<p>Childhood acute myeloid leukemia (AML) is frequently characterized by chromosomal instability. Approximately 50% of patients have disease relapse, and novel prognostic markers are needed to improve risk stratification. We performed genome-wide genotyping in 446 pediatric patients with de novo AML enrolled on Children's Oncology Group (COG) studies, AAML0531 (NCT01407757), AAML03P1 (NCT00070174), and CCG2961 (NCT00003790). Affymetrix and Illumina Omni 2.5 platforms were used to evaluate copy number alterations (CNAs) and determine their associations with treatment outcome. Data from Affymetrix and Illumina studies were jointly analyzed with ASCAT and GISTIC software. An average of 1.14 somatically acquired CNAs per patient were observed. Novel reoccurring altered genomic regions were identified, and the presence of CNAs was found to be associated with decreased 3-year overall survival (OS), event-free survival (EFS), and relapse risk from the end of induction I (HR 1.7, 95%CI 1.2-2.4, HR 1.4, 95%CI 1.0-1.8, and HR 1.4, 95%CI 1.0-2.0, respectively). Analyses by risk group demonstrated decreased OS and EFS in the standard risk group only (HR 1.9, 95%CI 1.1-3.3, and HR 1.7, 95%CI 1.1-2.6, respectively). Further studies are required to test the prognostic significant of CNA presence in disease relapse in AML patients.</p>
<p>While most children receive acute myeloid leukemia (AML) chemotherapy as inpatients, there is variability in timing of discharge after chemotherapy completion. This study compared treatment-related morbidity, mortality and cumulative hospitalization in children with AML who were discharged after chemotherapy completion (early discharge) and those who remained hospitalized. Chart abstraction data for 153 early discharge-eligible patients enrolled on a Children's Oncology Group trial were compared by discharge strategy. Targeted toxicities included viridans group streptococcal (VGS) bacteremia, hypoxia and hypotension. Early discharge occurred in 11% of courses post-Induction I. Re-admission occurred in 80-100%, but median hospital stay was 7 days shorter. Patients discharged early had higher rates of VGS (adjusted risk ratio (aRR) = 1.67, 95% CI = 1.11-2.51), hypoxia (aRR = 1.92, 95% CI = 1.06-3.48) and hypotension (aRR = 4.36, 95% CI = 2.01-9.46), but there was no difference in mortality. As pressure increases to shorten hospitalizations, these results have important implications for determining discharge practices in pediatric AML.</p>
<p><strong>PURPOSE: </strong>Reporting of adverse events (AEs) in clinical trials is critical to understanding treatment safety, but data on AE accuracy are limited. This study sought to determine the accuracy of AE reporting for pediatric acute myeloid leukemia clinical trials and to test whether an external electronic data source can improve reporting.</p>
<p><strong>METHODS: </strong>Reported AEs were evaluated on two trials, Children's Oncology Group AAML03P1 and AAML0531 arm B, with identical chemotherapy regimens but with different toxicity reporting requirements. Chart review for 12 AEs for patients enrolled in AAML0531 at 14 hospitals was the gold standard. The sensitivity and positive predictive values (PPV) of the AAML0531 AE report and AEs detected by review of Pediatric Health Information System (PHIS) billing and microbiology data were compared with chart data.</p>
<p><strong>RESULTS: </strong>Select AE rates from AAML03P1 and AAML0531 arm B differed significantly and correlated with the targeted toxicities of each trial. Chart abstraction was performed on 204 patients (758 courses) on AAML0531. AE report sensitivity was < 50% for eight AEs, but PPV was > 75% for six AEs. AE reports for viridans group streptococcal bacteremia, a targeted toxicity on AAML0531, had a sensitivity of 78.3% and PPV of 98.1%. PHIS billing data had higher sensitivity (> 50% for nine AEs), but lower PPV (< 75% for 10 AEs). Viridans group streptococcal detection using PHIS microbiology data had high sensitivity (92.3%) and PPV (97.3%).</p>
<p><strong>CONCLUSION: </strong>The current system of AE reporting for cooperative oncology group clinical trials in pediatric acute myeloid leukemia underestimates AE rates. The high sensitivity and PPV of PHIS microbiology data suggest that using external data sources may improve the accuracy of AE reporting.</p>
