Personalized Daily Doses of Imatinib By Therapeutic Drug Monitoring Increase the Rates of Molecular Responses in Patients with Chronic Myeloid Leukemia. Final Results of the Randomized OPTIM Imatinib Study

[Graphic][1] Background Imatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007). We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17). Patients and Methods Pts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months. Results One hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 ( p