Nelarabine in the treatment of refractory T-cell malignant diseases.
T-cell haematological malignancies are uncommon, difficult to treat and, with the exception of T-cell acute lymphoblastic leukaemia, often associated with a poor prognosis. Nelarabine (2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine), a synthesised guanosine nucleoside and water-soluble prodrug of ara-G (9-beta-D-arabinofuranosylguanine), has recently been approved by the FDA for the treatment of relapsed/refractory T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma in adults and children. Similar to other nucleoside analogues, nelarabine acts by inhibiting DNA synthesis and inducing apoptosis in susceptible cells. Ara-G itself is a water-insoluble molecule, making its clinical use difficult. However, nelarabine is water soluble and rapidly converted to ara-G in vivo. Interestingly, it has been demonstrated that ara-GTP accumulates more readily in T-cells than in B-cells, and this discovery created interest in the development of nelarabine for the treatment of T-cell malignancies. The results of early-phase clinical trials evaluating the use of nelarabine in adults and children with refractory T-cell malignancies have been promising. This article describes the development, pharmacology, toxicity and clinical activity of nelarabine, as well as discusses its potential role in the treatment of T-cell haematological malignancies.
Kline
Justin
J
Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL, USA. jkline@medicine.bsd.uchicago.edu
Larson
Richard A
RA
D000818:Animals; D001087:Arabinonucleosides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy*; D016896:Treatment Outcome
D001087:Arabinonucleosides; C104457:nelarabine