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)

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-alpha (IFN-alpha), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-alpha results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-alpha on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-alpha therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-alpha, whereas 22, 23, and 25 patients received IFN-alpha for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-alpha therapy administered for > or = 6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2. 1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-alpha therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight > or = 110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-alpha for less than 6 months before transplant, who were < or = 50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% +/- 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-alpha when the patient is < or = 50 years of age and has an HLA-compatible unrelated volunteer donor.
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PMID:Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase. 965 36

Allogeneic marrow transplantation is curative therapy for thalassemia, but fewer than 30% of patients have an HLA-identical sibling marrow donor. Selection of alternative donors of hematopoietic stem cells (unrelated individuals or HLA-nonidentical family members) has been aided by establishment of world-wide donor registries now exceeding 3.6 million volunteers and by DNA-based HLA typing to more closely match potential donors. Coupled with improved methods to control graft-versus-host disease and prevent fungal and cytomegalovirus infection, remarkable progress has been made in alternative donor transplantation. For patients 50 years of age or younger, with recently diagnosed chronic myelogenous leukemia (CML) in chronic phase, 1- and 5-year survivals after HLA-A, B, DRB1 identical unrelated marrow transplantation in Seattle are 82% and 74%, respectively. These results are essentially identical to outcome in similar patients given HLA-matched sibling allografts. However, the world-wide number of alternative donor transplants for thalassemia remains limited to date: 4 unrelated and 60 HLA-nonidentical related transplants have been reported to the IBMTR since 1969 with actuarial overall survival of 75%. Using the paradigm of CML, it is likely that access to curative therapy of thalassemia will improve with optimal HLA typing and donor selection early in the course of disease.
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PMID:Unrelated and HLA-nonidentical related donor marrow transplantation for thalassemia and leukemia. A combined report from the Seattle Marrow Transplant Team and the International Bone Marrow Transplant Registry. 966 53

In this retrospective study, 23 recipients of peripheral blood progenitor cells (PBPC) were compared to 23 recipients of bone marrow (BM). The donors were 12 HLA-A-B-DR identical siblings and 11 HLA-A-B-DR identical unrelated donors in the PBPC and BM groups, respectively. Diagnoses in the PBPC group were CML seven, AML, nine, ALL three, lymphoma one, myeloma two and aspartylglucosaminuria (AGU) one. The median age was 40 (5-55) years. The BM group was matched for diagnosis, age, conditioning therapy, GVHD prophylaxis and G-CSF treatment after BMT. A higher number of MNC (P<0.001), CD34+ (P = 0.05), CD3+ (P<0.001) and CD56+ (P<0.001) cells in the graft, a reduced number of platelet transfusions (P = 0.03) and a significant hastening of neutrophil and platelet recovery were seen in the PBPC group compared to the BM group. In logistic regression analysis, the following factors were important for engraftment of ANC >0.5 x 10(9)/l: peripheral blood progenitor cell transplantation (PBPCT) (P = 0.003) and mononuclear cells (MNC) > or =2.5 x 10(8)/kg recipient in the graft (above median) (P = 0.009) in univariate analysis. For recovery of platelets >30 x 10(9)/l: PBPCT (P = 0.03) and HLA-identical sibling donors (P = 0.05) were significant in multivariate analysis. A trend towards a lower incidence of bacteremia was seen in the PBPC group, ie 22 vs 48% (P = 0.06) in the BM group. GVHD, TRM and survival did not differ between the two groups.
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PMID:Faster neutrophil and platelet engraftment, but no differences in acute GVHD or survival, using peripheral blood stem cells from related and unrelated donors, compared to bone marrow. 970 19

