INTRODUcTION There is increasing evidence supporting a role of BCR-ABL kinase activity in the induction of genomic instability in chronic myeloid leukemia (CML) cells by multiple mech anisms, including generation of reactive oxygen species. 1 Clinical and laboratory data suggest that prolonged exposure to BCR-ABL kinase activity probably leads to development of clonal disease and acquisition of BCR-ABL kinase domain (KD) mutation in the exposed cells. 2,3

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1689 Background: Approximately half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) fail imatinib treatment, both in interventional (Deininger et al., Blood 2009 114: abstract 1126) and observational trials (Michallet et al., Curr Med Res Opin 2010;26(2): 307–17), primarily due to the development of resistance and/or toxicity (Kantarjian and Cortes. J Clin Oncol 2011; 29(12): 1512–16). Clinical evidence suggests that optimal outcomes are achieved when dasatinib is administered early after imatinib failure (Quintas-Cardama et al., Cancer 2009;115(13): 2912–21); however, limited data are available regarding outcome of patients intolerant to imatinib in the real-life setting. Aims: FORTE (Factors impacting On Response To dasatinib in Europe) is a European observational study that aims to estimate the relationship between time elapsed from first detection of imatinib resistance/intolerance until initiation of dasatinib and best response to dasatinib, adjusted for other potentially explanatory factors. Methods: Data were collected retrospectively and prospectively from medical records. Best response to dasatinib, as recorded in patient's charts, was reported by an ordered categorical variable, combining all types of response achieved by a patient and selecting the “highest” level. A predefined list of covariates (sex; age at dasatinib initiation; time from diagnosis to dasatinib initiation; best response to prior imatinib and last imatinib dose) were entered/removed in a Proportional Odds model to identify factors potentially influencing dasatinib best response over a 12-month observation period. Results presented here focus on the imatinib-intolerant subpopulation. Results: FORTE enrolled 549 adult patients with imatinib-resistant/intolerant CP-CML at 124 sites across 12 European countries. Of 457 eligible patients, 176 (39%) were imatinib intolerant, including 71 (16%) who were both resistant and intolerant to imatinib. Approximately half (47%) of intolerant patients were male. Median age at dasatinib initiation was 59 years and median times from CML diagnosis to imatinib and dasatinib initiation were 1.5 and 39.8 months, respectively. Sokal and Hasford scores were intermediate/high in 74% and 72% of assessed patients, respectively. Overall, 54% of 171 imatinib-intolerant patients had achieved a complete cytogenetic response (CCyR) or major molecular response (MMR) on imatinib. During the 12 month observation period, 72% of imatinib-intolerant patients achieved a CCyR or MMR with dasatinib. Adjusting for the effect of best imatinib response, an analysis of 161 evaluable patients showed strong statistical evidence (p<0.0001) that shortening the time elapsed between imatinib intolerance and dasatinib initiation was more likely to result in a better response to dasatinib (including CCyR/MMR), with an estimated odds ratio of 0.96 [95% CI: 0.943–0.977]. Conclusions: Results from the imatinib-intolerant population of the FORTE study suggest that an early switch to dasatinib provides a clinical advantage to CP-CML patients intolerant to imatinib. Findings from this real-life observation are consistent with data from interventional trials. Disclosures: Marin: Bristol-Myers Squibb: Research Funding. Morra:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen Cilag: Speakers Bureau. Niederwieser:Bristol-Myers Squibb: Speakers Bureau. Schloegl:AOP Orphan: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ho:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Ossenkoppele:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Guerra:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Mori:Bristol-Myers Squibb: Employment. Pans:Bristol-Myers Squibb: Employment. van Baardewijk:Bristol-Myers Squibb: Employment. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau.

Introduction: Imatinib mesylate trough plasma level is suggested to be one of the determinants of clinical efficacy in the treatment of patients with CML. Maintaining an imatinib trough level at or higher than 1000 ng/mL is suggested to be important for achieving optimal response. Aim: Evaluation of clinical relevance of monitoring imatinib trough plasma level. Material: Forty-seven imatinib treated CML patients (23 male/24 female, mean age 50±15.8 (SD) years) were included. Fifty one blood samples for pharmacokinetic analysis were taken. Patients treated with 400 mg of imatinib were in the first chronic phase. Patients treated with 600 mg of imatinib were in the first chronic phase resistant to imatinib 400 mg (loss of cytogenetic response) or accelerated phase at diagnosis. Mean imatinib treatment duration was 20 months (range 0.75–84 months). Blood samples were collected at 24 hours (most within ±3 hours) after the last dose of imatinib (steady state trough level). Results: Mean trough imatinib plasma levels (Cmin) in patients treated with 400 mg and with 600 mg were 1102±574 (SD) ng/mL (females 1091ng/mL, males 1118 ng/mL) and 1337±577 (SD) ng/mL (females 1498 ng/mL, males 1287 ng/mL) respectively. In patients treated with 400 mg of imatinib optimal response was achieved in 82.8% (N=29) with Cmin=1153 ng/mL (range 370 –2524). Suboptimal response was achieved in 2.8% (N=1) of patients with Cmin=820 ng/mL. Resistance was showed in 14% (N=5) with Cmin=865 ng/mL (range 10–2436). In patients achieving CCyR and MMR Cmin was 731.4 ng/mL and 1305 ng/mL respectively. In patients treated with 600 mg of imatinib optimal response was achieved in 58.8% (N=10) with Cmin=1358 ng/mL (range 790–2133). Suboptimal response was achieved in 11.7% (N=2) of patients with Cmin=1347 ng/mL (range 1302–1392). Resistance was found in 17.6% (N=3) with Cmin=1007 ng/mL (range 250–2085). There was no correlation between Cmin and age, body mass or body surface area. Discussion: Imatinib is the drug of choice for most patients with chronic and accelerated phase of CML. The mechanisms of resistance to imatinib are being investigated and the issue of non-compliance is considered. The data presented confirms the opinion that mean imatinib trough plasma level results should be analyzed together with other clinical data. In previous papers the importance of imatinib concentration monitoring in compliance evaluation was emphasized. The analysis presented suggests moreover considerable value of imatinib serum level monitoring in early diagnosis of resistance to treatment when analyzed together with fluctuations of the transcript level. High serum imatinib levels in resistant patients provide other than noncompliance mechanisms of resistance. Isolated cases when CMR is achieved and imatinib level is significantly below desirable value (581 and 383 ng/mL) remain remarkable. Imatinib serum level monitoring may appear particularly useful in monitoring of response in slow responders, when CCR and MMR is achieved beyond 12 months and 18 months of treatment respectively. Conclusions: The data presented confirms the importance of monitoring imatinib trough plasma level as an adequate evaluation of treatment efficacy and allows taking optimal therapeutical decisions when considered together with cytogenetic and molecular assessments.

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