ABO blood type incompatibility lost the unfavorable impact on outcome in unrelated bone marrow transplantation

Abstract

The effects of ABO incompatibility on hematopoietic stem cell transplantation remain controversial. Large cohorts are required to obtain findings that allow for definite conclusions. We previously demonstrated poor overall survival and increased treatment-related mortality (TRM) in ABO-incompatible unrelated bone marrow transplantation (UR-BMT) performed during the period from 1993 to 2005. To improve our understanding of ABO-incompatible transplantation, we reanalyzed the effects of ABO mismatch in a UR-BMT cohort in Japan after 2000. Multivariate analyses for the 2000–2006 cohort showed that major ABO mismatch was associated with poor overall survival (HR, 1.211; 95% CI, 1.062 to 1.381; p = 0.004) and increased TRM (HR, 1.357; 95% CI, 1.146 to 1.608; p < 0.001). In the 2007–2015 cohort, major incompatibility had no effect on overall survival (HR, 0.987, p = 0.804) or TRM (HR, 1.020, p = 0.790). Delayed engraftment of erythrocytes, platelets, and neutrophils in cases of major mismatch was common between the two cohorts. In conclusion, the adverse effect of ABO major incompatibility has become less significant over time.

Introduction

The two major histocompatibility antigen systems that must be considered in the context of transplantation are human leukocyte antigen (HLA) and ABO antigens. ABO blood type incompatibility appears to have less effect than HLA mismatch on outcomes after hematopoietic stem cell transplantation. However, the magnitude of the effect of ABO mismatch remains controversial [1]. One of the problems in studying ABO incompatibility in the context of hematopoietic stem cell transplantation is the number of patients who have been evaluated to date. Data from many patients who have undergone transplantation will be necessary to analyze the independent effects of three types of ABO incompatibility: minor, major, and bidirectional mismatch. In addition, the effect of ABO mismatch may differ in ways dependent on stem cell origin, the type of procedure used for transplantation, and the local transfusion policies before, during, and after stem cell transplantation. Many studies have failed to distinguish related from unrelated donors in the context of bone marrow transplantation (BMT) [1]. One large cohort analysis included 5179 patients (who had received transplants from related or unrelated donors), for whom medical records had been collected by the Center for International Blood and Marrow Transplantation. This study reported that major and minor mismatch were associated with poor overall survival (OS) and increased treatment-related mortality (TRM) [2]. In a study that included 5549 Japanese who had undergone unrelated BMT (UR-BMT) during the period from 1993 to 2005, we found that the effect of major or minor ABO mismatch on survival was inversely correlated with TRM and incidence of grades 3–4 acute GVHD [3]. However, one recent report indicated that ABO mismatch did not affect outcomes of transplantation, regardless of stem cell source [4]. That study was based on a cohort that included 312 BMT patients who had received transplants from related or unrelated donors.

The clinical impact of HLA mismatch in the context of UR-BMT has changed over time. Early reports showed that an HLA-A or HLA-B allele mismatch was associated with worse OS than an HLA-C or HLA-DRB1 allele mismatch [5, 6]. A later study revealed that the presence of single HLA allele mismatches at the HLA-A, HLA-B, HLA-C, or HLA-DRB1 loci equivalently affect the outcome of HSCT [7]. After high-risk HLA allele mismatch combination was reported to increase risk for acute graft-versus-host disease (GVHD), this type of donor was largely avoided by clinicians [8]. The impact of a high-risk HLA allele mismatch combination was nearly negligible among the patients transplanted in 2002–2011 [9]. Although no single factor explained these changes, sophistication or intensification of GVHD prophylaxis may have reduced the detrimental effects of HLA mismatch. This view raised the possibility that the effects of ABO incompatibility on Japanese patients undergoing UR-BMT may have changed since 2006.

Before 2000, many UR-BMT procedures were performed according to the principle of HLA serological matching (antigen matching). HLA allele typing was unavailable in our previous report. This is a second reason to reevaluate the effect of ABO mismatch on modern UR-BMT procedures, which are often performed with consideration of HLA genetic matching during the process of donor selection. In addition, our previous study included malignant lymphoma, multiple myeloma, and aplastic anemia. If nothing else, aplastic anemia may have different aspect of relapse from leukemia. In this study, we extracted a sufficient number of medical records for patients who underwent UR-BMT for leukemia or myelodysplastic syndrome after 2000 from the Japanese registry to improve our understanding of ABO incompatibility. The findings presented below indicate that the effect of ABO mismatch on OS was negligible after 2007.

