Effect of Time to Dasatinib Initiation On Outcome of Imatinib-Intolerant Patients with Chronic-Phase Chronic Myelogenous Leukemia (CP-CML): Results From a European Observational Study (FORTE; CA180–211)

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.

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.

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.

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].

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.

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.