Nelarabine

Abstract

Nelarabine (2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine) is a water-soluble prodrug of 9-β-D-arabinofuranosylguanine (ara-G). Nelarabine is demethoxylated to ara-G by adenosine deaminase in the blood. The ara-G is subsequently transported into cancer cells via nucleoside transporters. Inside the cells, ara-G is phosphorylated by either deoxycytidine kinase to cytosolic ara-G monophosphate or by deoxyguanosine kinase to mitochondrial ara-G monophosphate; these are further phosphorylated to ara-G triphosphate, an intracellular active metabolite, by nucleotide kinases. Ara-G triphosphate is incorporated into DNA strands, thereby inhibiting DNA synthesis and eventually inducing apoptosis. Nelarabine is approved as a treatment for relapsed/refractory T-cell acute lymphoblastic leukemia/T-cell lymphoblastic lymphoma. The recommended dose of the drug in adult patients is 1500 mg/m² by intravenous (IV) infusion given over 2 h on days 1, 3, and 5 and repeated every 21 days. In pediatric patients, the recommended dose is 650 mg/m² IV given over 1 h for five consecutive days and repeated every 21 days. In a large phase II study conducted by the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia, nelarabine at 1500 mg/m² was administered on days 1, 3, and 5 in patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Thirty-six percent of the patients achieved a complete remission, and 10% achieved a partial remission.