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)

The degree of tumor load reduction after therapy, which is determined by the degrees of cytoreduction and cytogenetic response, is an important prognostic factor for patients with chronic myelogenous leukemia (CML). Conventional metaphase analysis is considered to be the "gold standard" for evaluating cytogenetic response. The frequency of cytogenetic analysis can be reduced considerably if patients are monitored by molecular methods, such as quantitative Southern blot, fluorescence in situ hybridization (FISH), quantitative western blot, or competitive reverse transcriptase polymerase chain reaction (RT-PCR). Molecular methods can be performed on peripheral blood specimens and are therefore less invasive than cytogenetic analyses of bone marrow metaphases. Furthermore these techniques are applicable to Ph-negative/BCR-AbL-positive cases. Results obtained by Southern blotting, western blotting, and FISH are readily quantifiable but their sensitivity is not generally superior to that of cytogenetic methods. RT-PCR is by far the most sensitive method. Quantitative RT-PCR analysis is the method of choice for monitoring patients after bone marrow transplantation (BMT). Using competitive PCR in patients after BMT, reappearance and/or rising levels of BCR-ABL transcripts can be detected prior to relapse. All complete cytogenetic responders to interferon-alpha are positive for BCR-ABL transcripts. The level of residual disease spans a range over found orders of magnitude. In both interferon-alpha-treated patients and patients after BMT a good correlation between BCR-ABL transcript numbers per microgram of RNA and cytogenetic results has been found. Variables in the competitive PCR assay may be controlled for by quantification of transcripts of the normal ABL gene as an internal standard. We suggest a stepwise strategy for diagnosis and follow-up of CML patients employing molecular methods.
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PMID:Molecular monitoring of residual disease in chronic myelogenous leukemia patients after therapy. 930 5

The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.
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PMID:Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. 933 56

Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by an initial chronic phase of expanded clonal myelopoiesis followed by inevitable progression to accelerated phase and finally to fatal blast crisis. Although interferon therapy results in hematologic control of disease in most patients and major cytogenetic responses in 30% to 35%, resulting in better survival than with conventional therapy with hydroxyurea or busulfan, most patients have residual disease detectable by molecular methods. Allogeneic bone marrow transplantation may cure selected patients with CML and should be considered early in the course of disease. Newer approaches to therapy include autografting using mobilized peripheral blood stem cells. Selection and expansion of nonleukemic progenitors may improve outcome following autologous transplantation. Advances in understanding of mechanisms of action of antisense oligonucleotides, ribozymes, and tyrosine kinase inhibitors and the immunologic responses to CML cells are also likely to lead to novel approaches to therapy.
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PMID:Bone marrow transplantation for chronic myelogenous leukemia. 955 30

We investigated a new method using fluorescence in situ hybridization and DNA probes that span the common breakpoints of t(9;22)(q34;q11.2) and that detect double BCR/ABL fusion (D-FISH) in bone marrow cells with this translocation, one on the abnormal chromosome 9 and one on the Philadelphia chromosome (Ph chromosome). D-FISH patterns were abnormal in 30 of 30 specimens with classic, simple, complex, and masked Ph chromosomes. Based on 200 nuclei from each of 30 normal specimens, the mean percentage of false-positive cells was 0.25 +/- 0.39. Thirty-seven specimens from 10 patients were studied before treatment and two or more times at 4-month intervals after treatment with interferon-alpha2b (IFN-alpha2b) with or without ara-C. Based on 200 nuclei, the results of D-FISH in these specimens correlated closely with quantitative cytogenetics and accurately quantified disease within a few percent. We studied 6, 000 nuclei for each of six specimens, three normal and three from patients with chronic myeloid leukemia (CML) in cytogenetic remission. The normal cutoff for 6,000 nuclei was 0.079% and patients in cytogenetic remission had residual disease ranging from 7 (0.117%) to 53 (0.883%) Ph-positive nuclei. We conclude that D-FISH can detect the Ph chromosome and its variant translocations and accurately quantify disease in CML at diagnosis and at all times after treatment, including cytogenetic remission.
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PMID:Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia. 955 93

Interest in autografting for chronic myeloid leukaemia and its clinical relevance has revived in recent years. This followed observations that with various chemotherapeutic regimens it was possible to achieve, temporarily at least, peripheral blood and bone marrow that were Philadelphia negative. Bone marrow or peripheral blood progenitor cells could then be harvested and reinfused following a high dose procedure, hopefully eliminating any residual disease, and resulting in prolonged disease free survival. This ideal has not yet been successfully achieved with current strategies. Recent results indicate that eliminating residual disease with current chemotherapy is not normally achievable. The use of more sensitive technologies such as polymerase chain reaction has revealed persistent disease in most if not all apparently Philadelphia negative cases. This is confirmed by results where disease relapse occurs following transplant in these cases. Despite this, clinically relevant remissions are obtained and further trials are indicated. In this review present treatment is discussed and future strategies, using novel techniques as an adjunct to current treatment, are proposed that might improve on present results or even lead to the elusive goal of cure.
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PMID:Autografting as first line treatment for chronic myeloid leukaemia. 960 79

