Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML

Background: Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45-55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. Methods: We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019. Results: In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. Conclusion: CRc rates drop progressively with sequential exposure to FLT3i's in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.