DNA Typing for HLA-A and HLA-B Identifies Disparities Between Patients and Unrelated Donors Matched by HLA-A and HLA-B Serology and HLA-DRB1

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 399-409 ◽  
Author(s):  
Vinod K. Prasad ◽  
Nancy A. Kernan ◽  
Glenn Heller ◽  
Richard J. O’Reilly ◽  
Soo Young Yang
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Dna Typing ◽  
Outcome Studies ◽  
Cancer Center ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Variation ◽  
Unrelated Donors

Abstract High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci. To identify the extent and pattern of allelic disparities at HLA-A and HLA-B loci, 128 patients and 484 potential URD were evaluated by DNA typing. DNA typing for HLA-A, HLA-B, and HLA-DRB1 was performed at Memorial Sloan Kettering Cancer Center. HLA-A and HLA-B serotyping on URD was provided by the registries. By original typing (serology for HLA-A and HLA-B; DNA typing for DRB1) 187, 164, and 133 URD were 6/6, 5/6, and 4/6 matches, respectively. Following DNA typing, however, only 52.9% of the originally 6/6 matched URD remained 6/6, while 38.5%, 7.5%, and 1.1% were found to be 5/6, 4/6, and 3/6 matches. The level of disparity was higher in the originally 5/6 (P< .01) and 4/6 (P < .01) matched URD. A higher level of disparity was seen for HLA-B as compared to HLA-A. In addition, a serotype related variation was also noticed. For example, 24.1% of HLA-A2 and 60.1% of HLA-B35 seromatched URD were genotypically disparate, but no disparities were seen for HLA-A1 and HLA-B8. A higher percentage of HLA-A (67.4%) compared with HLA-B (35.4%) serologic homozygous URD remained genotypically homozygous (P = .01). The level of allelic disparity was lower (P < .01 for 6/6; P = .02 for 5/6) if the patient had one of the 15 most common haplotypes (A1B8DR3, A2B7DR15, A3B7DR15, etc) in comparison to the rest of the group. Outcome studies will answer the question whether these disparities are associated with a higher rate of immunological complications seen with URD-BMT.

DNA Typing for HLA-A and HLA-B Identifies Disparities Between Patients and Unrelated Donors Matched by HLA-A and HLA-B Serology and HLA-DRB1

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 399-409 ◽  
Author(s):  
Vinod K. Prasad ◽  
Nancy A. Kernan ◽  
Glenn Heller ◽  
Richard J. O’Reilly ◽  
Soo Young Yang
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Dna Typing ◽  
Outcome Studies ◽  
Cancer Center ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Variation ◽  
Unrelated Donors

High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci. To identify the extent and pattern of allelic disparities at HLA-A and HLA-B loci, 128 patients and 484 potential URD were evaluated by DNA typing. DNA typing for HLA-A, HLA-B, and HLA-DRB1 was performed at Memorial Sloan Kettering Cancer Center. HLA-A and HLA-B serotyping on URD was provided by the registries. By original typing (serology for HLA-A and HLA-B; DNA typing for DRB1) 187, 164, and 133 URD were 6/6, 5/6, and 4/6 matches, respectively. Following DNA typing, however, only 52.9% of the originally 6/6 matched URD remained 6/6, while 38.5%, 7.5%, and 1.1% were found to be 5/6, 4/6, and 3/6 matches. The level of disparity was higher in the originally 5/6 (P< .01) and 4/6 (P < .01) matched URD. A higher level of disparity was seen for HLA-B as compared to HLA-A. In addition, a serotype related variation was also noticed. For example, 24.1% of HLA-A2 and 60.1% of HLA-B35 seromatched URD were genotypically disparate, but no disparities were seen for HLA-A1 and HLA-B8. A higher percentage of HLA-A (67.4%) compared with HLA-B (35.4%) serologic homozygous URD remained genotypically homozygous (P = .01). The level of allelic disparity was lower (P < .01 for 6/6; P = .02 for 5/6) if the patient had one of the 15 most common haplotypes (A1B8DR3, A2B7DR15, A3B7DR15, etc) in comparison to the rest of the group. Outcome studies will answer the question whether these disparities are associated with a higher rate of immunological complications seen with URD-BMT.

