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Journal Article

PMID

(26297284)

Authors

Muppidi MR, Portwood S, Griffiths EA, Thompson JE, Ford LA, Freyer CW, Wetzler M, Wang ES

Title

Decitabine and Sorafenib Therapy in FLT-3 ITD-Mutant Acute Myeloid Leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical lymphoma, myeloma & leukemia	15 Suppl		2015 Jun	S73-9	Clin Lymphoma Myeloma Leuk

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Abstract Text

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.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.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.Further investigation is warranted to confirm these responses.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Decitabine + Sorafenib	Case Reports/Case Series	Actionable	In a clinical study, treatment with Nexavar (sorafenib) in combination with Dacogen (decitabine) was well tolerated and resulted in an overall response rate of 83% (5/6, 1 complete remission (CR) and 4 CR with incomplete count recovery) with a median overall survival of 155 days in patients with acute myeloid leukemia (AML) harboring a FLT3 internal tandem duplication (FLT3-ITD) mutation, and the combination synergistically inhibited growth of a FLT3-ITD positive AML cell line in culture (PMID: 26297284).	26297284

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