Homoharringtonine is a
cephalotaxine ester derived from Cephalotaxus harringtonia, which is a Chinese evergreen tree. A limited clinical evaluation of this
drug in China revealed antileukemic activity, which prompted clinical trials in the United States. We have treated 43 patients with a variety of refractory
malignancies using a daily iv treatment for 5 days at 3-4-week intervals. The starting dose of
homoharringtonine was 0.2 mg/m2/day and it was escalated to a maximum of 8 mg/m2/day. The dose-limiting toxic effect was
hypotension, which was generally mild with daily dose levels of 3-4.5 mg/m2/day and required no specific treatment besides iv fluid supplements in some patients.
Hypotension became increasingly severe at the higher dose levels and resulted in cardiovascular collapse in four of 16 patients treated with dose levels of 5-6 mg/m2/day. A moderately severe degree of myelosuppression was observed with
homoharringtonine doses of greater than or equal to 3 mg/m2. Myelosuppression was clearly related to the extent of prior treatment and was minimal in patients who had not received extensive prior treatment. Gastrointestinal toxic effects of
nausea,
vomiting, and
diarrhea were observed in approximately two-thirds of the patients but these side effects were generally mild and self-limited.
Drug-related
fever and
alopecia were also observed in some patients. No major responses were observed, although three patients with solid
tumors evidenced minor responses and three of five patients with acute
leukemia showed some degree of antileukemic activity. For phase II studies of
homoharringtonine in solid
tumors, a daily dose of 3 mg/m2 for 5 days in patients with extensive prior treatment and 4 mg/m2/day for 5 days in patients with good bone marrow reserve will be utilized. The daily dose must not exceed 4 mg/m2 to avoid serious
hypotension; further dose escalations should be accomplished by extending the number of days of treatment beyond 5 days.