Methods

Data collection

Hematopoietic stem cell transplantation recipient clinical data were collected by the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the Japanese Data Center for Hematopoietic Cell Transplantation using the Transplant Registry Unified Management Program (TRUMP) [10,11,12]. All patients provided written informed consent for research. The study was approved by the Institutional Review Board of the National Defense Medical College, the Data Management Committees of the JSHCT, and the Japanese Data Center for Hematopoietic Cell Transplantation. All procedures were conducted in accordance with the Declaration of Helsinki.

Inclusion and exclusion criteria

All age patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) who underwent the first BMT from unrelated donor (UR-BMT) between 2000 and 2015 were eligible for this study. Any medical record missing information related to ABO or HLA allele compatibility (HLA-A, B, C, and DRB1) was excluded from analysis. Finally, 8908 patients were included and were divided into three groups depending on transplantation year: 2000–2006, 2007–2011, and 2011–2015. The break points among groups were determined to make the number of patients in each group equivalent (n = 3016, 2736, and 3156, respectively). ABO incompatibility had a significant impact on OS in 2000–2006 group, but not in 2007–2011 and 2011–2015 group (log-rank test, p = 0.0127, 0.7735, and 0.3951, respectively). To increase statistical power for strict evaluation of an impact by ABO mismatch, 2007–2011 and 2011–2015 group were combined, and the following analyses were separately performed in 2000–2006 and 2007–2015 cohort (n = 5892).

Definitions

There are three types of incompatibilities: major incompatibility, which occurs when a patient has anti-A/B against donor red cells; minor incompatibility, which occurs when donor plasma has anti-A/B against the recipient red cells; and bidirectional incompatibility, which occurs when both donor and recipient have anti-A/B against each other. For the purposes of this study, standard-risk diseases were considered to be acute leukemia in first or second remission, CML in first or second chronic phase, and MDS without leukemic transformation. All other diseases were considered high risk. All causes of death except disease progression were considered TRM. Neutrophil engraftment was defined as a peripheral neutrophil count of >0.5 × 109/L for 3 successive days. Platelet engraftment was defined as the first day of unsupported platelet count of ≥20 × 109/L or ≥50 × 109/L for 7 consecutive days. Erythrocyte engraftment was defined as ≥1% reticulocyte for 3 successive days. The occurrence of acute GVHD was evaluated according to standardized grading criteria [13]. The occurrence of chronic GVHD was evaluated according to the traditional criteria in patients who survived more than 100 days after transplantation [14]. Myeloablative (MAC) or reduced intensity conditioning (RIC) regimen was classified according to the criteria outlined by the Center for International Blood and Marrow Transplant Research [15].

Transfusion policy

In minor mismatch, red cells of donor ABO group are transfused after transplant, and plasma and platelets of recipient-type blood group are used until recipient-type red cells disappear. In major mismatch, red cells of recipient ABO group are transfused until antibody against donor-type red cells disappear, and plasma and platelets of donor type are used after transplant. In bidirectional mismatch, group O red cells are transfused from transplant until antibodies against donor-type red cells disappear, and group AB plasma and platelets are used until recipient-type red cells are no longer detected.

Statistical analysis

Background characteristics of patients and transplants were compared with the chi-square test for categorical variables and the Kruskal–Wallis test for continuous variables. The probability of OS was estimated according to the Kaplan–Meier method, and the groups were compared using the log-rank test. The probabilities of TRM; engraftment of neutrophil, platelet, and erythrocyte; acute and chronic GVHD; and GVHD and bleeding as a cause of death were estimated on the basis of a cumulative incidence method to accommodate competing risks. Patients with second transplantation were excluded in analysis for cause of death. Cox or Fine and Gray proportional hazards models were used to assess the effects of ABO incompatibility. Variables considered included patient age, patient gender, donor age (<40 years, ≥40 years), gender combination of patient and donor, disease risk, diagnosis (AML, ALL, CML, MDS), cytomegalovirus status, RIC, GVHD prophylaxis, ATG use, HLA allele compatibility (8/8, 7/8, ≤6/8), and performance status (0–1, ≥2). P values of <0.05 were considered significant. Stata version 14 statistical software (Stata Corp., College Station, TX) was used to conduct all statistical analyses.

Results

Patients

Table 1 showed characteristics of patient, donor, and transplant in the 2000–2006 and 2007–2015 cohorts. The median follow-up period of survivors was 121 and 37 months, respectively. In comparison of both cohorts, almost all factors except patient gender showed significant difference. Reduced intensity transplant was increased (12 vs. 27%) according to advancing patient’s age (median 36 vs. 48 years old). Use of tacrolimus-based GVHD prophylaxis has recently increased (65 vs. 86%), as has use of ATG.