<p>International Classification of Diseases, 9th Revision (ICD-9) code(s) for neuroblastoma do not exist, preventing identification of these patients in administrative databases. To overcome this challenge, a three-step algorithm, using ICD-9 codes, exclusion criteria, and manual review of chemotherapy billing data, was utilized to assemble a high-risk neuroblastoma cohort (n = 952) from the Pediatric Health Information System (PHIS) Database and validated at a single institution [sensitivity 89.1%; positive predictive value (PPV) 96.1%]. This cohort provides a data source for future comparative effectiveness and clinical epidemiology studies in high-risk neuroblastoma patients.</p>
<p><strong>BACKGROUND: </strong>Deaths during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL) account for one-tenth of ALL-associated mortality and half of ALL treatment-related mortality. We sought to ascertain patient- and hospital-level factors associated with induction mortality.</p>
<p><strong>PROCEDURE: </strong>We performed a retrospective cohort analysis of 8,516 children ages 0 to <19 years with newly diagnosed ALL admitted to freestanding US children's hospitals from 1999 to 2009 using the Pediatric Health Information System database. Induction mortality risk was modeled accounting for demographics, intensive care unit-level interventions, and socioeconomic status (SES) using Cox regression. The association of ALL induction mortality with hospital-level factors including volume, hospital-wide mortality and payer mix was analyzed with multiple linear regression.</p>
<p><strong>RESULTS: </strong>ALL induction mortality was 1.12%. Race and patient-level SES factors were not associated with induction mortality. Patients receiving both mechanical ventilation and vasoactive infusions experienced nearly 50% mortality (hazard ratio 122.30, 95% CI 66.56-224.80). Institutions in the highest induction mortality quartile contributed 27% of all patients but nearly half of all deaths (47 of 95). Hospital payer mix was associated with ALL induction mortality after adjustment for other hospital-level factors (P = 0.046).</p>
<p><strong>CONCLUSIONS: </strong>The overall risk of induction death is low but substantially increased in patients with cardio-respiratory and other organ failures. Induction mortality varies up to three-fold across hospitals and is correlated with hospital payer mix. Further work is needed to improve induction outcomes in hospitals with higher mortality. These data suggest an induction mortality rate of less than 1% may be an attainable national benchmark.</p>
<p><strong>BACKGROUND: </strong>Limited data exist on induction mortality of pediatric patients with acute promyelocytic leukemia in the United States, usage of all-trans retinoic acid (ATRA) during acute promyelocytic leukemia induction, and the resources needed to deliver induction therapy.</p>
<p><strong>PROCEDURE: </strong>Using the Pediatric Health Information System database we established a retrospective cohort of patients treated for newly diagnosed acute promyelocytic leukemia with ATRA between January 1999 and September 2009 in 32 of 43 PHIS contributing free-standing pediatric hospitals in the United States. Standard statistical methods were used to determine in-hospital induction mortality, ATRA administration, and resource utilization during a 60-day observation period.</p>
<p><strong>RESULTS: </strong>A total of 163 children were identified who met eligibility criteria for cohort inclusion; 52% were female and 76% were white with an average age of 12.7 years. A total of 12 patients (7.4%) died, with 7 (58.3%) dying within the first 7 days of first admission. The mean time to first ATRA exposure increased with decreasing age (P = 0.0016). Resource utilization for management of retinoic acid syndrome was higher than anticipated based on prior studies and differed significantly from patients with non-M3 acute myeloid leukemia.</p>
<p><strong>CONCLUSIONS: </strong>The induction mortality for pediatric acute promyelocytic leukemia remains substantial with wide variation in ATRA administration and high rates of resource utilization.</p>
<p>Pediatric Health Information System data were used to establish a multi-center cohort of 1,686 children treated for newly diagnosed acute myeloid leukemia (AML). The cohort assembly process, which included myeloid leukemia ICD-9 discharge diagnosis codes and manual review of induction chemotherapy, was validated by chart review at a single institution. The use of ICD-9 codes alone resulted in a poor positive predictive value (PPV; 31%). Inclusion of the results from the chemotherapy review improved the PPV to 100% without compromising sensitivity (95.7%). This cohort provides a reliable source for future comparative effectiveness and clinical epidemiology studies in pediatric AML.</p>
