Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of accurate and reproducible high-resolution DNA-based HLA typing methods has significantly improved the prospects for identifying well-matched donors for patients undergoing HCT, particularly those who lack a matched relative to serve as donor. Analysis of high-resolution typing data has shown that donor-recipient compatibility for HLA alleles is an important predictor of transplant outcome. The risk of graft failure is increased by patient incompatibility for HLA alleles expressed by the donor, and by the presence of patient anti-donor alloantibody. The impact of HLA class I and class II allele disparity on transplant outcome in unrelated HCT has been demonstrated in several large studies, and it is now evident that complete donor-recipient matching for HLA-A,-B,-C,-DRB1 and -DQB1 genes can significantly reduce the incidence of GVHD and risk of mortality. Patient-donor disparity for multiple HLA class I and class II alleles is clearly related to poor outcome, in terms of both risk of severe GVHD and mortality. Important questions for future investigation include elucidation of the relative importance of matching for different HLA genes ("permissive" versus "non-permissive" alleles), and the potential synergistic impact of multi-locus class I and II disparities.
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PMID:HLA matching and hematopoietic cell transplant outcome. 1297 57

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder caused by a somatic mutation of the X-linked phosphatidylinositol glycan class A gene. Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning is the only curative treatment; however, it is associated with high treatment-related mortality. Here, we report on allogeneic HCT for PNH after minimal conditioning. Seven adult patients with high-risk PNH underwent peripheral blood HCT from HLA-A-, -B-, -C-, -DRB1-, and -DQB1-matched related (n = 2) and unrelated (n = 5) donors. Conditioning included fludarabine 30 mg/m(2)/d on days -4 to -2 and 2 Gy of total body irradiation on day 0. After HCT, patients were given immunosuppressive therapy with oral cyclosporine starting on day -3 and mycophenolate mofetil starting on day 0. All 7 patients attained durable engraftment. After 28 days, a median of 77% (range, 53%-96%) T-cell donor chimerism was found in bone marrow and peripheral blood. T-cell chimerism increased to 91% (range, 76%-100%) on day +180 and to 100% in all surviving patients after 12 months. All 7 patients attained complete remissions of their disease. Four patients are alive 13 to 38 months after HCT. Three patients died of treatment-related mortality, 1 because of complications after acute pancreatitis and multiorgan failure, 1 because of infection related to chronic graft-versus-host disease (GVHD), and 1 because of bleeding after liver biopsy for late subacute/chronic GVHD. Allogeneic HCT from related and unrelated donors after minimal conditioning is a new and potentially curative option for patients with advanced PNH.
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PMID:Hematopoietic cell transplantation from related and unrelated donors after minimal conditioning as a curative treatment modality for severe paroxysmal nocturnal hemoglobinuria. 1465 52

An 11-year-old boy with acute lymphoblastic leukemia received unrelated cord blood transplantation at the second remission. Because of early graft failure, he was given a second non-T-cell depleted bone marrow transplant from his HLA 2 loci (HLA-A and -DRB1)-mismatched mother 36 days after the first transplantation. Feto-maternal microchimerism was verified before transplantation. The second transplantation was performed with fludarabine/melphalan as a conditioning regimen, and tacrolimus/short-course methotrexate as graft-versus-host disease (GVHD) prophylaxis. Engraftment was prompt with a recovery of neutrophils (> 0.5 x 10(9)/1) by day +10, reticulocytes (> 1%) by day +17 and platelets (> 50 x 10(9)/l) by day +18. Mild regimen-related toxicities (grade I gastrointestinal, grade II hepatic) were observed and acute GVHD was grade I (skin: stage 2). No severe complication was noted. At 6 months post-transplantation, he had no chronic GVHD or leukemia relapse. This experience indicates the future feasibility of a back-up non-T-cell depleted transplantation from HLA 2 loci-mismatched and feto-maternal microchimerism-positive mothers in cases with primary graft failure.
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PMID:[Acute lymphoblastic leukemia in childhood treated with non-T-cell depleted bone marrow transplantation from an HLA 2 loci (HLA-A and-DRB1)-mismatched mother after early graft failure of cord blood transplantation]. 1468 75

The aim of this study was to identify significant prognostic factors by using unrelated genomically HLA-A, -B and -DRB1-identical donors. Such data could help to choose the best donor. We studied 136 consecutive patients with hematologic malignancies and a median age of 32 years (range, 0-55 years) who received hematopoietic stem cell transplantation. Bone marrow grafts were given to 83 and peripheral blood stem cells to 53 patients. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 30% and of chronic GVHD was 54%. At 5 years, the overall transplant-related mortality (TRM) was 34%, and patient survival was 50%. In Cox multivariate analysis, 32 potential risk factors were analyzed. Monoclonal antibody OKT-3 during conditioning was correlated with grade II to IV acute GVHD, chronic GVHD, and TRM. HLA-DP mismatch was associated with poor TRM and poor survival. Cytomegalovirus-seropositive patients with a seronegative donor had a decreased leukemia-free survival. Five-year TRM was 14% with no risk factor, 38% with 1 risk factor, and 87% with 2 risk factors. The 5-year survival was 72%, 48%, and 30% with 0, 1, and 2 risk factors, respectively. We concluded that unrelated hematopoietic stem cell transplantation may be improved if an optimal donor and immunosuppression are chosen.
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PMID:Which donor should be chosen for hematopoietic stem cell transplantation among unrelated HLA-A, -B, and -DRB1 genomically identical volunteers? 1475 78

