Nelarabine in T-cell acute lymphoblastic leukemia: intracellular metabolism and molecular mode-of-action.

T-cell acute lymphoblastic leukemia (T-ALL) patients often have a poor 5-year event-free survival. The only T-ALL specific drug in clinical practice is nelarabine. A prodrug of the deoxyguanosine analog ara-G, nelarabine is a rationally designed agent selective for the treatment of T-cell malignancies. Originally approved for relapsed/refractory T-ALL, it is increasingly used in T-ALL therapy and is currently being evaluated in upfront treatment. Whilst the clinical use of nelarabine has been the topic of multiple review articles, a thorough overview of the preclinical data detailing the molecular underpinnings of its anti-leukemic activity is lacking, which is critical to inform mechanism-based use. Thus, in the present article we conducted a semi-systematic review of the literature and critically evaluated the preclinical knowledge on the molecular pharmacology of nelarabine. Whilst early studies identified ara-G triphosphate to be the principal active metabolite and nuclear DNA synthesis to be a key target, many fundamental questions remain that could inform upon future use of this therapy. These include the nature of nelarabine-induced DNA lesions and their repair, together with additional cellular targets of ara-G metabolites and their role in efficacy and toxicity. A critical avenue of research in need of development is investigation of nelarabine combination therapies, both in the context of current T-ALL chemotherapy regimens and with emerging anti-leukemic agents, and we highlight some areas to pursue. Altogether, we discuss what we can learn from the preclinical literature as a whole and present our view for future research regarding nelarabine treatment in T-ALL.