<p><strong>BACKGROUND: </strong>Invasive fungal infections cause significant morbidity and mortality for children with acute myeloid leukemia (AML). Data on the comparative effectiveness of antifungal prophylaxis in this population are limited.</p>
<p><strong>METHODS: </strong>A pediatric AML cohort was assembled from the Pediatric Health Information System database using ICD-9 codes and pharmacy data. Antifungal prophylaxis status was determined by pharmaceutical data review within 21 days of starting induction chemotherapy. Patients were followed until end of induction, death, or loss to follow-up. Cox regression analyses compared induction mortality and resources utilized between patients receiving and not receiving antifungal prophylaxis. A propensity score accounted for variation in demographic factors, location of care, and severity of illness at presentation.</p>
<p><strong>RESULTS: </strong>Eight hundred seventy-one AML patients were identified; the induction case fatality rate was 3.7%. In the adjusted Cox regression model, patients receiving antifungal prophylaxis (57%) had a decreased hazard for induction mortality (hazard ratio [HR], 0.42; 95% confidence interval [CI], .19-.90). Children receiving prophylaxis were less frequently exposed to broad-spectrum gram-positive (incidence rate ratio [IRR], 0.87; 95% CI, .79-.97) and antipseudomonal β-lactam agents (HR, 0.91; 95% CI, .85-.96), had fewer blood cultures (IRR, 0.78; 95% CI, .71-.86), and had fewer chest CT scans (IRR, 0.73; 95% CI, .60-.88).</p>
<p><strong>CONCLUSIONS: </strong>Antifungal prophylaxis in pediatric AML patients was associated with reduced induction mortality rates and supportive care resources. Further investigation is necessary to determine whether antifungal prophylaxis should include antimold activity.</p>
<p><strong>OBJECTIVE: </strong>Children with acute myeloid leukemia are at risk for sepsis and organ failure. Outcomes associated with intensive care support have not been studied in a large pediatric acute myeloid leukemia population. Our objective was to determine hospital mortality of pediatric acute myeloid leukemia patients requiring intensive care.</p>
<p><strong>DESIGN: </strong>Retrospective cohort study of children hospitalized between 1999 and 2010. Use of intensive care was defined by utilization of specific procedures and resources. The primary endpoint was hospital mortality.</p>
<p><strong>SETTING: </strong>Forty-three children's hospitals contributing data to the Pediatric Health Information System database.</p>
<p><strong>PATIENTS: </strong>Patients who are newly diagnosed with acute myeloid leukemia and who are 28 days through 18 years old (n = 1,673) hospitalized any time from initial diagnosis through 9 months following diagnosis or until stem cell transplant. A reference cohort of all nononcology pediatric admissions using the same intensive care resources in the same time period (n = 242,192 admissions) was also studied.</p>
<p><strong>INTERVENTIONS: </strong>None.</p>
<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>One-third of pediatric patients with acute myeloid leukemia (553 of 1,673) required intensive care during a hospitalization within 9 months of diagnosis. Among intensive care admissions, mortality was higher in the acute myeloid leukemia cohort compared with the nononcology cohort (18.6% vs 6.5%; odds ratio, 3.23; 95% CI, 2.64-3.94). However, when sepsis was present, mortality was not significantly different between cohorts (21.9% vs 19.5%; odds ratio, 1.17; 95% CI, 0.89-1.53). Mortality was consistently higher for each type of organ failure in the acute myeloid leukemia cohort versus the nononcology cohort; however, mortality did not exceed 40% unless there were four or more organ failures in the admission. Mortality for admissions requiring intensive care decreased over time for both cohorts (23.7% in 1999-2003 vs 16.4% in 2004-2010 in the acute myeloid leukemia cohort, p = 0.0367; and 7.5% in 1999-2003 vs 6.5% in 2004-2010 in the nononcology cohort, p < 0.0001).</p>
<p><strong>CONCLUSIONS: </strong>Pediatric patients with acute myeloid leukemia frequently required intensive care resources, with mortality rates substantially lower than previously reported. Mortality also decreased over the time studied. Pediatric acute myeloid leukemia patients with sepsis who required intensive care had a mortality comparable to children without oncologic diagnoses; however, overall mortality and mortality for each category of organ failure studied was higher for the acute myeloid leukemia cohort compared with the nononcology cohort.</p>