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

TitleHomoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia
Authors
Issue Date2016
PublisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://www.sciencemag.org/marketing/stm/
Citation
Science Translational Medicine, 2016, v. 8 n. 359, article no. 359ra129 How to Cite?
AbstractAn 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.
Persistent Identifierhttp://hdl.handle.net/10722/234709
ISSN
2015 SCImago Journal Rankings: 8.931
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLam, SY-
dc.contributor.authorHo, SK-
dc.contributor.authorHe, B-
dc.contributor.authorWong, WW-
dc.contributor.authorCher, CY-
dc.contributor.authorNg, KL-
dc.contributor.authorMan, CH-
dc.contributor.authorSingh, GHH-
dc.contributor.authorCheung, MS-
dc.contributor.authorIp, HW-
dc.contributor.authorSo, JCC-
dc.contributor.authorTamburini, J-
dc.contributor.authorSo, CWE-
dc.contributor.authorHo, DN-
dc.contributor.authorAu, CH-
dc.contributor.authorChan, TL-
dc.contributor.authorMa, ESK-
dc.contributor.authorLiang, RHS-
dc.contributor.authorKwong, YL-
dc.contributor.authorLeung, AYH-
dc.date.accessioned2016-10-14T13:48:46Z-
dc.date.available2016-10-14T13:48:46Z-
dc.date.issued2016-
dc.identifier.citationScience Translational Medicine, 2016, v. 8 n. 359, article no. 359ra129-
dc.identifier.issn1946-6242-
dc.identifier.urihttp://hdl.handle.net/10722/234709-
dc.description.abstractAn 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.-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://www.sciencemag.org/marketing/stm/-
dc.relation.ispartofScience Translational Medicine-
dc.rightsScience Translational Medicine. Copyright © American Association for the Advancement of Science.-
dc.titleHomoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia-
dc.typeArticle-
dc.identifier.emailHe, B: alexhe@hku.hk-
dc.identifier.emailMan, CH: csman729@hku.hk-
dc.identifier.emailSingh, GHH: gillhsh@hku.hk-
dc.identifier.emailCheung, MS: cheungms@hku.hk-
dc.identifier.emailIp, HW: iphowan@hku.hk-
dc.identifier.emailSo, JCC: scc@pathology.hku.hk-
dc.identifier.emailMa, ESK: eskma@hkucc.hku.hk-
dc.identifier.emailLiang, RHS: rliang@hku.hk-
dc.identifier.emailKwong, YL: ylkwong@hku.hk-
dc.identifier.emailLeung, AYH: ayhleung@hku.hk-
dc.identifier.authorityMan, CH=rp02543-
dc.identifier.authoritySingh, GHH=rp01914-
dc.identifier.authorityCheung, MS=rp01572-
dc.identifier.authoritySo, JCC=rp00391-
dc.identifier.authorityLiang, RHS=rp00345-
dc.identifier.authorityKwong, YL=rp00358-
dc.identifier.authorityLeung, AYH=rp00265-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1126/scitranslmed.aaf3735-
dc.identifier.pmid27708062-
dc.identifier.scopuseid_2-s2.0-84990886673-
dc.identifier.hkuros270340-
dc.identifier.volume8-
dc.identifier.issue359-
dc.identifier.spagearticle no. 359ra129-
dc.identifier.epagearticle no. 359ra129-
dc.identifier.isiWOS:000389441200001-
dc.publisher.placeUnited States-

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