. Two patients had missing onset dates and 1 patient died 1 day posttransplant. Overall aGVHD (I-IV) was detected in 75 (50%), aGVHD (II-IV) in 51 (34%), and aGVHD (III-IV) in 25 (17%) patients.
aGVHD (II-IV) was diagnosed in 16 (28%) patients in the ABO-identical group, in 10 (33%) patients with major ABO-mismatched donors, in 17 (40%) patients with minor AB-mismatched donors, and in 8 (36%) patients with bidirectionally ABO-mismatched donors. Cumulative incidences of aGVHD (II-IV) at day 75 were: 31% (95% CI: 17%-42%) for the ABO matched group, 39% (95% CI: 18%-55%), for the major ABO-mismatched group, 44% (95% CI: 26%-58%), for the minor ABO-mismatched group, and 37% (95% CI: 13%-55%) for the bidirectionally ABO-mismatched group (Figure 1A). Cumulative incidences for severe aGVHD (III-IV) at day 75 were: 18% (95% CI: 5%-28%) for the ABO-matched group, 10% (95% CI: 0%-23%) for the major ABO-mismatched group, 37% (95% CI: 18%-51%) for the minor ABO-mismatched group, and 14% (95% CI: 0%-28%) for bidirectionally ABO-mismatched group (Figure 1B).
Figure 1
Cumulative incidence of aGvHD (grades II-IV) (A) and aGvHD (grades III-IV) (B) according to the ABO matching status; p denotes probability.
Simple and competing risk analyses did not show an association of minor ABO-mismatches with aGVHD (II-IV). The minor mismatches, however, increased the risk for aGVHD (III-IV) about 2.5-fold (P=.036, HR=2.57, 95% CI: 1.06-6.19), as shown by simple analysis. Adjustment by significant clinical variables—TCD and age of donor—showed that patients with minor ABO-mismatched donors were at a significantly increased risk of both aGVHD (II-IV) (P=.003, HR=2.92, 95% CI: 1.43-5.95) and aGVHD (III-IV) (P=.002, HR=4.24, 95% CI: 1.70-10.56), when compared to the ABO-matched group. Rh matching status between patients and donors was not associated with aGVHD.
Other variables associated with an increased risk of aGVHD (II-IV) were TCD (P=6.1×10−6, HR=0.16, 95% CI: 0.07-0.36), and donor age older than 37 years (P=.024, HR=0.51, 95% CI: 0.29-0.92). The only other risk factor for aGVHD (III-IV) was TCD (P=.0005, HR=0.14, 95% CI: 0.05-0.42).
TRM
Thirty of 154 (19%) patients died of treatment-related causes including infections in 23 and organ toxicity in 7 patients. Seven of the patients additionally had aGVHD. TRM was observed in 8 (14%) patients with ABO-matched, in 5 (17%) patients with major ABO-mismatched, in 12 (27%) patients with minor ABO-mismatched and in 5 (23%) patients with bidirectionally ABO-mismatched donors, respectively. The probability of TRM within 3 years was 15% (95% CI: 5%-24%) for the ABO-matched group, 18% (95% CI: 2%-31%) for the major ABO-mismatched group, 28% (95% CI: 13%-40%) for the minor ABO-mismatched group, and 25% (95% CI: 3%-42%) for the bidirectional ABO-mismatched patient group, respectively.
When the ABO and Rh matching status of the patients were modeled as risk factors for TRM by simple analyses, no associations were seen. After relapse was considered in the analysis as a competing risk for TRM, the effect of the minor ABO-mismatches was borderline significant (P=.035, HR=2.86, 95% CI: 1.07-7.60). After adjusting of the simple analysis by clinical factors in the multiple model, no significance was found (Table 2).
Table 2. Influence of ABO and Rh Matching Status on HSCT Outcome According to Multiple Cox-Regression Models
| Variable | aGVHD (II-IV) | Relapse | TRM | OS | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | |
| ABO mm | 1.93 | 1.06-3.55 | .032 | 0.83 | 0.47-1.47 | .530 | 1.31 | 0.57-3.02 | .530 | 1.32 | 0.78-2.25 | .300 |
| ABO major mm | 1.63 | 0.74-3.62 | .230 | 1.05 | 0.52-2.13 | .890 | 1.34 | 0.43-4.15 | .610 | 1.47 | 0.76-2.84 | .470 |
| ABO minor mm | 2.92 | 1.43-5.95 | .003 | 0.69 | 0.33-1.46 | .330 | 1.28 | 0.49-3.37 | .610 | 1.27 | 0.66-2.44 | .470 |
| TCD | 0.16 | 0.07-0.36 | <.00001 | na | na | na | na | na | na | na | na | na |
| dage >37 years | 0.51 | 0.29-0.92 | .024 | na | na | na | na | na | na | na | na | na |
| ABO bidirect. mm | 1.37 | 0.58-3.22 | .480 | 0.77 | 0.32-1.84 | .560 | 1.32 | 0.43-4.07 | .630 | 1.19 | 0.54-2.64 | .670 |
| Rh match stat (1) | 1.68 | 0.82-3.46 | .160 | 0.81 | 0.36-1.84 | .610 | 0.96 | 0.33-2.83 | .940 | 0.99 | 0.49-1.99 | .980 |
| Rh match stat (2) | 1.70 | 0.87-3.34 | .120 | 1.15 | 0.56-2.35 | .710 | 1.19 | 0.50-2.84 | .700 | 1.28 | 0.69-2.36 | .440 |
Relapse and OS
Relapse was detected in 42 of 154 patients (34%), and 65 patients (42%) had died by the end of the follow-up. Cumulative incidence of relapse at 3 years in the ABO-matched group was 41% (95% CI: 26%-53%), in the major ABO-mismatched group 46% (95% CI: 23%-63%), in the minor ABO-mismatched group 34% (95% CI: 15%-48%), and in the bidirectionally mismatched group 37% (95% CI: 11%-55%). Probability of survival at 3 years was 36% (95% CI: 23%-47%) in the ABO-matched group, 53% (95% CI: 32%-68%) in the major ABO-mismatched group, 43% (95% CI: 26%-56%) in the minor ABO-mismatched group and 41% (95% CI: 16%-58%) in the bidirectionally mismatched group. In summary, no statistical evidence of association of the ABO or Rh matching status with relapse or OS have been seen (Table 2).
