Aladjidi et al 2003; Wells et al 2003). However, long-term survival for children with relapsed AML ranges between 20% and 33% (Aladjidi et al 2003; Castellino et al 2007). Prognosis is related to speciﬁc cytogenetic abnormalities and the duration of ﬁrst remission. Patients relapsing after a CR1 1 year have a better survival. The need remains for therapeutic options which are both less toxic and more effective than the conventional treatment. New agents for relapsed and refractory childhood leukemias Novel therapeutic agents are needed to improve the cure rate of patients with relapsed or refractory ALL and AML. Emerging new treatments for ALL include next generation nucleoside analogs such as the deoxyadenosine analog clofarabine (Clolar®, Genzyme), which was approved by the FDA in December 2004 for the treatment of pediatric patients with relapsed or refractory ALL who have received at least two prior chemotherapy regimens (Pui and Jeha 2005), and the deoxyguanosine analog nelarabine (Arranon®, GlaxoSmithKline), which has been approved by the FDA for third-line treatment of patients with T-cell leukemia or lymphoma (Kurtzberg 2007). In acute promyelocytic leukemic, arsenic trioxide has shown beneﬁt in randomized trials (Powell et al 2006, 2007). In AML, preliminary data suggest an EFS advantage for addition of gemtuzumab to conventional induction chemotherapy (Burnett et al 2006) and an induction rate advantage for addition of the FLT-3 inhibitor lestaurtinib for patients with AML with FLT-3 internal tandem repeats (Levis et al 2005) . Other promising new agents include monoclonal antibodies against leukemia- speciﬁc antigens, such as rituximab, a humanized anti-CD20 antibody, and epratuzamab, targeting CD22. Over 100 gene mutations and genetic abnormalities have been reported in AML, reﬂecting the heterogeneity of the disease and the presence of multiple active pathways (Tallman 2006). Mutations that activate signal transduction pathways lead to proliferative survival advantages and may be targeted with small molecule inhibitors of the speciﬁc mutations, such as FLT3, C-Kit, and RAS, while mutations that lead to inhibition of differentiation may be targeted with differentiating agents (eg, all-trans-retinoic acid [ATRA] for patients with acute promyelocytic leukemia [APL]). Targeted therapy may interfere with host support for the leukemia cell. The mechanisms of treatment failure in ALL remain to be elucidated. One does well to remember that neither ATRA alone nor imatinib alone is curative for APL or chronic myelogenous leukemia, respectively. A gene may Therapeutics and Clinical Risk Management 2008:4(2) Clofarabine in pediatric leukemias be over-expressed, yet not critically necessary for leukemic de-differentiation or proliferation. New agents have been developed for multiple molecular targets in AML, including antibodies to cell surface antigen CD33, inhibitors of multi-drug resistance proteins, farnesyl transferase inhibitors, FLT3-targeted tyrosine kinase inhibi- tors, and inhibitors of the antiapoptotic protein Bcl-2 and the mammalian target of rapamycin (mTOR). New alkyl- ating agents and purine analogs such as cloretazine and clofarabine, which target DNA and ribonucleotide reduc- tases, respectively, are also under investigation. Targeted agents will likely need to be used in combination with other targeted agents and/or cytotoxic agents to inhibit the multiple pathways present in AML and to improve response rates (Tallman 2006). Clinical beneﬁt will require the right stuff, ie, the right drug be used against the right target in the right disease at the right dose and schedule in the right population with the right accompanying therapy (Gaynon 2005). Clinical development of these therapies is challenging in view of the multitude of intriguing possibilities, the background hetero- geneity of leukemias, and the current absence of compelling preclinical models (Schein 2001). Clofarabine The nucleoside analog family includes the guanosine analogs, thioguanine and mercaptopurine, which were among the ﬁrst agents to show activity against ALL (Hitchings et al 1950; Elion et al 1951; Skipper et al 1954). The clinical use of the deoxyadenosine analogs cladribine and ﬂudarabine has been restricted due to dose-limiting neurotoxicity (Kantarjian et al 2007). Clofarabine (2-chloro-2'-ﬂuoro- 2'deoxy-9-B-D-arabinofuranosyladenine), a next-generation deoxyadenosine analog (see Figure 1), was rationally designed to incorporate the best qualities and improve the therapeutic index of cladribine and ﬂudarabine. The drug received accelerated approval by the FDA in December 2004 and EMEA approval in 2006 for the treatment of patients with childhood ALL who have received two or more prior therapeutic regimens. Clofarabine retains the 2-halogenated aglycone of the deoxyadenoside analogs cladribine and ﬂudarabine (Figure 1), which confers resistance to cellular degradation by adenosine deaminase (Parker et al 1991, 1999; Pui et al 2005). However, clofarabine also possesses a second halogen atom (ﬂuorine) at the 2' carbon in the arabino conﬁguration, which inhibits cleavage of the glycosidic bond by bacterial purine nucleoside phosphorylase and stabilizes the compound in acidic environ- ments, thus improving oral bioavailability and preventing the 329