Pharmacokinetics of Dasatinib as a First Line Therapy In Newly Diagnosed CML Patients (OPTIM dasatinib trial): Correlation with Safety and Response.

Dasatinib 100 mg QD is now validated as a first line option in patients with chronic myelogenous leukaemia in chronic phase (CML in CP). Our hypothesis was that significant adverse events observed with dasatinib including fluid retention, pleural effusions and grade 3–4 cytopenias, may be driven by the level of the residual dosage of dasatinib (Cmin). We initiated an optimization study based on the monitoring of dasatinib plasma levels (Cmin and Cmax) in patients with CML in chronic phase newly diagnosed and treated with dasatinib as front line therapy.

Patients aged 18 years old or more were eligible if they were diagnosed with CML in CP for less than 3 months without having being exposed to tyrosine kinase inhibitors. Dasatinib was initiated at the daily dose of 100 mg QD. Dasatinib daily dose adaptation was randomized in patients with a Cmin over 3nM. For all other patients, dasatinib was given at the dose of 100 mg QD. The pharmacokinetic (PK) evaluation (Cmin and Cmax measurements) was performed after 7 to 10 days of therapy and then every 15 days in the treatment adaptation arm (until a level of Cmin under 3nM) and every 3 months therafter as in the non-adapted arm. Cmax was assessed 2 hours after dasatinib intake.

The results of the first 78 patients included in the trial from May 2009 to May 2010 are reported. Median age was 47 years (19 – 77) with a sex ratio M/F of 1.85. The Sokal score distribution was 51.9%, 30.7% and 17.4% for Low, intermediate and high risk respectively. Median Cmin and Cmax values were 2.1 nM (range 0.2–18.7) and 107.6 nM (range 20.5–353) at first PK analysis. The median Cmin value was significantly lower in patients with age <47y compared to patients >47y (1.6 nM versus 2.8 nM, p=0.0028). By contrast, the median Cmax value was comparable in both age groups. Efficacy analysis was performed on the 53 patients with a 3 months follow-up and on the 36 patients with a 6 months follow-up. The complete cytogenetic response (CCR) rates at 3 and 6 months were 83.3% and 90.9% respectively. At 3 and 6 months, the major molecular response (MMR) rates were 15.1% and 69.4%. All patients in cytogenetic failure had high Sokal score values (p=0.023). Median PK values at months 3 and 6 were not statistically different compared to initial PK values, suggesting a stable exposure to the treatment with time. With a median follow-up of 7.2 months, the rate of significant adverse events was 11.5%. Fluid retention (n=2) and pleural effusion (n=1) were observed in patients with high Cmin values (mean 3.7 nM). A trend was observed between the Cmax and response at month 3 (CCR, p=0.05 and MMR, p=0.08). Patients with lymphocytosis may have a higher MMR rate (p=0.07).

Dasatinib 100 mg QD as first line therapy in CP CML provided a high rate of MMR and CCR rates. Pharmacokinetic parameters of dasatinib were different in aged patients. A trend was observed first between Cmax and responses and second between Cmin and fluid retention or pleural effusion. A complete analysis with correlation to response and safety will be presented on more patients with 6 and 12 months follow-up.

Rousselot:Bristol Myers Squibb: Research Funding. Off Label Use: Dasatinib as first line therapy for CML.