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)

We analyzed molecular responses in 55 newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients enrolled in a phase 3 study (the IRIS trial) comparing imatinib to interferon-alfa plus cytarabine (IFN+AraC). BCR-ABL/BCR% levels were measured by real-time quantitative RT-PCR and were significantly lower for the imatinib-treated patients at all time points up to 18 months, P<0.0001. The median levels for imatinib-treated patients continued to decrease and had not reached a plateau by 24 months. A total of 24 IFN+AraC-treated patients crossed over to imatinib. Once imatinib commenced, the median BCR-ABL/BCR% levels in these patients were not significantly different to those on first-line imatinib for the equivalent number of months. The incidence of progression in imatinib-treated patients, defined by hematologic, cytogenetic or quantitative PCR criteria, was significantly higher in the patients who failed to achieve a 1 log reduction by 3 months or a 2 log reduction by 6 months, P=0.002. A total of 49 patients were screened for BCR-ABL kinase domain mutations. Mutations were detected in two imatinib-treated patients who crossed over from IFN+AraC and both lost their imatinib response. In conclusion, first-line imatinib-treated patients had profound reductions in BCR-ABL/BCR%, which significantly exceeded those of IFN+AraC-treated patients and early measurements were predictive of subsequent response.
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PMID:Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. 1452 61

Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.
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PMID:[Imatinib therapy for patients with chronic myelogenous leukemia]. 1579 12

In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P < .001, P = .004, and P < .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.
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PMID:Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. 1662 56

Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a shortened chromosome 22 which is the result of a reciprocal translocation between chromosome 9 and 22. The fusion gene is called BCR-ABL. After transcription and translation the constitutively activated p210 BCR-ABL oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL transformed cells is the result. Expression of the BCR-ABL oncoprotein is sufficient and necessary for the development of a CML phenotype. Imatinib mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and blocks downstream signalling events. Imatinib is very effective in the treatment of CML in all stages of the disease. Patients with newly diagnosed chronic phase CML were randomized to imatinib or to interferon plus cytarabine in the IRIS trial. Imatinib showed significantly superior tolerability, hematologic and cytogenetic resposes and increased time to progression. In patients with advanced phase CML, imatinib is less effective and response duration is short. Median overall survival of blast crisis patients is 6.9 months only. Additional BCR-ABL independent chromosomal abnormalities are common in advanced phase CML and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are frequently found in imatinib resistant patients and confer diminished sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors, which are effective against most of the known mutations are currently tested in clinical trials.
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PMID:[Tyrosine kinase inhibitors for the treatment of CML]. 1668 55

The treatment of chronic myeloid leukemia (CML) has considerably evolved since imatinib mesylate has been introduced as a new therapeutic weapon for this disease. The 5-year updated results of the IRIS study confirmed that imatinib mesylate is the best first line therapy for chronic phase CML with an overall survival of 90%. Responses improve with time and complete cytogenetic and major molecular levels reach 87 and 70% respectively at 5 years. However, despite these remarkable improvements, new problems arise as sub-optimal responses, imatinib-resistances with recently identified BCR-ABL protein point mutations, responsible for a variety of therapeutic consequences : imatinib dose increase, alternative treatments with second generation tyrosine kinase inhibitors (TKIs : dastinib, nilotinib) or allogeneic stem cell transplantation. The treatment of accelerated and blastic phases relies on imatinib +/- conventional chemotherapy, ideally followed by allogeneic stem cell transplantation, as newly developed TKIs are currently evaluated within this frame. Finally, BCR-ABL(T315I) mutations remain a new therapeutic critical challenge as none of the three TKIs (imatinib, nilotinib, dasatinib) can efficiently control such diseases.
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PMID:[Treatment of chronic myeloid leukemia in 2007]. 1796 80

