Lower Dose of Imatinib Provides Outcomes Similar to the Standard Dose Imatinib in Japanese Patients with Early Chronic-Phase CML: The Interim Analyses of JALSG CML202 Study.

Background: The dose of imatinib 400 mg is considered to be standard for chronic-phase chronic myeloid leukemia (CML) based on the IRIS study. However, the optimal dose of imatinib is not yet settled and the response of lower dose imatinib has not been investigated. Lower dose of imatinib might be enough in Asian patients since the results of PK in IRIS study showed weak correlation between imatinib trough level and body weight. We showed the results of the interim analysis of JALSG CML202 study and analyzed the efficacy of imatinib according to the mean daily dose level. Methods: The objectives of CML202 study are to determine the efficacy of imatinib monotherapy in patients with newly diagnosed chronic-phase CML, and to test whether combining imatinib with IFN or cytarabine ocfosfate overcome the resistance of imatinib and to estimate the frequency and severity of toxicities. Primary end point of imatinib monotherapy was overall survival, and that of combination therapy was cytogenetic response after 9 months. Newly diagnosed patients with chronic phase CML will receive imatinib at a dose of 400mg daily. At 9 months, if patients don’t achieve major cytogenetic response (MCR), they were randomized to the combination therapies, imatinib plus conventional IFN or imatinib plus cytarabine ocfosfate. Results: From 2002 to 2006, 489 patients were enrolled to this study. On July 2007, 36 months median follow-up data were analyzed. Only 2 patients were enrolled to the combination therapy because a majority of patients achieved good response. 13 patients underwent HSCT. The estimated cumulative rates of complete hematologic response (CHR), MCR and complete cytogenetic response (CCR) were 97%, 97% and 91%, respectively. The estimated major molecular response (MMR) rate at 24 months was 55%. The estimated survival without AP/BC progression rate at 60 months was 94%. The overall estimated survival at 60 months was 94%. 95% of low risk patients achieved CCR significantly as compared with intermediate and high-risk patients according to Sokal risk. The mean daily dose of imatinib for the first 2 years was 400mg or more in 54% patients (400mg group), 300–399mg in 27% (300mg group), 200–299mg (200mg group) in 11%, and 100–199mg in 9% (100mg group), respectively. The cumulative rate of MCR and CCR at 60 months was 99% and 97% in 400mg group, 99% and 98% in 300mg group, 92% and 85% in 200mg group, and 81% and 48% in 100mg group, respectively (p=0.003 and p<0.0001). The cumulative rate of MMR at 18 months was 33% in 400mg group, 33% in 300mg group, 27% in 200mg group and 0% in 100mg group, respectively. The estimated rate of overall survival and progression-free survival at 60 months was 97% and 97% in 400mg group, 98% and 98% in 300mg group, 92% and 92% in 200mg group, and 87% and 87% in 100mg group, respectively (p=0.0002 and p=0.0009). Conclusion: The results of interim analyses of JALSG study were almost similar to those of IRIS study. However, the mean daily dose of imatinib was lower in our study than in IRIS study. The patients received imatinib 300mg showed outcomes similar to 400mg, suggesting that imatinib 300mg might be enough for Japanese patients. The comparative studies with PK measurement will ellucidate the optimal dose of imatinib.