Imatinib mesylate

A protein-tyrosine kinase inhibitor with specificity for c-kit platelet-derived growth factor, and Bcr/Abl pathways.

Marketed as Gleevec.

Causes apoptosis in cells that express Bcr/Abl in CML and acute lymphocytic leukemia cell lines.

Has demonstrated activity in all phases of Philadelphia chromosome positive chronic myelogenous leukemia.

Produces complete hematologic remission in more than 95% of patients and complete cytogenetic responses in 60-75% of pateints with CML.

Binds to adenosine triphosphate binding site Abl, inhibiting phosphorylation of substrates and malignant cell transformation in CML.

Binds the inactive configuration of ABL kinase and competitive inhibits the ATP binding site of BCR/ABL.

Has an overall response rate of 60-70% and a complete response rate of 17-30% in Philadelphia positive patients with acute lymphoblastic leukemia who failed chemotherapy, but duration of response is short

Principal effect of binding is to lock the autophosphorylation of the kinase, which is critical for kinase activation and signal transduction.

Adverse effects include nausea, vomiting and fluid retention.

The most frequently reported adverse reactions are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain.

Cardiac dysfunction, hepatotoxicity, tumor lysis syndrome, and GI perforations have been reported.

Benign reversible skin hyperpigmentation may occur.

Should be weighed and monitored regularly for fluid retention.

Fluid retention with ascites, pleural effusion, pericardial effusion or anasarca seen in 1-3% of CML patients.

Probability of edema increases over the age of 65 and at higher doses.

Congestive heart failure and left ventricular dysfunction occasionally reported.

Hepatotoxicity is an occasional complication and may be severe.

Patient should have monthly liver function tests.

25% dose reduction is recommended for patients with severe hepatic impairment.

May be associated with shock and left ventricular dysfunction in patients with hypereosinophilic syndrome and cardiac involvement.

Dermatologic reactions have rarely been reported.

May be associated with hypothyroidism.

Metabolized by CYP3A4 isoenzyme, and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9.

Significant reductions in drug concentration occur when this drug is administered with strong induces of CYP3A4 such as rifampin and phenytoin.

Drugs that me interact include ketoconazole, acetaminophen, warfarin, erythromycin and metoprolol.

Grapefruit juice should be avoided in patients taking imatinib.

Patients with moderate renal impairment should receive a 50% decrease in recommended dosage.

Cytopenias can occur and complete blood counts should be performed weekly for the first month, biweekly for the second month and periodically thereafter.

Has a clear dose-response rate.

Imatinib is normally given with food to prevent or minimize nausea.

Associated with nausea, myalgias, arthralgias, and fluid retention more frequently even in patients treated with other TKIs.

Associated nausea and fluid retention or easily manage, but arthralgias and myalgia may persist as late side effects in the minority of patients.

Approximately 70% of patients who received this agent is first-line therapy for chronic myelogenous leukemia achieve a complete cytogenetic response by 12 months, and 80% do so by five years.

In a study of 282 patients at the Hammersmith Hospital in London eight year probability of overall survival on an intention to treat basis was 84%, the eight-year probability of being alive and complete cytologic remission was 77%, the eight year probability of a imatinib failure free survival was 50% (Marin D et al).

In a single institution study of CML patients receiving imatinib after interferon failure, with a median follow-up of 114 months: 67% had a complete cytogenetic response, 63% achieved a major molecular response, and at seven years 35% were in complete cytogenetic remission, 32% were in major molecular response and 11% had undetectable BCR/ABL levels on molecular testing (Kantarjian H et al).

In the above study the tenure estimated survival was 68% with a progression free survival rate of 67%. Higher dosages may be associated with better disease control and can overcome resistance to imatinib.

2-year incidence of resistance is 80% in blastic phase, 40-50% in accelerated phase and 8-10% in chronic phase (Silver).

Standard dose is 400 mg per day in CML

Approximately 40% of patients in chronic phase CML who fail to respond to the standard dose may respond when the dose is increased to 800 mg per day.

Starting doses of 600-800 mg per day in CML may improve response rate with more than 90% of patients achieving a complete cytogenetic response and 25% achieving undetectable BCR/ABL levels.

