Acute myeloid leukemia is a difficult disease to treat under the best of circumstances, and the subtype containing internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) tends to be particularly challenging. Lam et al. performed a high-throughput drug screen and identified homoharringtonine as a candidate treatment for this type of leukemia and then confirmed its effectiveness in cancer cells, in mouse models, and in patients. The treatment showed promising results in a phase 2 clinical trial, which included elderly patients and those who have failed all previous treatments, paving the way for further development of this drug.
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.
Stephen S. Y. Lam1,*, Eric S. K. Ho1,*, Bai-Liang He1, Wui-Wing Wong1, Chae-Yin Cher1, Nelson K. L. Ng1, Cheuk-Him Man1, Harinder Gill1, Alice M. S. Cheung1,2, Ho-Wan Ip3, Chi-Chiu So3, Jerome Tamburini4,5, Chi Wai Eric So6, Dona N. Ho7, Chun-Hang Au7, Tsun-Leung Chan7, Edmond S. K. Ma7, Raymond Liang8, Yok-Lam Kwong1 and Anskar Y. H. Leung1,†
+ Author Affiliations
↵†Corresponding author. Email: [email protected]
↵* These authors contributed equally to this work.
Science Translational Medicine 05 Oct 2016:
Vol. 8, Issue 359, pp. 359ra129