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)

Intensive cytoreductive therapy may be curative in certain hematopoietic malignancies, but its administration is limited by lethal marrow toxicity. Bone marrow transplantation (BMT) provides a way of rescue from this toxicity. The donor may be a human leukocyte antigen (HLA) "matched" sibling (allogeneic), an identical twin (syngeneic), or the patient (autologous). Long remissions and possible cures of 50% to 60% have been reported in acute leukemia after intensive treatment with chemotherapy, with and without total body irradiation, followed by allogeneic BMT. A similar approach has been used in chronic myelocytic leukemia (CML) and in non-Hodgkin's lymphoma with encouraging results. Results are best in younger patients and those transplanted early in their disease (i.e., in the first remission for acute leukemia and in the chronic phase of the disease in CML). Solutions to major problems associated with allogeneic BMT, such as graft-versus-host disease and viral infections, are being actively pursued. Syngeneic BMT avoids some of the above problems, but relapses appear to be greater. Nevertheless, this approach has produced a significant number of cures. Autologous BMT is the newest approach, and the demonstration that marrow may be purged of residual tumor cells by immunologic or pharmacologic means has engendered enthusiasm for this area of clinical therapeutic investigation.
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PMID:Bone marrow transplantation in leukemia. Current status. 638 15

Eighty consecutive patients were transplanted with human leukocyte antigen (HLA)-identical sibling marrow for acute myelogenous leukemia (AML, N = 29), acute lymphoid leukemia (ALL, N = 23), or chronic myelogenous leukemia (CML, N = 28). Donor marrow was depleted of lymphocytes using counterflow centrifugation. Median age of the recipients was 31 years. Pretransplant conditioning consisted of cyclophosphamide and fractionated total body irradiation (TBI). Graft failure occurred in 4 of 77 evaluable patients (5%). The probability of acute graft-versus-host disease (GVHD) > or = grade 2 at day 100 after transplantation was 15%. The projected 3-year estimate of extensive chronic GVHD was 12%. The projected 3-year probability of relapse was 30% in transplants for AML in first complete remission (CR1), 35% after transplantation for ALL in CR1, and 38% after transplantation for CML in first chronic phase (CP1). The projected 3-year probability of leukemia-free survival (LFS) was 56% after transplantation for AML-CR1, 42% in patients transplanted for ALL-CR1, and 49% after transplantation for CML-CP1. The chance of relapse was significantly reduced in a cohort of 72 standard risk patients conditioned with a regimen intensified by the addition of anthracyclines. This resulted in DFS at 4 years after BMT of 63% compared to 39% in a historical control group. Enrichment of the donor marrow with NK-cells did not increase the incidence of GVHD, but did neither decrease the relapse rate after BMT. In bone marrow transplantation for leukemia, counterflow centrifugation is a useful technique for the prevention of GVHD. Further efforts should be made to reduce relapse-rate, particularly in high risk patients.
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PMID:Allogeneic bone marrow transplantation for leukemia with marrow grafts treated by counterflow centrifugation. 812 52

We have developed an in vivo model of human chronic myeloid leukemia (CML). A peripheral blood (PB) sample of Philadelphia (Ph) chromosome-positive CML cells in lymphoid blast crisis was transplanted intravenously (IV) into sublethally irradiated severe combined immunodeficient (SCID) mice, and this resulted in engraftment with systemic proliferation. Growth of leukemia was monitored by PB cell morphology and by flow cytometric analysis of murine PB cells labelled with an anti-human leukocyte antigen (HLA) monoclonal antibody. Human cells were first detected in the PB at 4 weeks and comprised a mean of 57% of the total nucleated cells in the PB of these mice by 15 weeks. The Ph chromosome was retained and the population has been successfully passaged. BCR/ABL fusion gene expression was detected in a subsequent passage. Experiments are underway to use this in vivo model to assess the antileukemic activity of BCR/ABL antisense oligonucleotides.
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PMID:Human Philadelphia chromosome-positive chronic myeloid leukemia: a potential model for antisense therapy. 850 May 81

A 25-yr-old Caucasian man presented in 1988 with Philadelphia chromosome (Ph) negative, bcr-abl rearranged, chronic phase chronic myeloid leukemia (CML). He was treated with human leukocyte antigen matched sibling allogeneic bone marrow transplantation but relapsed 5 yrs later. At this time he was given donor leukocyte infusions from the original bone marrow donor, seeking an immune anti-leukemic effect. This treatment induced graft versus host disease and severe bone marrow aplasia, requiring immunosuppression and repeat donor marrow infusion (without prior conditioning). Graft versus host disease was controlled and full donor hematopoiesis was restored, resulting in complete eradication of the leukemic clone at a molecular level. The patient remains in complete clinical and molecular remission and off all immunosuppression 24 mths later. This emphasizes a potentially powerful graft versus leukemia effect in CML.
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PMID:Donor leukocyte infusions in the treatment of chronic myeloid leukemia in relapse post bone marrow transplantation. 871 72

