Table 5 Response to combination of clofarabine/cyclophosphamide/ etoposide in pediatric leukemia patients Responses/Total (%) Response ALL AML CR 7/14 (50%) CRp 2/14 (8%) 3/3 (100%) PR CR + CRp 9/ 14 (64%) 3/3 (100%) Adapted from Hijaya et al 2007. Abbreviations: CR, complete remission; CRp, complete remission without full platelet recovery; PR, partial remission. myelosuppression is dose-limiting (Kantarjian et al 2003b). The dose-limiting toxicity in pediatric leukemia patients is hyperbilirubinemia and transient elevations in liver enzymes, which reversed by day 14, as well as grade 3 skin rash (Jeha et al 2004). Some patients experienced CNS irritability with the 1-hour infusion, which resolved when the clofarabine was given over 2 hours. Other adverse events greater than or equal to grade 3 which occurred in 10% or more of patients included febrile neutropenia, anorexia, hypotension, nausea, sepsis, and pleural effusion (Jeha et al 2006a, b). Drug-related fevers and skin rash generally responded to antihistamines and may require low-dose corticosteroids, once infection is excluded. Clofarabine administration has been associated with rapid decreases in blasts even in non-responders; this may be accompanied by tumor lysis syndrome or systemic inﬂammatory response and capillary leak syndrome, with respiratory distress, fever, and hypotension. Cytokine-release like events may have contributed to a decline in cardiac func- tion that was observed in several patients. Drug interactions and concomitant medications No clinical drug-drug interaction studies have been conducted to date. Clofarabine is primarily excreted by the kidneys, thus it may potentiate the toxicity of known nephrotoxic drugs, including aminoglycoside antibiotics. Tumor lysis and hyperuricemia may also contribute to renal toxicity. The concomitant use of medications known to induce hepatic toxicity should also be avoided, since hepato-biliary toxicities were observed in pediatric trials. In addition, patients taking medications known to affect blood pressure or cardiac func- tion should be closely monitored during the administration of clofarabine, as symptoms of cytokine release and capillary leak syndrome, including hypotension, tachycardia, and pulmonary edema, have been reported in patients undergoing treatment with clofarabine (Clolar® package insert). Therapeutics and Clinical Risk Management 2008:4(2) Clofarabine in pediatric leukemias Dosage The recommended dose and schedule of clofarabine as a single agent for pediatric patients is 52 mg/m2 administered by intravenous (IV) infusion over 2 hours daily for 5 con- secutive days. The dosage is based on the patient’s BSA, calculated using the actual height and weight before the start of each cycle. Treatment cycles are repeated following blood count recovery or return to baseline organ function, approximately every 2–6 weeks (Clolar® package insert). To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. Clofarabine should be administered along with IV infusion ﬂuids to reduce the effects of tumor lysis and other adverse events. Allopurinol may be administered prophylactically if hyperuricemia is expected. The use of prophylactic steroids (eg, 100 mg/m2 hydrocortisone on days 1 through 3) may be of beneﬁt in preventing signs or symptoms of systemic inﬂammatory response syndrome (SIRS)/capillary leak syn- drome. If signs or symptoms of SIRS or capillary leak occur (eg, hypotension), clofarabine should be discontinued and the use of steroids, diuretics, and albumin considered. According to the manufacturer, clofarabine can be re-instituted when the patient is stable and organ function has returned to baseline, generally with a 25% dose reduction. Conclusions Better use of existing drugs has dramatically improved survival rates for childhood acute leukemias over the past few decades. However, relapsed and refractory childhood leukemias remain a signiﬁcant therapeutic challenge. Relapse after multi-agent therapy may arise from mutations in shared cell-death pathways, rather than alterations in speciﬁc drug activation, drug elimination, or drug targets. In addition to resistant disease, heavily pretreated patients often have underlying infection and pre-existing organ dysfunction. New candidate agents need be evaluated in combination. Agents may have substantial single agent activity, yet contribute nothing in combination, eg, ifosfamide in rhabdomyosar- coma (Miser et al 1987; Crist et al 2001). Conversely, an agent may have no single agent activity, yet still contribute in combination, eg, leukovorin in colon cancer (Iqbal and Lenz 2004). Clofarabine is safe and active in both myeloid and lymphoid relapsed/refractory pediatric acute leukemias in single agent phase I and II trials. Myelosuppression was an acceptable effect in this population, and the neurotoxicity associated with previous generation nucleoside analogs was not observed with clofarabine. Responses in relapsed 333