Correlation of Pharmacokinetic Data with Cytogenetic and Molecular Response in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib - An Analysis of IRIS Study Data.

A total of 551 pts with newly diagnosed CML-CP received imatinib (IM) 400 mg orally once daily as part of the IRIS study (O’Brien et al, NEJM 2003). We now summarize the correlation of clinical responses with the steady-state trough plasma concentrations (Cmin) of IM and its major active metabolite CGP74588. Cmin is a reflection of IM clearance and metabolism in CML pts. Trough PK samples (24 hrs post dose) were obtained in IM pts at Day 1 and steady state (Day 29). The plasma concentrations of IM and CGP74588 were determined by liquid chromatography/mass spectrometry. Estimated rates of complete cytogenetic response (CCyR - 0% Ph+) and major molecular response (MMR - ≥ 3 log reduction in BCR-ABL/BCR ratio from a standardized baseline value for untreated pts) were given for the lower and upper quartiles (below Q1=25^th percentile, above Q3=75^th percentile) and the inter-quartile range of PK trough levels. After 4 weeks of IM at 400 mg, the overall mean (±SD, CV%) steady-state trough levels (Cmin) for IM and CGP74588 (n=351 pts) were 979 (±530, 54.1%) and 242 (±106, 43.6%) ng/mL, respectively. Median (Q1–Q3, min-max) values (in ng/mL) were 879 (647–1170, 153–3910) for IM and 223 (169–291, 50–841) for CGP74588. Times to CCyR and MMR within CCyR pts were significantly different between the three groups of IM plasma exposure (low/intermediate/high; p<0.025). The same was observed for CGP74588, since the parent drug and metabolite levels were highly correlated (0.77, Spearman correlation coefficient). Overall, Cmin of IM was statistically significantly higher in pts who achieved CCyR (1009±544 ng/mL vs. 812±409 ng/mL, p=0.0116). The estimated MMR rate among all pts was significantly lower in pts with low IM levels: only an estimated 59%x43%=25% of all pts with IM levels <647 ng/mL achieved a MMR at 1 year (yr), compared to 40% of all other pts. By 4 yrs an estimated 53% achieved MMR despite low steady state Cmin levels compared with 80% for pts with high Cmin (and 72% for pts within inter-quartile range).

CCyR and MMR rates [95% CI] within 1, 2, and 4 yrs by categories of IM trough plasma concentrations measured on Day 29

The trough plasma level following the 1^st dose also showed a correlation with CCyR and MMR responses, but appeared to be less predictive than the trough level at steady state. Although all CML-CP pts had received 400 mg qd IM, CCyR and MMR rates at 1 to 4 yrs were depending on their IM trough level (24 hrs after the last dose) after 4 weeks of IM. Similar results were observed for the major active metabolite of IM. These results suggest that achieving and maintaining an adequate plasma concentration of IM is important for a good clinical response, and that therapeutic drug monitoring could be done by measuring trough levels at steady state conditions.