Homoharringtonine: history, current research, and future direction

Abstract

Background: Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S.

Methods: The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors.

Results: HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-alpha and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy.

Conclusions: HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued.