Dasatinib Exposure and Relationship to Efficacy and Safety In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Dasatinib 100 mg once daily (QD) has superior efficacy compared with imatinib in patients with newly diagnosed CML-CP, as demonstrated by a randomized phase 3 trial in this setting (CA180-056/DASISION; Kantarjian et al, N Engl J Med 2010;362:2260-70). Exposure-efficacy response was characterized by examining the relationship between weighted time-averaged dasatinib concentration (wC_avg) and the probability of achieving a confirmed complete cytogenetic response (cCCyR; defined as CCyR detected in 2 consecutive assessments), the primary endpoint of DASISION. Exposure-safety response was characterized by describing the relationship between dasatinib trough concentration (C_min) and occurrence of pleural effusion in DASISION.

wC_avg and C_min were determined by a population pharmacokinetic (PPK) model that described concentration-time data from 235 subjects in DASISION. wC_avg was calculated within the treatment duration up to the time of cCCyR or discontinuation (whichever occurred earlier) excluding dose interruptions. The probability of cCCyR was described by a logistic regression model with respect to C_avg and the following covariates as predictors: cumulative duration of dose interruption (calculated as a percentage of the overall treatment duration [P_intr] until cCCyR or discontinuation, whichever occurred earlier), age, gender, and race. The relationship of C_min to the hazard of pleural effusion (any grade) was characterized using a Cox proportional-hazards model that also examined the following covariates: age, gender, race, history of cardiac disease, and dasatinib treatment status (first line/after prior imatinib).

Concentration-time data for dasatinib were described by a linear two-compartment PPK model with first-order absorption. No statistically significant or clinically relevant differences in dasatinib PK were found between patients with newly diagnosed disease or those with prior imatinib therapy. Within the limited range of exposure produced by dasatinib 100 mg QD treatment and measured in the analysis dataset, the probability of achieving cCCyR in patients with newly diagnosed CML-CP was similar irrespective of dasatinib wC_avg: high rates of cCCyR (>70% by 12 months) were observed across the exposure range. The probability of cCCyR decreased by 14% for each doubling in duration of dose interruption (P_intr; p<0.01). Among analyzed patients, pleural effusion (any grade) was reported in 10% of patients at 1 year in the DASISION trial. The risk of pleural effusion increased with dasatinib steady-state C_min (hazard ratio of 1.1 for every unit increase of C_min; 95% confidence interval [CI]: 1.04–1.17; p<0.01) and age (hazard ratio of 2.01 for every decade increase in life; 95% CI: 1.73–2.34; p<0.01).

These analyses show that the probability of cCCyR in patients with newly diagnosed CML-CP was similarly high across the exposure range/wC_avg produced by dasatinib 100 mg QD treatment. C_min and age are associated with the risk of pleural effusion.

CCyR = odds ratio (logistic regression); pleural effusion = hazard ratio (Cox proportional hazards).

CCyR coefficients are with respect to log₂ of predictor variable; log₂ P_intr increases by 1 unit for each doubling in value.

Pleural effusion coefficients are with respect to C_min and age/10; age/10 coefficient increases by 1 unit for each additional 10 years.

Wang: Bristol-Myers Squibb: Employment. Off Label Use: First-line treatment of CML with dasatinib. Agrawal: Bristol-Myers Squibb: Employment. Damokosh: Bristol-Myers Squibb: Employment, Equity Ownership. Roy: Bristol-Myers Squibb: Employment, Equity Ownership.