Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As the number of successful marrow transplants has increased, the lack of HLA-identical sibling donors for 60 to 70 percent of transplant candidates has become a serious problem. Pilot studies established that marrow transplantation between phenotypically HLA-identical, unrelated individuals can be accomplished successfully. Therefore, the National Marrow Donor Program was established to develop a large file of volunteer marrow donors and to serve as a center for the coordination of the donor search and donor-recipient matching processes. By November 1991, 63 months after the program was established, 457,205 potential marrow donors typed for HLA-A and -B antigens had agreed to be listed in the marrow donor registry. A donor search had been initiated for 8481 patients. At least one potential donor matched for at least three of the four HLA-A and -B antigens was located for 99.8 percent of patients. Among the 3156 searches that were completed, 940 (29.8%) resulted in a transplant. The median time in which to locate a matched donor, complete all predonation evaluations, and obtain donor consent was 208 days. The most common diagnosis in patients who underwent transplantation was chronic myelogenous leukemia (42.0%). When this analysis was completed in November 1991, the National Marrow Donor Program was operating a national network of 99 donor centers and 53 transplant centers. The donor file was increasing rapidly, and a follow-up system was in place to determine the effects of donation on the donors and the outcome in the patients who underwent transplantation. This national network of donor and transplant centers exists and is now facilitating unrelated-donor marrow transplants. The National Marrow Donor Program made it possible to locate donors for many patients in need of a transplant and helped to determine the role of unrelated-donor marrow transplants in the treatment of many diseases.
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PMID:The National Marrow Donor Program. 833 20

To help elucidate the mechanism responsible for graft failure (GF) following a T-cell depleted bone marrow transplant (BMT) from an unrelated donor, five patients (2 chronic myelogenous leukemia, 1 acute undifferentiated leukemia, 2 myelodysplastic syndrome) who experienced this complication were studied. All patients were HLA class I identical with their donors as determined by serology and one-dimensional isoelectric focusing (IEF); two were serologically matched with their donors for HLA class II antigens, whereas three donor-recipient pairs were serologically mismatched for one HLA-DR antigen. All patients received total body irradiation (fractionated, 1,500 rads), VP-16 (750 mg/m2), and cyclophosphamide (120 mg/kg) pre-BMT and antithymocyte globulin (15 mg/kg every other day) and methylprednisolone (2 mg/kg) post-BMT. Three patients experienced primary nonengraftment and two experienced secondary GF. Peripheral blood mononuclear cells obtained from the patients at the time of GF were studied to examine their functional and phenotypic characteristics. Emerging cells were of host origin and were found to be specifically cytotoxic to donor target cells and suppressive to the in vitro growth of donor BM, especially in the cases of primary nonengraftment. Peripheral blood mononuclear cells from these patients were expanded to form T-cell lines (TcLs). The cytotoxic activities of TcLs were tested in the presence of blocking MoAbs directed against various HLA determinants in an attempt to determine if HLA antigens expressed on donor cells were the target for cytotoxicity. The observed cytotoxic activity was blocked by antibodies to HLA-B, -C (1 patient), HLA-DR (1 patient), and HLA-DQ (1 patient). In two cases, antidonor cytotoxicity could not be blocked by MoAb directed against HLA-A, -B, -C, or -DR. Phenotypic characterization of four successfully maintained TcLs showed 100% CD3+ cells with 100% CD4+ (3 patients) or 50% CD4+/50% CD8+ (1 patient). In two of the three patients with 100% CD4+ cells, antidonor cytotoxicity was blocked by an anti-HLA class II MoAb. In contrast to our previous findings in cases of GF following T-cell-depleted HLA nonidentical family member BMT in which host T cells were CD8+ and cytotoxicity was directed against HLA class I antigens, our present study indicates host T cells emerging at the time of GF following BMT from an HLA class I IEF-identical unrelated donor can be of the CD4+ subset and seem to be capable of recognizing antigenic disparities in the HLA class II region.
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PMID:Characterization of cells emerging at the time of graft failure after bone marrow transplantation from an unrelated marrow donor. 833 33

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) chromosomal translocation resulting in the expression of a novel bcr-abl fusion protein. The region spanning the fusion point is novel to the immune system and hence represents a potential leukemia-specific antigen. The ability of a 21-mer b3a2 fusion peptide to induce an in vitro lymphoproliferative response in a panel of 54 normal donors has been tested. This gave a mean stimulation index of 2.73 (95% CI 2.42-3.05) and 50/54 (93%) of donors gave responses that were greater than those with bcr or abl control peptides. The mean stimulation index relative to that of the control peptides was 1.80 (95% CI 1.63-1.97; p < 0.001). Responses were optimal at concentrations ranging from 0.3-150 micrograms/mL and in most cases peaked at 9 days. There was no clear relationship between level of responsiveness to the b3a2 fusion peptide and the presence of any single HLA-A, -B, -DR, or -DQ allele. HIA-DRB1*0404 was the only allele that was not associated with responsiveness. It is therefore likely that the b3a2 fusion peptide can be presented to T cells during a primary immune response in the context of several different class II HLA allelic products, albeit at low efficiency. The implications for specific active immunotherapy of CML patients are discussed.
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PMID:The influence of class II HLA type on the lymphoproliferative response of normal donors to a bcr-abl fusion peptide. 886 41

From September 1988 to December 1995 forty-four children (age < 17 years) with Ph1 Chronic Myelogenous Leukemia (CML) received unrelated donor marrow transplantation in 8 European Countries. Thirty-three evaluable children were typed by serological testing on HLA-A, B, and DR loci. Thirty of them were further DR subtyped by DNA techniques. Twenty-four pairs were 6 antigen matched. Seven were mismatched at 1 locus (2 pairs at A and B loci respectively and 3 at DR locus). Two out of 30 pairs evaluated by molecular biology had one antigen mismatched at DRB1 locus. Thirty-two (96%) out of 33 evaluable children reached a sustained granulocyte count higher than 0.5 x 10(9)/l at a median of 21 (range 14-88) days after transplantation. The remaining child failed to engraft. Two children developed secondary graft failure. A platelet count greater than 50 x 10(9)/l sustained for at least seven consecutive days without transfusion support was reached at a median of 25 (range: 20-144) days by 24 out of 33 evaluable children and 9 children never recovered to above 50 x 10(9)/l. Twenty-one out of 33 evaluable children developed grade I (n = 7), grade II (n = 8), grade III (n = 2) or grade IV (n = 4) acute GvHD (63%). Seven of the 30 evaluable children surviving more than 100 days developed chronic GvHD (20%) which was limited in 4 cases and extensive in 3. Relapse occurred in 3 of the 44 (7%) children at 2 to 24 months (median 14). Twenty-four month relapse rate was 14%. Seventeen out of 44 children (38%) died of transplant related mortality (TRM), 4 (9%) of secondary tumor, 4 (9%) of infections, 3 (7%) of organ failure, 1 (2%) of interstitial pneumonia, 5 (11%) of unknown causes. Actuarial TRM was 61% for children grafted before December 1991 and 33% for children grafted after January 1992 (p = .01). EFS was 49.7%; it was 65% for children receiving more than 3.5 x 10(9)/Kg MNC.
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PMID:Unrelated-donor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children: experience of eight European Countries. The EBMT Paediatric Diseases Working Party. 893 5

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 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

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


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