Imatinib leukemia

Chung YJ, Kim TM, Kim DW et al. Gene expression signatures associated with the resistance to imatinib. Leukemia 2006 20 1542-1550. 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

Discuss treatment options for chronic myelogenous leukemia (CML) with special emphasis on imatinib. 

Deininger MWN, O Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003 21 1637-1647. 

Imatinib Mesylate (Gleevec) Tyrosine kinase inhibitor bcr-abl, c-kit Chronic myelogenous leukemia Hematologic and cytogenetic response rate. Phase III GIST ... 

Cohen, M.H. et al.. Approval summary for Imatinib Mesylate capsules in the treatment of chronic myelogenous leukemia, Clin. Can. Res., 8, 935-942, 2002. 

Imatinib mesylate (Gleevec, Novartis) tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (refer to Exhibit 7.3)... 

Imatinib mesylate (Gleevec, Novartis Glivec in countries other than the United States) is a drug for the treatment of chronic myeloid leukemia (CML). CML is a result of a chromosomal problem and gives rise to high levels of white blood cells. An enzyme called BCR-ABL is involved. The BCR-ABL gene encodes a protein with elevated tyrosine kinase activity (see Exhibit 7.3). 

In some circumstances, the FDA processes drug reviews under the accelerated scheme. This mechanism is to review and approve drugs speedily for cases where effective therapies are lacking or in situations of rare diseases. One of the fastest approval times to date is the case of imatinib mesylate (Gleevec, Novartis—Exhibit 7.3) for the treatment of chronic myeloid leukemia (CML) it was approved in less than 3 months after the filing of an NDA with the FDA. Another example is the new AIDS drug indinavir (Crixivan, Merck), which was approved in a mere 42 days. 

Imatinib caused a revolution in the treatment of chronic myelocytic leukemia... 

Imatinib was the first anticancer drug that specifically targets a molecular defect in tumor cells. It is a breakthrough drug for chronic myelogenous leukemia (CML). Others have followed and more are yet to come. 

Balabanov S, Bartolovic K, Komor M et al. Gene expression profiling of normal hematopoietic progenitor cells under treatment with imatinib in vitro. Leukemia 2005 19 1483 1485. 

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

Reed SD, Anstrom KJ, Ludmer JA, Glendeiming GA, Schulman KA. Cost-effectiveness of imatinib versus interferon-alpha plus low-dose cytarabine for patients with newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2004 101 2574-83. 

Nilotinib is a phenylaminopyrimidine structurally related to imatinib (Glivec) . It is a signal transduction inhibitor that potently and selectively inhibits tyrosine kinases. It was developed (Phase 11/111) for treatment of leukemias. ... 

Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. B/ooii2005 105 2640-2653. 

BCR-ABL Mutations and Imatinib Resistance in Chronic Myeloid Leukemia Patients... 

Key Words Chronie myeloid leukemia imatinib resistanee BCR-ABLl Mutations dasatinib nilotinib tyrosine kinase inhibitors... 

In 1960, a minute acrocentric chromosome was noted in cells from seven patients with chronic myeloid leukemia (CML) (1). The subsequent identification of this abnormal chromosome 22, which came to be referred to as the Philadelphia chromosome, has become the basis for an explosion in knowledge over the past 40-plus years that culminated in the development of imatinib mesylate (IM), a highly effective targeted therapy of CML that is producing long-term disease control and a possible cure (2). 

Fig. 2. Structure of the ABLl kinase portion of the BCR-ABLl protein. The activation loop (blue) is in the closed (inactive) conformation on the left and in the open (active) conformation on the right. A molecule of imatinib is positioned in the ATP-binding site and is in green. (Reprinted with permission from U S. Healthcare Communications, LLC. LitzowMR, Tefferi A. Chronic myeloid leukemia problems propel progress. Amer J Hematol/Oncol, 2007 6(5) supplement 7 19-22).

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