Volume 13, Issue 6 , Pages 675-682, June 2007
Major ABO Blood Group Mismatch Increases the Risk for Graft Failure after Unrelated Donor Hematopoietic Stem Cell Transplantation
Article Outline
- Abstract
- Introduction
- Patients and Methods
- Results
- Discussion
- Conclusion
- Acknowledgments
- References
- Copyright
Abstract
Two hundred twenty-four patients with leukemia transplanted with an unrelated donor between 1991 and 2003 at the Karolinska University Hospital were analyzed according to association between graft failure and ABO, RhD, MNSs, and Kidd blood group antigen compatibility. Median age was 29 years (range: 0-55). Conditioning consisted of total-body irridiation or busulfan-based myeloablative conditioning. A bone marrow graft was given to 152 patients, and 72 patients received peripheral blood stem cells. Most patients received graft-versus-host disease prophylaxis with cyclosporine and MTX. Graft failure (GF) was seen in 6 (2.7%) patients. In the multivariate analysis major ABO mismatch (odds ratio [OR] 14.9, 95% confidence interval [CI] 2.01-110, P = .008) and HLA-allele mismatch (6.42, 1.19-34.8, P = .03) was significantly associated to GF. In patients with and without major ABO mismatch the incidence of GF was 7.5% and 0.6% (P = .02), respectively. Using an ABO major mismatched graft increases the risk for GF after unrelated donor hematopoietic stem cell transplantation.
Key Words: Blood group antigens, HSCT, GVHD, Graft failure
Introduction
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for patients with various hematologic malignancies, bone marrow failure syndrome, and some inherited metabolic disorders [1, 2, 3, 4]. Successful treatment is mainly hindered by relapse, infections, graft-versus-host disease (GVHD), and rejection of the graft [5, 6]. Donor T cells in the graft encourage engraftment, whereas remaining recipient T cells increase the risk for rejection. Known risk factors for rejection/graft failure are HLA-mismatched graft, T cell depletion of the graft, and reduced intensity conditioning [7, 8, 9]. When using alternative donors, the risk for graft failure is increased compared to when using HLA-identical sibling donors [10, 11]. For this reason, many transplant centers treat the recipients of unrelated donor stem cells with anti-T cell antibodies (ATG) before infusion of the graft [12, 13]. This strategy intends to deplete in vivo T cells in patients. In the past, studies have not considered the incompatibility in the ABO blood group between donor and recipient an important factor for outcome after HSCT [14]. More recent studies, however, conclude that ABO differences can play a role in graft rejection and overall survival (OS) [15, 16]. Some studies suggest that ABO incompatible HSCT is associated with reduced relapse rates and improved overall survival in patients with acute leukemia [17]. Until now, in most centers ABO incompatibility between donor and recipient was not considered when selecting the optimal donor. In addition, studies have not extensively examined the differences in other blood group systems between donor and recipient and the relevance of the outcome after HSCT. The Rh antigen is assumed to be expressed only on red blood cells, but other blood group systems such as MNS and Duffy are coexpressed on organs and tissue. This study isolates factors associated with rejection/graft failure in conventional full-dose conditioned recipients of HLA-matched unrelated donor stem cells.
Patients and Methods
Patients
This study includes 224 patients with leukemia who received transplants from unrelated donors between 1991 and 2003 at the Karolinska University Hospital. There were 120 males and 104 females, with a median age of 29 years (<1-55). The diagnoses were acute leukemia (139), chronic leukemia (71), and myelodysplastic syndrome (14) (Table 1). At the time of the transplant, 107 (48%) patients were in first complete remission (CR1) or chronic phase.
Table 1. Characteristics of Patients and Donors
| n = 224 | |
|---|---|
| Diagnosis | |
 Acute leukemia | 139 |
| Chronic leukemia | 71 |
| Myelodysplastic syndrome | 14 |
| Disease stage (early/late)⁎ | 107/117 |
| Sex (male/female) | 120/104 |
| Age | 29(<1-55) |
| Nucleated cell-dose (×108/kg) | 3.5(0.2-63.8) |
| CD34 cell dose (×106/kg) | 5.9(0.4-56.4) |
| Donor sex (male/female) | 136/86 |
| Donor age | 36(19-56) |
| Donor | |
| HLA-A, -B, -DR match | 200 |
| Allele mismatch | 24 |
| Conditioning | |
| TBI 10 Gy + Cy | 119 |
| Fractionated TBI + Cy | 48 |
| Busulfan + Cy | 57 |
| ATG (Thymo/ATG-F/OKT-3) | 161/18/45 |
| GVHD prophylaxis | |
| CsA+MTX | 210 |
| CsA+Pred or MMF | 14 |
| SC source (BM/PBSC) | 152/72 |
| Graft failure | 6(2.7%) |
⁎Early: CR1 or CP1, late; all other. |
HLA Typing
Before 1997, HLA class I typing was serologic. Since 1997, we have used PCR-SSP low-resolution typing for class I. Since July 1992, we have used the PCR methods that use sequence-specific primer pairs [18]. All patients have recently been retrospectively retyped using PCR-SSP high-resolution typing for both HLA class I and II antigens [19].
