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)

Responses can be achieved with dasatinib or nilotinib after failure of 2 prior tyrosine kinase inhibitors (TKIs). We report on 48 chronic myeloid leukemia patients sequentially treated with 3 TKIs: 34 with dasatinib after imatinib/nilotinib failure and 14 with nilotinib after imatinib/dasatinib failure. Before the third TKI, 25 patients were in chronic phase (CP), 10 in accelerated phase (AP), and 13 in blast phase (BP). Best response to third TKI in CP was 5 major molecular responses (MMR), 3 complete cytogenetic (CCyR), 2 partial cytogenetic (PCyR), 3 minor cytogenetic (mCyR), 6 complete hematologic responses (CHR), and 6 with no response (NR). In AP, 1 patient achieved MMR, 1 CCyR, 2 PCyR, 1 mCyR, 4 CHR, and 1 NR. In BP, 1 achieved MMR, 2 CCyR, 1 PCyR, 1 mCyR, 2 returned to CP, and 6 NR. Median CCyR duration was 16.3 months; 3 CP patients achieving CCyR had a response more than 12 months. Median failure-free survival was 20 months for patients in CP, 5 months in AP, and 3 months in BP. Use of second-generation TKI after failure to 2 TKIs may induce responses, but these are usually not durable except in some CP patients. New treatment options are needed.
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PMID:The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. 1972 17

The discovery of the Philadelphia (Ph) chromosome represented the first step towards understanding the molecular basis of haematological malignancies. Subsequent developments including the characterisation of t(9;22)(q34;q11) translocation, the identification of the breakpoint cluster region as well as the demonstration that retrovirally mediated insertion of a human BCR-ABL gene into murine haematopoietic stem cells induced a leukaemia-like picture and the creation of BCR-ABL transgenic mice established the central role of BCR-ABL in chronic myeloid leukaemia (CML) beyond all reasonable doubt. Many years later an important goal was achieved, that is, the use of BCR-ABL as a therapeutic target. However, it is uncertain whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML. There is an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events leading to advanced-phase disease.
Best Pract Res Clin Haematol 2009 Sep
PMID:CML: a model for targeted therapy. 1995 80

Reliable epidemiological information on chronic myeloproliferative disorders (CMPDs), notably Philadelphia (Ph)/BCR-ABL-positive chronic myeloid leukaemia (CML), is rare. Incidence rates vary from 0.6 to 2.0 cases per 100 000 inhabitants, increase with age and are higher in men than in women. Geographic and/or ethnic variations might contribute to the variability of incidences among registries. Prevalence rate has increased by use of tyrosine kinase inhibitors. In daily clinical practice, some CML management areas are not in line with the current recommendations. Problematic areas are sub-optimal timing of treatment decisions under monitoring, and unawareness of new molecular monitoring techniques and of beneficial new tyrosine kinase inhibitors. Median age differs between cancer registries and clinical trials by 10-20 years. Reports of clinical studies underestimate the true age of the CML population. Elderly CML patients are underrepresented in clinical studies and thus have a reduced access to investigational therapies.
Best Pract Res Clin Haematol 2009 Sep
PMID:Epidemiology of chronic myeloid leukaemia (CML). 1995 81

Little important progress was made in terms of prolongation of life for patients with chronic myeloid leukaemia (CML) until the advent of interferon-alpha and allogeneic stem cell transplantation in the 1980s. However, in 1998 the introduction of imatinib, the first tyrosine kinase inhibitor (TKI) that specifically targets the BCR-ABL1 oncoprotein, has fundamentally altered treatment strategies for patients in all phases of CML. Imatinib is now recommended as initial treatment for all patients who present in chronic phase (CP) and about two-thirds of patients so treated will be in continuing complete cytogenetic response 7 or more years after starting therapy. A small proportion of these patients can stop the drug without molecular evidence of relapse. For the minority of patients who are judged to have failed initial treatment with imatinib at standard dosage or increased dosage, the use of second-generation TKI or allogeneic stem cell transplantation must be considered.
Best Pract Res Clin Haematol 2009 Sep
PMID:Treatment strategies for CML. 1995 82

Imatinib has revolutionized the therapy of chronic myeloid leukaemia. However the complete eradication of leukaemic stem cells is still a matter of discussion. Interferon (IFN) has been used in the past with success. However the proportion of patients who achieved sustained complete cytogenetic response was small. Recently, in addition to its direct antineoplastic effect and immunomodulatory activity, IFN has been shown to stimulate the quiescent leukaemic stem cells. Thus there is now a rational for combining Imatinib and IFN. Large prospective phase III trials are in good progress to demonstrate in humans the usefullness of a combination therapy using Imatinib and IFN.
Best Pract Res Clin Haematol 2009 Sep
PMID:Interferon in chronic myeloid leukaemia: past and future. 1995 83