Outcome of unrelated donor marrow transplantation is influenced by donor-recipient matching for HLA. Prior studies assessing the effects of mismatches at specific HLA loci have yielded conflicting results. The importance of high-resolution matching for all HLA loci has also not been established. We therefore examined the effects of HLA matching (low or high resolution or both) on engraftment, graft-versus-host disease (GVHD), and mortality in 1874 donor-recipient pairs retrospectively typed at high resolution for HLA-A, -B, -C, -DRB1, -DQ, and -DP. Mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality. Only HLA-A mismatches demonstrated significant adverse effects on GVHD. These adverse effects on outcome were more evident in transplants with low-resolution versus only high-resolution mismatches. Mismatches for HLA-DQ or -DP did not significantly affect outcome. When high-resolution mismatches at HLA-A, -B, -C, and -DRB1 were considered together, adverse effects on survival and GVHD were observed. We therefore conclude that matching for HLA-C should be incorporated into algorithms for unrelated donor selection. High-resolution mismatches at HLA-A, -B, -C, and -DRB1 adversely affect outcome, but less so than low-resolution mismatches. When clinical circumstances allow, high-resolution class I typing may help optimize donor selection and improve outcome.
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PMID: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. 1519 52

To explore a method of predicting acute graft versus host disease (aGVHD) after unrelated cord blood transplantation (UCBT), the HLA-A, -B, -DRB1 molecular three-dimensional structures in 25 patients with blood disorder who underwent UCBT and their donors were modeled by using molecular modeling technique. First, full amino acid sequences of each HLA antigen from HLA data banks were loaded down, and then amino acid sequence of extracellular antigen binding region was chosen. Third step, SPDBV software of SWISS-MODEL server was used to modeling the three-dimensional structures of each different allele of HLA-A, -B and -DRB1 between patients and donors and the parameter "root mean square deviation" (RMSD) was used to indicate the structure differences. Last, RMSD of each different HLA allele of each donor-patient pair were added together to get total RMSD. The 25 patients were divided into 3 groups: the first group did not develop aGVHD; the second group developed aGVHD graded I-II and the third group developed aGVHD graded III-IV. The results showed that in the 25 patients divided into three groups, 8 patients in the first group did not develop aGVHD (32%); 13 patients in the second group developed grade I-II of aGVHD (52%) and 4 patients in the third group developed aGVHD III-IV (16%). The total RMSDs of each group were 0.24 +/- 0.15, 0.25 +/- 0.14 and 0.47 +/- 0.22 respectively. The total RMSD of the third group was significantly higher than that of the other two groups. In conclusion, utilization of modeling HLA molecular three-dimension can predict the severe aGVHD after UCBT quickly, simply and accurately. It provides scientific basis in choosing a optimal cord blood donor to avoid severe aGVHD for physicians and the cord blood banks. And it is instructive too to direct the application of immunosuppressive agents after transplantation in clinic.
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PMID:[Prediction of acute GVHD after umbilical cord blood transplantation by HLA three-dimensional structure matching]. 1522 51

The Cord Blood Transplantation study group conducted a prospective study of unrelated cord blood transplantation (CBT) to better define the role of this stem cell source for subjects requiring unrelated allogeneic transplantation. We report on 1 stratum of the study designated for adult subjects. The primary end point of the study was survival at 180 days. Secondary end points included engraftment, graft-versus-host disease, relapse, and long-term survival. Eligibility criteria for malignant and nonmalignant diseases were specified. Subjects with active central nervous system disease, Karnofsky performance status <70%, grade 3 or 4 or primary myelofibrosis, or suitable related donors were excluded. Enrollment required a single cord blood unit containing >10(7) nucleated cells per kilogram of recipient weight and matched at > or =4 HLA-A and -B (low or intermediate resolution) and -DRB1 (high resolution) types. Thirty-four subjects were entered, with a median age of 34.5 years (range, 18.2-55 years). Most subjects (n = 23) had a 4 of 6 match, 10 subjects had a 5 of 6 match, and 1 subject had a 6 of 6 match. Diagnoses at transplantation included acute myelogenous leukemia (n = 19), acute lymphoblastic leukemia (n = 9), chronic myelogenous leukemia (n = 3), myelodysplastic syndrome (n = 1), paroxysmal nocturnal hemoglobinuria (PNH) (n = 1), and non-Hodgkin lymphoma (n = 1); 94% were classified as poor risk according to National Marrow Donor Program criteria. Subjects received total body irradiation/cyclophosphamide (n = 27) or busulfan/melphalan (n = 7) conditioning regimens. Four subjects died before CBT and are described here but are not included in the main analysis. The cumulative incidence rates and median times to neutrophil (500/microL) and platelet (>20,000/microL) engraftment were 0.66 by day 42 (median, 31 days) and 0.35 by day 180 (median, 117 days). The cumulative incidence rate for grade II-IV GVHD was 0.34 by day 100. For the primary end point, survival at 180 days, Kaplan-Meier survival estimates were 0.30 (95% confidence interval, 0.14-0.46) by day 180 after transplantation. To date there are 2 survivors, and both are >36 months from enrollment. A retrospective analysis was performed by using high-resolution HLA-A and -B typing, which revealed that approximately one third of subjects had 1 or more additional HLA mismatches compared with results of low- or intermediate-resolution HLA typing. The findings of high treatment-related mortality and slow engraftment kinetics indicate that CBT should continue to be performed in specialized centers with a research focus on cord blood cells.
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PMID:Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT). 1568 76