Imatinib mesylate, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment of chronic myelogenous leukemia (CML) due to its high level of activity, low toxicity, and durability. Five-year data from the pivotal trial of imatinib, the IRIS trial, suggests durable responses in a high proportion and reduction and almost elimination of the incidence of imatinib failure over time. The imatinib dose of 400 mg is considered to be standard based on the IRIS trial. Recently, new tyrosine kinase inhibitors (TKI) have been developed, which can overcome imatinib resistance, and comparative studies between each TKI and imatinib are ongoing for imatinib-resistant CML and newly-diagnosed CML. TKI will be chosen based on the profiles of mutation of the ABL kinase domain. On the other hand, the results of hematopoietic stem cell transplantation in patients treated with imatinib were reported, and pretreatment of imatinib did not influence TRM. However, the optimal dose, duration of imatinib treatment and the indication of reduced intensity conditioning transplantation have not been established. Longer follow-up, the accumulation of results of the new TKI therapy and HSCT are required.
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PMID:[An advance in the treatment of CML]. 1807 18

Chronic myeloid leukemia has become a paradigm for the discovery of target therapeutic approaches in the field of onco-hematology. Recognition of the tyrosine kinase activity of the p210Bcr-Abl oncoprotein led to the development of compounds targeting against BCR-ABL and then controlling the leukemic proliferation. Imatinib mesylate, one of the first tyrosine kinase inhibitors developed, was found effective and safe. According to five-years experience with this drug, it is recommended that the golden standard for initial treatment of newly diagnosis chronic myeloid leukemia patients should be 400 mg Imatinib daily. In this brief review, we discuss the current tools for the effective management of chronic myeloid leukemia with Imatinib, providing the updated results of IRIS and RIGHT clinical trials and then the suggestions how Imatinib-treated patients should be monitored.
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PMID:Imatinib mesylate in chronic myeloid leukemia. 1822 Sep 8

Philadelphia (Ph) chromosome at (9; 22) reciprocal chromosomal translocation producing BCR-ABL fusion gene, emerges in almost all patients with chronic myeloid leukemia (CML). The protein product of BCR-ABL is a constitutively active tyrosine kinase that drives the abnormal proliferation of CML cells. Blast crisis (BC) is the terminal phase of CML, which is often associated with additional chromosomal and molecular secondary changes. Although the mechanisms responsible for transition of CML chronic phase (CP) into BC remain poorly understood, ample evidence suggests that it depends on synergy of BCR/ABL with other genes dysregulated during disease progression, and signaling pathways are abnormally activated by BCR/ABL. With the application of imatinib, a ABL-specific tyrosine kinase inhibitor, its remarkable therapeutic effects suggest that blast crisis transition will be postponed in most patients with CML. Rate of cumulative best response in CML-CP patients from the IRIS trial after 5 years are 98% for complete hematologic response, 92% for major cytogenetic response and 87% for complete cytogenetic response. However, a minority of CML-CP patients and most patients in progression either fail or respond suboptimally to imatinib. There are many distinct patterns of resistance, and ABL kinase mutations is a common finding associated with clinical resistance. Dasatinib and nilotinib can restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase. This review illustrates the molecular mechanisms underlying transition to CML-BC, also addresses oneself to how and why imatinib resistance occurs.
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PMID:[Research advance on molecular genetics of CML blast crisis]. 1831 35

Imatinib is the therapeutic standard for newly diagnosed patients with chronic myeloid leukemia (CML). Recent updates of the IRIS trial, a study of standard-dose imatinib in newly diagnosed chronic-phase patients treated with 400 mg imatinib daily, suggest a stabilization of progression-free survival curves at a high level, implying that the majority of patients will do well on standard therapy. However, some 20% to 30% of patients will fail on imatinib and require alternative therapies. Identification of those patients likely to fail would be desirable to allow for more intensive therapy up front. After a brief overview of the history of CML, this paper will review current recommendations for staging of CML patients at diagnosis. Next, the various tests used to monitor their response to imatinib will be discussed in the context of the currently accepted criteria for imatinib failure and suboptimal response. Last, approaches to identify high-risk patients at diagnosis will be addressed.
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PMID:Milestones and monitoring in patients with CML treated with imatinib. 1907 20

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.
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PMID:Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group. 1926 56


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