A 46-year-old man with chronic myelogenous leukemia received allogeneic bone marrow transplantation (BMT) from a partially human leukocyte antigen (HLA)-mismatched sibling. Cyclosporine (CYA)-related encephalopathy developed on days 10 and 21 following BMT, and CYA-related thrombotic thrombocytopenic purpura (TTP) developed on day 45 following BMT. We measured serum concentrations of thrombomodulin (TM) as a marker of endothelial injury. The concentrations of TM were increased during the encephalopathy or TTP and decreased following recovery. Since CYA can cause endothelial injury, we suggest that CYA-induced endothelial injury is common to the pathogenesis of both the encephalopathy and the TTP. CYA therapy should be reinstituted with extreme caution in patients with a past history of CYA-related encephalopathy, since readministration of a low-dose CYA can evoke the immediate return of the encephalopathy.
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PMID:Cyclosporine-related encephalopathy following allogeneic bone marrow transplantation. 886 27

A 46-year-old woman with chronic myelogenous leukemia received allogeneic bone marrow transplantation from an unrelated human leukocyte antigen (HLA) matched (but mixed lymphocyte culture (MLC) positive to graft-versus host disease (GvHD) donor. The blood type of the recipient was A type Rh (+) while the donor blood type was B type Rh (+). The patient received busulfan 8 mg/kg, cyclophosphamide 120 mg/kg, and total-body irradiation 10 Gy before bone marrow transplantation. Short-term administration of methotrexate and cyclosporin was given for prophylaxis of GvHD. The mononuclear cells harvested from the donor were concentrated by COBE Spectra before bone marrow transplantation. Although engraftment of transplanted bone marrow in the recipient was confirmed on day 11, the patient suffered from severe anemia on day 10. Since the direct Coombs' test to A type red blood cells was positive, and anti-A antibody titer increased 16-fold, we diagnosed her anemia as hemolytic anemia caused by ABO mismatched transplantation. In addition to hemolytic anemia, she had skin symptoms of acute GvHD grade II, microangiopathic hemolytic anemia, and died of multiple organ failure on day 44. This experience indicated that some allogeneic transplant recipients are at risk of severe hemolytic anemia in the early stage after unrelated ABO mismatched donor and that it is necessary to establish proper treatment and prophylaxis.
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PMID:[Rapid onset of hemolytic anemia after allogeneic bone marrow transplantation from an unrelated ABO major mismatched donor]. 902 56

At present, allogeneic bone marrow transplantation (BMT) is the only curative treatment for chronic myeloid leukemia (CML) in chronic phase (CP). The graft-vs.-leukemia (GVL) effect appears to play an important role in this treatment. Direct evidence for a GVL effect has been reported in Ph1-positive CML patients who relapsed after allogeneic BMT and who were treated with leukocyte transfusion from the original marrow donor. Alpha-interferon (alpha-IFN) may have facilitated this GVL effect since many patients were treated with it also. We investigated whether leukemia-reactive cytotoxic T lymphocytes (CTLs) can be generated from human leukocyte antigen (HLA)-genotypically identical sibling bone marrow (BM) donors who donated marrow for two patients with Ph1-positive CML in CP and one patient with Ph1-positive acute lymphoblastic leukemia (ALL). We also investigated alpha-IFN's ability to facilitate the generation of CTLs. In the absence of alpha-IFN, CTL lines with only low cytotoxicity and no CTL clones could be generated. In the presence of alpha-IFN, however, alloreactive, leukemia-reactive CTL lines with high cytotoxicity could be generated, and CD8+ CTL clones could be established with HLA class I restricted minor histocompatibility antigen (mHa)-specific recognition. In a cell-mediated clonogenic cytotoxicity assay, the CTL clones showed specific growth inhibition of leukemic precursor cells from the recipient and a second CML patient, but the clones did not inhibit growth of hematopoietic precursor cells (HPCs) from the donor. The normal HPCs from an unrelated donor with the HLA class I restriction molecule were also recognized by the CTL clones, illustrating that the antigen recognized is not leukemia-specific. The mechanism of the immunomodulating effect by alpha-IFN is not clear. Addition of alpha-IFN to medium did not alter the expression of HLA or adhesion molecules on CML cells. In the treatment of CML, administration of alpha-IFN as adjuvant immunotherapy after allogeneic BMT may increase GVL reactivity.
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PMID:Minor histocompatibility antigen-specific, leukemia-reactive cytotoxic T cell clones can be generated in vitro without in vivo priming using chronic myeloid leukemia cells as stimulators in the presence of alpha-interferon. 907 52