Blood Group Serology
ABO and RhD blood typing was done according to routine methods, both in the solid-phase technique and manual tube methods. In the latter case, agglutination was read microscopically. Rh, MNSs, and Kidd phenotypes were performed in tubes according to the manufacturer’s instruction either by direct agglutination or by indirect antiglobulin test. The phenotyping included Rh, MNS, and Kidd on both the donor and recipient. Titration of ABO antibodies in the patient sample against donor erythrocytes, or if donor erythrocytes were not available, test erythrocytes, was done with the standard tube technique.
Stem Cell Source
A bone marrow graft was given to 152 patients, and 72 patients received stem cells from peripheral blood after the donor had been mobilized with granulocyte colony-stimulating factor (G-CSF) [20]. Red blood cells (RBCs) were depleted when patients received ABO major incompatible bone marrow and exhibited high titer anti-A and/or anti-B. Nucleated cell dose was determined after RBC depletion.
Donors
Median age of the donors (136 males and 86 females) was 36 years (19-56). Two hundred patients and donor pairs were HLA-A, -B, and -DR identical, and 24 patients had an allele-level mismatched donor (2 HLA-A, 9-B, and 13-DR).
Conditioning
Conditioning consisted of 120 mg/kg cyclophosphamide in combination with 10 Gy single-dose total-body irradiation (TBI) (n = 119), 4 × 3 Gy fractionated TBI (n = 48), or 16 mg/kg busulfan (Bu) (n = 57) [21]. All patients received antithymocyte globulin (ATG; Thymoglobulin, Genzyme, MA; or ATG-Fresenius, Fresenius, Gräfelfing, Germany) or OKT-3 for 2-5 days during conditioning [12]. One hundred sixty-one patients received thymoglobulin (2 mg/kg/day), 18 patients received ATG-Fresenius (5 mg/kg/day), and 45 patients received OKT-3 (5 mg/day).
GVHD Prophylaxis
As prophylaxis against GVHD, most patients received cyclosporine (CsA) combined with methotrexate (MTX) [22]. Because of anticipated liver toxicity, MTX was replaced by prednisolone in 11 patients. CsA combined with mycophenolate mofetil (MMF) was given to 3 patients [9].
Supportive Care
As a prophylactic gut decontamination, the patients received ciprofloxacin 500 mg twice daily in combination with oral amphotericin-B. G-CSF was given as prophylaxis to 157 (70%) patients after HSCT until neutrophil engraftment (>0.5 × 109/L) [23, 24].
Definitions
An ABO blood group incompatibility occurred if the recipients and the donors’ blood groups were not identical. A minor mismatch occurred when the graft contained anti-A and/or anti-B antibodies against ABO blood group antigens on the recipient erythrocytes. A major mismatch occurred when the patient had anti-A and/or anti-B antibodies against ABO blood group antigens on the donor erythrocytes. Bidirectional mismatch was defined as when both a minor and major mismatch occurred, such as A to B or B to A.
Chimerism Analysis
For chimerism analysis, peripheral blood (PB) samples were collected from the donor and recipient before transplant and from the recipient on days +14, +21, +28, and usually every other week up to 3 months and monthly thereafter [25]. DNA from donor and recipient pretransplantation samples was extracted using standard protocols (Qiagen, Hilden, Germany). To evaluate lineage specific chimerism, CD3-, CD19-, and CD33-positive cells were selected from PB using immunomagnetic beads (Dynal, Oslo, Norway).
The methodology and sensitivity of chimerism analysis in the various cell lineages has been described elsewhere [25]. Briefly, pretransplant recipient and donor DNA samples were amplified with 5 different minisatellite primer pairs to obtain at least 1 informative locus. PCR analysis, using the chosen primer pair, was done on sequential patient samples. PCR amplified products were separated, using a ready-to-use polyacrylamide gel electrophoresis (PAGE) system (Pharmacia Biotech, Uppsala, Sweden), by 12.5% nondenaturing PAGE. PCR amplified band patterns were analyzed in visible light after a 90-minute automated silver staining procedure (Pharmacia Biotech, Uppsala, Sweden). We used a semiquantitative estimation of mixed chimerism that compared recipient-band intensity and donor-band intensity to a serial 10-step dilution assay by mixing patient and donor DNA.
