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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1150-1156
TRANSPLANTATION
From the Transplantation Biology and Clinical Statistics Programs,
Clinical Research Division, Fred Hutchinson Cancer Research Center; and
the Departments of Medicine and Biostatistics, University of
Washington, Seattle, WA.
The gradual disappearance of host antidonor isohemagglutinins after
major ABO-mismatched hematopoietic stem cell (HSC) allografts has been
attributed to the gradual destruction of host plasma cells by
graft-versus-host effects. To corroborate this hypothesis, we
retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between
1983 and 1998. All patients were conditioned by high-dose pretransplant
therapy and given methotrexate/cyclosporine for graft-versus-host
disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched
related and 228 had unrelated grafts. We asked whether unrelated
recipients experienced a more rapid disappearance of isohemagglutinins
than related recipients, and whether, within the groups of related and
unrelated recipients, the titer disappeared faster in patients with
GvHD than in those without GvHD. The median time to reach undetectable
antidonor IgG and IgM titers was significantly shorter in unrelated
recipients (46 versus 61 days; P = .016). In addition,
related recipients with GvHD had a 2.2-fold increased likelihood
(1.12-4.39,95% CI; P = .02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of
antidonor isohemagglutinins led to significantly increased red blood
cell (RBC) transfusion requirements in the ABO-mismatched related
patients compared with ABO-matched counterparts. However, time to
neutrophil and platelet engraftment, incidence of GvHD, and survival
were not influenced by ABO incompatibility. In conclusion, our results
corroborate the hypothesis that the rate of disappearance of antidonor
isohemagglutinins after ABO-mismatched allogeneic HSC grafts is
influenced by the degree of genetic disparity between donor and
recipient, suggesting a graft-versus-plasma cell effect.
(Blood. 2000;96:1150-1156)
ABO incompatibility between donor and recipient is not
a barrier for successful allogeneic hematopoietic stem cell (HSC)
transplantation even though it is well established that major ABO
incompatibility may lead to prolonged destruction of donor-derived
erythrocytes and prolonged transfusion requirements.1-8
Plasma exchange in the recipient and red blood cell (RBC) depletion of
the donor marrow are widely adopted strategies to minimize the
possibility of acute hemolytic complications associated with infusion
of major ABO-mismatched grafts.9-12 Antibody-producing
plasma cells are terminally differentiated and nonproliferative and
therefore relatively resistant to chemotherapy and
radiotherapy.13-15 This, in turn, explains persistence of
isohemagglutinins for extended periods in some recipients of major
ABO-mismatched allografts. If prolonged survival of
isohemagglutinin-producing plasma cells in the patient was the
key mechanism accounting for elevated posttransplant antidonor isohemagglutinin titers, it is reasonable to speculate that the degree
of genetic disparity between donor and recipient with a resulting
graft-versus-host (GvH) effect might influence the rate of
titer disappearance after ABO-mismatched allogeneic HSC transplantation.
In this study we addressed this question and asked, (1) whether
unrelated recipients of HSC transplants experienced a more rapid
disappearance of isohemagglutinins than related recipients because of
the greater degree of genetic disparity between donors and hosts; and
(2) whether within the groups of related and unrelated recipients, the
rates of titer disappearance were faster in patients with
graft-versus-host disease (GvHD) than in those without this complication. We retrospectively analyzed results from 383 major or
major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998 for treatment of leukemia, lymphoma, and myelodysplastic syndromes. We found that the median time to reach
clinically irrelevant isohemagglutinin titers was significantly shorter
in unrelated recipients than in related recipients. In addition,
related recipients with GvHD had a significantly increased likelihood
of reaching undetectable isohemagglutinin titers within 100 days after
transplant than patients without GvHD. Persistence of antidonor
hemagglutinins was also associated with increased RBC transfusion
requirements; however, time to neutrophil and platelet engraftment,
incidence of GvHD, and survival were not influenced by ABO
incompatibility. These findings suggest that the degree of genetic
disparity between donor and host influences the rate of
isohemagglutinin titer disappearance in the host, which is evidence for
a graft-versus-plasma cell effect.
Patients
Standard procedures for ABO-incompatible transplants
Major ABO-mismatch.
(Presence of hemagglutinins in the recipient against erythrocyte
antigens of the donor.) For MRD transplants, donor marrow was
RBC-depleted; for MUD transplants, plasma exchange with pooled AB-plasma was performed in the recipient when antidonor erythrocyte IgG
or IgM titers were greater less 1:16. Posttransplant isohemagglutinin IgG and IgM titers were followed on a weekly basis, and RBC units with
blood group O were used for transfusions until isohemagglutinin titers
were undetectable for 2 consecutive weeks. At that point, RBC
transfusions were switched over to stem cell donor blood type.
Minor ABO-mismatch.
