title: Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia.
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.
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Stephen S Y
authors.initials: SS
authors.lastname: Lam
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Eric S K
authors.initials: ES
authors.lastname: Ho
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Bai-Liang
authors.initials: BL
authors.lastname: He
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Wui-Wing
authors.initials: WW
authors.lastname: Wong
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chae-Yin
authors.initials: CY
authors.lastname: Cher
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Nelson K L
authors.initials: NK
authors.lastname: Ng
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Cheuk-Him
authors.initials: CH
authors.lastname: Man
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Harinder
authors.initials: H
authors.lastname: Gill
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China. Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Alice M S
authors.initials: AM
authors.lastname: Cheung
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Ho-Wan
authors.initials: HW
authors.lastname: Ip
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Chi-Chiu
authors.initials: CC
authors.lastname: So
authors.affiliation: Institut Cochin, Département Développement, Reproduction, Cancer, CNRS, UMR 8104, INSERM U1016, Paris 75014, France. Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
authors.affiliation: Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, Rayne Institute, 123 Coldharbour Lane Denmark Hill, London SE5 9NU, U.K.
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
authors.affiliation: Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
authors.forename: Dona N
authors.initials: DN
authors.lastname: Ho
authors.affiliation: Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
authors.forename: Chun-Hang
authors.initials: CH
authors.lastname: Au
authors.affiliation: Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
authors.forename: Tsun-Leung
authors.initials: TL
authors.lastname: Chan
authors.affiliation: Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
authors.forename: Edmond S K
authors.initials: ES
authors.lastname: Ma
authors.affiliation: Department of Medicine, Hong Kong Sanatorium and Hospital, Hong Kong, China.
authors.forename: Raymond
authors.initials: R
authors.lastname: Liang
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.affiliation: Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China. ayhleung@hku.hk.
authors.forename: Anskar Y H
authors.initials: AY
authors.lastname: Leung
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D020440:Gene Duplication; D006248:Harringtonines / Q000494:pharmacology / Q000627:therapeutic use*; D000077863:Homoharringtonine; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D014176:Protein Biosynthesis / Q000187:drug effects; D012074:Remission Induction; D000077157:Sorafenib; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006248:Harringtonines; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077863:Homoharringtonine; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3