Imatinib mesylate myeloid leukemia

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. 

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). 

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. 

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. 

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

B. J. Druker, Imatinib mesylate in the treatment of chronic myeloid leukemia. Expert Opin. Pharmacother 4 (2003), 963-971. 

Peggs, K. Mackinnon, S. Imatinib mesylate-the new gold standard for treatment of chronic myeloid leukemia. The New England Journal of Medicine 2003, 348, 1048-1050. 

Imatinib mesylate, a drug recently approved for the treatment of chronic myeloid leukemia (CML), can also be affected by St. John s wort. Because imatinib is primarily metabolized by CYP3A4 and is also a Pgp substrate, the usage of St. John s wort in combination with imatinib has resulted in a significant reduction in exposure to the drug compared to imatinib alone. This is potentially significant because therapeutic outcomes for patients with CML have been shown to correlate with the dose and drug concentrations of imatinib (87). 

Cortes J, Giles P, O Brien S, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer 2003 97 2760-2766. 

Imatinib mesylate (Gleevec , Novartis) is a small-molecule compound that inhibits a specific tyrosine kinase enzyme, the Bcr-Abl fusion oncoprotein. It is used for gastrointestinal stromal tumor and chronic myeloid leukemia. 

Imatinib mesylate (Gleevee, A -(4-methyl-3-(4-(pyridin-3-yl)-pyrimidin-2-ylamino) phenyl)-4-((4-methyl piperazin-l-yl)methyl) benzamide methane-sulfonate, STI571) is known as an inhibitor of tyrosine kinases and is used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. It was developed by Novartis Pharma AG and is a 2-phenylamino-pyrimidine derivative. 

Elias MH, Baba AA, Husin A, Sulong S, Hassan R, Sim GA, Wahid SEA, Ankathil R. HOXA4 gene promoter hypermethylation as an epigenetic mechanism mediating resistance to imatinib mesylate in chronic myeloid leukemia patients. Biomed Res Int 2012 2013 129715. doi 10.1155/2013/129715. 

A 74-year-old man with chronic myeloid leukemia took imatinib mesylate 400 mg bd. His other medications were perindopril and ator-vastatin. After 2 months he developed angio-edema, probably related to perindopril, which was withdrawn and replaced by amlodipine 10 mg/day. After 2 weeks he developed typical symptoms of imatinib toxicity nausea, marked periorbital, and ankle edema. Diuretics improved the edema, but after 10 days he complained of numbness of the chin and bilateral pain and numbness in the soles of the feet. Light touch and vibration sense were reduced, but power and reflexes were intact. Imatinib was reduced to 400 mg/day and amlodipine was withdrawn. The edema, numbness and neuropathic pain resolved. Despite residual plantar numbness he was able to increase the dose of imatinib to 600 mg/day without worsening symptoms. About 1 month later he took two doses of amlodipine in error and developed nausea and palpitation, which resolved when the amlodipine was withdrawn. Nerve conduction testing 1 month later showed a mild sensorimotor axonal neuropathy. After 9 months the neuropathy had resolved despite continuing imatinib therapy. 

Gorre ME, Ellwood-Yen K, Chiosis G et al. (2002) BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 100 3041-3044... 

Imatinib mesylate Phenylaminopyrimidine Chronic myeloid leukemia. Inhibits BCR-ABL Rash Angio Pr SJS Hypersensitivity pn Incidence 31 14 % cutaneous... 

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