Characteristics of Chronic-Phase CML Patients Having Durable Cytogenetic Response to Low-Dose Imatinib

Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, has been established as first-line treatment of chronic-phase chronic myeloid leukemia (CML). On the basis of the IRIS study, 400mg/day IM has been recommended as an initial dose for adult CML patients. Although most patients usually tolerate the recommended dose, serious adverse effects such as grade 3 or 4 cytopenia may occur and require dose reduction of IM to 200–300mg/day. In fact, 8% of patients were receiving less than 400mg IM during 5-year follow-up in the IRIS study (Druker et al, New Engl J Med, 2006). In clinical settings, low-dose IM is actually effective for some patients; however, clinical and laboratory features of such patients have not been well investigated. Recently, it was demonstrated that the effective plasma threshold for trough IM levels should be maintained above 1,002 ng/ml to obtain maximal effects in CML patients (Picard et al, Blood, 2007). In this regard, determination of trough IM plasma levels may help to predict efficacy of low-dose IM. To evaluate the association of optimal IM doses with trough IM levels and patients’ basic characteristics such as body surface area (BSA), we assessed trough plasma concentrations of IM using high performance liquid chromatography (Hamada et al, J Pharmacol Exp Ther, 2003) in 31 chronic-phase CML patients, who were treated in Kumamoto University Hospital during 2003 to 2007. An optimal dose of IM was determined by a favorable response to IM achieving complete cytogenetic response and tolerable adverse events. Twenty-seven patients tolerated IM therapy during the observation period: optimal doses of IM were 400mg/day in 13 patients, 300mg/day in 9 patients, and 500 or 600 mg/day in 5 patients. Four patients discontinued IM for some reasons: two for toxicity, one for a concomitant unrelated disease and one for inefficacy due to drug-resistance. The trough plasma concentrations of IM were 1.64±0.68 μg/ml (mean±SD) in patients on the standard dose of 400mg/day IM (standard dose group) and 1.38±0.53 μg/ml in patients on the reduced dose of 300mg/day IM as an optimal dose (reduced dose group). Both mean trough levels of two groups showed no significant difference and exceeded the effective plasma threshold. Interestingly, BSA was significantly smaller in patients of the reduced dose group than those of the standard dose group (1.50± 0.16 vs. 1.75 ± 0.15 m² (mean± SD), p=0.001). An optimal IM dose was found to be significantly associated with age and gender as well as BSA. These results suggest that the reduced dose of 300mg/day IM may be sufficient for the treatment of CML patients with smaller body sizes. Monitoring of trough IM levels should enable proper management of individual patients in combination with regular monitoring of optimal response to IM.