homoharringtonine and Hypotension

Five phase II trials of the antitumor agent homoharringtonine were conducted in 80 patients who had advanced solid tumors. The five categories of solid tumors included malignant melanoma; sarcoma; and head and neck, breast, and colorectal carcinomas. The starting dose of homoharringtonine was 3.0-4.0 mg/m2 by short iv infusion daily X 5 days every 21 days. Seventy-eight of 80 patients had had prior chemotherapy and 49 had had prior radiation therapy. Among the 74 evaluable patients in the five tumor categories, there were no complete or partial remissions. Homoharringtonine was generally well-tolerated. Nausea and vomiting, diarrhea, and fever and chills were the most common side effects. Serious reversible cardiovascular toxicity, which occurred in three patients, included symptomatic hypotension in two and short runs of ventricular tachycardia in one. The investigations thus conclude that homoharringtonine given by intermittent schedule is an inactive drug against these solid tumors previously exposed to chemotherapy.

Topics: Adolescent; Adult; Aged; Alkaloids; Bone Marrow; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Drug Evaluation; Female; Harringtonines; Head and Neck Neoplasms; Heart; Homoharringtonine; Humans; Hypotension; Male; Melanoma; Middle Aged; Rectal Neoplasms; Sarcoma

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.

Topics: Acute Disease; Adolescent; Adult; Aged; Alkaloids; Antineoplastic Agents; Bone Marrow; Bone Marrow Transplantation; Drug Evaluation; Harringtonines; Homoharringtonine; Humans; Hyperglycemia; Hypotension; Infusions, Parenteral; Leukemia; Leukocyte Count; Middle Aged; Platelet Count

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.

Topics: Adult; Aged; Alkaloids; Bone Marrow Diseases; Dose-Response Relationship, Drug; Drug Evaluation; Female; Harringtonines; Homoharringtonine; Humans; Hypotension; Leukemia; Male; Middle Aged; Neoplasms