Engraftment
Marrow engraftment was monitored by daily blood counts. When appropriate, marrow aspirate cellularity and chimerism was analyzed. Engraftment was defined as the first of 2 consecutive days when ANC was >0.5 × 109/L. Graft failure was defined as failure to produce a persistent donor cell engraftment measured by chimerism analysis. Primary GF or rejection was defined as marrow hypoplasia (<10% cellularity in marrow) with a peripheral PMN less than 0.5 × 109/L persisting beyond day 21 post-HSCT as confirmed by chimerism analysis. Patients were considered to have secondary GF if they initially showed signs of engraftment and later developed marrow hypoplasia that required frequent transfusions beyond day 60 and showed no signs of donor cells according to chimerism analysis.
Statistics
For assessment of factors predicting GF, a methodology was used in a competing risks setting, death within 180 days after HSCT without GF being treated as a competing event. Univariate and multivariate analyses were then performed using Gray’s test and the proportional subdistribution hazard regression model of Fine and Gray. A stepwise backward procedure was used to construct a set of independent predictors for the endpoint. All predictors with a P-value <.10 were considered and were sequentially removed if the P-value in the multiple model was >.05. All tests were 2 sided. The type I error rate was fixed at .05 for factors potentially associated with time-to-event outcome. Several potential risk factors were studied (Table 2). This analytic approach is designed to generate predictive factors for GF after HSCT. The incidence of graft failure was estimated using a nonparametric estimator of cumulative incidence curves. All analyses were carried out using the cmprsk package (developed by Gray, June 2001) on Splus 2000 software and Statistica software.
Table 2. Results from the Univariate Analysis of Factors Associated with Graft Failure after HSCT with Matched Unrelated Donors
| Factor | OR | CI | P |
|---|---|---|---|
| ABO match | |||
| Identical | 1.0 | ||
| Mismatch | 3.38 | 0.38-29.8 | .27 |
| Minor mismatch | ⁎ | ⁎ | .036 |
| Major mismatch | 12.2 | 1.43-104 | .021 |
| Bidirectional MM | 6.96 | 1.28-37.7 | .024 |
| RhD match | |||
| Identical | 1.0 | ||
| Mismatch | 1.64 | 0.29-9.29 | .58 |
| MNSs match | |||
| Identical | 1.0 | ||
| Mismatch | 0.55 | 0.11-2.80 | .47 |
| Kidd match | |||
| Identical | 1.0 | ||
| Mismatch | 0.62 | 0.11-3.51 | .59 |
| Sex | |||
| Male | 1.0 | ||
| Female | 2.36 | 0.42-13.3 | .33 |
| Age | |||
| ≥10 years | 1.0 | ||
| <10 years | 2.36 | 0.57-16.6 | .19 |
| Disease stage | |||
| CR1/CP1 | 1.0 | ||
| Later | 4.61 | 0.54-39.3 | .16 |
| NC-dose | |||
| Continuous | 0.98 | 0.86-1.11 | .72 |
| CD34 cell dose | |||
| Continuous | 0.94 | 0.79-1.13 | .51 |
| Donor sex | |||
| Male | 1.0 | ||
| Female | 0.31 | 0.03-2.72 | .29 |
| Donor age | |||
| Continuous | 0.94 | 0.83-1.05 | .25 |
| HLA-A, -B, -DR match | |||
| Match | 1.0 | ||
| Allele mismatch | 4.30 | 0.79-23.3 | .09 |
| HLA-C | |||
| Match | 1.0 | ||
| Mismatch | 3.06 | 0.62-15.2 | .17 |
| HLA-C, -DP, -DQ | |||
| Match | 1.0 | ||
| No of mismatches | 2.01 | 0.87-4.67 | .10 |
| Conditioning | |||
| Busulfan | 1.0 | ||
| TBI | 0.67 | 0.12-3.82 | .65 |
| ATG type | |||
| All others | 1.0 | ||
| Thymoglobulin | 1.99 | 0.22-17.6 | .53 |
| Stem cell source | |||
| Bone marrow | 1.0 | ||
| Peripheral blood | 1.06 | 0.19-5.94 | .95 |
⁎Indicates that it is not possible to determine, as no patients with minor mismatch had graft failure. |
Results
Blood Group Antigens
One hundred thirty-five (60%) patients received an ABO mismatched graft and 89 received an ABO matched graft. Of the mismatched grafts, 67 (30%) were major mismatched and 68 (30%) minor mismatched. A bidirectional mismatch was found in 16 (7%) cases. A blood group antigen RhD mismatch was found in 53 (24%) cases, MNSs mismatch in 144 (64%), and Kidd (Jka/b) mismatch in 99 (44%) cases.
