Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have explored the efficacy and toxicity of hematopoietic stem cell transplantation from unrelated donors for hematologic malignancies and other disorders. While most marrow donors have been identified through the National Marrow Donor Program in cooperation with many international registries, the recent development of unrelated donor umbilical cord blood (UCB) banks has allowed us to also evaluate this stem cell source. Analysis of the first 211 URD BMT performed at the University of Minnesota shows an overall survival of 33%, with older recipient age and transplant from a donor with a major HLA-A or B mismatch independently associated with poorer survival. Analysis of engraftment of URD marrow shows increasing risk of delayed or incomplete engraftment with increasing HLA disparity between URD and recipient. GVHD is increased in recipients of URD marrow compared with recipients of related donor marrow. Malignant relapse, however, is less frequent in URD marrow recipients, perhaps due to an increased graft-versus-leukemia effect. Formal assessment shows quality of life in long term URD BMT survivors (beyond 2 years) is excellent, and not different from that seen in sibling marrow recipients. Data from patients receiving unrelated donor UCB transplantation at the University of Minnesota indicate that UCB is an acceptable alternate source of stem cells, at least for young recipients, and may be associated with a reduced incidence of GVHD. Ongoing studies at the University of Minnesota include examination of the applicability of unrelated UCB transplantation to adult recipients, and of the degree of HLA-incompatibility which can be tolerated in UCB transplantation. Studies to identify the optimal GVHD prophylaxis for URD BMT, and to examine the role of class II matching in transplant outcome are in progress.
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PMID:Unrelated donor bone marrow transplantation for hematological malignancies-current status. 903 Nov 2

One hundred and ninety-one patients with acute leukaemia who received bone marrow from HLA-A, -B and -DR identical unrelated donors and were reported to EBMT and/or IMUST, were matched with 382 patients receiving autologous bone marrow for diagnosis, age, stage of disease and year of transplantation. Transplant-related mortality (TRM) was significantly higher in recipients of unrelated marrow compared to autograft recipients, 44 +/- 4% (+/- 95% confidence interval) and 15 +/- 3% at 2 years in the two groups, respectively (P < 10(-4)). In contrast, relapse probability was lower in recipients of unrelated marrow, being 32 +/- 5% at 2 years compared to 55 +/- 3% in recipients of autografts (P < 10(-4)). Two-year leukaemia-free survival (LFS) in patients with acute lymphoblastic leukaemia was 39 +/- 5% and 32 +/- 3% in the two groups, respectively. Among patients with acute myeloid leukaemia (AML), the corresponding figures were 36 +/- 6% and 46 +/- 5% in the two groups, respectively (P = NS). In AML in first remission (CR-1), the 2-year survival was 42 +/- 10% in recipients of unrelated bone marrow, compared to 69 +/- 8% in autograft recipients (P = 0.008). When all patients with acute leukaemia were included, the 2-year LFS was 38% in recipients of unrelated marrow, compared to 37% in autograft recipients (NS). In conclusion, this retrospective analysis supports the design of a prospective randomized study in patients with high-risk/advanced acute leukaemia who lack a suitable related bone marrow donor, to ascertain which of the two strategies, if any, should be favoured.
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PMID:Donor search or autografting in patients with acute leukaemia who lack an HLA-identical sibling? A matched-pair analysis. Acute Leukaemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) and the International Marrow Unrelated Search and Transplant (IMUST) Study. 916 39

Bone marrow transplantation from unrelated donors is increasingly used to treat haematological malignancies. There are almost 4 million volunteer donors now available. Therefore, it is possible to find an HLA-A, -B and -DR-identical donor for around 70% of the patients. The major obstacles to unrelated bone marrow transplantations have been rejection, severe acute graft-versus-host disease (GVHD) and prolonged immune recovery leading to frequent infections and a high transplant-related mortality. However, with improved tissue typing using DNA techniques, immunosuppression using T-cell depletion in vitro or in vivo, the frequency of acute GVHD is acceptable and the results approach those obtained with HLA-identical siblings. For patients with chronic myeloid leukaemia, the worldwide 3-year survival is around 40%. Other indications for bone marrow transplantation with unrelated marrow include acute leukaemia and myelodysplastic syndromes with high-risk features. Unrelated cord blood cells and unrelated peripheral blood progenitor cells will be increasingly used as alternative haematopoietic stem cell sources to bone marrow. Improved immunosuppression, more accurate tissue typing, growth factors and better management of infections is expected to improve outcome using unrelated haematopoietic stem cells for transplantation in the near future.
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PMID:Bone marrow transplantation using unrelated donors for haematological malignancies. 923 6