Discussion
Here we report a significantly increased incidence of aGVHD (II-IV) in patients given minor ABO-mismatched stem cell grafts from HLA matched unrelated donors. The Rh matching status had no impact on the transplantation outcome.
The stringent donor selection criteria applied: 10/10, and in the case of Vienna patients (79%) 12/12 HLA allele matching, suggest that mismatches in mHags, rather than in HLA alleles, play a role in the development of the aGVHD.
Recently it has been shown that A and B glycosyltransferase enzymes may act as mHags, eliciting T cell response [11]. Considering that aGVHD is predominantly a T cell-mediated disease, it is conceivable that donors' T cells directed against patients' A and B glycosyltransferases play a role in the pathophysiology of GVHD. In addition to the T cell response, in minor ABO-mismatched transplantation, donor A and B specific antibodies may bind and cause damage to the host endothelium, which expresses A and B antigens [9]. In this transplant setting, the potential role of antibodies coacting with T cells becomes evident. Endothelium damage together with conditioning regimens can trigger a cytokine storm, which enhances GVHD in patients [14]. In major mismatched transplantations, isoagglutinins do not damage endothelium, and indeed, in that transplant setting we have not observed an increased incidence of aGVHD using bone marrow (BM) and peripheral blood stem cell (PBSC)-derived stem cells. It still has to be investigated whether this conclusion is true for cord blood (CB) as a stem cell source. The B cell clones in cord blood may not have been previously sensitized to ABO antigens, and therefore GVHD related to ABO mismatches may be of lesser significance.
Previously, we analyzed the effect of the HLA-DPB1 matching status on the HSCT outcome in the same patient cohort. We showed that HLA-DPB1 mismatches, as well as TCD and donor age, were significant risk factors for aGVHD (II-IV) [23]. The association of minor ABO-mismatches with increased aGVHD (II-IV) and severe aGVHD (III-IV) that we report here is independent from the HLA-DPB1 matching status (data not shown).
Our findings are in line with a study showing an association of minor ABO-mismatches with aGVHD (II-IV) in 174 patients given T cell replete, HLA-identical sibling grafts [28]. A similar association was seen in a larger group of 481T cell-depleted patients, 48% of which were HLA mismatched with corresponding donors [12]. In yet a larger analysis of 562 patients, minor ABO-mismatches were shown to be a risk factor for overall aGVHD (I-IV), but not for aGVHD (II-IV) [16]. Other studies, however, showed no effect of ABO matching status between patients and donors on aGVHD under similar conditions 13, 18. The substantial variability between the studies in the degree of HLA matching, joint analyses of both sibling and unrelated transplantations, and different patient treatment protocols might partly account for these discrepancies. Beside ABO, other mHags may also play a role in GVHD development 29, 30. Ubiquitously expressed mHags are targets for GVH effects [31]. However, the increased aGVHD in minor ABO-mismatched patients we report did not translate into increased cGVHD (data not shown) or TRM of patients. Also, no evidence of association of ABO or Rh matching status of transplants on relapse or OS was seen. This indicates that ABO antigens do not mediate GVL effects. Similar findings have been reported by Klumpp and colleagues [18] and Seebach and colleagues [13], who analyzed a cohort of 3013 patients. Most studies published to date suggest no difference in relapse rates after transplantation with ABO-mismatched grafts. Also, no associations of ABO matching status with the OS were observed in large studies of patients with HLA matched sibling or unrelated donors 13, 19.
In our center it has previously been shown that the subgroup of ABO minor mismatched patients receiving reduced intensity conditioning and cyclosporine (CsA) as the only GVHD prophylaxis, have a significantly higher TRM rate than patients in other subgroups. In our study, only 2 among the 154 patients belonged to this risk group, but none developed aGVHD or died because of the TRM. Important differences, however, exist between the 2 study setups. Most notably, the previous study included patients receiving both HLA matched and mismatched grafts from corresponding related or unrelated donors, and no adjustment for clinical factors was performed.
In summary, our study adds to the body of evidence that minor ABO-mismatches represent a significant risk factor for developing moderate and severe aGVHD in HSCT where the selection of unrelated donors was based on 10/10 HLA allele matches. To lower the risk of aGVHD, ABO matching should be taken into account for donor selection. If no donors are available, minor ABO mismatches should be considered an indication for intensification of GVHD prophylaxis.
Acknowledgments
Financial disclosure: This work was supported in part by the European Commission Grant MCRTN-CT-2004-512253 (TRANSNET).
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Financial disclosure: See Acknowledgments on page 1405.
PII: S1083-8791(09)00322-X
doi:10.1016/j.bbmt.2009.07.002
© 2009 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 15, Issue 11 , Pages 1400-1406, November 2009