Graft Failure
Graft failure (GF) was seen in 6 (2.7%) patients with a median of 64 days (range 23-132) after HSCT (Figure 1). Of these 6 patients, 3 had primary GF or rejected their grafts and 3 had a secondary GF. In the univariate analysis, 4 factors were significantly associated with GF (Table 2). In the multivariate analysis, major ABO mismatch (odds ratio [OR] 14.9, 95% confidence interval [CI] 2.01-110, P = .008) and HLA-A, -B, or -DR allele level mismatch (6.42, 1.19-34.8, P = .03) were the only factors significantly associated with GF. No correlation between other blood group antigens (Rh, MNSs, and Kidd) and GF was found (Table 2). In patients with and without major ABO mismatch, the incidence of GF was 7.5% (5 of 67) and 0.6% (1 of 157) (Figure 2a, P = .02), respectively. In patients with and without HLA allele-level mismatch, the incidence of GF was 8.3% (2 of 24) and 2.0% (4 of 200) (Figure 2b, P = .09), respectively. In patients with both a major ABO mismatched and an HLA-allele mismatched donor (n = 5), the incidence of GF was 20%. None of the 138 patients with no risk factors developed GF (Figure 3). Patients with GF are displayed in Table 3.
Figure 1.
Cumulative incidence of graft failure (GF) and death without GF in 224 patients with leukemia who received hematopoietic stem cell transplantation (HSCT) from unrelated donors.
Figure 2.
Cumulative incidence of graft failure (GF) depending on a) ABO compatibility and b) grade of HLA match, in 224 patients with leukemia who received hematopoietic stem cell transplantation (HSCT) from unrelated donors.
Figure 3.
Cumulative incidence of graft failure (GF) depending on number of risk factors (RF) found in the multivariate analysis (ABO major mismatch and HLA allele mismatch) in 224 patients with leukemia who received hematopoietic stem cell transplantation (HSCT) from unrelated donors.
Table 3. Patient Characteristics for Patients with Graft Failure after Unrelated Donor Stem Cell Ttransplantation
| UPN | Age | Gender | Diagnosis | SC dose ×108/kg | SC Source | Conditioning | Immune Suppression | Donor Blgr | Recip blgr | HLA Mismatch | GF Day |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 397 | 1 | M | AML PR | 14 | BM | FTBI/Cy/VP | CsA+MTX | A | O | DP | 90(gf) |
| 523 | 29 | F | ALL PR | 2.1 | BM | TBI/Cy | CsA+MTX | B | O | 90(gf) | |
| 620 | 47 | F | AML CR1 | 8.4 | PBSC | TBI/Cy | CsA+MTX | B | A | C+DP | 38(gf) |
| 679 | 13 | F | ALL CR2 | 0.7 | BM | FTBI/Holoxan | CsA+MTX | A | O | DR⁎+C+DP+DQ | 23(rej) |
| 850 | 27 | M | AML CR2 | 5.8 | PBSC | Bu/Cy | CsA+MTX | O | O | B⁎+C+DP | 132(gf) |
| 911 | 3 | F | AML CR2 | 2.2 | BM | Bu/Cy | CsA+MTX | A | B | DP | 27(rej) |
⁎Allele level mismatch. |
The procedure of removal of RBCs from ABO major mismatched bone marrow (BM) grafts led to a decrease in total nucleated cell (NC) count by ≤20%. However, when comparing the NC counts in ABO major mismatched BM grafts (RBC removal) with all ABO nonmajor mismatched BM grafts (no RBC removal) no statistical difference was seen (2.5 [0.2-17.0] versus 2.6 [0.7-13.1], P = .5). Furthermore, there was no difference in cell counts in grafts with ABO major mismatched BM grafts with and without GF (2.2 [0.7-14.0] versus 2.5 [0.2-17.0], P = .8). Among patients receiving a peripheral blood stem cell graft, the 2 patients with GF were both HLA-C mismatched (Table 3), raising the possibility that HLA-C may be responsible for these GF. In total, there were 21 HLA-C mismatches in the PBSC group, and 2 of these suffered a GF (9.5%). However, it is not possible to statistically determine this in our model as the numbers of graft failures were too few.
