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

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.
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PMID:Selective depletion of CD8+ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. 214 40

Bone marrow transplantation is the only therapy currently available with the potential to cure chronic myelogenous leukemia. The best results and most experience have been in HLA-matched transplants for patients with CML in the chronic phase. Various protocols have resulted in lengthy disease-free survival in 49-69% of patients. The limitation to greater success is significant mortality associated with graft-versus-host disease. Attempts to improve results have focused on decreasing GVHD by drug regimens or removing donor T-cells. Studies using T-cell depletion by different techniques have improved survival in groups with higher median patient age. These methods have had varying effects on incidence of GVHD, graft failure, and relapse. Transplant for patients in the advanced phases of CML have produced lower disease-free survival rates, due mainly to resistant disease. Early experience with busulfan and cyclophosphamide conditioning have shown improved survival in these patients.
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PMID:Bone marrow transplantation for chronic myelogenous leukemia. 215 Mar 21

Retrospectively we analyzed the histocompatibility data and clinical results of bone marrow transplantation in 51 patients who received marrow from unrelated donors (UD) from 1977 to 1987 at one of four UK BMT centers. We compared the results with those obtained in 51 transplants carried out at the same centers using HLA-identical (ID) sibling donors. Of the UD/recipient pairs 32 (63%) were serologically identical for HLA A, B, and DR antigens, and 37% showed varying degrees of mismatch. UD-BMT primary diagnoses were: severe aplastic anemia or Fanconi's anemia (n = 17), acute leukemia (n = 11), chronic myeloid leukemia (n = 21), and other conditions (n = 2). T cell depletion of the graft was associated with a significant improvement in survival in both UD and ID-BMT. Graft failure was more common in recipients of UD than of ID transplants (13 [25%] vs. 5 [10%] P = 0.05) but there was no significant difference in the frequency of acute or chronic graft-versus-host disease. Actuarial survival was superior for recipients of ID transplants (UD vs. ID: 49% vs. 78%, respectively, at 3 months; 32% vs. 63% at one year). Reduced survival for recipients of UD-BMT was confirmed in case control regression analysis (relative risk 3.0, P = 0.01). Nevertheless in patients whose only alternative is a partially mismatched family donor we think that UD-BMT is justified.
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PMID:Unrelated donor marrow transplantation between 1977 and 1987 at four centers in the United Kingdom. 218 Jan 50

Bone marrow transplantation is the only treatment that can result in long-term disease-free survival and possible cure in a significant number of patients with CML. Several prognostic features influence relapse and survival following allogeneic BMT for CML. The most important factor is treatment of patients during chronic phase. The timing of BMT in chronic phase CML remains controversial, because the Seattle findings that BMT done within a shorter interval from diagnosis to transplant was associated with improved survival has not been confirmed by the IBMTR. No factor can predict in the individual patient the timing of transformation, even in patients with low-risk chronic phase CML, but we believe that allogeneic BMT should be offered as soon as possible for newly diagnosed patients who have histocompatible siblings. More widespread application of BMT in CML is possible because of effective methods for preventing GVHD, the major cause of morbidity after allogeneic BMT. However, in vitro techniques for the depletion of donor marrow T cells have resulted in higher graft failure and relapse rates. More precise understanding of the immune mechanisms involved may permit more selective depletion techniques which not only abrogate GVHD but also permit sustained engraftment and preserve GVL effect. This may extend application of BMT for patients with mismatched related or histocompatible unrelated donors. It is of interest that cytogenetic relapse after BMT is not invariably followed by hematologic relapse. It is likely that the use of polymerase chain reaction techniques which detect the bcr-abl rearrangement at a very low level will identify the persistence of the malignant clone after allogeneic BMT in even more patients. At present, the significance of such findings is unclear, but further study of the kinetics of disappearance of the CML clone post-BMT may increase our understanding of the immune mechanisms involved in suppression of the malignant clone and determine whether in fact CML can be cured using BMT approaches.
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PMID:The evolving role of bone marrow transplantation in the treatment of chronic myelogenous leukemia. 218 97

