indicine-n-oxide and Leukemia--Myeloid--Acute

We treated 31 children with acute lymphoblastic leukemia (ALL), 14 children with acute nonlymphoblastic leukemia (ANLL) in relapse, and 1 child with chronic myelogenous leukemia (CML) in blast crisis (CALLA negative) with indicine N-oxide in a Phase II study. The efficacy and toxicity of the drug were assessed at two dose levels: 2,000 mg/m2/day for 5 consecutive days (14 patients) and 2,500 mg/m2/day for 5 consecutive days (17 patients). One patient with ALL at each dose level achieved a complete response (CR) lasting 6 months and 1 month, respectively. The patient with CML achieved a partial response lasting 4 months. None of the patients with ANLL achieved a CR. Hepatotoxicity was mild (grade 1 or 2) in 63% and moderate (grade 3) in 9% of mild (grade 1 or 2) in 63% and moderate (grade 3) in 9% of patients; 3 patients (9%) experienced severe hepatotoxicity. Although indicine N-oxide has some antileukemic activity in ALL and is safe at the doses used in this study, the antileukemic activity is significantly less at these two doses than at greater than or equal to 3,000 mg/m2/days for 5 consecutive days. Unfortunately, when the higher doses are administered to children, they are associated with an unacceptably high incidence of severe, irreversible hepatotoxicity.

Topics: Acute Disease; Antineoplastic Agents, Phytogenic; Child; Drug Evaluation; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrrolizidine Alkaloids

Indicine N-oxide, the first pyrrolizidine alkaloid N-oxide to be studied in the treatment of cancer in humans, was administered to ten patients: four children and two adolescents with refractory acute lymphocytic leukemia and four adults with refractory acute nonlymphocytic leukemia (three acute myelocytic, one myelomonocytic). Two patients, a 4-year-old boy with acute lymphocytic leukemia and a 22-year-old man with acute myelocytic leukemia, achieved complete remission lasting 3 and 5+ months, respectively. Another 15-year-old male with acute lymphocytic leukemia had a partial remission for four months. Toxicities included bone marrow suppression, mild anorexia and nausea, and transient elevation of liver enzymes. Jaundice and liver failure, presumably induced by drug, occurred in two patients.

Topics: Adolescent; Adult; Antineoplastic Agents, Phytogenic; Child; Child, Preschool; Clinical Trials as Topic; Cyclic N-Oxides; Drug Administration Schedule; Female; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Pyrrolizidine Alkaloids

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents, Phytogenic; Autopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Pancytopenia; Pyrrolizidine Alkaloids; Vascular Diseases

Indicine N-oxide is the first member of the large class of compounds comprised of pyrrolizidine alkaloids and their N-oxides to be studied in the treatment of cancer in humans. Twenty-two patients with refractory acute leukemia received indicine N-oxide daily for 5 consecutive days in a dose-seeking study. Of eight patients with refractory acute lymphocytic leukemia, one had a complete remission, and one had a partial remission. Of 11 patients with refractory acute nonlymphocytic leukemia, 2 patients had complete remissions. Of three patients with blast crisis of chronic granulocytic leukemia, one patient had a partial remission. Five patients had severe hepatic toxicity, probably due to veno-occlusive disease induced by the drug. Whether hepatotoxicity and antileukemic activity are a result of the same mechanism of action of indicine N-oxide is not known.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Child; Child, Preschool; Drug Administration Schedule; Drug Resistance; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Middle Aged; Pyrrolizidine Alkaloids

Indicine N-oxide, a pyrrolizidine alkaloid, was given to a five-year-old boy with refractory acute myelocytic leukemia. Three days after receiving the drug the patient developed signs and symptoms of acute hepatic failure. The patient died nine days after receiving the drug and an autopsy showed massive hepatic necrosis. The acute hepatic failure observed in this patient may have been secondary to indicine N-oxide toxicity.

Topics: Antineoplastic Agents, Phytogenic; Chemical and Drug Induced Liver Injury; Child, Preschool; Humans; Leukemia, Myeloid, Acute; Liver Diseases; Male; Pyrrolizidine Alkaloids