Abstract
The HLA class II DRB1 antigen DR15 (common alleles *1501, *1502) is an important marker in the pathobiology of severe aplastic anemia (SAA). We studied 1204 recipients of HLA-matched sibling bone marrow transplantation for SAA to determine whether HLA-DR15 status (as determined by allele-level typing) affected hematopoietic recovery, graft-versus-host disease (GvHD) or overall survival. In multivariate analysis, secondary graft failure rate at 2-years was lower in patients who are HLA-DR15+ (hazard ratio 0.46, p=0.01). However, neutrophil recovery at day-28, platelet recovery at day-100, acute GvHD, chronic GvHD and overall mortality were independent of DR15 status. The 5-year probabilities of overall survival, after adjusting for age, race, performance score, transplant-conditioning regimen and year of transplantation, were 78% and 81% for patients who are HLA-DR15+ and HLA-DR15-, respectively (p=0.35). In conclusion, DR15 status is associated with secondary graft failure after HLA-matched sibling bone marrow transplantation for SAA but has no significant impact on survival.
Keywords: DR15, SAA, GvHD, Survival, Graft Failure
INTRODUCTION
The HLA Class II DRB1 antigen DR15 (common alleles *1501, *1502) is observed with a frequency between 20–30% in various ethnic populations (1). DR15 is involved in the pathobiology of T-lymphocyte mediated marrow failure states such as severe aplastic anemia (SAA), myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH) (2–7). Serological HLA DR2, subsequently resolved as HLA DR15 (or HLA DR16, respectively) by high resolution HLA typing, has been found to be overrepresented in patients with SAA in several ethnic groups. Of the 30 different DR15 alleles, only *1501 and *1502 have been shown to have significantly higher frequencies in SAA patients compared with the normal population. Both common alleles of DR15, *1501 and *1502, are associated with the pathogenesis of SAA, with subtle differences; *1501 is associated with PNH and *1502 is over-represented in older patients with SAA (8). Diazepam-binding Inhibitor-related Protein-1, a candidate auto-antigen in SAA has been shown to be presented by DR15 (9).
The DR15 antigen is also reported to predict response to immunosuppressive therapy in SAA although this is controversial (10–12). Although the exact mechanism for the association of HLA DR15 with autoimmune marrow failure states remains unknown, it is thought that DR15 may play a role in presenting immunodominant myeloid epitopes. Since epitope presentation also mediates the graft-versus-leukemia effect, and susceptibility to immunosuppressive therapy may reflect the responsiveness of graft-versus-host disease (GvHD) to treatment, several groups have explored the impact of DR15 expression after HLA matched sibling transplantation for malignant diseases. These reports suggest lower acute GvHD and higher progression free survival in patients positive for DR15 (DR15+) (13–16). Another explanation for immunobiologic outcomes related to DR15 could be linkage disequilibrium with other non-HLA immunogenetic factors, such as TNFa (17). Given the involvement of DR15 in the pathobiology of immunosuppression-responsive marrow failure states and reports of DR15 impacting outcomes after HLA-matched sibling transplantation for malignant diseases, we examined whether outcomes after HLA-matched sibling bone marrow transplantation for SAA differed by HLA DR 15 status.
METHODS
Data Source
Patient, disease and transplant characteristics and outcome data were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The CIBMTR is a voluntary working group of over 400 transplant centers worldwide that contribute data on consecutive hematopoietic transplantations to a Statistical Center at the Medical College of Wisconsin. All patients are followed longitudinally, annually. The Institutional Review Boards of the Medical College of Wisconsin and the National Marrow Donor Program approved this study.
Inclusion criteria
Included are patients with acquired SAA who underwent HLA-matched sibling bone marrow transplantation between 1990 and 2006. Patients with secondary SAA, inherited bone marrow failure syndromes or abnormal karyotypes were excluded. Also excluded were recipients of ex vivo T-cell depleted bone marrow grafts, peripheral blood progenitor cells and unrelated donor transplantation. Selection was confined to HLA-A, -B and -DRB1 matched transplantations to eliminate HLA-disparity as a driving force for any observed differences. To avoid inclusion of DR2 splits other than *15, we further confined the study to those subjects for whom high-resolution (allele-level) typing at the DR locus was available.
