A B S T R A C T PurposeTo improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and MethodsChildren, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m 2 /dose) administered once in induction course 1 and once in intensification course 2 (two of three). ResultsThere were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P ϭ .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P ϭ .39). Although remission was not improved (88% v 85%; P ϭ .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P ϭ .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P ϭ .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P ϭ .07). ConclusionGO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML. J Clin Oncol 32:3021-3032. © 2014 by American Society of Clinical Oncology INTRODUCTIONAcute myeloid leukemia (AML) is among the most difficult to treat of the childhood cancers because of its disease heterogeneity, high relapse, and toxic mortality.1,2 Therapeutic advances have included chemotherapy intensification and adding allogeneic stem-cell transplantation (SCT). Children's Oncology Group (COG) legacy AML trials evaluated time-intensive induction and observed improvement in event-free survival rates (EFS) from 27% to 42%. 3,4 Matched family-donor (MFD) transplantation improved disease-free survival rates (DFS) by between 8% and 10% and postremission overall survival (OS) by between 5% and 13% in two previous phase III trials. 4,5 However, treatmentrelated mortality (TRM) increased substantially with therapy intensification. Supportive care improvements reduced TRM (from 19% to 12%). 4 However, it is increasingly evident that the limits of treatment intensification have been reached, 4,6,7 necessitating alternative approaches. JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R TVOLUME 3021The cell-surface antigen, CD33, is present in more than 80% of patients with AML but is absent from pluripotent hematopoietic stem cells and is a well established immunoconjugate target. 8,9 Early studies ...

Introduction Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear. Methods This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18–49: HR 3.57, CI 2.54–5.02), frailty (CFS 8 vs 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1–3: OR 7.00, CI 5.27–9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusions Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.

BACKGROUND. Although medication errors are 1 of the most common types of medical errors, their frequency in pediatric patients receiving oral outpatient chemotherapeutic agents is unknown. The prescribing, dispensing, and parental administration of these medications to children receiving treatment for acute lymphoblastic leukemia (ALL) were systematically reviewed to determine the rate and types of medication errors occurring in these patients. METHODS. During a 2‐month study period, parents of children with ALL were contacted and asked to participate in the study before a regularly scheduled clinic appointment. At the visit, the parent demonstrated how each medication was administered. A pediatric oncologist reviewed the medical record to determine the correct treatment regimen for study patients. After comparing the correct treatment regimen with what was administered, a classification of “no medication error,” “medication error,” or “cannot determine” due to insufficient information was made for each indicated drug. Identified medication errors were subclassified as prescribing, dispensing, or administration errors. RESULTS. Data on 172 chemotherapeutic medications for 69 patients were analyzed. One or more errors occurred with 17 of the 172 (9.9%) medications; a classification of “cannot determine” was made for 12 (7.0%) medications. Among the 17 medication errors there were 12 (7.0%) administration errors and 5 (2.9%) prescribing errors. There were no pharmacy dispensing errors. All errors were due to incorrect dosing or failure to administer an indicated medication. At least 1 medication error occurred in 13 of the 69 (18.8%) study patients. CONCLUSIONS. Prescribing and administration medication errors occurred with nearly 10% of chemotherapeutic drugs administered to outpatient children with ALL. Systematic changes, including computerized physician order entry and simplification of treatment protocols, should be considered. Cancer 2006. © 2006 American Cancer Society.

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors’ group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.