BMT is the only curative therapy for CML, a uniformly lethal malignant disorder of the hematopoietic stem cell. Younger patient age and transplant in CP are associated with better outcome. Transplant within 1 year of diagnosis may provide a greater chance of survival than transplant at a longer interval from diagnosis. T-cell depletion of donor BM significantly reduces the incidence of acute and chronic GVHD, but is associated with an increased risk of graft failure and a marked increase in rate of relapse. Early results suggest that HLA-matched or partially HLA-mismatched unrelated donors may be used successfully in cases in which a suitably matched related donor is not available. Autologous transplantation of BM or PB stem cells can result in successful engraftment and possibly prolonged survival in some patients with CML. Following allogeneic BMT, some patients relapse cytogenetically without progressing to hematologic relapse. The use of PCR methodology to amplify bcr-abl transcripts has revealed persistence of the malignant clone in a substantial number of patients who are in hematologic and cytogenetic remission. The clinical significance and biologic mechanism(s) of this form of molecular relapse remain to be defined.
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PMID:Treatment of chronic myelogenous leukemia with bone marrow transplantation. 219 13

The use of intensive therapy together with transplantation of marrow from a suitable donor is the only established curative treatment for patients with chronic myeloid leukemia (CML). However, marrow transplantation is hazardous, costly and applicable to relatively few patients. Therefore, we evaluated the results and limitations of marrow transplantation for CML and discussed new treatment strategies. We decided to select a limited number of papers that focused on the relevant issues rather than to undertake an exhaustive comparison of treatment results from different centres. Patients with CML in the chronic phase who receive marrow from a sibling with the same human leukocyte antigen type can expect to have a long-term disease-free survival rate of 50%. However, the procedure is associated with a mortality rate of 30%, mainly because of graft-versus-host disease (GVHD) and interstitial pneumonitis. Moreover, because of the requirements for age and histocompatibility only 10% of patients with chronic-phase CML are currently eligible. Transplantation earlier in the chronic phase (within 1 year after diagnosis), the use of marrow from matched, unrelated donors and the development of improved methods for reducing the incidence of GVHD all hold promise. In addition, the preliminary results of intensive therapy followed by transplantation with cultured autologous marrow have been encouraging. If further progress is to be made, continued optimism coupled with carefully developed and executed studies will be necessary.
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PMID:An overview of bone marrow transplantation for chronic myeloid leukemia. 219 9

From May 1985 to July 1989, 76 patients with leukemia (30 acute myelogenous leukemia, 24 acute lymphoblastic leukemia and 22 chronic myeloid leukemia) were randomized to receive either cyclosporin (CSP) alone (n = 39) or CSP combined with methotrexate (CSP + MTX, n = 37) for graft-versus-host disease (GVHD) prophylaxis. Patients were conditioned with total body radiation and cyclophosphamide followed by bone marrow infusion from an HLA-identical sibling. Engraftment of the transplanted bone marrow was similar in both groups. The incidence of moderate to severe acute GVHD was significantly higher in the CSP group compared with the CSP + MTX group (20 (51%) versus 9 (25%), chi 2 = 4.76, p less than 0.02). There was no significant difference in the incidence of chronic GVHD. Survival was significantly better for the CSP + MTX group (63 +/- 16%) compared to CSP alone (42 +/- 18%). Leukemia-free survival tended to be better for the CSP + MTX group (55 +/- 17% versus 32 +/- 16%).
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PMID:Combination of cyclosporin and methotrexate for prophylaxis of acute graft-versus-host disease after allogeneic bone marrow transplantation for leukemia. 220 50