(Presence of hemagglutinins in the donor against erythrocyte antigens
of the recipient.) Unmanipulated donor marrow was infused when
antirecipient hemagglutinin titers were less than 1:128. Plasma
depletion of donor marrow was performed if antirecipient-ABO titers
were greater than 1:128. RBCs of stem cell donor blood group were
transfused after transplant.
Major plus minor ABO-mismatch.
(Bi-directional presence of hemagglutinins.) In addition to the
antibody-removal guidelines used for major ABO-mismatched MRD and MUD
transplants, donor marrow was plasma depleted if
antirecipient-ABO titers were greater than 1:128. Posttransplant RBC
transfusion guidelines were according to major ABO-mismatched transplants.
Monitoring of hemagglutinin titers after transplant
Statistical methods Summary statistics such as medians and ranges are presented. Wilcoxon rank sum tests were used to compare time to events in which all subjects reached the titer endpoints. Kaplan-Meier estimates summarize survival within ABO compatibility groups for MRD and MUD patients.18 For survival analysis, follow-up time was censored at the date of last contact for surviving patients. Incidences for acute GvHD and attainment of hemagglutinin titer endpoints were calculated using cumulative incidence estimates.19 The time each patient contributed to these analyses was the minimum of time to the endpoint of interest, death, or last contact. Death before reaching the endpoint was treated as a competing risk, and time was censored at the date of last contact for surviving patients who did not reach the endpoint of interest. Log rank statistics were used for comparisons between all time-to-event endpoints involving censored data.19 Cox proportional hazard regression models were used to assess the impacts of MRD versus MUD, acute GvHD and plasma exchange on time to hemagglutinin titer endpoints.20 Acute GvHD was treated as a time-dependent covariate in this analysis. For acute GvHD and hemagglutinin titer endpoints, when using the log rank statistic and Cox proportional hazards regression, the censoring time was either the date of last contact or death for patients not reaching the endpoint of interest.
Donor-directed hemagglutinin titers after MRD versus MUD marrow transplantation To investigate whether the time course of isohemagglutinin titer disappearance was influenced by genetic disparity between donor and recipient, we determined the number of posttransplant days required to reach different isohemagglutinin titer endpoints in major or major/minor ABO-mismatched MRD versus MUD recipients. The results are summarized in Table 2 and demonstrate that all 3 chosen titer endpoints were reached significantly earlier in recipients of MUD compared with recipients of MRD transplants. This analysis, however, only considered patients who reached the titer endpoints during the follow-up period. Figure 1 shows the cumulative incidence curves and Table 3 the relative risks (RR) from Cox regression analysis for attaining different titer endpoints for MRD versus MUD patients. This approach also included patients who did not reach the titer endpoints during follow-up and showed that MUD patients had a significantly higher probability of clearing their IgG isohemagglutinins ("IgG-undiluted") than MRD patients (P < .001; Cox regression analysis). The P-value for using "IgM-undiluted" as an endpoint, however, was only borderline significant (P = .057). When "IgG/IgM-nil" was used as an endpoint, isohemagglutinin titer disappearance was not significantly different between the MUD and MRD groups (P = .61). In addition, a Cox proportional hazard regression analysis was performed to evaluate the effect of donor type on titer disappearance while adjusting for the effects of TBI. The results of this analysis showed no effect of TBI use or dose on titer disappearance, nor did they change the effect donor type had on titer disappearance. In summary, accounting for the difference in TBI use and dose between MRD and MUD recipients did not ameliorate the difference in hemagglutinin titer disappearance seen between MRD and MUD transplants.
Influence of acute GvHD on time to disappearance of isohemagglutinin titers To determine whether GvH reactions could constitute a mechanism to explain the more rapid clearance of isohemagglutinin titers in the MUD group, we carried out a Cox proportional hazard regression analysis to evaluate the RR of reaching different titer endpoints using acute GvHD as a time-dependent covariate (Table 4). In the group of MRD transplants, patients with acute GvHD grades II to IV had a 1.71- to 2.22-fold increased likelihood of reaching all 3 titer endpoints compared with patients with acute GvHD grades 0 to I; these differences were statistically significant (P < .02). A trend in the same direction was observed in the group of MUD patients (increase in RR between 1.26 and 1.59). However, these differences did not reach statistical significance. Figures 2 and 3 show the probabilities of reaching different isohemagglutinin titer endpoints until day 100 in the groups of MRD and MUD transplants according to the presence or absence of clinically significant acute GvHD. To create these figures, however, groups were formed based on GvHD, which is a time-dependent covariate, and differences may have become exaggerated as a result of a selection bias. Therefore, the data presented in Figures 2 and 3 should be interpreted in conjunction with the regression analysis shown in Table 4.
