Low-Level FLT3-ITD Mutations Do Not Predict for Higher Relapse Rate in AML with Standard Risk Karyotpye.

Abstract 1591

Poster Board I-617

High-level FLT3-ITD mutations predict for a higher relapse rate and inferior survival among patients with standard risk karyotype AML. The influence of low-level FLT3-ITD mutations is less clear, although the MRC group (Gale et al, 2008) reported that low-level mutations are associated with an inferior prognosis as compared to an unmutated group. In the absence of FLT3-ITD, NPM1 mutations predict for a lower relapse rate. We analyzed outcomes of intensive chemotherapy in patients with standard risk karyotype AML (n=131) between 2004-2008. Patients received uniform induction chemotherapy consisting of cytarabine plus daunorubicin (7+3), followed by 2 consolidations consisting of high-dose cytarabine plus daunorubicin for pts under age 60 (n=96) or 7+3 followed by NOVE for pts age 60+ (n=35). Patients were divided into 3 groups based on the ratio of FLT3-ITD:FLT3-wt: There were 73 patients with negative FLT3-ITD (defined as FLT3-ITD:wt ratio < 0.01), 30 patients with low-level ITD (ratio > 0.01 – 0.37), and 28 patients with high-level ITD (ratio > 0.37). The mean presenting WBC was 32.2 ×10⁹/L in the group with negative ITD, 49.4 ×10⁹/L in the group with low-level ITD and 97.2 ×10⁹/L in the group with high-level ITD (p < 0.0001). At a median follow-up of 19 months (range 2-95 months), the median OS of the entire group was 21.3 months. Patients with high-level ITD had a significantly inferior RFS (p = 0.0009) and OS (p = 0.003) as compared to the low-level and negative groups. Comparing the negative ITD and low-level ITD groups, there was no significant difference in RFS (p = 0.65) or OS (p = 0.18). The frequency of NPM1 mutations was not significantly different between these two groups (42% vs. 35%). These data were re-analyzed using a different cutoff according to % FLT-ITD positivity: negative < 1% (n=73), low-level 1 – 50% (n=42), high level > 50% (n=16). Using these ranges, the low-level FLT3-ITD group had a significantly lower CR rate (74% vs. 93%, p = 0.004) and OS (36% vs. 61%, p = 0.01) as compared to the group with negative FLT3-ITD, but there was no significant difference between these two groups with respect to RFS (2 year RFS 48% in low-level ITD group vs. 40% in negative ITD group). The high-level ITD group demonstrated significantly inferior RFS (p = 0.02) and OS (p = 0.01) as compared to the other two groups. These findings confirm the poor prognosis associated with high-level FLT3-ITD mutations due to high relapse rates. However, in contrast to previously reported data, we did not find that low level FLT3 –ITD mutations were associated with inferior RFS, although we did find, unexpectedly, that this low-level group had a lower CR rate.