Plasma Imatinib Trough Level Is a Predictor For 3-Month Early Molecular Response In New CP CML Patients

Abstract

BackgroundRecent studies have demonstrated that measurements of BCR-ABL1 transcript levels at 3 and 6 months were able to identify high-risk patients treated with IM. However, the value of early molecular response has not been fully defined. New European Leukemia Net (ELN) recommendations concluded that a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is not sufficient to define failure necessitating a change of treatment. The aim of this study was to identify predictive factors for an achievement of 3-month EMR. For the purpose, we explored contributing factors including trough plasma concentrations of IM, precise IM dose schedule. Additionally, in the same population, prognostic implications of 3- month EMR were analyzed. MethodsBetween December 2009 and June 2012, 102 patients with newly diagnosed CP CML were enrolled. They started IM (400 mg/day) therapy without prior treatment except hydroxyurea or anagrelide and molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). All qRT-PCR tests were performed in a single laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea). Measurements of IM plasma concentrations were performed on day 29. ResultsA total of 102 newly diagnosed CP CML patients (including 61 men and 41 women) were analyzed. With a median age of 41 years (range, 18-75 years), the distribution of low, intermediate and high Sokal risk scores were 42%, 42% and 16%, respectively. All patients, except one patient who showed less than complete hematologic response, were evaluable for molecular analyses at 3 months. Day 29 trough IM level data were available from 99 patients. The median trough concentrations of IM were 1,252 (range, 439-3,491) and cut-off IM levels for Q1 and Q4 quartiles were 958 and 1767 ng/mL on day 29, respectively.Univariate analyses revealed that age of ≥ 40 years (P = 0.046), high Sokal risk (P = 0.066), high Euro risk (P = 0.004), increased platelet count (P = 0.028), increased blast percentage (0.023), and large spleen size (P = 0.046) were potential predictive factors for no achievement of 3-month EMR. In addition, plasma IM trough level of ≤ Q1 quartile on day 29 was associated with no achievement of 3-month EMR. After adjusting for factors affecting achievement of 3-month EMR on univariate analyses, multivariate analyses showed that large spleen size (RR of 0.79, P = 0.030) was predictor for no achievement of 3-month EMR and patients in ≤ Q1 of plasma IM trough level on day 29 had a lower 3-month EMR, compared with those in Q2-4 (RR of 15.61, P = 0.005).To evaluate the prognostic value of 3-month EMR in our cohort, we analyzed CCyR at 6 months, MMR at 12 months, and the 3-year CI of CCyR, MMR, and UMRD. In addition, the 3-year EFS, FFS, and PFS were also assessed. In patients with BCR-ABL1 ≤10% at 3 months, significantly higher rates of CCyR at 6 months (79% vs 13%, P < 0.001) and MMR at 12 months (54% vs 10%, P = 0.014) were observed, compared with that of patients with BCR-ABL1 >10%. They also had significantly better 3-year CI of CCyR (100% vs 63.0%, P<0.001) and MMR (100% vs 30.4%, P = 0.001), EFS (62.2% vs 26.3%, P = 0.002), and FFS (89.6% vs 73.7%, P = 0.044). However, there were no significant differences in 3-year PFS. ConclusionsThis study analyzed various factors, such as baseline biological characteristics, adherence to IM, IM dose intensity, pharmacokinetics. It provides predictors for 3-month EMR and re-confirmed the prognostic significance of 3-month EMR. The considering of IM plasma concentrations for 3-month EMR should be needed in the clinical decision of changing therapy at this time point. Further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures:No relevant conflicts of interest to declare.