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 799-803 ◽  
Author(s):  
Seiji Kojima ◽  
Takaharu Matsuyama ◽  
Shunichi Kato ◽  
Hisato Kigasawa ◽  
Ryoji Kobayashi ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Graft Versus Host Disease ◽  
Dna Typing ◽  
Hla Class I ◽  
Severe Aplastic Anemia ◽  
Host Disease ◽  
Graft Versus Host ◽  
Improved Outcomes ◽  
Unrelated Donors ◽  
Acquired Severe Aplastic Anemia

Abstract We retrospectively analyzed results for 154 patients with acquired severe aplastic anemia who received bone marrow transplants between 1993 and 2000 from unrelated donors identified through the Japan Marrow Donor Program. Patients were aged between 1 and 46 years (median, 17 years). Seventy-nine donor-patient pairs matched at HLA-A, -B, and -DRB1 loci, as shown by DNA typing. Among the 75 mismatched pairs, DNA typing of 63 pairs showed that 51 were mismatched at 1 HLA locus (18 HLA-A, 11 HLA-B, 22 HLA-DRB1) and 12 were mismatched at 2 or more loci. Seventeen patients (11%) experienced either early or late graft rejection. The incidence of grade III/IV acute graft versus host disease and chronic graft versus host disease was 20% (range, 7%-33%) and 30% (range, 12%-48%), respectively. Currently, 99 patients are alive, having survived for 3 to 82 months (median, 29 months) after their transplantations. The probability of overall survival at 5 years was 56% (95% confidence interval, 34%-78%). Multivariate analysis revealed the following unfavorable factors: transplantation more than 3 years after diagnosis (relative risk [RR], 1.86; P = .02), patients older than 20 years (RR, 2.27; P = .03), preconditioning regimen without antithymocyte globulin (RR 2.28; P = .04), and HLA-A or -B locus mismatching as determined by DNA typing. Matching of HLA class I alleles and improvement of preparative regimens should result in improved outcomes in patients with severe aplastic anemia who receive transplants from unrelated donors.

scholarly journals Selective depletion of CD8+ T lymphocytes for prevention of graft- versus-host disease after allogeneic bone marrow transplantation

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 418-423 ◽  
Author(s):  
R Champlin ◽  
W Ho ◽  
J Gajewski ◽  
S Feig ◽  
M Burnison ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Myelogenous Leukemia ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host ◽  
Donor Bone Marrow ◽  
Leukemia Relapse ◽  
Acute Graft

The effects of selectively depleting CD8+ cells from donor bone marrow were assessed in 36 patients receiving transplantation from an HLA- identical sibling as treatment for leukemia. Donor bone marrow underwent ex vivo treatment using anti-Leu-2 monoclonal antibody and complement. Patients received cyclosporine post-transplant for 6 months. Thirty-three patients had initial engraftment. Three failed to have hematologic recovery, and one patient with initial engraftment had late graft failure. The actuarial incidence of grade greater than or equal to 2 acute graft-versus-host disease was 28% +/- 18% and was usually confined to the skin. Of 33 patients with engraftment, 32 were complete chimeras and one had mixed chimerism. The tempo of hematologic and immunologic recovery was comparable with that reported with transplantation of unmodified bone marrow, although CD4+ and CD8+ T cells recovered at comparable rates. The actuarial rate of leukemia relapse was 11% +/- 10%, occurring in three patients with acute leukemia but in none of 13 patients transplanted for chronic myelogenous leukemia. Actuarial survival was 57% +/- 17% at 2 years. These data indicate that after transplantation of marrow depleted of CD8+ cells, engraftment with prompt hematologic and immunologic recovery generally occurs, with a relatively low rate of acute graft- versus-host disease. Graft failure remains a problem despite retention of CD4+ cells within the donor marrow. The lack of leukemia relapse in patients with chronic myelogenous leukemia suggests retention of a graft-versus-leukemia effect, at least for this malignancy.

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Abstract Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

scholarly journals HLA-matched sibling bone marrow transplantation for β-thalassemia major

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1745-1750 ◽  
Author(s):  
Mitchell Sabloff ◽  
Mammen Chandy ◽  
Zhiwei Wang ◽  
Brent R. Logan ◽  
Ardeshir Ghavamzadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Thalassemia Major ◽  
Host Disease ◽  
Risk Class ◽  
Graft Versus Host ◽  
Matched Sibling

Abstract We describe outcomes after human leukocyte antigen-matched sibling bone marrow transplantation (BMT) for 179 patients with β-thalassemia major. The median age at transplantation was 7 years and the median follow-up was 6 years. The distribution of Pesaro risk class I, II, and III categories was 2%, 42%, and 36%, respectively. The day 30 cumulative incidence of neutrophil recovery and day 100 platelet recovery were 90% and 86%, respectively. Seventeen patients had graft failure, which was fatal in 11. Six of 9 patients with graft failure are alive after a second transplantation. The day 100 probability of acute graft-versus-host disease and 5-year probability of chronic graft-versus-host disease was 38% and 13%, respectively. The 5-year probabilities of overall- and disease-free survival were 91% and 88%, respectively, for patients with Pesaro risk class II, and 64% and 62%, respectively, for Pesaro risk class III. In multivariate analysis, mortality risks were higher in patients 7 years of age and older and those with hepatomegaly before BMT. The leading causes of death were interstitial pneumonitis (n = 7), hemorrhage (n = 8), and veno-occlusive disease (n = 6). Proceeding to BMT in children younger than 7 years before development of end-organ damage, particularly in the liver, should improve results after BMT for β-thalassemia major.

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