Twenty-six patients received peripheral blood progenitor cells (PBPC) from unrelated donors at five European Centres. Twenty-five donors were HLA-A, -B and -DR identical and one had a one antigen mismatch. PBPC were mobilised by treatment with G-CSF for 4-5 days. Eleven patients receiving PBPC were compared to 11 patients receiving unrelated bone marrow with comparable prognostic factors. The median mononuclear cell count, the CD3+ cells and the CD56+ cells were seven to 10 times higher in PBPC, compared to bone marrow (P < 0.001). The median CD34+ cell content was 6.1 x 10(6)/kg recipient weight with PBPC, compared to 4.3 with bone marrow (NS). Time from transplantation to neutrophils >0.5 x 10(9)/l was a median of 11 (range 6-21) days using PBPC vs 15 (10-22) days after transplantation of bone marrow (P = 0.03). Transfusions and time to discharge did not differ between the two groups. All 26 patients receiving PBPC engrafted. Acute GVHD grades II-IV was seen in 8/26 (31%) and chronic GVHD in 8/18 (44%). Overall, 13/26 (50%) of the patients are alive and well with a median follow-up of 9 (2-35) months.
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PMID:Faster engraftment of peripheral blood progenitor cells compared to bone marrow from unrelated donors. 971 3

HLA-DP incompatibility is not considered as an exclusion criterion for bone marrow donors, because such incompatibility was not shown to affect significantly the risk for acute graft-versus-host disease (GVHD). In line with this clinical observation, it was proposed that in the context of bone marrow transplantation, HLA-DP determinants did not function as transplantation antigens in the same way as HLA-A, -B or -DR. In contrast to the above conclusion, we recently demonstrated the presence of HLA-DPB1*0501 specific T cell clones in a skin biopsy of a patient who developed aGVHD after receiving a bone marrow transplant (BMT) in which the only mismatched allele in the GVHD direction was HLA-DPB1*0501. At that time, this case was unique and occurred in a relatively uncommon graft setting where the patient received purified CD34+ BM cells from an unrelated donor. In the present study, we analyzed the immunological events associated with an aGVHD which occurred in the context of a 'regular' allogeneic BMT involving a single HLA-DPB1*1001 mismatch between donor and recipient in the GVHD direction. To this end, we analyzed several amplified T cell subsets present within a T cell line derived from a skin biopsy performed at the onset of GVHD. Our results demonstrated that T cell populations belonging to the TCRBV2, TCRB6.7, TCRBV14 and TCRBV17 subsets were specific for the HLA-DPB1*1001 mismatched allele. These data strengthen and generalize our first conclusion that a single HLA-DP mismatch between donor and recipient can activate a strong T cell response in vivo and consequently challenge the notion that HLA-DP incompatibility should not be taken into account in the choice of BM donors. Moreover, they also underline the idea that HLA-DP antigens may represent an interesting immune target for future therapeutic approaches.
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PMID:Acute graft-versus-host disease after bone marrow transplantation with a single HLA-DPB1*1001 mismatch: involvement of different TCRBV subsets. 972 75

Eleven leukemia patients who had undergone bone marrow transplants from HLA-A, B, DR genotypically mismatched unrelated donors received FK506 and short-term methotrexate as prophylaxis for graft-versus-host disease (GVHD). Grade III-IV acute GVHD developed in 2 of the patients, and chronic GVHD developed in 4 of the other patients. Adverse drug reaction included reversible nephrotoxicity, hyperglycemia (all patients) and hypertension (9 patients). Hyperglycemia and hypertension of grade 3 or higher occurred mostly in the patients who were on supplemental steroids. However, severe nephrotoxicity was not observed. Complications included cystitis (4 patients), cytomegalovirus colitis (3 patients), Interstitial Pneumonitis (IP) (3 patients), tuberculosis (1 patient), and thrombotic microangiopathy (1 patient). None of patients relapsed. Although close monitoring of FK506 blood concentration and patient clinical signs are required, we concluded that FK506 is effective for GVHD prophylaxis after bone marrow transplantation from HLA-A, B, DR genotypically mismatched unrelated donors, and that adverse reactions due to FK506 are controllable. To determine the long-term effectiveness of this drug, it will be necessary to conduct prospective randomized studies that compare it wiht cycloporin A as a preventive treatment against GVHD in patients who receive bone marrow transplants from HLA genotypically mismatched unrelated donors.
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PMID:[FK506 for the prophylaxis of graft-versus-host-disease after bone marrow transplantation from HLA-genotypically mismatched unrelated donor]. 978 75

