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

Authors :
Lam SS
Ho ES
He BL
Wong WW
Cher CY
Ng NK
Man CH
Gill H
Cheung AM
Ip HW
So CC
Tamburini J
So CW
Ho DN
Au CH
Chan TL
Ma ES
Liang R
Kwong YL
Leung AY
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.)

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