Table 1 Patient and transplant characteristics according to date of transplantation

The background characteristics of ABO compatibility groups within the two cohorts are shown in Table 2. In the 2000–2006 cohort, gender combination, GVHD prophylaxis, HLA allele compatibility, and performance status were significantly different among the ABO-matched (M), minor mismatched (MI), major mismatched (MA), and bidirectional mismatched (IA) group. More HLA-mismatched unrelated donors were selected in the context of ABO-incompatible transplantation (M, 45%; MI, 58%; MA, 66%; IA, 61%); in this context, tacrolimus tended to be used as GVHD prophylaxis (M, 62%; MI, 65%; MA, 69%; IA, 69%). Female to male transplant was more frequent in ABO mismatch groups (M, 17%; MI, 21%; MA, 21%; IA, 19%). Among the 2007–2015 cohort, these factors other than HLA allele match disappeared as a significant background difference, and ATG use became a new additional one. More HLA-mismatched unrelated donors were consistently chosen in ABO-incompatible transplantation (M, 40%; MI, 53%; MA, 52%; IA, 57%), but the fraction was decreased in the all groups compared with 2000–2006 cohort. Use of ATG was increased in ABO mismatched transplantation among the 2007–2015 cohort (M, 6%; MI, 9%; MA, 8%; IA, 9%).

Table 2 Patient and transplant characteristics according to ABO incompatibility and transplantation date

Transplantation outcomes

In UR-BMT before 2006, unadjusted 3 year OS of ABO-matched, minor, major, and bidirectional ABO-incompatible transplant was 53% (M, 95% CI, 50–55%), 52% (MI, 95% CI, 48–56%), 46% (MA, 95% CI, 42–50%), and 50% (IA, 95% CI, 44–55%), respectively, with significant difference (Fig. 1a, log-rank test, p = 0.0127). High incidence of TRM was observed in major mismatch (Fig. 1c). After 2007, however, unadjusted 3 year OS of these four groups was 55% (M, 95% CI, 53–56%), 56% (MI, 95% CI, 53–59%), 54% (MA, 95% CI, 50–57%), and 56% (IA, 95% CI, 51–60%), respectively, and the difference of survival among ABO compatibility groups was lost (Fig. 1b, log-rank test, p = 0.8553). Cumulative incidence of TRM was also similar among four groups (Fig. 1d). In 2000–2006 cohort, the difference in OS was more obvious in MAC transplantation (Supplementary Fig. 1a, n = 2506, log-rank test, p = 0.0024), and there was no significant difference in RIC (Supplementary Fig. 1b, n = 365, log-rank test, p = 0.6860). Among the 2007–2015 cohort, the survival difference was not significant in either conditioning (Supplementary Figs. 1c and 1d; MAC, n = 4314; RIC, n = 1574; log-rank test, p = 0.6706 and p = 0.8952, respectively). The OS of major mismatch caught up with that of match cohort after 2007.

Fig. 1
figure1

Overall survival and treatment-related mortality (TRM) by ABO compatibility. In the 2000–2006 cohort, major mismatch impaired overall survival (a) and TRM (c). Among the 2007–2015 cohort, ABO compatibility had no effect on overall survival (b) or TRM (d)

Multivariate analyses in 2000–2006 cohort showed that major ABO mismatch had poor OS (Table 3, HR 1.211, p = 0.004) and increased TRM (HR 1.357, p < 0.001). The incidence of 3 year TRM post-transplantation was 30% (M, 95% CI, 27–32%), 32% (MI, 95% CI, 28–36%), 40% (MA, 95% CI, 36–45%), and 33% (IA, 95% CI, 28–40%). Among the 2007–2015 cohort, Cox proportional hazard analysis indicated that major ABO incompatibility had no effect on OS (HR 0.987, p = 0.804). Effects of ABO mismatch on TRM were also disappeared in the Fine–Gray model analysis of the cohort after 2007. All the ABO compatibility groups of the 2007–2015 cohort had similar incidence of 3 year TRM (M, 29%; MI, 28%; MA, 30%; IA, 28%). There was no effect in either cohort of ABO mismatch on the incidence of acute or chronic GVHD. As a cause of death, however, the occurrence of GVHD was significantly higher in major mismatch transplant than in match of the 2000–2006 cohort (HR 1.665, p = 0.015, Table 4, Supplementary Table). Bleeding was also observed to contribute the increase in TRM in major mismatch (HR 1.993, p = 0.014). These differences in the cause of death disappeared in the 2007–2015 cohort. As GVHD prophylaxis, ATG administration improved OS (HR 0.792, 95% CI, 0.673–0.932, p = 0.005) with decreasing TRM (HR 0.622, 95% CI, 0.491–0.788, p < 0.001) in the 2007–2015 cohort. We also observed that the use of tacrolimus had a favorable impact on OS (HR 0.859, 95% CI, 0.765–0.964, p = 0.010) and TRM (HR 0.823, 95% CI, 0.703–0.964, p = 0.016) in the 2007–2015 cohort. In contrast, both ATG and tacrolimus had no significant effect on OS and TRM in the 2000–2006 cohort (p = 0.536, p = 0.623, respectively).