In unrelated marrow transplantation, the benefit of matching class II HLA-DRB1 and DQB1 alleles of the donor and recipient is well documented. Little is known about the clinical relevance of matching for class I HLA-A, B, and C alleles. We used DNA-amplification methods to identify the HLA-A, B, and C alleles of 300 patients and their donors. The incidence of graft failure was correlated with multiple class I mismatching in the donor. The risk of grades III-IV acute graft-versus-host disease was highest with class II mismatching in the recipient. Mismatching for a single class I or class II allele had no effect on survival, but mortality was increased by mismatching for more than one class I allele and by simultaneous mismatching for class I and class II alleles. We conclude that matching HLA class I and class II alleles of the donor and recipient can improve outcome after unrelated marrow transplantation.
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PMID:Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. 980 42

In comparison with HLA-matched sibling bone marrow transplants, unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due to HLA incompatibilities not identified by current matching strategies. High resolution DNA-based typing methods for HLA class II loci have improved donor selection and treatment outcome in unrelated donor bone marrow transplantation. By using DNA-based typing methods for HLA-A and -B on a cohort of 100 potential bone marrow donor/patient pairs, we find that serological typing for HLA class I is limited in its ability to identify incompatibilities in unrelated pairs. Furthermore, the incompatibilities identified are associated with the presence at high frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing also indicates that HLA-C mismatches are common in HLA-A and -B serologically matched pairs. Such mismatches appear to be significantly less immunogenic with respect to cytotoxic T-lymphocyte recognition, but are expected to influence natural killer cell activity. Thus, improved resolution of HLA class I shows many previously undisclosed mismatches that appear to be immunologically functional. Use of high resolution typing methods in routine matching is expected to improve unrelated donor selection and transplant outcome.
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PMID:Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection. 984 54

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.
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PMID: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. 986 87

Transplants from related donors who share one HLA haplotype and are variably matched with the recipient for HLA-A, B, or DRB1 loci on the unshared haplotype are associated with increased risks of graft failure and graft-versus-host disease (GVHD) that correlate with the degree of HLA mismatch. Survival, however, is not necessarily inferior if recipient incompatibility is limited to one HLA locus. Available methods for post-transplant immunosuppression have not allowed similar success with transplants incompatible for two or three HLA loci. GVHD incidence and severity can be decreased by depletion of donor T cells from the marrow inoculum. However, the potential benefit is offset by increased graft failure and leukemia relapse with no improvement in survival. Since fewer than 30% of the patients in North America or Europe have an HLA-matched sibling and less than 5% have a one HLA-locus mismatched relative, most candidates for an allogeneic marrow transplant are in need of an unrelated donor. As of October 1993, the National Marrow Donor Program (NMDP) has accrued more than 1 million volunteers typed for HLA-A and B, including 200,000 typed for HLA-DR, and has provided donors for more than 2000 transplants. The probability of finding an HLA-A, B, DR match at the initial search has increased from 10-15% in 1987, to 50-55% in 1992. An additional 12% of patients will find a match when available HLA-A and B matched donors are typed for DR, and 20% of patients have a one HLA-locus incompatible unrelated donor. Through an international network of regional registries a search for an unrelated donor can now be conducted among 1.7 million volunteers worldwide. Unrelated donor transplants have allowed long-term disease-free survival of patients with a variety of hematological disorders. When compared to HLA-matched sibling transplants, unrelated donor transplants are associated with an increase in the incidence of graft failure and GVHD. Such an increase may be due to undetected HLA disparities or to non-HLA-linked histocompatibility genes. At our center patients with CML in chronic phase, the most common indication for unrelated donor transplantation, have a 50-55% probability of survival 2-6 years after an unrelated donor transplant, whereas patients with aplastic or refractory anemia have a 25-35% probability of survival.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of HLA incompatibility in marrow transplantation from unrelated and HLA-mismatched related donors. 1015 43


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