BCR-ABL^IS Expression at Diagnosis and After 3 or 6 Months of Treatment Predicts CML Response to IMATINIB Therapy.

Abstract 3426

Imatinib mesylate (IM) has shown remarkable efficacy for the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, while most individuals achieve an optimal response to conventional IM therapy, approximately 30% either fail IM or develop intolerance to the drug. Thus, there is a growing need for biological parameters predictive of IM response (at diagnosis or during the first months of therapy) in order to recognize pts with a more aggressive disease that should receive alternative treatments. We examined the outcomes of the first 193 CML pts accrued to the observational SCREEN (Sicily and Calabria CML REgional ENterprise) multicenter non-sponsored study, and analyzed the responses of this unselected population. Pts characteristics were as shown in Table 1. All subjects received IM 400 mg daily. Median follow-up was 26 months (range 3–60). Complete hematological (CHR), cytogenetic (CCyR) and major molecular responses (MMR) were rated according to the European Leukemia Net 2006 guidelines. Peripheral blood samples were used for BCR-ABL determination by quantitative real-time polymerase chain reaction according to the International standardized Scale (IS). To identify parameters predictive of IM response, pts were stratified according to clinical and molecular responses or BCR-ABL transcript levels at diagnosis and analyzed for their outcome on an intention to treat basis. At 12 months, cumulative incidences of CHRs, CCyRs and MMRs were 100%, 82% and 43%, respectively. At 24 months, incidences of CCyR and MMR increased to 87% and 67%. According to the ELN criteria, 121 pts (62%) achieved an optimal response; 36 pts (19%) had a suboptimal response; 32 pts (17%) failed IM because of either primary (20 pts) or secondary (12 pts) resistance. Only 4 pts (2%) were intolerant to IM. Kaplan-Meyer estimates for overall, progression-free, event-free and failure-free survival at 60 months were 99%, 96% 80% and 72%. When we clustered all subjects in optimal responders (ORs) and suboptimal/resistant (S/R) pts and correlated response to therapy with various molecular characteristics we found that the amount of BCR-ABL^IS transcripts at diagnosis predicted response to IM. Indeed, the median amount of BCR-ABL^IS at diagnosis displayed by patients that failed IM or achieved a suboptimal response was significantly higher (104.154^IS) than that of patients obtaining an optimal response (53.478^IS; p=0.000611). As WBC counts were not significantly different between ORs and S/R pts (p=0.2065), increased amounts of BCR-ABL^IS transcripts were probably representative of the aggressiveness of the leukemic clone. We also observed that pts displaying >10% BCR-ABL^IS after 3 or 6 months of IM had a significantly lower chance of achieving a CCyR compared to pts with BCR-ABL^IS levels lower than 10% (p<0.001). IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR, CCyR and MMR. However, 35–40% of newly diagnosed CML pts will either fail IM or obtain a suboptimal response. High levels of BCR-ABL^IS transcripts at diagnosis may allow the rapid identification of CML pts that are likely to fail IM or to achieve a suboptimal response. Furthermore, failing to achieve BCR-ABL^IS transcript levels <10% after 3 or 6 months of IM treatment significantly reduces the probability of subsequently obtaining a CCyR.