Influence of plasma exchange on time to disappearance of isohemagglutinin titers Plasma exchange significantly decreased the likelihood of reaching the titer endpoints in both MRD and MUD patients. In the group of MRD transplants, plasma exchange significantly decreased the likelihood of reaching the titer endpoints to 0.07 to 0.09 (P < .015). In the MUD group, plasma exchange also decreased the likelihood of a relatively rapid disappearance of isohemagglutinin titers (RR 0.33-0.45; P < .001). Therefore, plasma exchange could only transiently lower antibody titers without long-lasting effects presumably because of production of new antibodies as well as redistribution from peripheral tissue.Red blood cell transfusion requirements The median numbers of RBC units transfused within the first 60 days after transplant were compared between ABO-matched and major or major/minor-mismatched transplants (Table 5). ABO-matched MRD patients received a median of 6 RBC units (range 0-73), whereas ABO-mismatched MRD patients required 10 RBC units (range 0-49) within the same period. This difference was statistically significant (P < .0001). In contrast, there was no difference in RBC transfusion requirements between ABO-mismatched and matched recipients of MUD marrow (10 RBC units vs 10 units; range 0-65 and 0-74, respectively; P = .11), although ABO-matched MUD recipients required more transfusions than their MRD counterparts (P < .0001).
ABO-incompatibility and hematopoietic reconstitution Neutrophil and platelet recoveries were compared between ABO-matched and ABO-major or major/minor mismatched transplants. Separate analysis of MRD (Figure 4A) and MUD (Figure 4B) transplants did not show significant differences in median neutrophil and platelet counts during 60 days after transplant between major or major/minor ABO-matched and mismatched transplants. The median time (range) to reach absolute neutrophil counts (ANC) greater than 1 000/µL and platelet counts greater than 50 000/µL were 24 (10-50) days and 25 (10-94) days in the ABO-matched and mismatched MRD groups (P = .18 and .50), and 24 (9-44) days and 24 (11-94) days in the MUD groups (P = .18 and .50), respectively.
ABO-incompatibility and probability of acute GvHD We compared the probability of developing acute GvHD between subgroups with different degrees of ABO-incompatibilities. The overall incidence of acute GvHD grades II to IV was 47% in MRD transplants (n = 918), and 83% in MUD transplants (n = 748). Within the group of MRD transplants, the incidence of acute GvHD in recipients of ABO matched, major mismatched, minor mismatched, and major/minor mismatched marrow was 47%, 45%, 43%, and 60% (P > .22 [ABO matched vs mismatched]), respectively. Among recipients of MUD allografts, the corresponding GvHD incidence was 83%, 83%, 85%, and 82% (P = .81 [ABO matched vs mismatched]), respectively. Therefore, mismatching for ABO antigens did not influence incidence of GvHD in MRD and MUD transplants.Survival Overall survival was analyzed by comparing ABO-matched transplants with subgroups of major, minor, and major/minor ABO-mismatched transplants (Figure 5). Surviving patients were followed for a median of 6.5 (range .2-14.3) and 4.4 (range .3-6.2) years for patients with MRD and MUD, respectively. The overall survival at 5 years after transplant was 51% in MRD and 36% in MUD transplants. In both groups, ABO incompatibility did not appear to influence survival (P = .51 and .89 for MRD and MUD transplants, respectively; log rank test).
The comparison of posttransplant isohemagglutinins titers between MRD and MUD patients in our study showed that the median times required to reach the 3 different titer endpoints was between 8 and 15 days shorter in MUD compared with MRD recipients (P < .016) (Table 2). Because acute GvHD is a much more frequent complication after MUD than after MRD transplantation,21,22 we analyzed whether there was a correlation between development of acute GvHD and relatively rapid disappearance of isohemagglutinins. We clearly demonstrated that a more rapid clearance of donor-directed anti-A and B was positively correlated with the development of acute GvHD in MRD recipients (Table 4; Figure 2). However, this correlation did not reach statistical significance in MUD recipients, although a trend in the same direction was consistently apparent in this group (Table 4; Figure 3). The less striking correlation between acute GvHD and disappearance of isohemagglutinins in the MUD group may be due to the small sample size of MUD patients with minimal or no acute GvHD (n = 38) that limited the statistical power of the analysis. Furthermore, MUD recipients without clinically significant acute GvHD may still experience subclinical GvH effects that exceed those seen in their MRD counterparts.
We thank Helen Crawford and Bonnie Larson for typing the manuscript.
Submitted November 8, 1999; accepted March 11, 2000.
Supported in part by grants HL36444, CA15704, CA18221, DK51417, and CA18029 from the National Institutes of Health, DHHS, Bethesda, MD.
Reprints: Marco Mielcarek, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024; email: mielcar{at}u.washington.edu.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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Top
Abstract
Introduction
a retrospective case-matched study from the European Group for Blood and Marrow Transplantation.
Blood.
1996;88:4711-4718