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• W2133072316 abstract "The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor–recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA–matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA–matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen–mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA–matched donors. The study’s limited power due to small sample size precludes conclusions about other mismatches. The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor–recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA–matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA–matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen–mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA–matched donors. The study’s limited power due to small sample size precludes conclusions about other mismatches. Unrelated donors have provided a vital resource for patients who do not have an HLA-matched relative. Approximately 50% of allogeneic hematopoietic cell transplantations (HCTs) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) use unrelated donors. Over the past decade, the number of peripheral blood stem cell (PBSC) grafts facilitated by the National Marrow Donor Program (NMDP) has grown substantially, such that currently around 75% of unrelated grafts are PBSC (NMDP statistics). In addition, approximately 30% of all PBSC products are mismatched for one or more of the recipient’s HLA loci. Previous NMDP/CIBMTR studies evaluating the effects of HLA mismatch included predominantly bone marrow (BM) recipients. Given that the number of unrelated donor PBSC transplantations in the NMDP registry has now reached sufficient quantity for preliminary analysis, the present study was designed to determine the association of HLA mismatch in PBSC transplantation with survival, relapse, graft-versus-host disease (GVHD), and transplantation-related mortality (TRM). Previous studies from the NMDP/CIBMTR in the setting of BM transplantation have shown an association between HLA mismatch and with worse outcomes [1Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (586) Google Scholar, 2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar]. In particular, single mismatches at HLA-A, -B, -C, or DRB1 were associated with increased risk for TRM and acute GVHD compared with 8/8 HLA–matched pairs. Isolated HLA-DQ mismatches did not appear to be detrimental. Reports from the Fred Hutchinson Cancer Research Center and the Japanese Marrow Donor Program also support the concept that disparities involving HLA class I alleles are independent risk factors for acute GVHD, TRM, and overall survival [3Petersdorf E.W. Anasetti C. Martin P.J. et al.Limits of HLA mismatching in unrelated hematopoietic cell transplantation.Blood. 2004; 104: 2976-2980Crossref PubMed Scopus (233) Google Scholar, 4Sasazuki T. Juji T. Morishima Y. et al.Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program.N Engl J Med. 1998; 339: 1177-1185Crossref PubMed Scopus (458) Google Scholar]. In the 1990s, collection of granulocyte-colony stimulating factor (G-CSF)-mobilized PBSCs was introduced as an alternative to BM donation for volunteer unrelated donors [5Ringden O. Remberger M. Runde V. et al.Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation.Blood. 1999; 94: 455-464PubMed Google Scholar]. Advantages of PBSCs over BM include more rapid engraftment of neutrophils and platelets for patients and the ability to avoid the operating room for donors and physicians. Retrospective studies have found similar rates of acute GVHD, TRM, relapse, and survival with unrelated donor PBSCs and BM, but an increased incidence of extensive chronic GVHD with PBSCs [6Remberger M. Beelen D.W. Fauser A. et al.Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors.Blood. 