R E V I E W Treating refractory leukemias in childhood, role of clofarabine Theresa M Harned Paul S Gaynon Department of Hematology-Oncology, Childrens Hospital Los Angeles, Los Angeles, CA, USA Correspondence:Theresa M Harned 4650 Sunset Blvd MS 54, Los Angeles, CA 90027, USA Tel +1 323 361 2121 Fax +1 323 361 7128 Email tharned@chla.usc.edu Abstract: Approximately 4000 children and adolescents under the age of 20 years develop acute leukemia per year in the US. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Despite impressive improvements in outcome, relapsed ALL is the fourth most common pediatric malignancy. Therapy for relapsed ALL remains unsatisfactory, and the majority of relapse patients still succumb to leukemia. Between one-third and one-half of patients with acute myelogenous leukemia (AML) relapse, and no standard therapy is recog- nized for patients with relapsed and/or refractory AML. Novel therapeutic agents are needed to improve the cure rate for relapsed ALL and AML. Clofarabine is a next-generation nucleoside analog, designed to incorporate the best features and improve the therapeutic index of cladrib- ine and ﬂudarabine. Clofarabine inhibits both DNA polymerase and ribonucleotide reductase, leading to impaired DNA synthesis and repair, and directly induces apoptosis. Phase I and II single-agent trials in children have shown that clofarabine is safe and active in both myeloid and lymphoid relapsed/refractory acute leukemias. Clofarabine has been approved by the FDA for pediatric patients with relapsed/refractory ALL after at least 2 prior therapeutic attempts. Rational combinations of clofarabine with other active agents in refractory leukemias are cur- rently under investigation. Keywords: clofarabine, leukemia, refractory, pediatric, childhood Introduction Approximately 4000 children and adolescents under the age of 20 years develop acute leukemia per year in the US. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, accounting for one-fourth of all childhood cancers and approximately 75% of all cases of childhood leukemia. In the US alone, approximately 3000 cases of pediatric ALL are diagnosed annually, with an incidence of 29.2 cases per million per year (Grovas et al 1997; Jemal et al 2004). Primary treatment of pediatric ALL is “risk-adapted,” ie, treatment allocation is based on an estimate of risk of relapse based on presenting features, eg, age at diagnosis, initial white blood cell count, immunophenotype, and cytogenetics and response to therapy, eg, disappearance of peripheral blasts, microscopic marrow response, and/or laboratory measurement submicroscopic leukemia, termed minimal residual disease (MRD) (Schultz et al 2007). Increasingly effective post induction intensiﬁcation employing conventional agents has steadily improved event-free survival. According to the US population-based Surveillance and End Results survey, 5-year survival for children aged 1–14 years has increased from 53% in 1974–76 to 85% in 1992–1999 (Jemal et al 2004). Despite the impressive improvements in outcome, relapsed ALL remains the fourth most common pediatric malignancy, with an incidence of approximately 6 cases per million in 2007 (Gaynon et al 1998). Therapy for patients with relapsed ALL remains unsatisfactory, especially for patients with early bone marrow relapse Therapeutics and Clinical Risk Management 2008:4(2) 327–336 © 2008 Dove Medical Press Limited. All rights reserved 327