We found no difference in ABO antibody titers between patients with and without GF in major ABO mismatched transplants. The IgG antibody titers were 16 (8-128) and 32 (1-1000), the IgM titers 8 (1-32) and 32 (1-1000) in patients with and without GF, respectively (ns).
Discussion
Known factors increasing the risk for rejection/GF include HLA-mismatched graft, T cell-depleted graft, and reduced intensity conditioning (RIC) [7, 8, 9]. However, in HLA-matched full-dose conventional conditioning and non-T cell depleted HSCT, the risk for GF is increased when using unrelated donors compared to HLA-identical sibling transplants [11]. The reason for this may be minor histocompatibility antigen differences and other unknown factors. In this study, we analyzed 224 consecutive patients with HLA antigen-matched unrelated donors receiving an unmanipulated graft and conventional full-dose conditioning. Historically, the risk for GF in this population is approximately 5%. We found the incidence to be 2.7% in our material. One reason for the low incidence may be that we treat all recipients of an unrelated donor graft with ATG, and that we use high-resolution genomic HLA typing [19, 21]. When using ATG, the recipient’s in vivo T cells are depleted, which may reduce the risk for GF.
In this study, patients with an HLA-A, -B, or -DR allele-level mismatched donor had an increased risk for GF. This is not surprising, as even small differences within the HLA-system may increase the risk for immunologic reactions such as GVHD and rejection. In the multivariate analysis, we found no association between HLA-C mismatch, or additional mismatches within the HLA-DP and -DQ antigens, and GF. However, among patients receiving a PBSC graft the 2 with GF were both HLA-C mismatched (Table 3), raising the possibility that HLA-C may be responsible for these GF [8].
Graft cell dose has previously been shown to be associated to GF [26]. In the present study we were not able to verify that finding.
We studied the effect of differences in various blood group antigens between the recipient and donor. We found that a major ABO mismatched graft was a factor associated to an increased risk for GF (OR 14.9, 95% CI 2.01-110, P = .008). In the univariate analysis, a bidirectional ABO mismatch also was associated with GF, but in the multivariate analysis major ABO mismatch was the strongest factor. A major mismatch implies that the patient had isohemagglutinins against ABO blood group antigens on the donor erythrocytes. Among the other blood group antigens studied, no antibodies occur naturally; they occur only after immunization after transfusions or pregnancies.
There are many reports concerning the effect of ABO incompatibility on results after HSCT. These reports present conflicting results regarding the role of ABO match between patient and donor in HSCT. However, there are now some reports showing a delayed recovery of neutrophils and graft rejection in major ABO mismatched transplants [27, 28, 29]. The explanation for the finding of delayed neutrophil engraftment and increased graft failure may be the presence of antidonor A/B or neutrophil antibodies [30]. It seems likely that high pretransplantation levels of antidonor isoagglutinins and/or residual host B and plasma cells escaping the conditioning regimen may be responsible for these effects. Antidonor A/B antibodies may bind to A/B antigens absorbed on the surface of neutrophils or their precursors in the bone marrow, a condition that could lead to elimination or suppression. At any rate, this process seems slow and time consuming, because graft failure was not acute in any case and appeared between 23 and 90 days after transplantation (Table 3). This is in contrast to T cell-mediated rejection, which can cause either allogeneic resistance with no engraftment of donor cells or an acute rejection occurring within days. However, in this material no correlation between titers of antidonor A/B antibodies and GF was found.
Conclusion
This study shows for the first time that is an increased risk for graft failure may exist when using a major ABO mismatched unrelated donor. With increasing availability of HLA matched unrelated donors, the ABO compatibility between donor and recipient may be considered when selecting the donor. Especially when using HLA allele mismatched donors, a major ABO mismatch should be avoided if possible.
Acknowledgments
We thank Lars-Gunnar Persson for excellent technical and administrative assistance. This study was supported by grants from the Swedish Cancer Society (0070-B03-17XBC), the Children’s Cancer Foundation (02/074 and 03/039), the Swedish Research Council (K2003-32X-05971-23A), the Tobias Foundation, the Stockholm Cancer Society, the Swedish Medical Society, and the Karolinska Institutet.
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PII: S1083-8791(07)00145-0
doi:10.1016/j.bbmt.2007.01.084
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 6 , Pages 675-682, June 2007
