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)

In a series of studies spanning 14 years, investigators from M.D. Anderson Cancer Center (Houston, TX) documented the activity of interferon-alfa (IFN-alpha) in chronic myelogenous leukemia (CML). Beginning with partially purified IFN-alpha, we demonstrated that this biologic compound has clinical activity against CML, that some malignancies are resistant to IFN-alpha, and that the effect is selective whereby the malignant clone can be restored to normalcy. These observations were confirmed by us and others when larger quantities of IFN-alpha became available through recombinant DNA technology (rIFN-alpha). In contrast with our experience with chemotherapy, myelosuppression was not required for cytogenetic remission; this dissociation may be the basis for the selectivity of IFN-alpha against CML. Recently, another group demonstrated that patients randomized to receive rIFN-alpha 2a survived longer than those treated with standard hydroxyurea chemotherapy. New tests are needed to identify the subset of patients most likely to benefit from IFN-alpha therapy and to distinguish cytogenetic responders who are truly cured from those with minimal residual disease.
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PMID:Use of interferon in the treatment of chronic myelogenous leukemia. 799 97

Cure of leukemia by allogeneic BMT is achieved by the combined effect of the myeloablative preparative regimen and an allo-immune response of donor cells to residual leukemia termed the graft-versus-leukemia (GVL) effect. In the first year following BMT for CML, PCR used to detect the leukemia-specific BCR/ABL message frequently reveals subclinical levels of persisting leukemia. In a meta-analysis of reports on qualitative PCR findings after BMT for CML in 12 recently published series, we found that for unmanipulated BMT in chronic phase, PCR detection was not associated with a higher relapse risk and that most patients became PCR negative within 2 years post-BMT. In contrast, PCR detection of BCR/ABL transcripts was a more reliable predictor in recipients of T cell-depleted BMT and in those transplanted in accelerated or blastic phase of their disease. For accurate prediction of relapse, serial quantitative PCR is necessary. It could also be used to monitor efficacy of experimental treatments of relapse with interferon or donor lymphocyte transfusions. Furthermore, studies of the association of GVHD with PCR detection of BCR/ABL message may shed light on the relationship of GVL with minimal residual disease in CML.
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PMID:Minimal residual disease after bone marrow transplantation for chronic myelogenous leukemia and implications for graft-versus-leukemia effect: a review of recent results. 799 33

We have sought to determine whether peripheral blood or bone marrow is more sensitive for assessment of minimal residual disease in chronic myeloid leukaemia (CML). Contemporaneous blood and marrow specimens were taken from 21 patients at various times after allogeneic bone marrow transplant (BMT) and from one patient in complete cytogenetic remission on alpha-interferon. Samples were analysed for evidence of BCR-ABL mRNA by RT-PCR: four were PCR negative and 19 PCR positive. Results with blood and marrow were concordant in all cases. BCR-ABL transcripts were quantified in PCR-positive samples using a competitive PCR titration assay. Results ranged from < 10 to 2 x 10(6) BCR-ABL transcripts/micrograms RNA. In all 19 cases a high degree of concordance in BCR-ABL levels with blood and marrow (r = 0.99) was found. We conclude that either tissue may be used for residual disease studies after BMT for CML.
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PMID:A comparison of the sensitivity of blood and bone marrow for the detection of minimal residual disease in chronic myeloid leukaemia. 773 83