The availability of an HLA-matched sibling donor in only 30% to 35% of patients requiring allogeneic bone marrow transplantation (BMT) has led to the proposal of unrelated donors as an alternative source of bone marrow. The greater HLA incompatibility, which, although present, was undetected until recently in many unrelated donor BMT cases, has resulted in a higher rate of posttransplant complications and impaired acturial survival when compared with HLA-matched sibling BMT. Molecular HLA typing enables us to evaluate the impact of incompatibility at each locus in the outcome of unrelated donor BMT. The overall retrospective data would recommend that HLA-A, -B and -C allelic molecular matching should be implemented in addition to HLA-DR allelic matching. Further retrospective analysis is needed in order to assess which incompatibility or combinations are better tolerated than others. Only the definitive knowledge at the sequence level of the donor and the recipient HLA allelic diversity involved in controlling the allogeneic immune response will allow us to understand the precise biologic rationale of the graft-versus-host disease. Knowledge and control of the HLA incompatibilities should allow us to offset the detrimental effects of histoincompatibility while developing strategies to take advantage of the beneficial graft-versus-leukemia effect. Also the role of minor histocompatibility antigens remains largely unknown and will require careful evaluation before minor antigens can be used as a selection criterion in BMT. Carefully designed prospective studies will enable us to test the impact of each HLA locus. HLA typing and BMT represent a successful example of productive cooperation between basic and clinical sciences that should be pursued for the improvement of the clinical outcome of unrelated donor BMT.
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PMID:HLA matching in unrelated donor bone marrow transplantation. 937 12

The role of T lymphocytes in the control of chronic myeloid leukemia (CML) after bone marrow transplantations has been clearly shown. This effect closely correlates with graft-versus-host disease (GVHD). A specific graft-versus-leukemia (GVL) effect separate from GVHD has been postulated but has been difficult to show. One possible target for specific GVL activity is the bcr-abl fusion protein characteristic of CML. We have investigated the use of normal peptide-pulsed dendritic cells for the generation of cytotoxic, bcr-abl-specific T cells from normal donors. T cells (CD3+, CD8+, TCR alpha beta+, and NK receptor-negative) generated from a normal donor (HLA A24, B52, B59, Cw1) after stimulation with autologous dendritic cells, primed with a 16 mer peptide spanning the b3a2 breakpoint of bcr-abl, lysed CML cells from the peripheral blood of seven patients with CML with the b3a2 breakpoint. CML cells from four patients with only the b2a2 breakpoint were not lysed. Phytohemagglutinin (PHA) blasts derived from peripheral blood of patients with CML were not lysed, suggesting that cytotoxicity was not due to alloreactivity. Blocking experiments with anti-HLA-A,B,C indicated that cytotoxicity was dependent on recognition of major histocompatibility complex (MHC) class I molecules, although cytotoxicity was not MHC-restricted because not all patients shared HLA types with the T-cell donor. Specificity for bcr-abl and absence of alloreactivity was confirmed by the presence of lytic activity against autologous and allogeneic class I HLA-A matched monocytes pulsed with the 16 mer bcr-abl fusion peptide, but not against unpulsed monocytes or monocytes pulsed with other peptides. These results show that bcr-abl-specific T cells with marked cytotoxic activity against CML cells can be generated and amplified from normal donor peripheral blood. Recognition of HLA molecules is essential for cytotoxicity but strict HLA identity is not required.
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PMID:Dendritic cells stimulate the expansion of bcr-abl specific CD8+ T cells with cytotoxic activity against leukemic cells from patients with chronic myeloid leukemia. 944 59

