title: Decitabine and Sorafenib Therapy in FLT-3 ITD-Mutant Acute Myeloid Leukemia.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Further investigation is warranted to confirm these responses.
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY. Electronic address: monica.muppidi@roswellpark.org.
authors: Monica R
authors: MR
authors: Muppidi
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors: Scott
authors: S
authors: Portwood
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors: Elizabeth A
authors: EA
authors: Griffiths
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors: James E
authors: JE
authors: Thompson
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors: Laurie A
authors: LA
authors: Ford
authors: Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, NY.
authors: Craig W
authors: CW
authors: Freyer
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors: Meir
authors: M
authors: Wetzler
authors: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors: Eunice S
authors: ES
authors: Wang
mesh_terms: D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077209:Decitabine; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000077157:Sorafenib; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077209:Decitabine; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D001374:Azacitidine
keywords: Combination therapy; FLT-3 inhibitors; Hypomethylating agents; Targeted agents