Detection of minimal residual disease and relapse remain major problems in chronic myelogenous leukemia (CML) patients following bone marrow transplantation (BMT). In order to disclose the 9;22 Philadelphia translocation, we used a fluorescence in situ hybridization (FISH) technique. BCR and ABL gene fragments were used as probes for the detection of the BCR/ABL fusion product in peripheral blood and bone marrow cells from 11 CML patients in which 5 were post-BMT. The sensitivity and specificity of this approach were compared to conventional cytogenetic and polymerase chain reaction (PCR) methods. FISH demonstrated a high degree of sensitivity (1%) for the detection of the BCR/ABL translocation in these patients. A linear correlation was found between FISH detection of the BCR/ABL fusion product and routine chromosomal analysis (r = 0.995; p < 0.001). Detection of the BCR/ABL signal by FISH was observed in all patients showing a positive PCR signal. A significant reduction in BCR/ABL signal was observed post-transplant (p < 0.001). However, the BCR/ABL translocation was detected in four of five transplanted patients immediately (0.75-2.5 months) following transplant and was found in patients with a low expression of the translocation.
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PMID:Detection of minimal residual disease state in chronic myelogenous leukemia patients using fluorescence in situ hybridization. 807 54

Detection of minimal residual disease is one of the major goals in bone marrow transplantation. We used a fluorescence in-situ hybridization technique to detect residual Philadelphia-chromosome positive cells in chronic myelogenous leukemia (CML) patients after sex-mismatch BMT. We analyzed the level of detection using probes for the BCR/ABL fusion product by comparison with results obtained with probes for the Y and X sex chromosomes. Detection of sex-mismatch chromosomes was significantly higher than that of the BCR/ABL translocation. In contrast, a higher specificity of residual tumor cell detection by the BCR/ABL probe was demonstrated because most of the sex-mismatch cells detected by FISH had a normal karyotype. Tumor-specific markers probes are thus superior and more accurate than sex-mismatch probes for detection of MRD in CML patients after BMT.
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PMID:Detection of minimal residual disease after sex-mismatch bone marrow transplantation in chronic myelogenous leukemia by fluorescence in situ hybridization. 817 87

Various kinds of nonrandom chromosomal aberrations have been reported in hematopoietic malignancies. Since the 1980s, many translocation-associated oncogenes and several suppressor oncogenes have been identified and applied for the clinical diagnosis of these malignancies. The former is of major, clinical importance for specific diagnosis made on the basis of molecular detection of the chromosomal translocation, the deregulated expression, and the chimeric mRNA of those genes. Both BCL-1 and BCL-2 genes, associated with mantle zone lymphoma and follicular lymphoma, respectively, belong to the representative deregulated oncogenes by juxtaposition with an immunoglobulin gene enhancer as well as an MYC gene in Burkitt's lymphoma. On the other hand, the MLL gene, associated with infant leukemia, acute monocytic leukemia and secondary leukemia, produces chimeric mRNAs between LTG4, 9, and 19 genes as well as the BCR-ABL chimeric gene in chronic myelogenous leukemia. The detection of minimal residual disease (MRD) by either polymerase chain reaction (PCR) or reverse transcriptase (RT)-PCR is becoming an essential test during the course of treatment containing bone marrow transplantation, because positive results of the MRD are closely related to poor prognosis and would have great influence on the choice of treatment plans.
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PMID:[Molecular diagnosis of leukemia and lymphoma]. 817 45

Determining both lymphoid chimerism and the presence of minimal residual disease after allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML) could be helpful to the understanding of the biology of leukemic relapse in this disease. We prospectively investigated 32 patients with CML post-BMT by assessing T-cell chimerism and minimal residual disease using sensitive polymerase chain reaction (PCR) methodologies. Patients were studied between 1 and 24 months post-BMT. Thirty patients received a T-cell-depleted marrow grafts and 2 received unmanipulated marrow. All but 1 patient were conditioned with total body irradiation (TBI)+thiotepa+cyclophosphamide (Cy). The other patient received TBI+Cy as conditioning. The T cells were exclusively of donor origin in 12 of 16 patients who were tested at 1 month post-BMT, but were mixed chimeric in 11 of these patients by > or = 3 months. Once mixed T-cell chimerism was documented, no patient returned to having all donor T-cells. At a median follow-up of 12 months, minimal residual disease was present in 18 of 22 patients with mixed T-cell chimerism and in 3 of 10 patients with full donor chimerism. The actuarial molecular relapse rate at 24 months for the two groups is 91% and 33%, respectively (P < .02). The finding of BCR-ABL mRNA within the first 6 months of transplant or on two consecutive assays was highly predictive of subsequent cytogenetic or hematologic relapse (P = .032 and P < .02, respectively). Ten patients, 9 with mixed T-cell chimerism, have relapsed (4 clinical, 6 cytogenetic) at a median of 12 months post-BMT. These data suggest that mixed T-cell chimerism may be a marker for abrogation of graft-versus-leukemia activity that is thought to be pivotal in eradicating minimal residual disease after BMT for CML.
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PMID:Minimal residual disease is more common in patients who have mixed T-cell chimerism after bone marrow transplantation for chronic myelogenous leukemia. 819 79

