What is the role of imatinib mesylate in the treatment of chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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Answer

Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor (TKI) that inhibits the abnormal bcr-abl tyrosine kinase created by the Philadelphia (Ph1) chromosome translocation abnormality. Imatinib inhibits proliferation and induces apoptosis in cells positive for BCR/ABL. [3, 4, 7, 25, 26]

For patients with chronic-phase CML, imatinib at 400 mg/day is the best dosage for primary therapy, because it induces a complete hematologic response in almost all patients and causes a high cytogenetic response rate. With imatinib at 400 mg/day orally in patients with newly diagnosed Ph1-positive CML in the chronic phase, the complete cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%.

With higher doses of 800 mg/day, the complete cytogenetic response rate increases to 98%, the major molecular response rate is 70%, and the complete molecular response rate is 40-50%. Despite those improved early responses, however, randomized phase III studies suggest that higher-dose imatinib was not associated with lower rates of disease progression than imatinib, 400 mg, but was associated with higher rates of dose interruption, reduction, or discontinuation due to grade 3 or 4 adverse events. [21]

A study of imatinib in patients with newly diagnosed chronic phase CML found that imatinib maintained efficacy over median follow-up of 10.9 years, without unacceptable cumulative or late toxic effects. The IRIS (Randomized Study of Interferon vs STI571) trial was an open-label crossover trial that randomly assigned patients to receive either imatinib or interferon alfa plus cytarabine. Of patients assigned to imatinib, 48.3% completed study treatment with it, and 82.8% had a complete cytogenetic response. The estimated 10-year survival rate was 83.5%. [15]

Santos et al reported that the use of erythropoietic-stimulating growth factors with imatinib did not impact response rates or survival but increased risk for thrombosis. The presence of severe anemia in these patients was associated with worse survival and response. [27]

Kantarjian et al reported that in patients in the chronic phase who had failure or intolerance of interferon treatment, treatment with imatinib resulted in a complete hematologic response in 430 of 454 patients (95%), with a major cytogenetic response (ie, 0-35% of cells in metaphase positive for the Ph1 chromosome) in 60% of patients; 41% had a total response. [4] Among the study patients with features of accelerated-phase CML (n=17), rates of cytogenetic and hematologic responses were 59% and 88%, respectively and among those with features of blastic-phase CML (n=12), rates were 75% and 92%, respectively.

Talpaz et al reported that among 235 patients with accelerated-phase CML, treatment with imatinib yielded a hematologic response in 82% of patients (sustained in 69% and complete in 34%) and major cytogenetic response in 24% (complete in 17%). [6]

Sawyers et al found that among patients in myeloid blast crisis (260 patients), treatment with imatinib resulted in sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. Major cytogenetic responses occurred in 16% of patients, with 7% of the responses being complete. [28]

A study in 1106 patients with newly diagnosed, chronic-phase CML concluded that in terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib is superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed, chronic-phase CML. [29] The estimated rates of complete cytogenetic response were 76.2% for the imatinib group and 14.5% in the interferon alfa group. [29]

The estimated rate of a major cytogenetic response at 18 months was 87.1% in the imatinib group and 34.7% in the group given interferon alfa plus cytarabine. At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7% in the imatinib group and 91.5% in the combination-therapy group. Imatinib was better tolerated than combination therapy. [29]

Molecular remission is the goal as measured by PCR. Continuation of the drug is important because approximately 20% of patients lose complete cytogenic response, at a rate of 1.4 per 100 person-years. This is due to poor adherence or poor tolerance of the drug in patients who had an adherence rate of less than 85% as the main reason for complete cytogenic response loss. [30]

Treatment of patients with CML in the accelerated phase or in blast crisis has yielded dismal results. Although imatinib can induce a hematologic response in 52-82% of patients, the response is sustained for at least 4 weeks in only 31-64% of patients. The complete response rate is lower, at 7-34% of patients. Karyotypic response occurs in 16-24%, and complete cytogenetic response is observed in only 17%. [28] Higher doses (ie, 600 mg/d) result in improved response rates, cytogenetic response, and disease-free and overall survival.

Resistance of CML cells to imatinib occurs through multiple mechanisms such as overexpression of BCR/ABL and mutations of the abl gene. [8, 9, 31]  Kinase-domain mutations in BCR/ABL represent the most common mechanism of secondary or acquired resistance to imatinib, accounting for 50-90% of cases; 40 different mutations have currently been described. Because imatinib binds to the ABL kinase domain in the inactive, or closed, conformation to induce conformational changes, resistance occurs when the mutation prevents the kinase domain from adopting the specific conformation upon binding.

Patients whose CML demonstrates resistance to imatinib should be switched to a different TKI and considered for hematopoietic stem cell transplantation. [21, 22]

Kidney damage is an important adverse effect of imatinib. A study by Marcolino et al found that imatinib therapy in non–clinical trial patients with CML was associated with potentially irreversible acute kidney injury, and that long-term treatment may cause a clinically relevant decrease in the estimated glomerular filtration rate (GFR). [32]


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