2005; 105: 548-551Crossref PubMed Scopus (63) Google Scholar]. Although PBSCs have supplanted BM as the most common source of unrelated hematopoietic stem cells, the impact of HLA mismatch on outcomes after unrelated PBSC transplantation has not yet been well studied. The present study was undertaken to compare the outcomes of HLA-mismatched compared with HLA-matched unrelated donor transplantation using PBSCs as the graft source. Identification of mismatched HLA loci associated with particularly poor outcomes may help guide donor selection when an 8/8 HLA–matched donor is not available and allogeneic transplantation is recommended. The study population included all patients reported to the NMDP/CIBMTR registries who received an unrelated PBSC transplant between 1999 and 2006 for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia (CML) for whom retrospective high-resolution HLA typing results were available for both patient and unrelated donor. Diseases were categorized as early phase (acute leukemia in first complete remission [CR1], CML in first chronic phase, and MDS-refractory anemia [RA]), intermediate phase (acute leukemia in second remission [CR2] and CML in accelerated or second chronic phase), or advanced phase (acute leukemia advanced beyond CR2 or not in remission, CML in blast crisis, MDS-RA with excess blasts [RAEB] or in transformation [RAEB-T]). Conditioning regimens were defined as “myeloablative” if the patient received total body irradiation (TBI) at a dose >500 cGy if given as a single dose or >800 cGy if given in fractions, received busulfan at a dose ≥9.5 mg/kg, or received melphalan at a dose >150 mg/m2. All other regimens were considered either reduced-intensity conditioning (RIC) or nonmyeloablative (NM) conditioning [7Bacigalupo A. Ballen K. Rizzo D. et al.Defining the intensity of conditioning regimens: working definitions.Biol Blood Marrow Transplant. 2009; 15: 1628-1633Abstract Full Text Full Text PDF PubMed Scopus (1164) Google Scholar]. All patients received T cell–replete grafts. All patients included in this study signed informed consent for reporting of clinical information to the NMDP/CIBMTR registries in accordance with the Declaration of Helsinki. Twenty-seven (1.3%) of otherwise eligible patients were excluded to account for lack of consent to use the data of surviving patients or to adjust for potential bias by excluding appropriately the same percentage of deceased patients using a biased coin randomization, with exclusion probabilities based on characteristics associated with not providing consent for use of the data in survivors. High-resolution typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1, and -DPB1 was performed as described previously [1Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (586) Google Scholar]. Low-resolution (serologic or antigen level) disparities involved conversion of the DNA-based typing to its lower-level serologic equivalent, usually by collapsing the 4-digit typing result back to its first 2 digits, with the exception of a few HLA-B alleles that were mapped to their corresponding serologic specificities. Antigen and allele mismatches at HLA-DRB1 were combined. Mismatches at HLA-DQ were scored if there was disparity for either the -DQA1 or the -DQB1 sequence, because both -DQA1 and -DQB1 genes contribute to the expression of a single heterodimeric HLA-DQ protein. HLA-DQA1 was not considered for determination of antigen matching. Directional mismatches (graft-vs-host or host-vs-graft) were considered appropriate in the analysis of GVHD and engraftment, as described previously [8Petersdorf E.W. Gooley T.A. Anasetti C. et al.Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient.Blood. 1998; 92: 3515-3520PubMed Google Scholar]. Mismatches at homozygous alleles were considered single mismatches. Probabilities for mortality and leukemia-free survival (LFS) were calculated using the Kaplan-Meier estimator, and survival curves were compared using the log-rank test. All other outcomes were estimated using the cumulative incidence function [9Gooley T.A. Leisenring W. Crowley J. et al.Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.Stat Med. 1999; 18: 695-706Crossref PubMed Scopus (2285) Google Scholar]. Death was considered a competing risk for all of the endpoints except mortality and LFS. Relapse also was considered a competing event for TRM. Patients were censored if they underwent a second HCT or were alive at last follow-up. The association between number and type of HLA mismatches was evaluated using separate multivariate proportional hazards models, adjusting for significant clinical covariates. Similar to the 2007 NMDP/CIBMTR survey [2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar], this approach compares subgroups of HLA-mismatched pairs with 8/8-matched pairs. A P value <.01 was considered statistically significant because of multiple testing. All models were tested for significant clinical covariates including disease, disease stage, Karnofsky performance score (KPS), or Lansky performance score, patient race, patient age, GVHD prophylaxis, conditioning regimen, donor age, donor–patient cytomegalovirus (CMV) serology, T cell depletion, use of TBI, patient–donor sex match, and year of transplantation. Models were adjusted for any clinical factors that were related to a given outcome at P < .05. All variables were tested for affirmation of the proportional hazards assumption and for interactions with HLA matching. No significant interactions were identified. Characteristics of the study population are shown in Table 1. The median follow-up duration was 2 years (range, 0.3-7.4 years).Table 1Characteristics of 1933 Unrelated Donor PBSC Transplant RecipientsVariableNumber (%)Age, years, median (range)46 (<1-74)Age group, n (%) 0-9 years55 (3%) 10-19 years119 (6%) 20-29 years251 (13%) 30-39 years276 (14%) 40-49 years421 (22%) 50 and older811 (42%)Males, n (%)1078 (56%)KPS/Lansky Performance Score ≥90, n (%)1163 (66%)Disease, n (%) AML946 (49%) ALL359 (19%) CML218 (11%) MDS410 (21%)Disease stage, n (%) Early682 (35%) Intermediate453 (24%) Advanced (late)798 (41%)Conditioning regimen, n (%) Myeloablative1260 (65%) RIC/NM673 (35%)Year of HCT, n (%) 1999-2002395 (20%) 2003-20061538 (80%)Median follow-up of survivors, months, median (range)24 (3-89) Open table in a new tab HLA-DQ mismatch was not statistically associated with survival in patients otherwise matched for HLA-A, -B, -C, and -DRB1. The relative risk (RR) for mortality for single -DQ allele (n = 68) or antigen (n = 46) mismatch was 0.97 (95% confidence interval [CI], 0.71-1.34; P = .87) and 1.35 (95% CI, 0.95-1.96; P = .10), respectively, compared with a full match (n = 1125). Because there were no statistically significant differences in LFS, relapse, TRM, and acute and chronic GVHD, HLA-DQ mismatching was not considered further in the determination of HLA-matching status. Information on HLA-DP matching was available in only 20% of donor–recipient pairs, too few to be sufficient for analysis; accordingly, HLA-DP mismatch was not considered in the subsequent analyses. Table 2 shows the association between 1 or 2 allele and/or antigen mismatches and the transplantation outcomes evaluated. HLA-mismatched pairs that contained at least 1 antigen mismatch had statistically worse survival and disease-free survival than pairs who were 8/8 matched; however, survival of 7/8 allele mismatches was not statistically different than 8/8 matched pairs. Among 6/8-matched pairs, 29 pairs with double-allele mismatches did not have worse survival than 8/8-matched pairs (RR, 1.21; 95% CI, 0.77-1.90; P = .42), but the small number of patients limited the power of this analysis. The 6/8-matched pairs that had at least 1 antigen mismatch had statistically worse survival than the 8/8-matched pairs.Table 2Effect of the Number of Mismatched HLA Antigens or Alleles on Mortality and Relapse among Recipients of Unrelated PBSC Transplants, Adjusted for Patient and Transplant CharacteristicsnRR95% CIPMortality 8/8 match12431.00 One allele mismatch2081.110.91-1.35.30 One antigen mismatch2931.321.12-1.55.0007 Two allele/antigen mismatch992.321.78-3.02<.0001TRM 8/8 match12431.00 One allele mismatch2081.411.09-1.81.008 One antigen mismatch2931.541.24-1.91.0001 Two allele/antigen mismatch993.162.28-4.37<.0001LFS 8/8 match12431.00 One allele mismatch2081.150.95-1.38.15 One antigen mismatch2931.291.10-1.51.0013 Two allele/antigen mismatch992.251.74-2.92<.0001Relapse 8/8 match12431.00 One allele mismatch2080.900.68-1.20.48 One antigen mismatch2931.040.82-1.32.76 Two allele/antigen mismatch991.240.78-1.98.36Acute GVHD II-IV 8/8 match12431.00 One allele mismatch2080.930.93-1.37.24 One antigen mismatch2661.211.02-1.43.03 Two allele/antigen mismatch971.180.85-1.64.31Acute GVHD III-IV 8/8 match12431.00 One allele mismatch2081.591.20-2.09.0012 One antigen