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Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia.
- Source :
-
Science translational medicine [Sci Transl Med] 2016 Oct 05; Vol. 8 (359), pp. 359ra129. - Publication Year :
- 2016
-
Abstract
- 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.<br /> (Copyright © 2016, American Association for the Advancement of Science.)
- Subjects :
- 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
Harringtonines pharmacology
Homoharringtonine
Humans
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 metabolism
Gene Duplication
Harringtonines therapeutic use
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute genetics
fms-Like Tyrosine Kinase 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 8
- Issue :
- 359
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 27708062
- Full Text :
- https://doi.org/10.1126/scitranslmed.aaf3735