Outcomes
Time to neutrophil recovery was defined as the first of three consecutive post-transplant days that the absolute neutrophil count was ≥0.5×109/L. Patients who failed to achieve absolute neutrophil count ≥0.5×109/L were considered to have had primary graft failure. Secondary graft failure at 2 years was defined as the sustained loss of neutrophil counts to <0.5×109/L after initial neutrophil recovery or autologous reconstitution. Time to platelet recovery was defined as the first day of counts ≥20×109/L without transfusion for 7 days. Acute and chronic GvHD were defined according to the standard criteria (18). Surviving patients were censored at last follow-up. Death from any cause was considered an event.
Statistical analysis
Patient-, disease-, and transplant-related factors were compared between the DR15 + and the DR15 − groups using the Chi-square test for categorical variables and Mann-Whitney test for continuous variables. The probabilities of hematopoietic recovery and acute and chronic GvHD were calculated using the cumulative incidence function estimator treating death without the event as the competing risk (19). The probability of overall survival was calculated using the Kaplan-Meier estimator (20). Risk factors for transplant-outcomes were identified through a stepwise forward/backward model selection procedure. Cox proportional hazard regression models (21) were built for overall mortality, grade 2–4 acute GvHD and chronic GvHD (22, 23). Logistic regression model using the pseudo-value approach(24, 25) was built for hematopoietic recovery and secondary graft failure. Variables that attained a p-value ≤0.05 were held in the final multivariate models. The variable for DR15 status (DR 15 + vs. DR 15 −) was retained in all steps of model building and the final model regardless of significance level. Other variables tested were: age (≤20 vs. 21 – 40 vs. > 40 years), Karnofsky performance score (≤ 80% vs. 90–100%), time from diagnosis to transplantation (≤3 vs. >3 months), immunosuppressive therapy (yes vs. no), red blood transfusion (<20 vs. 20–50 vs. >50), conditioning regimen (cyclophosphamide [Cy] + antithymocyte globulin [ATG] vs. Cy alone vs. Cy + limited field irradiation vs. busulfan [Bu] + Cy vs. fludarabine containing regimens), donor-recipient gender match (female donor/male recipient vs. others), donor-recipient cytomegalovirus (CMV) serostatus (donor and recipient seronegative vs. donor and/or recipient seropositive) and year of transplant (1990–1995 vs. 1996–2000 vs. 2001–2006). All variables were tested to ensure they met the proportional hazard assumption. Variables that did not meet this assumption were adjusted by stratification; interval from diagnosis to transplantation did not meet the assumption, consequently the model for overall mortality was stratified for this variable. All p-values are two-sided. Analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC).
RESULTS
Patients and characteristics
One thousand two hundred and four patients with SAA who underwent HLA-matched sibling bone marrow transplantation were reported to the CIBMTR and all patients had high resolution typing at DRB1 available. Three hundred and forty-eight patients (29%) were DR 15+ and 856 patients (71%), DR15 −. All patients received bone marrow grafts and the median total nucleated cell dose in both treatment groups was 3 × 108/kg. The characteristics of patients, their disease and transplantations are shown in Table 1. Characteristics were similar except that patients with DR15+ were slightly older than patients who were DR15−. Patients who were DR15− were more likely to receive cyclophosphamide + ATG transplant conditioning regimen and, receive ATG. Seven patients were homozygous for DR15 and were included within the DR15 heterozygous group. The median follow-up of patients in both groups is 5 years.
Table 1.
