Journal
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
Volume 15, Issue -, Pages S73-S79Publisher
CIG MEDIA GROUP, LP
DOI: 10.1016/j.clml.2015.02.033
Keywords
Combination therapy; FLT-3 inhibitors; Hypomethylating agents; Targeted agents
Categories
Funding
- Cancer Clinical Investigator Team Leadership Award - National Cancer Institute (NCI) [P30CA016056]
- Jacquie Hirsch Leukemia Research Fund
- Szefel Foundation
- Leonard S. LuVullo Endowment for Leukemia Research
- Nancy C. Cully Endowment for Leukemia Research
- Babcock Family Endowment
- Heidi Leukemia Research Fund, Roswell Park Cancer Institute, Buffalo, NY
- NCI Cancer Center [CA016156]
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Patients with FLT-3 ITD mutant AML have poor outcomes following standard chemotherapy. We show pre-clinical data demonstrating the in vitro synergistic effects of the FLT-3 inhibitor, sorafenib, and the hypomethylating agent, decitabine, on FLT-3 mutant AML cells. Treatment of 6 FLT-3 ITD mutant patients with decitabine and sorafenib resulted in overall responses in 5 patients (83%) and prolonged median survival. Background: Acute myeloid leukemia (AML) characterized by Feline McDonough Sarcoma-like tyrosine kinase-3 (FLT-3) internal tandem duplication (ITD) mutations have poor outcomes. Treatment options are limited, because these mutations confer resistance to conventional chemotherapy. FLT-3 inhibitors such as sorafenib have been studied as a single agent and in combination with conventional chemotherapy or azacytidine with fair responses. Patients and Methods: Here we describe our preclinical and clinical experience with the combination of the DNA hypomethylating agent, decitabine and sorafenib for the treatment of FLT-3 ITD-mutant AML. Results: In vitro treatment of the human FLT-3 ITD-mutant AML cell line, MV4-11, with both drugs significantly improved growth inhibition over single-agent therapy and resulted in synergistic antitumor effects (combination index < 1). A case series of 6 patients treated with off protocol combination of decitabine and sorafenib demonstrated overall responses in 5 patients (83%) with a median survival of 155 days. Four of the 5 patients (80%) with relapsed/refractory AML achieved complete responses with incomplete count recovery. The combination was also well tolerated. Conclusion: Further investigation is warranted to confirm these responses. (C) 2015 Elsevier Inc. All rights reserved.
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