--The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols.

Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

--The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols.

Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.

The clinical course of late symptomatic anthracycline cardiomyopathy, and resultant changes of cardiac function, were described in 15 patients. They represented a subset of 300 patients who had cardiac evaluations to identify the prevalence of late cardiotoxicity more than 4 years after anthracycline therapy in these patients. The clinical course and all available cardiac evaluations including electrocardiography, continuous taped electrocardiography, echocardiography, radionuclide cardiac angiography, cardiac catheterization, and endomyocardial biopsy, of the 15 patients were reviewed. The patients had received 285-870 (median 540) mg/M2 of daunorubicin and/or doxorubicin 6-19 (median 12) years prior to the onset of late symptoms. Seven patients also had 2,100-4,000 cGy mediastinal radiotherapy. Five patients had required treatment for cardiac symptoms at the end of chemotherapy but 10 patients had no cardiac problems anteceding their late decompensation. Fractional shortening on echocardiogram at late decompensation was 8-20% (median 17%) and radionuclide left ventricular ejection fraction was 8-59% (median 38%). All were treated with digitalis and diuretics and 13/15 with afterload reduction, with at least transient improvement of symptoms. They were followed for 1-9 (median 3) years after late decompensation. One died of uncontrollable cardiac failure. Another underwent successful cardiac transplantation. Conduction abnormalities and dysrhythmias were present in 14/15 patients and 3 died suddenly. Two more had syncope, one requiring an automatic cardiac defibrillator. Endomyocardial biopsy or autopsy revealed hypertrophy and fibrosis in 10/10 patients. Our patients with early cardiac symptoms improved transiently but decompensated later and patients with no early symptoms developed cardiac symptoms more than 10 years after anthracycline therapy. Therefore, patients who have received anthracyclines should have continued cardiac evaluation.

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Background Although chemotherapy has improved outcome of osteosarcoma, 30–40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would 1) support escalation of the cumulative doxorubicin dose (600 mg/m2) and 2) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data.9 Procedure Children and adolescents with non-metastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for ‘standard responders’ (SR, <98% tumor necrosis at definitive surgery). Results Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450–600 mg/m2) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in 5 patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ±0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible. Conclusions Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification, increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.

A B S T R A C T PurposeTo determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML). Patients and MethodsA phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m 2 daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel. ResultsThe 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to Ն 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to Ն 160 weeks. Five patients (12%) remain alive post-transplantation at Ն 63, Ն 71, Ն 86, Ն 114, and Ն 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event. ConclusionClofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.