Responses in CML with higher doses occur more rapidly so that 85% of patients achieve complete cytogenetic remission with high dose compared to 55% with standard dose at 6 months.

Mechanisms of resistance are increased expression of Bcr/Abl kinase via gene amplification and mutations in BCR/ABL fusion gene affecting drug binding or kinase activity.

Most pregnancies in women exposed are successful (Pye).

Often associated with edema, and occasionally severe fluid retention.

Patients should be monitored for weight gain.

Patients should be weighed and monitored regularly for signs and symptoms of fluid retention.

Rapid weight gain tends to be more common among individuals older than 65 years of age and with higher doses.

Because of lowered blood counts have been reported complete blood counts should be performed weekly for the first month of treatment by monthly for the second month and periodically thereafter.

A 25% reduction in dose is recommended in patients with severe hepatic impairment.

Patients with moderate renal impairment with a creatinine clearance of 20-to 39 mils per minute should receive a 50% decrease in the recommended starting dose.

For patients with wave moderate renal impairment doses of greater than 400 mg a day and not recommended.

Majority of patients experience adverse reactions at some time and include: edema 77%, fatigue 70%, nausea about 60%,  of abdominal pain about 55%, rash about 60%, nausea and vomiting 37% and myalgia about 30%.

Chronic fatigue, often correlated with musculoskeletal pain and muscular cramps is a major factor in reducing quality of life in patients who take imatinib.

Hypophosphatemia and bone mineral density decrease noted in a small group of patients.

Skin hypo pigmentation has been reported.

Reversible renal dysfunction with prolonged use of imatinib has been reported.

Tablets should be taken with food and a large glass of water.

Because cytopenias may occur complete blood counts should be performance weekly for the first month, biweekly for the second month, and periodically thereafter.

In the IRIS study (International Randomized Study of Interferon And ST1571) compared imatinib with interferon and cytarabine and found that it 8 years the overall survival was 85% and the disease-free survival was 93% for imatinib.

In the above studies none of the patients who achieved a (MMR)major molecular response by 18 months had progression to accelerated whole blast phase disease versus 5% of those who did not.

After 8 years of follow-up the MMR with imatinib was 86%.

In the IRIS data the incidence of progression to accelerated or blast phase disease declined substantially after the first 3 years suggesting the major incidence of progression to accelerated or blast phase disease occurs relatively early in TKI therapy.

In the IRIS study (International Randomized Study of Interferon And ST1571) most adverse events in the imatinib group we’re grade 1-2, with most being superficial edema, nausea, muscle cramps and rashes.

In the IRIS study the most common nonhematologic grade 3-4 adverse events for patients on imatinib or musculoskeletal pain 2.7%, joint pain 2.4% and abdominal pain 2.4%.

In the IRIS study in the hematologic adverse events occurred with neutropenia in 14.3% of patients, thrombocytopenia and 7.8%, and 3.1% developed anemia with imatinib.

In the phase 1 studies doses up to 1600 mg daily have failed to identify a maximally tolerated dose.

IRIS study revealed a discontinuation of treatment by 7 years of 38%, 16% because of inadequate therapy, 6% because of toxicity, 3% for stem cell transplantation, and 3% for death.

Imatinib is an effective treatment in children in chronic phase with response rates similar to rates reported in adults.

Imatinib treatment in children is associated with a complete hematologic response, complete cytogenetic response and major molecular response rates of 98%, 61%, and 31% at 12 months, respectively (Millot F et al).

Severe lab abnormalities include neutropenia, anemia, thrombocytopenia, liver toxicity ( 5%), hemorrhage ( 1.8-19%), fluid retention, pulmonary edema, and ascites, musculoskeletal pain ( 2-9%).

In the IRIS study the most frequent serious adverse events were vomiting, fever, abdominal pain, and nausea.

Small risk that serious fetal malformation may occur following maternal exposure to this agent.

Exposure in pregnancy may result in spontaneous abortion.

May be used for dermatofibrosarcoma protuberans.

Women of childbearing age on this drug should avoid pregnancy, and if pregnancy develops risk benefit evaluation needs to be carried out on an individual basis.

Prolonged therapy can lead to fatigue, and long-term therapy is associated with a worse quality of life compared with healthy individuals.

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