Characteristics of patients by HLA DRB1 antigen DR15 status
| Variable | DR15 (−) | DR15 (+) | P-value |
|---|---|---|---|
| Number of patients | 856 | 348 | |
| Patient related: | |||
| Age, median (range), years | 18 (<1–61) | 21 (<1–58) | <0.001 |
| Age at transplantation, years | <0.001 | ||
| ≤20 | 528 (62) | 164 (47) | |
| 21–40 | 272 (32) | 151 (43) | |
| ≥40 | 56 (7) | 33 (9) | |
| Sex | 0.37 | ||
| Male | 510 (60) | 217 (62) | |
| Female | 346 (40) | 131 (38) | |
| Karnofsky score pre-transplantation | 0.50 | ||
| <90 | 308 (36) | 120 (34) | |
| ≥90 | 534 (62) | 225 (65) | |
| Unknown | 14 (2) | 3 (1) | |
| Disease related: | |||
| Time from diagnosis to transplant, months | 3 (<1–263) | 3 (<1–232) | 0.74 |
| Time from diagnosis to transplant, months | 0.29 | ||
| ≤3 | 476 (56) | 192 (55) | |
| >3 | 380 (44) | 155 (45) | |
| Unknown | 0 | 1 (<1) | |
| Immunosuppresive therapy prior to transplant | 0.52 | ||
| No | 464 (54) | 193 (55) | |
| Yes | 387 (45) | 151 (43) | |
| Unknown | 5 (1) | 4 (1) | |
| Transplant related: | |||
| Conditioning regimen | 0.04 | ||
| Cyclophosphamide + ATG | 546 (64) | 189 (54) | |
| Cyclophosphamide alone | 128 (15) | 54 (16) | |
| Cyclophosphamide + limited field irradiation ± ATG | 20 (2) | 14 (4) | |
| Busulfan + cyclophosphamide ± ATG | 111 (13) | 67 (19) | |
| Fludarabine + cyclophosphamide ± ATG | 26 (3) | 12 (4) | |
| Fludarabine + busulfan ± ATG | 17 (2) | 7 (2) | |
| Fludarabine + low dose TBI/limited field irradiation ± other | 2 (<1) | 1 (<1) | |
| Others | 6 (1) | 4 (1) | |
| ATG | 0.01 | ||
| No | 318 (37) | 156 (45) | |
| Yes | 538 (63) | 192 (55) | |
| Donor/Recipient gender match | 0.35 | ||
| Female donor-male recipient | 224 (26) | 91 (26) | |
| Others | 631 (74) | 255 (73) | |
| Unknown | 1 (<1) | 2 (1) | |
| Donor/Recipient CMV serostatus | 0.10 | ||
| Donor (+) and recipient (+) | 416 (49) | 197 (57) | |
| Donor (+) and recipient (−) | 40 (4) | 22 (6) | |
| Donor (−) and recipient (+) | 127 (15) | 34 (10) | |
| Donor (−) and recipient (−) | 216 (25) | 68 (19) | |
| Not tested/inconclusive/unknown | 57 (7) | 27 (8) | |
| Year of transplant | 0. 16 | ||
| 1990–1995 | 110 (13) | 33 (9) | |
| 1996–2000 | 387 (45) | 174 (50) | |
| 2001–2006 | 359 (42) | 141 (41) | |
| GvHD prophylaxis | 0.38 | ||
| Cyclosporine + methotrexate +-other | 748 (87) | 297 (85) | |
| Cyclosporine +/− other | 82 (10) | 40 (11) | |
| Tacrolimus +-other | 22 (3) | 7 (2) | |
| Tacrolimus alone | 4 (<1) | 4 (1) |
Hematopoietic recovery
The day-28 probabilities of neutrophil recovery were 87% (95% CI 84 – 89) and 87% (95% CI 82 – 90) in patients who were DR15− and DR15+, respectively. The corresponding probabilities of platelet recovery at day-100 were 89% (95% CI 87 – 91) and 88% (95% CI 84 – 91). In multivariate analysis, there were no significant differences in neutrophil recovery at day-28 or platelet recovery at day-100 in patients who are HLA DR15+ or HLA-DR15− (Table 2). The likelihood of neutrophil recovery was higher in patients aged 20–40 years compared to those aged <20 years and for transplantations that employed in vivo T-cell depletion with ATG. Karnofsky performance scores of 90 or 100 at transplantation were associated with higher platelet recovery rates where as immunosuppressive therapy and red blood cell transfusions ≥20 prior to transplantation lowered the likelihood of platelet recovery.
Table 2.
