Household income and health-related quality of life in children receiving treatment for acute myeloid leukemia: Potential impact of selection bias in health equity research.

OBJECTIVE: Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). DESIGN: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. EXPOSURE: Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. OUTCOME: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. RESULT: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. CONCLUSIONS: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research.

Association of the social disorganization index with time to first septic shock event in children with acute myeloid leukemia.

BACKGROUND: Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life-threatening complications, including septic shock (SS). An area-based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS-associated death (SS-death). METHODS: Children treated for de novo AML on two Children's Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS-death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front-line therapy, death, relapse, or removal from study. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group. RESULTS: The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI-5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference, SDI-1; SDI-2: HR, 0.84 [95% confidence interval (CI), 0.51-1.41]; SDI-3: HR, 0.70 [95% CI, 0.42-1.16]; SDI-4: HR, 0.97 [95% CI, 0.61-1.53]; SDI-5: HR, 0.72 [95% CI, 0.45-1.14]). Nine patients (4.4%) with SS experienced SS-death; seven of these patients (78%) were in SDI-4 or SDI-5. CONCLUSIONS: In a large, nationally representative cohort of trial-enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS.

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

The role of acuity of illness at presentation in early mortality in black children with acute myeloid leukemia.

Black patients with acute myeloid leukemia (AML) experience higher mortality than White patients. We compared induction mortality, acuity of illness prior to chemotherapy, and insurance type between Black and White patients to assess whether acuity of presentation mediates the disparity. Within a retrospective cohort of 1,122 children with AML treated with two courses of standard induction chemotherapy between 2004 and 2014 in the Pediatric Health Information System (PHIS) database, the association between race (Black versus White) and inpatient mortality during induction was examined. Intensive Care Unit (ICU)-level resource utilization during the first 72 hours following admission for initial AML chemotherapy was evaluated as a potential mediator. The total effect of race on mortality during Induction I revealed a strong association (unadjusted HR 2.75, CI: 1.18, 6.41). Black patients had a significantly higher unadjusted risk of requiring ICU-level resources within the first 72 hours after initial presentation (17% versus 11%; RR 1.52, CI: 1.04, 2.24). Mediation analyses revealed the indirect effect of race through acuity accounted for 61% of the relative excess mortality during Induction I. Publicly insured patients experienced greater induction mortality than privately insured patients regardless of race. Black patients with AML have significantly greater risk of induction mortality and are at increased risk for requiring ICU-level resources soon after presentation. Higher acuity amongst Black patients accounts for a substantial portion of the relative excess mortality during Induction I. Targeting factors affecting acuity of illness at presentation may lessen racial disparities in AML induction mortality.

Early discharge as a mediator of greater ICU-level care requirements in patients not enrolled on the AAML0531 clinical trial: a Children's Oncology Group report.

Previous data suggest that patients enrolled on clinical trials for treatment of cancer have better overall survival than patients who do not enroll; however, short-term outcomes relative to trial enrollment and corresponding mediators have not been assessed. A cohort of pediatric patients with newly-diagnosed acute myeloid leukemia was assembled from the Pediatric Health Information System. We evaluated whether patients not enrolled onto Children's Oncology Group trial AAML0531 had greater intensive care unit (ICU)-level requirements than enrolled patients and whether early discharge after chemotherapy administration mediated this association. Patients not enrolled on AAML0531 were more likely to be discharged early (aOR = 1.40, 95% confidence interval [CI]: 1.02, 1.90) and to require ICU-level care (aOR = 2.00, 95% CI: 1.06, 3.78) than enrolled patients, but early discharge explained only a small proportion (12.3%) of the absolute difference in ICU-level care risk. The direct effect of nonenrollment on the need for ICU-level care was significant (aOR = 1.89, 95% CI: 1.00, 3.94), whereas the indirect effect mediated through early discharge was not (aOR = 1.07, 95% CI: 0.95, 1.19). Factors other than postchemotherapy discharge strategy drive the difference in ICU utilization by trial enrollment status.

Volume-Outcome Relationships in Pediatric Acute Lymphoblastic Leukemia: Association Between Hospital Pediatric and Pediatric Oncology Volume With Mortality and Intensive Care Resources During Initial Therapy.

