Chemotherapy Foundation Symposium XIX: Innovative cancer therapy for tomorrow.

The standard therapy for acute myelogenous leukemia (AML) continues to be based on cytarabine (ara-C, DepoCyt, Enzon), typically in combination with anthracyclines such as idarubicin (Idamycin, Pfizer) or daunorubicin (Cerubidine, Bedford). Although 60% to 70% of patients achieve complete remissions (CRs), most patients relapse and ultimately die of the disease or of associated complications. This is particularly true for patients older than 60 years of age. Clofarabine (Clolar, Genzyme) is a next-generation nucleoside analogue, developed as a rational extension of the experience with fludarabine phosphate (Fludara, Berlex) and cladribine (Leustatin, Ortho Biotech). Clofarabine has a high affinity for the enzyme deoxycytidine kinase, the rate-limiting step in nucleoside phosphorylation. It is retained longer within the cells than other compounds in the same class. Although it has been approved by the Food and Drug Administration (FDA) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia (ALL), the focus has shifted to AML in adults. Clofarabine has shown single-agent activity in AML in a phase 2 study that included 39 patients with relapsed and refractory AML and myelodysplastic syndromes (MDS). The clofarabine dose was 40 mg/m2 IV daily for five days every three to six weeks. Of the 39 AML patients, 13 (42%) achieved CRs. In a different study of clofarabine plus cytarabine in patients with relapsed or refractory AML and high-risk MDS, clofarabine was administered as a one-hour IV infusion for five days, followed four hours later by cytarabine 1 g/m2 per day as a twohour IV infusion for five days. Of the 29 patients with AML and high-risk MDS, seven (24%) achieved CRs and five (17%) achieved partial remissions (PRs). The overall response rate was 41%. In another study of patients older than 50 years of age, a clofarabine/cytarabine combination produced an overall response rate of 60%. Toxicities were manageable, and the mortality rate after chemotherapy induction was low (below 10%). Clofarabine can be used either alone or in combination with other agents. Combinations with cytarabine in particular appear to be safe and effective. Clofarabine is especially appealing for the treatment of older individuals with AML who are considered to be either unsuitable for standard therapy or unlikely to benefit from it.