laromustine and Leukemia--Myeloid

Cloretazine is a new sulfonylhydrazine alkylating agent with antileukemic activity. Phase I studies have shown myelosuppression to be the dose limiting toxicity in both solid tumors and leukemias. A large Phase II study of single agent cloretazine (600 mg/m2) confirmed its activity in patients with relapsed acute myeloid leukemia, and in elderly patients with previously untreated acute myeloid leukemia or myelodysplastic syndrome. It also confirmed the limited nonhematological toxicity, even in elderly patients. Cloretazine can be safely combined with cytarabine, and this combination regimen is currently being tested in a large Phase III study in patients with relapsed acute myeloid leukemia. Cloretazine is a promising new antileukemic agent that may be incorporated into an intensive combination regimen.

Topics: Acute Disease; Antineoplastic Agents; Clinical Trials as Topic; Humans; Hydrazines; Leukemia, Myeloid; Sulfonamides

Cloretazine (VNP40101M) is a sulfonylhydrazine alkylating agent with significant anti-leukemia activity. A multicenter phase II study of cloretazine was conducted in patients with first relapse of acute myeloid leukemia (AML) following an initial complete remission (CR) of less than 12 months. Cloretazine was given as a single intravenous infusion at a dose of 600 mg/m(2). Fifty-three patients (median age 62 years (18-84), 41 of 44 (93%) evaluable with intermediate or high risk cytogenetics, 32 (60%) with initial CR durations < or =6 months) were treated on study. Two patients (4%) achieved a second CR. Five (9%) patients died within 30 days of receiving cloretazine therapy. Median overall survival (2.3 months) in the study cohort was directly comparable to that of 233 matched patients treated with other single agents. The study cloretazine regimen had minimal activity in a very high risk subset of patients with relapsed AML.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Cohort Studies; Female; Humans; Hydrazines; Infusions, Intravenous; Leukemia, Myeloid; Male; Middle Aged; Recurrence; Remission Induction; Risk Factors; Sulfonamides; Survival Rate; Treatment Outcome

VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS).. VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m(2) was escalated by approximately 33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8.. Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m(2) for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m(2) was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m(2) and 1 with acute myeloid leukemia treated with 600 mg/m(2), achieved complete remission.. VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Alkylating Agents; Area Under Curve; Humans; Hydrazines; Leukemia, Myeloid; Metabolic Clearance Rate; Middle Aged; Myelodysplastic Syndromes; Nausea; Sulfonamides; Survival Analysis; Thrombocytopenia; Treatment Outcome; Vomiting

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Clinical Trials, Phase I as Topic; Dacarbazine; Hematologic Neoplasms; Hematology; Humans; Hydrazines; Leukemia, Myeloid; Multiple Myeloma; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-kit; Sulfonamides; Temozolomide

Topics: Acute Disease; Adenine Nucleotides; Aged; Antineoplastic Agents; Arabinonucleosides; Cause of Death; Clofarabine; Humans; Hydrazines; Leukemia, Myeloid; Sulfonamides

Topics: Acute Disease; Animals; Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Hydrazines; Leukemia, Myeloid; Mutagenesis; Nitrogen Mustard Compounds; Sulfonamides