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

Clin Lymphoma Myeloma Leuk. 2015 Jun:15 Suppl:S73-9. doi: 10.1016/j.clml.2015.02.033.

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.

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.

Keywords: Combination therapy; FLT-3 inhibitors; Hypomethylating agents; Targeted agents.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / administration & dosage
  • Azacitidine / analogs & derivatives*
  • Azacitidine / therapeutic use
  • Cell Line, Tumor
  • Decitabine
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / mortality
  • Middle Aged
  • Mutation
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / therapeutic use*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use*
  • Sorafenib
  • Survival Analysis
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Niacinamide
  • Decitabine
  • Sorafenib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Azacitidine