Efficacy of Imatinib Mesylate Dose-Escalation in CML Patients Showing Suboptimal Response to Standard Dose.

Introduction: We report the results of our prospective single arm study performed to evaluate the efficacy of Imatinib mesylate (IMT) dose-escalation therapy and the influence of BCR/ABL mutational status on the treatment outcome.

Methods: Patients with chronic phase(CP) chronic myelogenous leukemia (CML) who had not achieved a complete hematologic response (CHR) after 3 months, a major cytogenetic response (MCyR) after 6 months, nor a complete cytogenetic response (CCyR) after 6-12 months of standard IMT therapy (400mg per day) were included. Patients in accelerated phase (AP) or blast crisis (BC) who had failed to achieve CHR after 3 months of IMT (400 or 600mg per day) were also eligible. 600mg of IMT had been administered for patients with CP CML per day, and 600mg or 800mg for AP or BC CML for at least 12 months. For each patient, BCR/ABL gene mutation test was performed on 6 loci. Cytogenetic response (CyR) was evaluated with the percentage of bcr/abl positive cells in bone marrow aspirate by means of FISH per 6 months. Molecular responses (MR) were assessed per 3 months with a logarithmic decrease in BCR-ABL/ABL gene ratio (BA/A) of peripheral blood or bone marrow aspirate from a standardized median value of BA/A in 56 patients with newly diagnosed CML.

Results: 77 patients were enrolled and 61 patients were assessable for the evaluation of MR. The median age was 50 years old (range: 20-70). Stages at the time of the enrollment were CP for 56, AP for 4, BC for 1 patient(s). The median time from the initiation of IMT therapy to dose-up was 20 months (range: 0-62). BCR/ABL gene mutational status could be obtained in 24 patients (wild:mutant=20:4). The median follow-up was 19.9 months (range: 6.5-24.3). For 34 patients whose 6th-month CyR is available, MCyR rate (MCyRR) was 26.5% and CCyR rate (CCyRR) was 23.5%. The 12th-month MCyRR was 61.1% and CCyRR was 50.0%. Patients with wild type showed a MCyRR of 20% and a CCyRR of 15% on the 12th month after dose-up, whereas no patient with mutant type showed a CCyR or a MCyR. CMR rate and MMR rate on the 12th-month were 16.7% and 26.7%. Among 20 patients with wild type, one patient achieved a 6th-month CMR, 2 patients MMR’s, whereas no patient with mutant type could achieve a MMR during the entire treatment period. Hematologic and non-hematologic toxicities were tolerable.

Conclusion: IMT dose-escalation could induce quite a number of durable CyR’s and MR’s without any serious toxicity in patients who had failed to achieve either a CHR or a CyR with a standard IMT therapy.