BACKGROUND: There are few contemporary studies of volume-outcome relationships in pediatric oncology. Children with acute lymphoblastic leukemia (ALL) are treated at a wide variety of hospitals. We investigated if inpatient hospital volume influences outcomes. The objective of this study was to evaluate the relationship between inpatient pediatric and pediatric oncology volume and mortality and intensive care resources (ICU care). We hypothesized an inverse relationship between volume and these outcomes. PATIENTS AND METHODS: This was a retrospective cohort study. Patients 0 to 18 years of age in the Pediatric Health Information System or Perspective Premier Database from 2009 to 2011 with ALL were included. Exposures were considered as the average inpatient pediatric and pediatric oncology volume. The primary outcome was inpatient mortality; secondary outcome was need for ICU care. RESULTS: The included population comprised 3350 patients from 75 hospitals. The inpatient mortality rate was 0.86% (95% confidence interval, 0.58%-1.2%). In the unadjusted analysis, mortality increased as pediatric oncology volume increased from low (0%) to high volume (1.3%) (P = .009). The small number of deaths precluded multivariable analysis of this outcome. Pediatric and pediatric oncology volume was not associated with ICU care when we controlled for potential confounders. CONCLUSION: Induction mortality was low. We did not observe an inverse relationship between volume and mortality or ICU care. This suggests that in a modern treatment era, treatment at a low-volume center might not be associated with increased mortality or ICU care in the first portion of therapy. This relationship should be evaluated in other oncology populations with higher mortality rates and with longer-term outcomes.

Comparison of in-patient costs for children treated on the AAML0531 clinical trial: A report from the Children's Oncology Group.

BACKGROUND: A better understanding of drivers of treatment costs may help identify effective cost containment strategies and prioritize resources. We aimed to develop a method for estimating inpatient costs for pediatric patients with acute myeloid leukemia (AML) enrolled on NCI-funded Phase III trials, compare costs between AAML0531 treatment arms (standard chemotherapy ± gemtuzumab ozogamicin (GMTZ)), and evaluate primary drivers of costs for newly diagnosed pediatric AML. PROCEDURE: Patients from the AAML0531 trial were matched on hospital, sex, and dates of birth and diagnosis to the Pediatric Health Information Systems (PHIS) database to obtain daily billing data. Inpatient treatment costs were calculated as adjusted charges multiplied by hospital-specific cost-to-charge ratios. Generalized linear models were used to compare costs between treatment arms and courses, and by patient characteristics. RESULTS: Inpatient costs did not differ by randomized treatment arm. Costs varied by course with stem cell transplant being most expensive, followed by Intensification II (cytarabine/mitoxantrone) and Induction I (cytarabine/daunorubicin/etoposide). Room/board and pharmacy were the largest contributors to inpatient treatment cost, representing 74% of the total cost. Higher AML risk group (P = 0.0003) and older age (P < 0.0001) were associated with significantly higher daily inpatient cost. CONCLUSIONS: Costs from external data sources can be successfully integrated into NCI-funded Phase III clinical trials. Inpatient treatment costs did not differ by GMTZ exposure but varied by chemotherapy course. Variation in cost by course was driven by differences in duration of hospitalization through room/board charges as well as increased clinical and pharmacy charges in specific courses.

Establishing a high-risk neuroblastoma cohort using the Pediatric Health Information System Database.

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.

Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States.

BACKGROUND: Clinical trials in pediatric acute myeloid leukemia (AML) determine induction regimen standards. However, these studies lack the data necessary to evaluate mortality trends over time and differences in resource utilization between induction regimens. Moreover, these trials likely underreport the clinical toxicities experienced by patients. METHODS: The Pediatric Health Information System database was used to identify children treated for presumed de novo AML between 1999 and 2010. Induction mortality, risk factors for induction mortality, and resource utilization by induction regimen were estimated using standard frequentist statistics, logistic regression, and Poisson regression, respectively. RESULTS: A total of 1686 patients were identified with an overall induction case fatality rate of 5.4% that decreased from 9.8% in 2003 to 2.1% in 2009 (P = .0023). The case fatality rate was 9.0% in the intensively timed DCTER (dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin [daunomycin]/idarubicin) induction and 3.8% for ADE (cytarabine, daunomycin, and etoposide) induction (adjusted odds ratio = 2.2, 95% confidence interval = 1.1-4.5). Patients treated with intensively timed DCTER regimens had significantly greater antibiotic, red cell/platelet transfusion, analgesic, vasopressor, renal replacement therapy, and radiographic resource utilization than patients treated with ADE regimens. Resource utilization was substantially higher than reported in published pediatric AML clinical trials. CONCLUSIONS: Induction mortality for children with AML decreased significantly as ADE use increased. In addition to higher associated mortality, intensively timed DCTER regimens had a correspondingly higher use of health care resources. Using resource utilization data as a proxy for adverse events, adverse event rates reported on clinical trials substantially underestimated the clinical toxicities of all pediatric AML induction regimens.