mismatch2661.931.53-2.44<.0001 Two allele/antigen mismatch972.431.64-3.59<.0001Chronic GVHD 8/8 match12431.00 One allele mismatch2081.000.81-1.23.97 One antigen mismatch2661.150.95-1.40.14 Two allele/antigen mismatch971.030.69-1.54.88 Open table in a new tab For TRM, any degree of HLA mismatch was associated with worse outcome. In contrast, HLA mismatch was not associated with a lower risk of relapse. Grade III-IV acute GVHD was increased with any degree of HLA mismatch (Table 2). There was no association between number and type of HLA mismatches and grade II-IV acute GVHD or chronic GVHD. Table 3 presents the results of locus-specific analysis of single mismatched pairs for the outcomes of interest. Note that the power of this analysis is limited for some subgroups because of small sample sizes. Thus, although evidence of a statistically significant worse outcome can be accepted, the absence of such a finding does not mean that a mismatch is “safe.” Mismatch of a single HLA-C antigen was associated with a statistically significantly higher risk for mortality, TRM, and grade III-IV acute GVHD and lower LFS. At 2 years, unadjusted survival was 32% for HLA-C mismatches, compared with 44% for 8/8 matches (P = .003); LFS was 26% compared with 40% (P = .0002); and cumulative incidence of TRM was 40% compared with 28% (P = .002). Mismatch at a single HLA-B allele or antigen was also associated with increased risk of grade III-IV acute GVHD. The risks of relapse and chronic GVHD were not statistically different for 8/8 matches compared with any locus-specific mismatch, including HLA-C antigen–mismatched pairs.Table 3Effect of the Locus of Mismatched HLA Antigens or Alleles on Mortality, Relapse, and GVHD among Recipients of Unrelated PBSC Transplants, Adjusted for Patient and Transplant CharacteristicsnRR95% CIPMortality 8/8 match12431.00 HLA-A allele mismatch511.160.80-1.67.43 HLA-A antigen mismatch851.170.88-1.55.29 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1361.170.93-1.47.19 HLA-B allele mismatch571.290.92-1.82.14 HLA-B antigen mismatch161.010.50-2.04.97 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.731.220.90-1.67.19 HLA-C allele mismatch610.820.57-1.19.30 HLA-C antigen mismatch1891.411.16-1.70.0005 HLA-DRB1 mismatch391.300.87-1.94.20TRM 8/8 match12431.00 HLA-A allele mismatch511.470.92-2.35.11 HLA-A antigen mismatch851.330.91-1.93.14 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1361.371.01-1.86.04 HLA-B allele mismatch571.751.14-2.69.01 HLA-B antigen mismatch161.650.81-3.38.17 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.731.741.20-2.51.004 HLA-C allele mismatch611.020.62-1.67.93 HLA-C antigen mismatch1891.611.25-2.08.0002 HLA-DRB1 mismatch391.530.94-2.51.09LFS 8/8 match12431.00 HLA-A allele mismatch511.200.84-1.71.31 HLA-A antigen mismatch851.110.84-1.48.46 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1361.150.91-1.44.24 HLA-B allele mismatch571.280.93-1.77.13 HLA-B antigen mismatch161.200.64-2.26.57 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.731.270.95-1.69.12 HLA-C allele mismatch610.920.65-1.30.62 HLA-C antigen mismatch1891.361.13-1.64.001 HLA-DRB1 mismatch391.270.86-1.87.22Relapse 8/8 match12431.00 HLA-A allele mismatch510.910.53-1.56.73 HLA-A antigen mismatch850.970.62-1.52.90 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1360.950.67-1.36.79 HLA-B allele mismatch571.030.62-1.71.91 HLA-B antigen mismatch160.420.10-1.74.23 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.730.890.55-1.44.64 HLA-C allele mismatch610.800.48-1.32.38 HLA-C antigen mismatch1891.090.83-1.44.53 HLA-DRB1 mismatch390.910.48-1.72.77GVHD grade II-IV 8/8 match12791.00 HLA-A allele mismatch540.990.67-1.44.93 HLA-A antigen mismatch791.331.00-1.77.05 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1361.180.94-1.50.16 HLA-B allele mismatch560.990.69-1.44.97 HLA-B antigen mismatch161.510.85-2.69.16 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.731.110.81-1.52.52 HLA-C allele mismatch641.160.83-1.62.40 HLA-C antigen mismatch1681.120.90-1.39.30 HLA-DRB1 mismatch341.601.06-1.80.03GVHD grade III-IV 8/8 match12791.00 HLA-A allele mismatch541.380.81-2.37.24 HLA-A antigen mismatch791.541.01-2.34.04 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1361.461.04-2.06.03 