Risk factors for hematopoietic recovery and secondary graft failure
| Outcome | N | Odds Ratio (95% CI) | p-value |
|---|---|---|---|
| Neutrophil engraftment at day 28 | |||
| DR15− | 831 | 1 | |
| DR15+ | 341 | 1.05 (0.71–1.57) | 0.80 |
| Other significant covariates: | |||
| Age at transplant, years | |||
| ≤20 | 676 | 1 | |
| 21–40 | 410 | 1.73 (1.16–2.59) | 0.007 |
| ≥40 | 86 | 1.77 (0.82–3.81) | 0.15 |
| ATG | |||
| No | 469 | 1 | <0.001 |
| Yes | 703 | 2.36 (1.66–3.35) | <0.001 |
| Platelet recovery at day 100 | |||
| DR15− | 821 | 1 | |
| DR15+ | 333 | 0.88 (0.56–1.37) | 0.56 |
| Other significant covariates: | |||
| Karnofsky score pre-transplant | |||
| <90 | 405 | 1 | 0.001 |
| ≥90 | 732 | 2.14 (1.43–3.22) | <0.001 |
| Unknown | 17 | 1.70 (0.21–13.53) | 0.62 |
| Immunosuppresive therapy prior to transplant | |||
| No | 636 | 1 | |
| Yes | 511 | 0.63 (0.42–0.94) | 0.03 |
| Number of blood transfusions | |||
| <20 | 331 | 1 | |
| 20–50 | 205 | 0.39 (0.21–0.71) | 0.002 |
| >50 | 166 | 0.44 (0.23–0.84) | 0.01 |
| Unknown | 452 | 0.54 (0.31–0.96) | 0.04 |
| Secondary graft failure at 2 years | |||
| DR15− | 787 | 1 | |
| DR15+ | 316 | 0.46 (0.24–0.86) | 0.02 |
| Other significant covariates: | |||
| Karnofsky score pre-transplant | |||
| <90 | 376 | 1 | <0.001 |
| ≥90 | 710 | 0.69 (0.41–1.16) | 0.16 |
| Unknown | 17 | 6.55 (2.10–20.47) | 0.001 |
| Conditioning regimen | |||
| Cyclophosphamide + ATG | 682 | 1 | |
| Cyclophosphamide alone | 167 | 2.04 (1.04–3.99) | 0.04 |
| Cyclophosphamide +limited field irradiation ± ATG | 31 | 0.62 (0.09–4.14) | 0.62 |
| Busulfan + cyclophosphamide | 164 | 2.32 (1.17–4.60) | 0.02 |
| Fludarabine + other agents | 59 | 3.88 (1.73–8.66) | <0.001 |
Secondary graft failure was associated with DR status; the likelihood of secondary graft failure at 2-years was significantly lower in patients who are HLA DR15 + compared to those who are HLA DR15 − (Table 2). 79 of 708 HLA DR15− patients had secondary graft failure compared to 21 of 316 patients with HLA DR15+ (p=0.03). Graft failure risks varied with transplant conditioning regimen. Compared to patients who received cyclophosphamide + ATG, risks were higher in patients who received cyclophosphamide alone, busulfan and cyclophosphamide or fludarabine-based conditioning regimens. The effect of transplant conditioning regimen is independent of DR status.
Acute and chronic GVHD
The day-100 probabilities of grade 2–4 acute GvHD were similar in patients who were DR15− and DR15+; 15% (95% CI 13–18) and 15% (95% CI 12–19), respectively. In multivariate analysis, grade 2–4 acute GvHD was not associated with HLA DR status (Table 2). Similarly, chronic GvHD risks were not associated with HLA DR status (Table 2). The 5-year probabilities of chronic GvHD were also similar in patients who were DR15− and DR15+; 17% (95% CI 1 – 20) and 19% (95% CI 15 – 23), respectively.
Overall mortality
Nine hundred and sixty eight patients were alive at last follow-up. HLA DR status was not associated with overall mortality (Table 2, Figure 1). However, mortality risks were lower in patients with Karnofsky performance scores of 90 or 100 and transplantations performed between 2001 and 2006. Overall mortality was also associated with type of transplant-conditioning regimen; mortality was lower after cyclophosphamide + ATG regimen compared to other regimens. The 5-year probabilities of overall survival, adjusted for age, performance score, conditioning regimen and transplantation period were 78% (95% CI 74% – 83%) for patients with DR15+ and 81% (95% CI 78% – 83%) for patients with DR15− (p=0.350). In the absence of an association between HLA DR status and survival advantage for either group, we did not explore whether differences exist between *1501 and *1502.
Figure 1.
The probabilities of overall survival in patients who are DR15+ and DR15− adjusted for patient age, performance score and transplant conditioning regimen.
