Imatinib chronic myeloid leukemia

Imatinib Chronic myeloid leukemia Gl distress (nausea, vomiting) blood disorders (anemia, neutropenia, thrombocytopenia) joint and muscle pain chest pain... 

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. 

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, 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. 

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. 

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... 

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).

Guilhot F. Sustained durability of responses plus high rates of cytogenetic responses result in longterm benefit for newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) treated with imatinib (IM) therapy update from the IRIS study, (abst 21). Blood2004 104 10a. 

Talpaz M, Silver RT, Druker BJ et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia results of a phase 2 study. Blood 2002 99 1928-1937. 

Hughes TP, Kaeda J, Branford S et al. Frequeney of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003 349 1423-1432. 

Druker BJ, Guilhot F, O Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. NEngl JMed2006 355 2408-2417. 

Larson RA, Druker B, Guilhot F et al. Correlation of pharmacokinetic data with cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib-An analysis of IRIS study data (Abstract 429). B/oorf 2006 108 131a. 

Jabbour E, Kantaqian H, Jones D et al. Frequeney and elinieal signifieanee of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006 20 1767-1773. 

Frank O, Brors B, Fabarius A et al. Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients. Leukemia 2006 20 1400-1407. 

Soverini S, Martinelli G, Amabile M et al. Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to Imatinib. Clin Chem 2004 50 1205-1213. Jaeobberger JW, Sramkoski RM, Frisa PS et al. Immunoreactivity of Stat5 phosphorylated on tyrosine as a eell-based measure of BCR-ABL kinase activity. Cytometry A 2003 54 75-88. 

Wang L, Knight K, Lueas C et al. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica 2006 91 235-239. 

Kantarjian HM, Cortes JE, O Brien S et al. Long-term survival benefit and improved complete eytogenetie and molecular response rates with imatinib mesylate in Philadelphia chromosomepositive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 2004 104 1979-1988. 

Hoehhaus A, Kantarjian HM, Baccarani M et al. Dasatinib induces notable hematologic and cytogenetic responses in ehronie-phase chronic myeloid leukemia after failure of imatinib therapy. Blood... 

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. 

Shah N, Pasquini R, Rousselot P et al. Dasatinib (SPRYCEL) vs. escalated dose of imatinib (IM) in patients (pts) with ehronie phase chronic myeloid leukemia (CP-CML) resistant to imatinib results of the CA180-017 START-R randomized study (Abstract 167). B/ooii2006 108 53a. 

Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). CritRev Oncol Hematol 2006 57 145-164. 

Kantarjian HM, Talpaz M, Giles F et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance.Hww/wrerwMed2006 145 913-923. 

Shah, N. P., Nicoll, J., Nagar, B., et al. (2002) Multiple BRC-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (ST1571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117-125. 

Advice for treatment decisions based on specific genetic conditions were found in four Pis, namely that prolastin (a 1-proteinase inhibitor) is not indicated in patients with certain otl -antitrypsin deficiency phenotypes, trastuzumab indicated only in patients with overexpression of the HER2 protein, tretinoin, and imatinib are to be given only in patients with either a specific subtype of acute myelogenous leukemia or Philadelphia chromosome-positive chronic myeloid leukemia, respectively. 

Cortes JE et al (2009) Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 23 1537-1544... 

Larson RA et al (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia a subanalysis of the IRIS study. Blood 111 4022-4028... 

Picard S et al (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109 ... 

Peng B et al (2004) Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 22 935-942... 

---