HLA-B allele mismatch561.911.21-3.02.006 HLA-B antigen mismatch163.251.66-6.36.0006 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.732.221.51-3.25<.0001 HLA-C allele mismatch641.170.69-1.97.56 HLA-C antigen mismatch1681.981.50-2.62<.0001 HLA-DRB1 mismatch341.871.05-3.35.03Chronic GVHD 8/8 match12791.00 HLA-A allele mismatch540.990.68-1.45.97 HLA-A antigen mismatch791.240.90-1.69.19 HLA-A allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.1361.120.87-1.43.38 HLA-B allele mismatch560.870.56-1.36.55 HLA-B antigen mismatch161.140.59-2.22.69 HLA-B allele or antigen mismatch∗From a separate model in which allele and antigen mismatches were combined for the A and B loci.730.940.64-1.36.73 HLA-C allele mismatch641.030.73-1.45.86 HLA-C antigen mismatch1681.120.88-1.42.35 HLA-DRB1 mismatch341.110.68-1.84.67∗ From a separate model in which allele and antigen mismatches were combined for the A and B loci. Open table in a new tab Table 4 compares HLA-C antigen–mismatched pairs, other 7/8 antigen (non-C)– mismatched pairs, 7/8 allele–mismatched pairs, and 8/8-matched pairs by conditioning regimen intensity. HLA-C antigen mismatch is associated with an increased risk of mortality compared with 8/8 matches for patients given either myeloablative conditioning (n = 122; RR, 1.40; 95% CI, 1.10-1.78; P = .006) or nonmyeloablative conditioning or RIC (n = 65; RR, 1.40; 95% CI, 1.01-1.95; P = .04). In contrast, other 7/8 (non-C) antigen–mismatched pairs and 7/8 allele–mismatched pairs did not have statistically higher mortality compared with 8/8-matched pairs in either the myeloablative or nonmyeloablative/RIC group.Table 4Association of 7/8 HLA-C Antigen Mismatch with Mortality in Patients Conditioned with a Myeloablative or an RIC/NM RegimenMyeloablativeRIC/NMnRR∗Adjusted for disease and KPS; stratified by disease status and GVHD prophylaxis.95% CIPnRR∗Adjusted for disease and KPS; stratified by disease status and GVHD prophylaxis.95% CIP8/87961.004471.007/8 HLA-C antigen1221.401.10-1.78.006651.401.01-1.95.047/8 other antigen801.230.91-1.66.18260.930.54-1.61.807/8 allele1301.140.88-1.47.3278.820.82-1.55.45∗ Adjusted for disease and KPS; stratified by disease status and GVHD prophylaxis. Open table in a new tab To gain insight into whether using BM instead of PBSC would be advantageous when the use of an HLA-mismatched donor is planned, we compared the PBSC recipients in our research dataset with the recipients of BM grafts in the analysis reported by Lee et al. [2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar]. No statistically significant differences in mortality were seen when HLA-mismatched transplantations were performed with PBSC or with BM. The risk for mortality at 1 year did not differ between recipients of 7/8 antigen–mismatched BM grafts (n = 547) and recipients of 7/8 antigen–mismatched PBSC grafts (n = 293) (RR, 1.13; 95% CI, 0.93-1.40; P = .26), or between the subgroups of BM (n = 321) and PBSC (n = 187) recipients when the mismatch involved a single HLA-C antigen (RR, 1.08; 95% CI, 0.84-1.70; P = .55). These results, which are adjusted for disease, disease status, and KPS pretransplantation, suggest there is no advantage to changing the graft source from PBSC to BM when using a HLA-mismatched donor even if the antigen mismatch is at HLA-C. Year of transplantation and intensity of the conditioning regimen were not found to be statistically significant in these models. This study of HLA matching and outcomes of unrelated-donor PBSC transplantation shows that HLA mismatching in general, and HLA-C antigen and HLA-B allele and antigen mismatching in particular, are associated with statistically worse outcomes compared with 8/8 HLA matching. No statistically significant associations between HLA mismatching and relapse or chronic GVHD were observed. Mismatching at HLA-DQ was not associated with statistically significantly worse outcomes and thus was disregarded when determining HLA matching. Overall, our findings are similar to those from previous studies of the effects of HLA mismatching in BM transplantation in largely Caucasian cohorts [1Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (586) Google Scholar, 2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar]. Most