DISCUSSION
The current analysis was undertaken to determine the clinical impact of HLA DR15 status in HLA-matched sibling bone marrow transplantation for acquired SAA. There were no differences in hematopoietic recovery, acute and chronic GvHD and overall survival between patients with and without the DR15+ antigen, after adjusting for the other risk factors associated with transplant-outcomes. However, the likelihood of secondary graft failure is higher in patients who are HLA DR15−. Importantly, the higher secondary graft failure in these patients did not lead to higher mortality. Autologous recovery after transplantation is associated with transfusion independence and second transplantation is not routine. The reason for the association between secondary graft failure and DR15 status is unknown but it is possible to speculate that differential antiviral responses could be responsible. Our observations are contrary to that reported for response after immune suppressive treatment for SAA where response rates were higher in patients who are DR15+. Our inability to demonstrate differences in acute GvHD and survival amongst those who are DR15− and DR15+ is also contrary to that reported after allogeneic transplantation for hematologic malignancies.
While not the primary intent of this analysis, multivariable modeling in this large group of patients with SAA allows some generalizable conclusions regarding outcomes. Our findings confirm and extend that reported by others; mortality risks were higher after transplantation for older patients (>20 years) and those with performance scores less than 90 (26). In addition, mortality risks varied with transplant conditioning regimen; mortality was lower in patients who received cyclophosphamide + ATG. However, this might be a simple consequence of the practice of utilizing non-standard conditioning regimens for patients who are not ideal candidates for HSCT. In the current analysis, fludarabine and busulfan-containing conditioning regimens were used for older patients, performance score <90 and longer intervals from diagnosis to transplantation. The observed variance in secondary graft failure rates with conditioning regimens could also be a reflection of patient characteristics.
Despite overall improvements in transplant outcomes for severe aplastic anemia, graft failure remains a significant complication, with an incidence of approximately 10% (27–29) and the frequent need to resort to second transplantation (30). Hematopoietic stem cells (HSCs) belong to the select group of tissues that are capable of presenting HLA Class II, and if DR15 expression on HSCs protects against graft failure in the host-versus-graft direction this may occur independently of an equivalent impact in the graft-versus-host direction to reduce GvHD. Our study was confined to HLA-matched sibling transplants and the role, if any, of DR15 in unrelated or mismatched related donor transplantations cannot be determined. In conclusion, while HLA DR15 presence lowered secondary graft failure rates it did not impact other outcomes, particularly survival after HLA-matched sibling bone marrow transplantation for acquired SAA.
Table 3.
Risk factors for GvHD and overall mortality
| Factor | N | Relative Risk (95% CI) | p-value |
|---|---|---|---|
| Acute GvHD | |||
| DR15− | 850 | 1 | |
| DR15+ | 346 | 0.88 (0.64–1.22) | 0.44 |
| Other significant covariates: | |||
| Age at transplant, years | |||
| ≤20 | 691 | 1 | <0.001 |
| 21–40 | 419 | 1.82 (1.32–2.50) | <0.001 |
| ≥40 | 86 | 3.48 (2.26–5.37) | <0.001 |
| Year of transplant | |||
| 1990–2000 | 697 | 1 | 0.003 |
| 2001–2006 | 499 | 0.62 (0.45–0.85) | 0.003 |
| Chronic GvHD | |||
| DR15− | 836 | 1 | |
| DR15+ | 340 | 1.06 (0.78–1.44) | 0.73 |
| Other significant covariates: | |||
| Age at transplant, years | |||
| ≤20 | 673 | 1 | <0.001 |
