Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
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RESEARCH
Outcomes with sequential FLT3‑inhibitor‑based therapies in patients with AML Musa Yilmaz1†, Mansour Alfayez1†, Courtney D. DiNardo1, Gautam Borthakur1, Tapan M. Kadia1, Marina Y. Konopleva1, Sanam Loghavi2, Rashmi Kanagal‑Shamanna2, Keyur P. Patel2, Elias J. Jabbour1, Guillermo Garcia‑Manero1, Naveen Pemmaraju1, Sherry A. Pierce1, Issa Ghayas1, Nicholas J. Short1, Guillermo Montalban‑Bravo1, Koichi Takahashi1, Rita Assi1, Ahmad S. Alotaibi1, Maro Ohanian1, Michael Andreeff1, Jorge E. Cortes1, Hagop M. Kantarjian1, Farhad Ravandi1 and Naval G. Daver1*
Abstract 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. Keyword: FLT3 mutations, Sequential FLT3 inhibitors, Midostaurin, Sorafenib, Quizartinib, Gilteritinib, FLT3-PCR, Lowintensity therapy
*Correspondence: [email protected] † Musa Yilmaz and Mansour Alfayez have contributed equally to this work. 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit FC4.2012, Houston, TX 77030, USA Full list of author information is available at the end of the article
Background Multiple tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in FLT3-mutated acute myeloid leukemia (AML), including midostaurin, sorafenib, gilteritinib, quizartinib, and crenolanib [1, 2]. First-generation
© The Author(s) 2020. Open
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