There is a need for fast and sensitive methods to evaluate the response of patients with chronic myeloid leukaemia (CML) to interferon-alpha (IFN-alpha) therapy to complement cytogenetic analysis of Philadelphia (Ph) chromosome-positive metaphases. We have used interphase FISH (fluorescence in situ hybridization) and competitive RT-PCR (reverse transcriptase-polymerase chain reaction) techniques for detection of BCR-ABL-positive cells to measure suppression of leukaemic clone in a series of 51 follow-up samples from 24 CML patients undergoing IFN-alpha treatment. Interphase FISH analysis of the malignant clone in bone marrow using BCR and ABL probes was found to be highly correlated to conventional G-banding metaphase examination (r = 0.98). RT-PCR quantification of BCR-ABL mRNA transcripts in blood also showed a high degree of concordance with the proportion of Ph-positive metaphases (r = 0.93). In addition, the degree of cytogenetic response did not influence the equivalence between karyotype analysis and molecular methods. We concluded that interphase FISH and competitive RT-PCR provide reliable information on residual tumour burden and response to IFN-alpha in CML patients. These molecular methods may significantly improve the efficiency of residual disease monitoring during IFN-alpha therapy of CML.
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PMID:Interphase cytogenetics and competitive RT-PCR for residual disease monitoring in patients with chronic myeloid leukaemia during interferon-alpha therapy. 963 1

Cytogenetic, interphase fluorescent in situ hybridization (FISH) and RT-PCR methods were used to study minimal residual disease in peripheral blood stem cells collected for autografting in three chronic myeloid leukemia (CML) patients in sustained complete cytogenetic remission after treatment with interferon alpha (IFNalpha). Karyotypic analysis failed to reveal Ph-positive metaphases. FISH detected 9-16% nuclei with a BCR-ABL fusion gene, contrasting with RT-PCR, performed in two cases, which was negative in one case and weakly positive in the other. RT-PCR was also subsequently weakly positive in the third patient. This discrepancy suggests that the BCR-ABL genomic rearrangement persists unexpressed in quiescent cells. These preliminary results, which need to be confirmed in larger series, suggest that monitoring residual disease in CML should be performed both at DNA and RNA levels. Moreover, autografting following IFNalpha therapy should be considered with caution because of the persistence of the BCR-ABL genomic rearrangement in a sizeable proportion of the cells.
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PMID:Does BCR-ABL genomic rearrangement persist in CML patients in complete remission after interferon alpha therapy? 966 93

WT1 (Wilms tumor gene) expression is a new tumor marker of leukemic blast cells of AML, ALL, and CML. Minimal residual disease (MRD) of leukemia can be detected at frequencies as low as 1 in 10(3) to 10(4) normal bone marrow (BM) cells and 1 in 10(5) normal peripheral blood (PB) cells by means of the quantitation of expression levels of the WT1 gene using reverse transcriptase-polymerase chain reaction (RT-PCR). This is regardless of the types of leukemia or the presence or absence of tumor-specific DNA markers. Thus, the WT1 assay makes it possible to rapidly assess the effectiveness of treatment and to evaluate the degree of eradication of leukemic cells in individual leukemia patients. Moreover, molecular relapse using PCR can be diagnosed by the monitoring of WT1 expression levels in BM or PB 1-24 months (means, 7 months for BM and 8 months for PB) before the clinical relapse became apparent. In case of rapid or gradual increase in WT1 expression levels to or over 10(-2) after return to normal BM levels during CR; or retention of the WTI expression at levels near or over 10(-2) in BM without return to normal BM levels even in CR (WT1 expression level in K562 cells was defined as 1.0), it seems that clinical relapse is impending. Since WT1 antisense oligomers inhibit the growth of leukemic cells, it is apparent that the WT1 gene plays an important role in leukemogenesis.
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PMID:Wilms tumor gene (WT1) as a new marker for the detection of minimal residual disease in leukemia. 966 76

The advent of molecular biological techniques has led to a radical improvement in the evaluation of haematological disorders and offers exciting future prospects. In particular it has led to the improved recognition of distinct clinicopathological entities defined by a combination of morphological, immunophenotypic and chromosomal features. Antibody-based techniques, namely immunophenotyping and immunocytochemical techniques, are essential to malignant haematological diagnosis. More novel is the diagnostic use of antibodies against novel fusion proteins, for example in AML, M3 and anaplastic lymphoma. PCR-based techniques allow the identification of genetic mutations and translocations including such common translocations as t(14;18), t(9;22), inv 16 and t(8;21). Fish-based techniques are greatly improving the ability to detect genetic abnormalities including those conditions with low cell proliferation and current research-based techniques include the combination of FISH with cell surface markers (FICTION), FIBRE FISH and Comparative Genomic Hybridization. Molecular techniques are essential in monitoring residual disease which is best illustrated in CML. The development of real-time automated PCR offers exciting prospects in this field. The increasing number of tests, the need for an integrated approach to diagnosis and the need for cost effectiveness indicate that such services should be provided by a specialized haematology laboratory.
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PMID:Modern molecular diagnostics and the management of haematological malignancies. 968 Dec 27

We used a recently developed system for real-time quantitative polymerase chain reaction (PCR) to determine residual disease in patients with chronic myeloid leukaemia. The expression of the Bcr-Abl hybrid oncogene was determined and normalized by using the PBGD housekeeping gene product as endogenous reference. The sensitivity and reproducibility of the assay was tested on cell line K562. A dilution of Bcr-Abl-positive cell line K562 remained positive at up to 250 fg of RNA. 10 copies of Bcr-Abl DNA in water could still be detected. The dynamic range of the method spanned six orders of magnitude. Analysis of 10 identical assays on K562 RNA resulted in a variation of 15%. To test the feasibility of normalization of Bcr-Abl dosage by the PBGD product, we compared the efficiencies of the RT-PCRs in 150 patient analyses. We concluded that PBGD was a suitable and stringent quality control standard. Three patients who were treated with donor leucocyte infusions for chronic myeloid leukaemia who had relapsed after bone marrow transplantation were followed over time. The normalized Bcr-Abl dosage was compared to the results of cytogenetics. Cytogenetic analysis was negative below a normalized Bcr-Abl dose of about 3 x 10(-2). This semi-automated method is fast, sensitive and accurate and enables a high throughput of samples.
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PMID:Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. 972 5


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