We studied the in vitro effects of lymphokine-activated killer (LAK) cells from the peripheral blood of chronic myeloid leukemia (CML) patients after allogeneic and syngeneic bone marrow transplantation (BMT). LAK cells were generated by incubating peripheral blood mononuclear cells from patients post-BMT with recombinant interleukin-2 (IL-2) (500 U/mL) in 10% AB serum for 7 days. They were phenotyped and tested for activity in a standard 4-hour 51Cr release assay (n = 37) and in a CFU-GM assay (n = 24). We found that the LAK cells were mainly activated natural killer cells, but some were CD3+ T cells. In the 51Cr release assay LAK cells from 20 of 33 (61%) allogeneic and 2 of 4 syngeneic recipients killed recipient CML cells and in 22 of 37 (60%) cases also killed the HLA disparate CML cells. In the CFU-GM assay the LAK cells incubated together with the CML cells in liquid culture before plating inhibited (P less than .05) colony growth in 16 of 22 allogeneic and 2 of 2 syngeneic recipients. Cell-cell contact was necessary for optimal effect. There was little or no inhibition of proliferation of donor marrow CFU-GM. This in vitro graft-versus-leukemia (GVL) effect could also be demonstrated after LAK effectors were depleted of CD3+ T cells. It was inducible in recipients of both T cell-depleted and T cell-replete donor marrow and in recipients with or without graft-versus-host disease. These results suggest that a major histocompatibility complex-unrestricted GVL effect is inducible following allogeneic and syngeneic BMT. The use of IL-2/LAK cells after BMT could reduce the risk of relapse.
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PMID:Induction of in vitro graft-versus-leukemia activity following bone marrow transplantation for chronic myeloid leukemia. 224 25

Short term clinical results of bone marrow transplantation on 66 patients conditioned with fractionated total body irradiation (12 Gy in 6 fractions and 3 days) are presented here. An acute toxic effects incident, similar to that obtained previously, a 27.6% interstitial pneumonitis associated with acute severe graft versus host disease in 77% of cases, 19.2% relapses, and 41% total crude survival with an actuarial probability of surviving for more than two years of 46% for ALL, 64% for AML and 28% for CML, are the results obtained since now.
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PMID:Fractionated total body irradiation for bone marrow transplantation: clinical results on 66 patients. 224 43

We analyzed the relevance of HLA incompatibility to acute graft-versus-host disease, relapse, and survival in 281 patients with hematologic neoplasms who underwent bone marrow transplantation. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, -B, and -D antigens of the haplotype not shared; 29 were phenotypically identical, 119 were incompatible for one locus, 104 for two loci, and 29 for three loci. These 281 patients were compared with 967 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. Occurrence of severe acute graft-versus-host disease was evaluated in patients who achieved sustained engraftment. In recipients of haploidentical grafts occurrence of severe acute graft-versus-host disease was associated with (1) graft-versus-host disease prophylaxis containing the combination of methotrexate plus cyclosporine versus standard methotrexate, relative risk = 0.35; 95% confidence interval, 0.21-0.57, p less than 0.0001; and (2) the degree of recipient HLA incompatibility, relative risk = 1.95 for each locus incompatible; 95% confidence interval, 1.52-2.50, p less than 0.0001; (3) patient age, relative risk = 1.23 per decade; 95% confidence interval, 1.05-1.44, p = 0.0094. Acute graft-versus-host disease was associated with lower leukemic relapse after transplant in patients with acute lymphocytic leukemia, and chronic graft-versus-host disease was associated with lower relapse after transplant for acute nonlymphocytic leukemia in relapse or chronic myelogenous leukemia in blast crisis. After transplantation for acute nonlymphocytic leukemia in remission, the rate of leukemic relapse was 22% in 61 recipients of "one-locus" (A, B, or D)-incompatible grafts compared to 37% in 561 recipients of HLA-identical sibling grafts. Survival was decreased as the degree of HLA disparity increased. Survival of "one-locus"-incompatible transplant recipients, however, was equivalent to that of HLA-identical sibling transplant recipients.
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PMID:Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. 224 52


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