Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia

Sci Transl Med. 2016 Oct 5;8(359):359ra129. doi: 10.1126/scitranslmed.aaf3735.


An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models. Mechanistically, the effect was mediated by protein synthesis inhibition and reduction of short-lived proteins, including total and phosphorylated forms of FLT3 and its downstream signaling proteins. A phase 2 clinical trial of sorafenib and HHT combination treatment in FLT3-ITD AML patients resulted in complete remission (true or with insufficient hematological recovery) in 20 of 24 patients (83.3%), reduction of ITD allelic burden, and median leukemia-free and overall survivals of 12 and 33 weeks. The regimen has successfully bridged five patients to allogeneic hematopoietic stem cell transplantation and was well tolerated in patients unfit for conventional chemotherapy, including elderly and heavily pretreated patients. This study validated the principle and clinical relevance of in vitro drug testing and identified an improved treatment for FLT3-ITD AML. The results provided the foundation for phase 2/3 clinical trials to ascertain the clinical efficacy of FLT3 inhibitors and HHT in combination.

Publication types

  • Clinical Trial, Phase III

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cluster Analysis
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Female
  • Gene Duplication*
  • Harringtonines / pharmacology
  • Harringtonines / therapeutic use*
  • Homoharringtonine
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Mice
  • Middle Aged
  • Models, Biological
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Biosynthesis / drug effects
  • Remission Induction
  • Sorafenib
  • Treatment Outcome
  • Young Adult
  • fms-Like Tyrosine Kinase 3 / chemistry
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism


  • Antineoplastic Agents
  • Harringtonines
  • Phenylurea Compounds
  • Niacinamide
  • Homoharringtonine
  • Sorafenib
  • fms-Like Tyrosine Kinase 3