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Abstract Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of chronic myeloid leukemia (CML). Previously, we published the synthesis of this natural alkaloid and three of its derivatives: deoxyharringtonine (DHT), deoxyhomoharringtonine (DHHT), and bis(demethyl)-deoxyharringtonine (BDHT); and reported on its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1). In this study, we explored the extent of this resistance by first expanding the panel of established cell lines and second, using a panel of 21 leukemia patient derived primary cells. Here, we report a consistent resistance to HTT in K562 derived cells and in MES-SA/MX2 derived cells resistant to mitoxanthrone; all of them over-express MDR1, while we found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcome this resistance due to the changes made to the acyl chain of HTT rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via Caspase 3 cleavage leading to apoptosis. Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.