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

Recent 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.

Between 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.

A 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.

This 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.

No relevant conflicts of interest to declare.