Table 3 Multivariate analysis: effects of ABO incompatibility on outcomes of transplantation
Table 4 Multivariate analysis: effects of ABO incompatibility on the causes of death

In contrast to the effect on survival, ABO major incompatibility delayed erythrocyte recovery as ever (Fig. 2a). The 100 day cumulative incidence of erythrocyte engraftment in major and bidirectional mismatch was 89% (MA, 95% CI, 86–92%) and 91% (IA, 95% CI, 87–95%) compared with 96% of ABO-matched graft (M, 95% CI, 95–97%) in 2000–2006 cohort. The 100 day erythrocyte engraftment was 88% in the 2007–2015 cohort (M, 95% CI, 87–90%), 89% (MI, 95% CI, 87–91%), 78% (MA, 95% CI, 75–80%), and 86% (IA, 95% CI, 83–89%). Delayed engraftment of platelet (achievement of 20 × 109/L without platelet transfusion) was also observed in major mismatch transplant compared with that in ABO-compatible transplant (HR 0.818, p < 0.001). In minor and bidirectional mismatch, platelet engraftment tended to retard (HR 0.913 and 0.898, p = 0.012 and p = 0.022, respectively). The 100 day cumulative incidence of 20 × 109/L platelet in ABO match and mismatch groups was 88% (M, 95% CI, 87–89%), 85% (MI, 95% CI, 83–87%), 83% (MA, 95% CI, 80–85%), and 86% (IA, 95% CI, 83–89%, Fig. 2c). Achievement of 50 × 109/L platelet showed the similar results (Fig. 2d). Engraftment of neutrophil was significantly slower in major and bidirectional mismatch group (HR 0.893 and 0.908, p = 0.001 and p = 0.022) than ABO-compatible group, but the four groups showed the similar 100 day cumulative incidence (M, 99%; MI, 98%; MA, 98%; IA, 98%, Fig. 2b).

Fig. 2
figure2

Engraftment of erythrocytes, neutrophils, and platelets in the 2007–2015 cohort. Major mismatch delayed erythrocyte recovery (a). ABO compatibility had a significant effect on neutrophil engraftment, but the difference was negligible (b). Platelet recovery to 20 × 109/L (c) or 50 × 109/L (d) was slower among patients who received ABO-incompatible grafts

Discussion

Medical staffs concerning hematopoietic stem cell transplantation have been making a lot of efforts to improve the outcome of transplantation and overcome immunological barrier caused by HLA and other differences. The impact of certain HLA incompatibility has changed in the modern era of transplantation [7, 9]. Our primary approach for ABO-incompatible BMT was the removal of red blood cells and collection of mononuclear cells from major/bidirectional mismatched bone marrow using apheresis system, and removal of plasma from minor mismatched bone marrow. There was no great change in our processing technique between the 2000–2006 and 2007–2015 cohorts. However, our observations of a sufficiently large UR-BMT cohort showed that ABO mismatch no longer has a significant effect on OS. Before 2007, major ABO mismatch impaired OS through increased TRM. In comparison of the cohort before and after 2007, many factors of UR-BMT were changed. In the recent cohort, as shown in Table 1, more RIC transplantation was performed for older patients with disease containing decreased CML and increased MDS. GVHD prophylaxis was consolidated with more tacrolimus-based regimen and more use of ATG. The number of donors with ≥2 HLA allele mismatches decreased, and the performance status of patients improved.

In our analysis, no single factor explained the vanishing impact of ABO incompatibility. More tacrolimus-based GVHD prophylaxis tended to be used for ABO-incompatible transplant in the 2000–2006 cohort, and tacrolimus-based regimen showed high rate in all blood type combination after 2007. This change suggested that enhanced GVHD prophylaxis may have diminished the detrimental effect of ABO mismatch on OS and TRM. We previously reported on a trend toward increasing occurrence of GVHD in ABO mismatch UR-BMT. Although we did not observe an increase in the occurrence of GVHD even in the 2000–2006 cohort included in this study, we observed that higher number of cases of GVHD contributed to mortality in the 2000–2006 major mismatch. We also detected bleeding as another cause of death in major incompatible transplant in the 2000–2006 cohort. This was compatible with the delay in platelet engraftment observed in major mismatch. Progress in transfusion support may decrease mortality of major mismatch in the 2007–2015 cohort.