of the patients included in the previously reported sequential retrospective studies of high-resolution HLA matching received BM grafts. Compared with BM, PBSCs contain 10-fold more CD3+ cells and 4-fold more CD34+ cells on average [10Bensinger W.I. Martin P.J. Storer B. et al.Transplantation of bone marrow as compared with peripheral blood cells from HLA-identical relatives in patients with hematologic cancers.N Engl J Med. 2001; 344: 175-181Crossref PubMed Scopus (838) Google Scholar]. The relative contribution of cell subsets also differ; for example, PBSCs have a ∼3-fold higher CD3:CD34 ratio and a ∼25-fold higher CD14:CD34 ratio than BM, as well as a greater proportion of CD4 cells with an anti-inflammatory (Th2) phenotype [11Mielcarek M. Roecklein B.A. Torok-Storb B. CD14+ cells in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells induce secretion of interleukin-6 and G-CSF by marrow stroma.Blood. 1996; 87: 574-580PubMed Google Scholar, 12Talmadge J.E. Reed E.C. Kessinger A. et al.Immunologic attributes of cytokine mobilized peripheral blood stem cells and recovery following transplantation.Bone Marrow Transplant. 1996; 17: 101-109PubMed Google Scholar, 13Pan L. Delmonte Jr., J. Jalonen C.K. et al.Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease.Blood. 1995; 86: 4422-4429PubMed Google Scholar, 14Arpinati M. Green C.L. Heimfeld S. et al.Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells.Blood. 2000; 95: 2484-2490PubMed Google Scholar]. Other studies have indicated relatively more DC2 dendritic cells and skewing of the DC1:DC2 ratio to DC2 cells within PBSCs [14Arpinati M. Green C.L. Heimfeld S. et al.Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells.Blood. 2000; 95: 2484-2490PubMed Google Scholar]. All PBSC donors receive G-CSF, whereas most unrelated BM donors do not. The differences in cellular characteristics of the two products suggest, at a minimum, that the effect of HLA mismatching shown for BM transplants cannot be assumed to be applicable to PBSC products. Although our results do not define an “optimal” mismatch for a PBSC transplant, they clearly show that an HLA-C antigen mismatch is associated with lower survival and higher TRM in both the single- and double-mismatch settings. This conclusion is consistent with findings of Flomenburg et al. [1Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (586) Google Scholar] and Lee et al. [2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar]. In the study of Lee et al. [2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar], HLA-C antigen mismatch (RR, 1.22; 95% CI 1.06-1.39; P =.004), HLA-A antigen mismatch (RR, 1.24; 95% CI, 1.02-1.52; P <.001), and HLA-DRB1 allele mismatch (RR, 1.42; 95% CI, 1.13-1.80; P = .003) were associated with worse survival compared with the 8/8 match. Our study of PBSC transplantation also found a statistically significant relationship between HLA-B mismatch and increased risk for grade III-IV acute GVHD, but no association with survival. It is notable that the higher rates of severe acute GVHD observed in HLA-C antigen and HLA-B antigen and allele–mismatched pairs did not translate into higher chronic GVHD rates or lower relapse rates. We hypothesize that this could possibly be due to the higher TRM generally associated with grade III-IV acute GVHD, the fact that chronic GVHD is more closely linked with prevention of relapse, or our small sample size, which limited the study’s power. The main limitation of the present study is the small number of observations in some of the subgroups, which might have led to erroneous estimation of the effect of a specific HLA mismatch and limited power in comparisons. In addition, the median follow-up period of 2 years is relatively short compared with that in previous studies of HLA matching in BM transplantation. NM/RIC transplantations composed 35% of our study population, but represent approximately 50% of the procedures currently performed. As the number of PBSC transplants increases and follow-up lengthens, a subsequent analysis will be important to update our observations and to consider other factors that could possibly affect outcomes, such as killer Ig-like receptor (KIR) status [15Cooley S. Trachtenberg E. Bergemann T.L. et al.Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia.Blood. 2009; 113: 726-732Crossref PubMed Scopus (351) Google Scholar, 16Gagne K. Busson M. Bignon J.D. et al.Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2009; 15: 1366-1375Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 17Hurton L.V. Siddik R.I. Singh H. et al.Identifying candidate allogeneic NK-cell donors for hematopoietic stem-cell transplantation based on functional phenotype.Leukemia. 2010; 24: 1059-1062Crossref PubMed Scopus (5) Google Scholar, 18Ludajic K. Balavarca Y. Bickeboller H. et al.KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA–matched, hematopoietic stem cell transplantation.Bone Marrow Transplant. 2009; 44: 97-103Crossref PubMed Scopus (34) Google Scholar, 19Shaw B.E. Mayor N.P. Russell N.H. et al.Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles.Leukemia. 2010; 24: 58-65Crossref PubMed Scopus (78) Google Scholar] or HLA-DP matching [19Shaw B.E. Mayor N.P. Russell N.H. et al.Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles.Leukemia. 2010; 24: 58-65Crossref PubMed Scopus (78) Google Scholar, 20Crocchiolo R. Zino E. Vago L. et al.Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation.Blood. 2009; 114: 1437-1444Crossref PubMed Scopus (128) Google Scholar]. For example, in the BM setting, the earlier study of Flomenberg et al. [1Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (586) Google Scholar] (n = 1874) did not find an increased risk associated with single allele mismatches [1Flomenberg N. Baxter-Lowe L.A. Confer D. et al.Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.Blood. 2004; 104: 1923-1930Crossref PubMed Scopus (586) Google Scholar], whereas the larger Lee et al. study (n = 3857) found an association between a single allele or antigen mismatch and adverse outcomes [2Lee S.J. Klein J. Haagenson M. et al.High-resolution donor–recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007; 110: 4576-4583Crossref PubMed Scopus (986) Google Scholar]. Neither of these previous BM studies included substantial numbers of NM or RIC transplants, which typically use PBSC grafts. A reasonable concern with these conditioning regimens is that rejection of a mismatched graft or risk for relapse may be amplified because host T or natural killer (NK) cells might survive less-intensive conditioning. Our analysis showed that HLA-C antigen mismatch is associated with higher risk for overall mortality and TRM, but not relapse, after NM/RIC PBSC HCT, similar to that for myeloablative HCT (relapse data not shown). Unfortunately, we lack data on KIR genotyping to allow a refined analysis of possible NK cell effects. In cases when HLA-C antigen mismatching cannot be avoided, one might wonder whether a BM graft might be better tolerated than a PBSC graft. Our exploratory analysis found no advantage to using BM as the cell source from a donor with an isolated HLA-C antigen mismatch. We caution that the present retrospective analysis cannot take into consideration all factors that might introduce bias. Our presentation of these results is intended not to address the question of whether one graft source is preferable over the other, but rather to provide the best available data pending larger studies. In an analysis by Eapen et al. [21Eapen M. Rocha V. Sanz G. et al.Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis.Lancet Oncol. 2010; 11: 653-660Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar], outcomes of 7/8-matched BM and 7/8-matched PBSC transplantations appeared to be similar, although direct comparisons were not performed and locus-specific data were not provided. In October 2009, the Blood and Marrow Transplant Clinical Trials Network finished enrollment of a 550-patient prospective multicenter randomized trial to assess the risks and benefits of BM versus PBSCs from unrelated donors. A planned subgroup analysis of HLA-mismatched grafts has been included in the study design, the results of which will be important for addressing the issues raised in our analysis. It is important to remember that our results are not meant to imply that an HLA-mismatched graft should not be used, only that the greater risks compared with 8/8 