Twenty-seven patients above 40 years of age (range 40-55) with leukaemia underwent transplantation with haematopoietic stem cells from HLA-A, -B and -DR identical unrelated donors. They were compared to 69 younger patients, median age 23. In the older group, the diagnoses were acute myeloid leukaemia (AML) five, acute lymphoblastic leukaemia (ALL) three and chronic myeloid leukaemia (CML) 19. The corresponding figures in the younger patients were 21, 27 and 21, respectively. Conditioning consisted of cyclophosphamide (120 mg/kg) combined with 10 Gy total body irradiation. Immunosuppression was ATG or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporin A. The probabilities of grades II-IV acute graft-versus-host disease (GVHD) were 23 and 21%, and the cumulative incidences of chronic GVHD were 64 and 50% in the older and younger patient cohorts, respectively. Overall, 3-year transplant-related mortality rates were 46% in patients > or =40 years of age and 32% in patients <40 years of age (P = 0.16). Three-year patient survival rates were 54 and 46% in the two groups, respectively. In patients with chronic phase CML, the corresponding figures were 67 and 68%, respectively. We conclude that patients above 40 years of age should be considered for transplantation with marrow from unrelated donors.
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PMID:Transplantation with unrelated bone marrow in leukaemic patients above 40 years of age. 948 93

Three hundred and six patients with low- and intermediate-risk leukaemias undergoing allogeneic BMT between 1980 and March 1996 were studied regarding transplantation-related mortality (TRM), relapse, and leukaemia-free survival (LFS). Among the patients were 262 recipients of marrow from HLA-identical siblings and 44 patients receiving marrow from HLA-A, -B, and -DR identical unrelated donors. Between 1986 and 1993, 153 adult patients received ciprofloxacin continuously during Cy conditioning, but since November 1993 ciprofloxacin has not been given until after Cy treatment. TRM at 5 yr showed an incidence of 30%. Significant risk factors in Cox regression multivariate analysis comprised acute GVHD grades II-IV (p < 0.0001), seropositivity for 3-4 herpes viruses prior to BMT (p = 0.002), intermediate risk disease (p = 0.008), female donor to male recipient (p = 0.015), and a donor age over 17 yr (p = 0.025). The risk of relapse was studied from 90 d after BMT, and the overall 5-yr incidence was 32%. Significant risk factors comprised acute leukaemia, as compared to CML (p = 0.003), total body irradiation (TBI) compared to busulphan treatment (p = 0.011), gram-negative prophylaxis with ciprofloxacin during cyclophosphamide (Cy) conditioning (p = 0.024), GVHD prophylaxis using a combination of methotrexate (MTX) and cyclosporine (CSA), compared to monotherapy (p = 0.037) and absence of chronic GVHD (p = 0.050). The 5-yr probability of relapse in patients receiving ciprofloxacin prophylaxis during Cy conditioning was 40%, compared to 24% in patients not receiving this treatment (p = 0.01). Overall, LFS at 5 yr was 49%. LFS was evaluated from day 30 after BMT until relapse or death of the patient. We found no difference in TRM, relapse or LFS between recipients of HLA-identical sibling or unrelated bone marrow, risk factors significantly associated with an inferior LFS included acute GVHD grades II-IV (p = 0.0002), intermediate risk disease (p = 0.003), donor seropositivity for 3-4 herpes viruses (p = 0.046), and TBI conditioning (p = 0.048).
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PMID:Risk factors in bone marrow transplant recipients with leukaemia. Increased relapse risk in patients treated with ciprofloxacin for gut decontamination. 957 94

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

While HLA class II alleles identification by means of complement mediated lymphocytotoxicity (serology) is almost replaced by DNA typing techniques, serology is still widely used for routine class I typing. The aim of this prospective study was to compare PCR-based Amplification Refractory Mutation System with serology in clinical HLA class I alleles assignment in patients receiving marrow transplants and their potential donors. The total discrepancy rate in 114 consecutively typed individuals for HLA-A and HLA-C alleles was only in favor of ARMS-PCR, whereas HLA-B typing was discrepant also in favor of serology. The discrepancies were higher in patients, particularly in those with acute lymphoblastic leukaemia, than in healthy individuals. We conclude, that ARMS-PCR is clearly superior to serology in definition of class I alleles, which might be of clinical importance particularly for bone marrow transplantation.
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PMID:Serology versus ARMS-PCR in prospective HLA-class I typing for bone marrow transplantation. 979 77

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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