Bayesian semiparametric model for sequential treatment decisions with informative timing.

We develop a Bayesian semiparametric model for the impact of dynamic treatment rules on survival among patients diagnosed with pediatric acute myeloid leukemia (AML). The data consist of a subset of patients enrolled in a phase III clinical trial in which patients move through a sequence of four treatment courses. At each course, they undergo treatment that may or may not include anthracyclines (ACT). While ACT is known to be effective at treating AML, it is also cardiotoxic and can lead to early death for some patients. Our task is to estimate the potential survival probability under hypothetical dynamic ACT treatment strategies, but there are several impediments. First, since ACT is not randomized, its effect on survival is confounded over time. Second, subjects initiate the next course depending on when they recover from the previous course, making timing potentially informative of subsequent treatment and survival. Third, patients may die or drop out before ever completing the full treatment sequence. We develop a generative Bayesian semiparametric model based on Gamma Process priors to address these complexities. At each treatment course, the model captures subjects' transition to subsequent treatment or death in continuous time. G-computation is used to compute a posterior over potential survival probability that is adjusted for time-varying confounding. Using our approach, we estimate the efficacy of hypothetical treatment rules that dynamically modify ACT based on evolving cardiac function.

Applying machine learning to identify pediatric patients with newly diagnosed acute lymphoblastic leukemia using administrative data.

Case identification in administrative databases is challenging as diagnosis codes alone are not adequate for case ascertainment. We utilized machine learning (ML) to efficiently identify pediatric patients with newly diagnosed acute lymphoblastic leukemia. We tested nine ML models and validated the best model internally and externally. The optimal model had 97% positive predictive value (PPV) and 99% sensitivity in internal validation; 94% PPV and 82% sensitivity in external validation. Our ML model identified a large cohort of 21,044 patients, demonstrating an efficient approach for cohort assembly and enhancing the usability of administrative data.

Healthcare utilization disparities among children with high-risk neuroblastoma treated on Children's Oncology Group clinical trials.

INTRODUCTION: Disparities in relapse and survival from high-risk neuroblastoma (HRNBL) persist among children from historically marginalized groups even in highly standardized clinical trial settings. Research in other cancers has identified differential treatment toxicity as one potential underlying mechanism. Whether racial and ethnic disparities in treatment-associated toxicity exist in HRNBL is poorly understood. METHODS: This is a retrospective study utilizing a previously assembled merged cohort of children with HRNBL on Children's Oncology Group (COG) post-consolidation immunotherapy trials ANBL0032 and ANBL0931 at Pediatric Health Information System (PHIS) centers from 2005 to 2014. Race and ethnicity were categorized to reflect historically marginalized populations as Hispanic, non-Hispanic Black (NHB), non-Hispanic other (NHO), and non-Hispanic White (NHW). Associations between race-ethnicity and intensive care unit (ICU)-level care utilization as a proxy for treatment-associated toxicity were examined with log binomial regression and summarized as risk ratio (RR) and corresponding 95% confidence interval (CI). RESULTS: The analytic cohort included 370 children. Overall, 88 (23.8%) patients required ICU-level care for a median of 3.0 days (interquartile range [IQR]: 1.0-6.5 days). Hispanic children had nearly three times the risk of ICU-level care (RR 3.1, 95% CI: 2.1-4.5; fully adjusted RR [aRR] 2.5, 95% CI: 1.6-3.7) compared to NHW children and the highest percentage of children requiring cardiovascular-driven ICU-level care. CONCLUSION: Children of Hispanic ethnicity with HRNBL receiving clinical trial-delivered therapy were more likely to experience ICU-level care compared to NHW children. These data suggest that further investigation of treatment-related toxicity as a modifiable mechanism underlying outcome disparities is warranted.

Association between oral targeted cancer drug net health benefit, uptake, and spending.

BACKGROUND: Targeted cancer drugs (TCDs) have revolutionized oncology but vary in clinical benefit and patient out-out-pocket (OOP) costs. The ASCO Value Framework uses survival, toxicity, and symptom palliation data to quantify the net health benefit (NHB) of cancer drugs. We evaluated associations between NHB, uptake, and spending on oral TCDs. METHODS: We conducted a retrospective cohort study of patients aged 18-64 years with an incident oral TCD pharmacy claim in 2012-2020 in a nationwide de-identified commercial claims dataset. TCDs were categorized as having high (>60), medium (40-60), and low (<40) NHB scores. We plotted the uptake of TCDs by NHB category and used standard descriptive statistics to evaluate patient OOP and total spending. Generalized linear models evaluated the relationship between spending and TCD NHB, adjusted for cancer indication. RESULTS: We included 8,524 patients with incident claims for eight oral TCDs with nine first-line indications in advanced melanoma, breast, lung, and pancreatic cancer. Medium- and high-NHB TCDs accounted for most TCD prescriptions. Median OOP spending was $18.78 for the first 28-day TCD supply (IQR $0.00-$87.57); 45% of patients paid $0 OOP. Median total spending was $10,118.79 (IQR $6,365.95-$10,600.37) for an incident 28-day TCD supply. Total spending increased $1,083.56 for each 10-point increase in NHB score (95% CI $1,050.27-$1,116.84, p < .01 for H0=$0). CONCLUSION: Low-NHB TCDs were prescribed less frequently than medium- and high-NHB TCDs. Total spending on oral TCDs was high and positively associated with NHB. Commercially insured patients were largely shielded from high OOP spending on oral TCDs.

Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421. Methods: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%. Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF. Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

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.

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Background: Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Methods/design: Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. Discussion: This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.