HLA–matched grafts should be recognized when present. For many patients, the best hope for long-term LFS will remain allogeneic HCT, even with a less-than-optimal donor. Financial disclosure: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; NHLBI-NCI Grant/Cooperative Agreement 5U01HL069294; Health Resources and Services Administration Contract HHSH234200637015C; Office of Naval Research Grants N00014-06-1-0704 and N00014-08-1-0058; and grants from AABB, Aetna, American Society for Blood and Marrow Transplantation, Amgen Inc, anonymous donation to the Medical College of Wisconsin, Astellas Pharma US Inc, Baxter International Inc, Bayer HealthCare Pharmaceuticals, Be the Match Foundation, Biogen IDEC, BioMarin Pharmaceutical Inc, Biovitrum AB, BloodCenter of Wisconsin, Blue Cross and Blue Shield Association, Bone Marrow Foundation, Canadian Blood and Marrow Transplant Group, CaridianBCT, Celgene Corporation, CellGenix GmbH, Centers for Disease Control and Prevention, Children’s Leukemia Research Association, ClinImmune Labs, CTI Clinical Trial and Consulting Services, Cubist Pharmaceuticals, Cylex Inc, CytoTherm, DOR BioPharma Inc, Dynal Biotech (an Invitrogen company), Eisai Inc, Enzon Pharmaceuticals Inc, European Group for Blood and Marrow Transplantation, Gamida Cell Ltd, GE Healthcare, Genentech Inc, Genzyme Corporation, Histogenetics Inc, HKS Medical Information Systems, Hospira Inc, Infectious Diseases Society of America, Kiadis Pharma, Kirin Brewery Co Ltd, Leukemia & Lymphoma Society, Merck & Company, Medical College of Wisconsin, MGI Pharma Inc, Michigan Community Blood Centers, Millennium Pharmaceuticals Inc, Miller Pharmacal Group, Milliman USA Inc, Miltenyi Biotec Inc, National Marrow Donor Program, Nature Publishing Group, New York Blood Center, Novartis Oncology, Oncology Nursing Society, Osiris Therapeutics Inc, Otsuka America Pharmaceutical Inc, Pall Life Sciences, Pfizer Inc, Saladax Biomedical Inc, Schering Corporation, Society for Healthcare Epidemiology of America, Soligenix Inc, StemCyte Inc, StemSoft Software Inc, Sysmex America Inc, THERAKOS Inc, Thermogenesis Corporation, Vidacare Corporation, Vion Pharmaceuticals Inc, ViraCor Laboratories, ViroPharma Inc, and Wellpoint Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, Department of the Navy, Department of Defense, or any other agency of the US Government. Author contributions: Ann Woolfrey designed research, interpreted data, drafted the manuscript, and critically revised the manuscript. John P. Klein performed the statistical analysis, interpreted data, and critically revised the manuscript. Michael Haagenson designed research, performed the statistical analysis, interpreted data, drafted the manuscript, and critically revised the manuscript. Stephen Spellman designed research, interpreted data, drafted the manuscript, and critically revised the manuscript. Effie Petersdorf interpreted data and critically revised the manuscript. Machteld Oudshoorn interpreted data and critically revised the manuscript. James Gajewski interpreted data and critically revised the manuscript. Gregory A. Hale interpreted data and critically revised the manuscript. John Horan interpreted data and critically revised the manuscript. Minoo Battiwalla interpreted data and critically revised the manuscript. Susana R. Marino interpreted data and critically revised the manuscript. Michelle Setterholm interpreted data and critically revised the manuscript. Olle Ringden interpreted data and critically revised the manuscript. Carolyn Hurley designed research, interpreted data, drafted the manuscript, and critically revised the manuscript. Neal Flomenberg interpreted data and critically revised the manuscript. Claudio Anasetti interpreted data and critically revised the manuscript. Marcelo Fernandez-Vina interpreted data and critically revised the manuscript. Stephanie J. Lee designed research, interpreted data, drafted the manuscript, and critically revised the manuscript." @default.
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• W2133072316 title "HLA-C Antigen Mismatch Is Associated with Worse Outcome in Unrelated Donor Peripheral Blood Stem Cell Transplantation" @default.
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