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Imatinib mesylate (Gleevec®, Glivec®) is an orally administered competitive inhibitor of the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML).
In patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in the chronic phase, imatinib mesylate 400 mg/day, compared with interferon-α (IFNα) plus cytarabine, resulted in higher hematologic response (HR) and cytogenetic response (CR) rates and fewer patients progressing to the accelerated phase or blast crisis in a large comparative trial. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life (HR-QOL).
Imatinib mesylate was also effective in patients with chronic-phase CML refractory to or intolerant of treatment with IFNα (as 400 mg/day) and in those with blast-crisis or accelerated-phase CML (600 mg/day). In the latter groups, HR and CR rates were lower than those in patients with chronic phase CML.
Imatinib mesylate-associated adverse events were common in clinical trials, but were mostly mild to moderate in severity. The most frequently reported adverse events were superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash. Myelosuppression (thrombocytopenia and neutropenia) was also reported, especially in patients with advanced disease. In patients with previously untreated chronic-phase CML, serious adverse events (both hematologic and nonhematologic) were less common with imatinib mesylate than with IFNα plus cytarabine treatment.
Conclusion: Imatinib mesylate is a valuable therapy for patients with newly diagnosed Ph+ chronic-phase CML. It is better tolerated and produces higher HR, CR and freedom from progressive disease rates than conventional therapy with IFNα plus cytarabine. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher HR-QOL. Imatinib mesylate is also effective in patients with accelerated-phase and blast-crisis CML, and patients with chronic-phase CML who have failed IFNα therapy. Given its efficacy and generally manageable adverse event profile, imatinib mesylate offers an important early treatment option for patients with CML.
Imatinib mesylate blocks the tyrosine kinase activity associated with the Abelson (ABL) protein, selectively inhibits the proliferation and survival of leukemia cells expressing break cluster region (BCR)-ABL and suppresses the formation of BCR-ABL-induced tumors in murine models. In vitro studies suggest a synergistic or additive effect when imatinib mesylate is coadministered with other chemotherapy agents, including interferon-α (IFNα), cytarabine, doxorubicin, daunorubicin, and etoposide. Mechanisms of imatinib mesylate resistance include amplification of the BCR- ABL gene, overexpression of BCR-ABL, the development of point mutations in the catalytic domain of BCR-ABL and the development of novel chromosomal aberrations.
Imatinib mesylate is absorbed rapidly and extensively after oral administration; peak plasma concentrations (Cmax) are reached in 2–4 hours and bioavailability is 98%. Mean steady-state Cmax was 2.3 mg/L following administration of imatinib mesylate 400mg once daily to patients with chronic myeloid leukemia (CML). Accumulation is 2- to 3-fold at steady state with once-daily administration. Imatinib mesylate is 95% protein bound, predominantly to albumin and α1-acid glycoprotein. Metabolism is mainly through the action of the cytochrome P450 (CYP) isoform CYP3A4. The main metabolite (N-demethylated piperazine derivative) has similar in vitro potency to the parent compound. In patients with CML, the elimination half-life of imatinib mesylate is 13–16 hours. Excretion is primarily via the feces.
CYP3A4 inducers (e.g. phenytoin) increase the metabolism of imatinib mesylate and CYP3A4 inhibitors (e.g. ketoconazole and erythromycin) decrease it. Imatinib mesylate may inhibit the metabolism of other substrates of CYP3A4 (e.g. simvastatin) as well as substrates of CYP2C9, CYP2D6 and CYP3A4/5.
Oral imatinib mesylate 400 mg/day was more effective than subcutaneous IFNα plus cytarabine in patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in early chronic-phase in a randomized, multicenter, open-label, phase III trial (median treatment duration of 19 months). The estimated 18-month rate of freedom from progression to accelerated-phase or blast-crisis CML was 97% in imatinib mesylate recipients and 92% in IFNα plus cytarabine recipients (p < 0.001). Major cytogenetic response (MCR) rates were 85% and 22%, complete cytogenetic response (CCR) rates were 74% and 9% and complete hematologic response (CHR) rates were 95% and 56%, respectively (all p < 0.001). Molecular response (assessed according to quantitative polymerase chain reaction [PCR]-negativity) occurred in some of the imatinib mesylate recipients who achieved CCR; a >3 log reduction in BCR-ABL/BCR% values was estimated to be achieved in 39% of imatinib mesylate recipients versus 2% of IFNα plus cytarabine recipients (p < 0.001) at 12 months. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life.
Imatinib mesylate 400 mg/day was effective in patients with chronic-phase CML who had failed treatment with IFNα. In the largest phase II trial (median treatment duration of 18 months), MCR was achieved in 60% of patients, CCR in 41% and CHR in 95%. The 18-month estimated progression-free and overall survival rate was 89% and 95%.
In patients with accelerated-phase CML (median treatment duration of 11 months), imatinib mesylate 600 mg/day (n = 119) was effective as shown by the proportion of patients with responses (MCR 28%, CCR 19%, hematologic response [HR] 71%); the estimated 12-month progression-free and overall survival rates were 67% and 78%. Moreover, in patients with myeloid blast-crisis CML (n = 229; median treatment duration 4 months), imatinib was also effective, although the response rate (MCR 16%, CCR 7%, HR 31%) and the estimated median survival time (6.9 months) and the estimated 12-month overall survival rate (32%) were lower than those in the trial in patients with accelerated-phase CML.
The most frequently reported imatinib mesylate-associated nonhematologic adverse events (superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash) were mostly mild to moderate in severity. Grade 3 or 4 hepatotoxicity occurred in <5% of imatinib mesylate recipients.
Myelosuppression (thrombocytopenia and neutropenia) was frequently reported in clinical trials, and was more common in patients with advanced disease. In recipients of imatinib mesylate, the incidence of grade 3 or 4 neutropenia or thrombocytopenia was approximately 2- to 3-fold higher in myeloid blast-crisis or accelerated-phase CML than in chronic-phase CML, and was approximately 2-fold less than that in recipients of IFNα plus cytarabine.
Dosage and Administration
Imatinib mesylate is indicated for the treatment of newly diagnosed patients with Philadelphia chromosome-positive CML. Imatinib mesylate is also indicated for the treatment of patients with CML in blast crisis, accelerated phase, or chronic phase after failure of IFNα.
The recommended dosage of imatinib mesylate is 400 mg/day for patients with chronic-phase CML and 600 mg/day for patients with accelerated-phase or blast-crisis CML. Dosage increases from 400 to 600 mg/day in patients with chronic-phase CML or from 600 to 800 mg/day in patients with accelerated-phase or blast-crisis CML may be considered in disease progression, if a satisfactory HR is not achieved after ≥3 months of treatment, if CR is not achieved after 6–12 months of treatment or if loss of previously achieved HR or CR occurs (in the absence of severe non-leukemia-related neutropenia or thrombocytopenia). The dosage of imatinib mesylate should be adjusted or treatment interrupted if severe neutropenia or thrombocytopenia occurs. If a severe nonhematologic adverse event occurs, imatinib mesylate should be withheld until the event resolves.