| 21–40 | 416 | 2.30 (1.69–3.13) | <0.001 |
| ≥40 | 87 | 3.01 (1.87–4.86) | <0.001 |
| GvHD prophylaxis | |||
| Csa + MTX +-other | 1024 | 1 | 0.005 |
| CsA +/− other | 117 | 1.98 (1.31–3.01) | 0.001 |
| FK506+-other | 35 | 0.94 (0.34–2.56) | 0.90 |
| Donor/Recipient gender match | |||
| F-M | 311 | 1 | |
| Others | 865 | 0.72 (0.53–0.97) | 0.03 |
| Year of transplant | |||
| 1990–2000 | 693 | 1 | |
| 2001–2006 | 483 | 0.68 (0.49–0.93) | 0.02 |
| Overall mortality | |||
| DR15− | 837 | 1 | |
| DR15+ | 344 | 1.17 (0.87–1.55) | 0.27 |
| Other significant covariates: | |||
| Age at transplant, years | |||
| ≤20 | 680 | 1 | <0.001 |
| 21–40 | 414 | 1.39 (1.04–1.86) | 0.02 |
| ≥40 | 87 | 2.79 (1.88–4.14) | <0.001 |
| Karnofsky score pre-transplant | |||
| <90 | 415 | 1 | <0.001 |
| ≥90 | 749 | 0.61 (0.47–0.79) | <0.001 |
| Unknown | 17 | 1.58 (0.64–3.92) | 0.32 |
| Conditioning regimen | |||
| Cyclophosphamide +ATG | 722 | 1 | |
| Cyclophosphamide alone | 180 | 1.26 (0.88–1.82) | 0.21 |
| Cyclophosphamide +limited field irradiation ± ATG | 34 | 2.09 (1.13–3.86) | 0.02 |
| Busulfan + cyclophosphamide | 178 | 1.79 (1.27–2.52) | 0.001 |
| Fludarabine + other agents | 67 | 2.97 (1.73–5.11) | <0.001 |
| Year of transplant | |||
| 1990–2000 | 689 | 1 | |
| 2001–2006 | 492 | 0.59 (0.42–0.82) | 0.002 |
Acknowledgments
This research was supported [in part] by the Intramural Research Program of the NIH, NHLBI. 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 (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children’s Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Swedish Orphan Biovitrum; THERAKOS, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- 1.Middleton D, Menchaca L, Rood H, Komerofsky R. New Allele Frequency Database. Tissue Antigens 2003. 2011;61:403–407. doi: 10.1034/j.1399-0039.2003.00062.x. http://www.allelefrequencies.net. [DOI] [PubMed] [Google Scholar]
- 2.Chapuis B, Von Fliedner VE, Jeannet M, et al. Increased frequency of DR2 in patients with aplastic anaemia and increased DR sharing in their parents. Br J Haematol. 1986;63:51–57. doi: 10.1111/j.1365-2141.1986.tb07494.x. [DOI] [PubMed] [Google Scholar]
- 3.Nakao S, Yamaguchi M, Saito M, et al. HLA-DR2 predicts a favorable response to cyclosporine therapy in patients with bone marrow failure. Am J Hematol. 1992;40:239–240. doi: 10.1002/ajh.2830400319. [DOI] [PubMed] [Google Scholar]
- 4.Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood. 1994;84:923–927. [PubMed] [Google Scholar]
- 5.Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100:1570–1574. [PubMed] [Google Scholar]
- 6.Shao W, Tian D, Liu C, Sun X, Zhang X. Aplastic anemia is associated with HLA-DRB1*1501 in northern Han Chinese. Int J Hematol. 2000;71:350–352. [PubMed] [Google Scholar]
- 7.Song EY, Park S, Lee DS, Cho HI, Park MH. Association of human leukocyte antigen-DRB1 alleles with disease susceptibility and severity of aplastic anemia in Korean patients. Hum Immunol. 2008;69:354–359. doi: 10.1016/j.humimm.2008.04.009. [DOI] [PubMed] [Google Scholar]
- 8.Sugimori C, Yamazaki H, Feng X, et al. Roles of DRB1 *1501 and DRB1 *1502 in the pathogenesis of aplastic anemia. Exp Hematol. 2007;35:13–20. doi: 10.1016/j.exphem.2006.09.002. [DOI] [PubMed] [Google Scholar]
- 9.Feng X, Chuhjo T, Sugimori C, et al. Diazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood. 2004;104:2425–2431. doi: 10.1182/blood-2004-05-1839. [DOI] [PubMed] [Google Scholar]
- 10.Oguz FS, Yalman N, Diler AS, Oguz R, Anak S, Dorak MT. HLA-DRB1*15 and pediatric aplastic anemia. Haematologica. 2002;87:772–774. [PubMed] [Google Scholar]
- 11.Usman M, Adil SN, Moatter T, Bilwani F, Arian S, Khurshid M. Increased expression of HLA DR2 in acquired aplastic anemia and its impact on response to immunosuppressive therapy. J Pak Med Assoc. 2004;54:251–254. [PubMed] [Google Scholar]