Marrow transplantation from human leukocyte antigen (HLA) matched related donors offers a high probability of prolonged treatment-free survival for patients with chronic myeloid leukaemia in chronic phase. Delay, patient and donor gender, patient age and previous palliation with busulphan predict outcome in this setting. Because of the median age at diagnosis and the genetics of the HLA system, transplants from HLA-matched related donors are available to less than 15% of newly diagnosed patients. Alternative donors include relatives with minor degrees of incompatibility and HLA-compatible unrelated volunteers. The probability of finding suitable unrelated donors has increased with the development of a network of registries now containing more than 3.6 million donors worldwide. Survival prospects will be improved by transplantation earlier in the course of the disease, better-matched donors and the discovery of new approaches for the prevention of graft-versus-host disease and opportunistic infections.
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PMID:Allografting for chronic myeloid leukaemia. 937 67

Donor leukocyte therapy has resulted in a remission rate in excess of 70% in patients with relapse of chronic myeloid leukaemia (CML) following allogeneic bone marrow transplantation (BMT). Induction of remission with donor leukocyte infusions has been primarily successful for CML patients who have cytogenetic relapse or those with chronic-phase haematological relapse. Response rates appear to be lower in patients who have advanced-phase CML. The majority of patients with CML who enter remission have no detectable minimal residual disease when analysed for BCR-ABL mRNA transcripts by reverse-transcription polymerase chain reaction. The efficacy of donor leukocyte infusions and the ease of therapy are balanced by the potential for significant toxicity. The reported treatment-related mortality rate is almost 20%. The major toxicities of this treatment are secondary to marrow aplasia and graft-versus-host disease (GVHD) which may occur in up to 50% and 90% of responders respectively. Donor leukocytes with a T-cell content of only 1 x 10(7)/kg, approximately a factor of 10 fewer T cells than used in most early studies, are capable of inducing remissions in some patients. The use of lower doses of T cells or CD8+ depleted T cells may be associated with less GVHD. The optimal treatment schedule using donor leukocytes has yet to be determined. Factors which might influence outcome include phase of disease, use of interferon alpha, use of unrelated donors and human leukocyte antigen disparity, T-cell dose, CD8+ depletion of leukocytes and time from BMT to leukocyte infusion.
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PMID:Donor leukocyte infusions. 937 69

Some older patients (> or =40 years) with chronic myelogenous leukemia (CML) who lack human leukocyte antigen (HLA)-identical sibling donors are not offered unrelated marrow transplantation because of concerns over excessive regimen-related toxicity, in particular due to graft-vs.-host disease (GVHD). The purpose of this study was to determine the efficacy and toxicity of unrelated marrow transplantation in older CML patients using a regimen designed to minimize the severity of GVHD. Thirty-one consecutive patients over the age of 40 with CML received unrelated marrow transplants between January 1988 and June 1997. Twenty-one patients were transplanted in chronic phase while ten were transplanted in the accelerated phase of their disease. Fifteen patients received transplants from phenotypically matched donors while 16 received marrow grafts from donors who were mismatched at one HLA locus. GVHD prophylaxis consisted of ex vivo T cell depletion of the donor marrow graft plus posttransplant cyclosporine administration. Durable engraftment was achieved in 29 of 31 patients (94%). The probability of developing grades II-IV or severe grades III-IV acute GVHD was 39.2 and 7.1%, respectively. There was no difference in the incidence of grades II-IV acute GVHD between patients transplanted with marrow grafts from phenotypically matched (38.1%) vs. those transplanted from mismatched unrelated donors (40%, p = 0.99). The 2-year probability of relapse for the entire population was 29.4%. Relapse was significantly higher for patients transplanted in accelerated phase (60%) than for those in chronic phase (13.8%, p = 0.027). The 2-year probability of overall survival and disease-free survival for the entire cohort was 56 and 45%, respectively. There was no significant difference in survival or disease-free survival for patients receiving phenotypically matched vs. mismatched marrow grafts. Immunological reconstitution for this cohort was compared with a younger (<40 years) patient population that had been similarly transplanted over the same time period. Immune function as assessed by total T cell, B cell, NK cell, and T cell subset reconstitution posttransplant was quantitatively equivalent in the two groups with most parameters normalizing within 18 months of transplant. We conclude that CML patients over the age of 40 who have either phenotypically matched or one antigen-mismatched unrelated donors can successfully undergo allogeneic marrow transplantation. T cell depletion of the marrow graft may be advantageous in these older patients by reducing GVHD severity, particularly in those patients transplanted with HLA-disparate marrow grafts.
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PMID:Successful unrelated marrow transplantation for patients over the age of 40 with chronic myelogenous leukemia. 970 86


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