laromustine and Myelodysplastic-Syndromes

Preliminary therapeutic successes have prompted a new wave of clinical trials enrolling patients with myelodysplastic syndromes (MDS), using compounds with a broad range of potential mechanisms of action. This article discusses several of the agents currently in development for MDS, reviewing clinical trial data related to five classes of novel therapeutics: clofarabine, a halogenated purine nucleoside analog; ezatiostat (TLK199), a glutathione analog that indirectly activates c-Jun kinase; tipifarnib, a farnesyltransferase inhibitor; laromustine (cloretazine), an alkylating agent with a metabolite that inhibits one mechanism of DNA damage repair; and eight drugs that inhibit histone deacetylase. Although MDS are still difficult clinical problems, and most patients with MDS still succumb to disease-related complications within 3 to 5 years of diagnosis, ongoing development of novel agents promises that there will be new treatment options for patients within the next 5 to 10 years.

Topics: Adenine Nucleotides; Aged; Alkylating Agents; Antimetabolites; Arabinonucleosides; Clinical Trials as Topic; Clofarabine; DNA Repair; Drug Therapy, Combination; Drugs, Investigational; Enzyme Activation; Enzyme Inhibitors; Farnesyltranstransferase; Glutathione; Histone Deacetylase Inhibitors; Humans; Hydrazines; JNK Mitogen-Activated Protein Kinases; Myelodysplastic Syndromes; Quinolones; Sulfonamides; Therapies, Investigational

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