Chronic myelogenous leukemia imatinib

Chronic myelogenous leukemia Imatinib, busulfan, or interferon, bone marrow transplantation (selected patients) Vincristine, mercaptopurine, hydroxyurea, melphalan, interferon, allopurinol1... 

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

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 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. 

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... 

Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. Y EnglJMed 2002 346 645-652. 

Sawyers CL, Hochhaus A, Feldman E et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis results of a phase II study. B/ooc/2002 99 3530-3539. 

Larghero J, Leguay T, Mourah S et al. Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo. Biochem Pharmacol 2003 66 1907-1913. 

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Donato N, Wu J, Kong LY et al. Constitutive activation of SRC-family kinases in chronic myelogenous leukemia patients resistant to imatinib mesylate in the absence of BCR-ABL mutations a rationale use of SRC/ABL dual kinase inhibitor-based therapy (Abstract 1087). B/oo<7 2005 106 316a. 

Nicolini FE, Corm S, Le QH et al. Mutation status and elinieal outeome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients a retrospeetive analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006 20 1061-1066. 

Kantarjian HM, Talpaz M, O Brien S et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003 101 473 75. 

Cortes J, Guilhot F, Rosti Get al. Dasatinib (SPRYCEL) in patients (pts) with chronic myelogenous leukemia in aeeelerated phase (AP-CML) that is imatinib-resistant (TM-R) or intolerant (IM-I) updated results of the CA180-005 START-A phase 11 study (Abstract 2160). Blood 2006 108 613a. Cortes J, Rousselot R Kim DW et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007 109 3207-3213. 

Quintas-Cardama A, Kantarjian H, Jones Det al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure, fi/ooct 2007 109 497M99. 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

Deininger, M. W., Druker, B. J. Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol. Rev. 2003, 55, 401 123. 

Chronic myelogenous leukemia Translocation BCR-ABL BCR-ABL (tyrosine-kinase activity) Imatinib, Dasatinib, Nilotinib, Bosutinib... 

Hazarika M et al (2008) Tasigna for chronic and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 14 5325-5331... 

Imatinib (2),5 marketed by Novartis since 2001, is the first tyrosine kinase inhibitor approved as a treatment for chronic myelogenous leukemia (CML). It inhibits the BCR-ABL kinase that is highly specific to leukemic cells. Dasatinib (3)6 and nilotinib (4)7 are two other BCR-ABL kinase inhibitors marketed by Bristol-Myers Squibbs and Novartis, respectively. They are effective for the treatment of imatinib-resistant CML patients. 

Imatinib. Chronic myelogenous leukemia (CML) results from a genetic defect in the hematopoietic stem cells of the bone marrow. Nearly all CML patients possess the Philadelphia chromosome. It results from translocation between chromosomes 9 and 22 of the c-abl protooncogene, leading to the hybrid bcr-abl fusion gene on chromosome 22. The recombinant gene encodes a tyrosine kinase mutant with unregulated (constitutive), enhanced activity that promotes cell proliferation. Imatinib is a tyrosine kinase inhibitor that specifically affects this mutant but also interacts with some other kinases. It can be used orally in Philadelphia chromo-some-positive CML. 

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