- 12.Ilhan O, Beksac M, Koc H, et al. HLA-DR frequency in Turkish aplastic anemia patients and the impact of HLA-DR2 positivity in response rate in patients receiving immunosuppressive therapy. Blood. 1995;86:2055. [PubMed] [Google Scholar]
- 13.Battiwalla M, Hahn T, McCarthy PL., Jr HLA DR15 and immunobiologic outcomes. Biol Blood Marrow Transplant. 2007;13:371. doi: 10.1016/j.bbmt.2006.12.439. [DOI] [PubMed] [Google Scholar]
- 14.Battiwalla M, Hahn T, Radovic M, et al. Human leukocyte antigen (HLA) DR15 is associated with reduced incidence of acute GVHD in HLA-matched allogeneic transplantation but does not impact chronic GVHD incidence. Blood. 2006;107:1970–1973. doi: 10.1182/blood-2005-05-1958. [DOI] [PubMed] [Google Scholar]
- 15.Davidson JA, Tate DG, Poulton KV, et al. HLA-DR15, reduced relapse rate and improved survival after HLA identical sibling hemopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:493–494. doi: 10.1016/j.bbmt.2006.12.442. [DOI] [PubMed] [Google Scholar]
- 16.Stern M, Passweg J, Tiercy JM, et al. Human leukocyte antigen DR15 is associated with reduced relapse rate and improved survival after human leukocyte antigen-identical sibling hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12:1169–1175. doi: 10.1016/j.bbmt.2006.07.001. [DOI] [PubMed] [Google Scholar]
- 17.Newell LF, Gooley T, Hansen JA, Stirewalt DL, Petersdorf EW, Deeg HJ. Tumor necrosis factor polymorphism affects transplantation outcome in patients with myelodysplastic syndrome but not in those with chronic myelogenous leukemia, independent of the presence of HLA-DR15. Biol Blood Marrow Transplant. 2010;16:1700–1706. doi: 10.1016/j.bbmt.2010.06.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA matched sibling donors. Transplantation. 1974;18:295–304. doi: 10.1097/00007890-197410000-00001. [DOI] [PubMed] [Google Scholar]
- 19.Kalbfleish J, Prentice R. The statistical analysis of failure time data. Wiley; New York: 1980. [Google Scholar]
- 20.Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Statist Assn. 1958;53:457–481. [Google Scholar]
- 21.Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical Society Series B (Methodological) 1972;34:187–220. [Google Scholar]
- 22.Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828. [PubMed] [Google Scholar]
- 23.Flowers ME, Kansu E, Sullivan KM. Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am. 1999;13:1091–1112. viii–ix. doi: 10.1016/s0889-8588(05)70111-8. [DOI] [PubMed] [Google Scholar]
- 24.Klein JP, Anderson PK. Regression modeling of competing risks data based on pseudo-values of the cumulative incidence function. Biometrics. 2005;61:223–229. doi: 10.1111/j.0006-341X.2005.031209.x. [DOI] [PubMed] [Google Scholar]
- 25.Klein JP. Modeling competing risks in cancer studies. Statistics in Medicine. 2006;25:1015–1034. doi: 10.1002/sim.2246. [DOI] [PubMed] [Google Scholar]
- 26.Schrezenmeier H, Passweg JR, Marsh JC, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007;110:1397–1400. doi: 10.1182/blood-2007-03-081596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Champlin RE, Perez WS, Passweg JR, et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood. 2007;109:4582–4585. doi: 10.1182/blood-2006-10-052308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Passweg JR, Socie G, Hinterberger W, et al. Bone marrow transplantation for severe aplastic anemia: has outcome improved? Blood. 1997;90:858–864. [PubMed] [Google Scholar]
- 29.Champlin RE, Horowitz MM, van Bekkum DW, et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood. 1989;73:606–613. [PubMed] [Google Scholar]
- 30.Horan JT, Carreras J, Tarima S, et al. Risk factors affecting outcome of second HLA-matched sibling donor transplantations for graft failure in severe acquired aplastic anemia. Biol Blood Marrow Transplant. 2009;15:626–631. doi: 10.1016/j.bbmt.2009.01.023. [DOI] [PMC free article] [PubMed] [Google Scholar]