Cord blood transplants are now widely used for allogeneic hematopoietic stem cell transplants (HSCT) in patients with various hematologic disorders. One advantage of this source of stem cells is the decrease of graft-versus-host disease (GVHD) because of the immaturity of lymphocytes at birth. The role of human leukocyte antigen (HLA) for donor search and post-transplant outcomes is not very well described. The Eurocord Registry has analyzed more than 1,000 cases of unrelated cord blood transplants (UCBT). Results show that HLA matching is important for engraftment and graft versus leukemia but not for survival and GVHD. Allelic matching for HLA-A, -B, -C, -DRB1, and -DQB1 shows that the number of mismatches is very high and does not allow identification of prognostic factors. Contrary to the criteria of donor choice for an unrelated bone marrow transplant where HLA allelic matching is important, in the case of cord blood transplants the number of nucleated cells infused is the most important predictor of success.
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PMID:Human leukocyte antigen matching in cord blood transplantation. 1584 74

HLA-C matching is an important determinant of outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation. However, its importance in non-myeloablative stem cell transplantation (NST) is not known. We report a retrospective analysis of 111 patients who underwent URD NST, of whom 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1 and 33 were mismatched at one or more HLA-C antigen/allele (24 HLA-C only; nine HLA-C+other locus mismatch). Patients were conditioned with busulfan (0.8 mg/kg/day i.v. x 4 days) and fludarabine (30 mg/m(2)/day i.v. x 4 days). Graft-versus-host disease prophylaxis included cyclosporine/prednisone- or tacrolimus/mini-methotrexate-based regimens. HLA-C disparity did not impair engraftment. Median marrow donor chimerisms were >or=90% donor at day+30 and +100 in both groups. Overall survival at 2 years was 30% in HLA-C-mismatched and 51% in 10/10-matched patients (P=0.008). In Cox regression, HLA-C mismatch was an independent predictor of death (hazard ratio 1.85, P=0.04). Treatment-related mortality was higher in the HLA-C-mismatched group: 48 versus 16% (P=0.0001). Cumulative relapse incidence was 35% in the HLA-C-mismatched and 55% in the 10/10-matched cohort, P=0.09. HLA-C mismatch is associated with inferior survival after URD NST.
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PMID:HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation. 1653 20

Graft failure and nonrelapse mortality (NRM) are major obstacles after the first unrelated-donor bone marrow transplantation (UD-BMT) with reduced-intensity conditioning. We evaluated UD-BMT with fludarabine (5 x 25 mg/m2) and melphalan (2 x 90 mg/m2) treatment combined with short-term methotrexate and tacrolimus (n = 20) or cyclosporine (n = 2) therapy for 22 patients with hematologic malignancies who were ineligible for conventional conditioning. Only 9 patients were in remission at transplantation. Seventeen patients underwent HLA-matched or DRB1 allele-mismatched transplantation, and 5 patients underwent HLA-A allele-mismatched or serologically HLA-DR-mismatched transplantation. Regimen-related toxicities were tolerable, although transient oral mucositis, hepatobiliary enzyme elevation, and diarrhea were observed frequently. All evaluable patients achieved sustained neutrophil engraftment, and all patients tested showed complete donor chimerism on day 28. With a median follow-up of 16 months, NRM and overall survival rates at 1 year were 19% and 81%, respectively, among the patients who underwent HLA-matched or DRB1 allele-mismatched transplantation. Acute graft-versus-host disease (GVHD) of grades II to IV occurred in 26% of the patients. The cumulative incidence of chronic GVHD was 44%. Despite the small number of patients and the short follow-up period, this reduced-intensity regimen enabled satisfactory engraftment and achievement of rapid complete donor chimerism with tolerable toxicities in the patients, including those who underwent HLA-mismatched UD-BMT.
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PMID:Stable engraftment after a conditioning regimen with fludarabine and melphalan for bone marrow transplantation from an unrelated donor. 1675 39


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