The management of CML patients with some evidence of disease after BMT depends on the molecular, cytogenetic and hematological findings of relapse. Presently, a number of technical and biological problems do not allow to draw any definitive conclusion on the prognostic significance of Minimal Residual Disease detected by PCR. A positive PCR, particularly if observed late after BMT, leads to increase the frequency of cytogenetic examinations, but a therapeutic intervention is not justified. The criteria to define the cytogenetic relapse are not still established. Therefore it is difficult to interpret the reappearance of Ph-1 chromosome after BMT as disease recurrence invariably progressing towards the hematological phase. However, alpha-Interferon, donor buffy-coat infusion or their association should be considered in the treatment of patients for whom the cytogenetic relapse has been confirmed. The therapeutic approach to patients with hematological relapse is mainly depending on the phase of disease. The single, sequential or combined use of chemotherapy, alpha-IFN, donor buffy-coat infusion and second transplant has been shown to be effective in restoring donor hematopoiesis in several patients who relapsed either in chronic or advanced phase. Prospective, randomized, multicentre trials on CML relapse after BMT should be planned.
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PMID:What does one do for the CML patient in relapse after allogeneic bone marrow transplantation? 825 99

Immune mechanisms superimposed to the myeloablative conditioning regimens exert an additional powerful effect in eradicating leukemia and in achieving immunological control of minimal residual disease. The impact of GVHD-independent GVL has been evaluated to be absent, or near absent, in ALL, about 30% in AML and about 40% in CML. While until little time ago most of the evidence in favor of an immune antileukemia mechanism exerted by allo BMT in CML was indirect, based on the lack of GVL, there is now solid evidence of a positive type, based on the antileukemia effect of donor lymphocyte infusions in patients having relapsed after transplant. There are three lines of indirect clinical evidence for GVL in CML: they include the classical linkage between GVHD and reduced relapse rate, increased relapse rate after identical twin allografts, and increased relapse risk after effective GVHD prophylaxis, with T lymphocyte depletion in the foreground. The eradicating effects of donor lymphocyte infusions in relapsed patients are the ultimate demonstration that allogeneic immune competent cells are capable of recognizing and destroying the Ph-positive clone. However the frequency of irreversible aplasia indicates that donor lymphocytes act in the same way on residual host hematopoiesis, so that a second graft, without repeat conditioning, should be programmed for such cases.
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PMID:The graft versus leukemia (GVL) effect after allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML). 825

We describe the methodology and application of the polymerase chain reaction to detect BCR-ABL mRNA as a marker for CML cells. The technique is highly sensitive enabling the routine detection of 1 leukaemic cell in 10(5) or 10(6) normal cells and is therefore the most sensitive method available for detecting minimal residual disease. Analysis of marrow or blood from 80 patients after bone marrow transplantation for CML shows that residual leukemia is often detectable for several months but that most subsequently become PCR negative. Patients who relapsed were all PCR positive before the detection of Philadelphia positive metaphases in bone marrow aspirates.
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PMID:Minimal residual disease after bone marrow transplant for chronic myeloid leukaemia detected by the polymerase chain reaction. 825 14


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