In the recent cohort with increased RIC, we were unable to detect the influence of immune-hematological complications such as severe passenger lymphocyte syndrome. Our TRUMP registry, unfortunately, does not contain information regarding delayed hemolysis as a feature of passenger lymphocyte syndrome. Methotrexate (MTX) plus calcineurin inhibitor was used for 94.6% of the minor mismatched patients (299 of 316 cases) with RIC conditioning in the 2007–2015 cohort. Only 17 patients received mycophenolate mofetil as the GVHD prophylaxis. Use of MTX is known to reduce a risk of this syndrome, and might help in decreasing TRM in our analysis [16].

Bidirectional mismatch did not seem a simple combination of major and minor mismatch in our analysis. As shown in Supplementary Table of causes of death, high incidence of bleeding was observed in both major and bidirectional mismatch in the 2000–2006 cohort. GVHD death was more frequent in minor and major mismatch; however, there is no difference in the frequency of GVHD death between match and bidirectional mismatch. One possibility is that the mechanism promoting severe GVHD differs between cases of major and minor incompatibility. In bidirectional mismatched transplants, these effects might counteract each other.

Delayed neutrophil engraftment was also observed in other reports [17, 18]. They speculated that anti-donor isohemagglutinin may bind to A/B antigens adsorbed on the surface of neutrophils or their precursors. However, the difference was only one day, which could be detected in the analysis of large number of samples. We believed that this one-day delay of neutrophil engraftment had almost no implication in our clinical practice.

Genotype HLA matching has also changed our donor selection in UR-BMT. Genotyping of HLA-A, B, and DR was introduced as part of the Japan Marrow Donor Program (JMDP) in 2005; HLA-C became essential for donor searches in 2009. The increase in size of JMDP’s donor pool has made it easier to find an HLA-identical donor despite an ABO-incompatible combination. Accordingly, HLA allele mismatch transplantation was more common among the 2000–2006 cohort, compared with the 2007–2015 cohort. The effects of ABO mismatch may become more apparent through analyses that are limited to cases of HLA allele mismatch transplantation. Recently, ABO incompatibility was reported to have a significant clinical effect on survival and acute GVHD in patients undergoing haploidentical transplantation [19]. ABO major mismatch was identified as a risk factor for TRM in the context of transplantation from HLA-identical siblings or HLA-haplotype-matched relatives [20]. However, subgroup analysis for patients who received transplants characterized by HLA allele mismatch failed to demonstrate a significant effect of ABO mismatch in the 2006–2015 cohort included in this study (data not shown). These observations suggested that the effect of ABO mismatch may vary according to the particular type of graft and/or transplantation procedure. Analyses of medical records in the TRUMP registry showed that ABO incompatibility had no effect on OS in the context of BMT from matched sibling donors (unpublished observation). In order to ascertain whether there is any effect of ABO mismatch on transplant outcomes in cases involving use of cord blood, a sufficient number of patients should be analyzed. Outcomes must be analyzed with consideration of associated advancements in the technologies and procedures required for transplantation.

In conclusion, our registry analysis showed that ABO mismatch in the context of UR-BMT no longer affects survival or TRM but may delay engraftment of erythrocytes and/or platelets. Changes in the cause of death in ABO major mismatch transplant suggested that GVHD prophylaxis and platelet transfusion support might play crucial roles. When selecting an ABO major incompatible UR-BMT donor, we recommended that the clinician somewhat intensify GVHD prophylaxis and consider adequate transfusion support to anticipate a delay in recovery of erythrocyte and/or platelet levels, in addition to the removal of erythrocytes or plasma from the graft at the transplantation.

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Acknowledgements

This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from Japan Agency for Medical Research and Development, AMED under Grant Number 18ek0510023h0002. The authors thank all of the physicians and data managers at the centers that contributed valuable data on transplantation to the Japan Society for Hematopoietic Cell Transplantation and the Japan Marrow Donor Program.

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Kimura, F., Kanda, J., Ishiyama, K. et al. ABO blood type incompatibility lost the unfavorable impact on outcome in unrelated bone marrow transplantation. Bone Marrow Transplant 54, 1676–1685 (2019). https://doi.org/10.1038/s41409-019-0496-2

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