Imatinib is the standard front-line therapy of chronic myeloid leukaemia (CML). The evaluation of the response is based on blood counts and differential (haematologic response, HR), on the examination of marrow cell metaphases (cytogenetic response, CgR) and on a quantitative assessment of BCR-ABL transcripts level (molecular response, MolR). An optimal response to imatinib is defined by complete HR and at least minimal CgR (Ph + < 95%) at 3 months, at least partial CgR (Ph + < 35%) at 6 months, complete CgR at 12 months and major MolR (BCR-ABL: ABL < or = 0.1%) at 18 months. Failure is defined by incomplete HR at 3 months, no CgR (Ph + > 95%) at 6 months, less than partial CgR (Ph + > 35%) at 12 months, less than complete CgR at 18 months and loss of a complete HR or a complete CgR. In any other situation, the response is defined suboptimal. Treatment recommendations are to continue on imatinib in case of optimal response and to move to second-generation tyrosine kinase inhibitors (TKIs) and/or to allogeneic haematopoietic stem cell transplantation in case of failure. In case of suboptimal response, treatment may be continued with imatinib, at the same dose or a higher dose, but some patients may become eligible for second-generation TKIs. A provisional definition of the response to second-generation TKIs second line is provided.
Best Pract Res Clin Haematol 2009 Sep
PMID:Response definitions and European Leukemianet Management recommendations. 1995 84

Prognostic factors in patients with chronic myeloid leukaemia (CML) treated with conventional treatment include age, spleen size, platelet count, blood percentage of blasts, basophils and eosinophils, and cytogenetic abnormalities besides the Philadelphia chromosome. The value of traditional clinical and laboratory features to identify patients at increased risk of imatinib failure has not been established yet. Biological markers such as gene expression profile, v-crk sarcoma virus CT10 oncogene homologue (avian)-like (Crkl) phosphorylation or expression of imatinib transporter proteins have been shown to be useful to predict the response to imatinib. In practice, the response obtained at different time points from the initiation of imatinib is employed to predict the patient's outcome, with this especially applying to cytogenetic response. The prognostic relevance of early molecular response to imatinib has also been pointed out. Prognostic factors for response to second-generation tyrosine kinase inhibitors (TKI) after imatinib failure are currently being investigated.
Best Pract Res Clin Haematol 2009 Sep
PMID:Prognostic factors in chronic myeloid leukaemia. 1995 85

Molecular monitoring of chronic myeloid leukaemia (CML) patients by real time quantitative reverse transcriptase PCR (RQ-PCR) is of clinical value, but the use of diverse laboratory protocols and units of measurement make it difficult to compare results between and sometimes within centres. This review explores the intrinsic difficulties in standardising the RQ-PCR analysis, summarises the progress that has been made following the proposal for a new International Scale for BCR-ABL measurement and discusses how further improvements are likely to be made.
Best Pract Res Clin Haematol 2009 Sep
PMID:Standardisation of molecular monitoring for chronic myeloid leukaemia. 1995 86

A minority of patients treated with imatinib are either refractory to imatinib or eventually relapse. Relapse frequently depends on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression. Over 90 point mutations coding for single amino acid substitutions in the BCR-ABL kinase domain have been isolated from CML patients resistant to imatinib treatment. These mutations affect amino acids involved in imatinib binding or in regulatory regions of the BCR-ABL kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. The early detection of BCR-ABL mutants during therapy may aid in risk stratification as well as molecular-based treatment decisions. Therapeutic strategies of imatinib resistant disease include novel tyrosine kinase inhibitors with activity against imatinib-resistant mutations and/or with inhibition of alternative pathways, dose escalation to optimise imatinib levels, treatment interruption to stop selection of resistant cells and allogeneic stem cell transplantation in eligible patients.
Best Pract Res Clin Haematol 2009 Sep
PMID:Cause and management of therapy resistance. 1995 87

Imatinib (IM) is the gold standard for the treatment of chronic myeloid leukaemia (CML). However, there exists significant interpatient variability in plasma exposure for a given dose of the drug. Several recent studies have revealed a correlation between imatinib trough plasma levels and clinical response, suggesting that measurement of plasma levels could be a useful tool to optimise IM dose. Despite this apparent link, many important questions on the use of IM blood level testing remain unanswered. We recommend IM dosing for patients (1) who are not responding to IM as well as expected, (2) who are suspected to be poorly compliant to their IM regimen, (3) who experience adverse events that are unusually severe for the prescribed dosage and (4) when a drug-drug interaction is suspected.
Best Pract Res Clin Haematol 2009 Sep
PMID:Pharmacologic monitoring and determinants of intracytoplasmic drug levels. 1995 88


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