The molecular hallmark of childhood ALL is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA-seq is a powerful next-generation sequencing technology with the ability to simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multi-center phase 3 clinical trial for children with newly-diagnosed ALL. Patients enrolled on the DFCI ALL Consortium Protocol 16-001 who consented to optional studies and had available material underwent RNA-seq. RNA-seq was performed in 173 ALL patients. RNA-seq identified at least one alteration in 157 (91%) patients. Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-ALL subgroups: High hyperdiploid (n=36), ETV6-RUNX1/-like (n=31), TCF3-PBX1 (n=7), KMT2A-rearranged (n=5), iAMP21 (n=1), hypodiploid (n=1), BCR-ABL1/-like (n=16), DUX4-rearranged (n=11), PAX5 alterations (n=11), PAX5 P80R (n=1), ZNF384-rearranged (n=4), NUTM1-rearranged (n=1), MEF2D-rearranged (n=1) and Others (n=10). RNA-seq identified 141 nonsynonymous mutations in 93 (54%) patients; the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Ph-like gene signature prediction, results were concordant in 74 (94%) patients. In conclusion, RNA-seq identified several clinically-relevant genetic alterations not detected by conventional methods, supporting the integration of this technology in frontline pediatric ALL trials.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. Significance: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations. See related commentary by Bornhauser and Bourquin, p. 1322. This article is highlighted in the In This Issue feature, p. 1307

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Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is virtually absent from oncology clinical trials. Trial‐based SDoH data are essential to ensure representation of marginalized populations, contextualize outcome disparities, and identify health‐equity intervention opportunities. We report the feasibility of a pediatric oncology multicenter therapeutic trial‐embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted‐in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (88.9–93.1%) over 24 months. Trial‐embedded SDoH data collection is feasible and acceptable and must be consistently included within future oncology trials.

10025 Background: Poverty is associated with inferior psychosocial function among parents of children with cancer. Severe parental distress during treatment predicts future poor mental health for both parents and children. It is also associated with impaired parental cognitive bandwidth and executive function, which may have implications for treatment adherence. Efforts to identify poverty-exposures amenable to intervention are essential to improving survivorship quality of life for the > 90% of children with acute lymphoblastic leukemia (ALL) who will be long-term survivors. Household material hardship (HMH) is a targetable poverty exposure defined as at least 1 of 3 unmet basic needs including food, housing, or utilities. Dana-Farber Cancer Institute (DFCI) ALL Consortium trial 16-001 is the first pediatric oncology clinical trial to systematically evaluate HMH. We investigated the hypothesis that HMH exposure independently predicts severe parent psychological distress during ALL therapy. Methods: Patients with newly diagnosed ALL ages 1-17 years were enrolled on the DFCI 16-001 embedded HMH cohort study at 8 U.S. and Canadian centers. Secondary interim analyses used baseline (within 32-days of trial enrollment) and 6-mos parent-reported sociodemographic data, the Kessler-6 (K6) Psychological Distress scale, and trial-collected child and disease data. Severe psychological distress was defined as a K6 > = 13. Multivariable cox regression evaluated baseline HMH-exposure and parent distress at baseline and 6-mos adjusting for child’s initial ALL risk group (Very High Risk (VHR) vs other) and marital status (single vs dual parent). Results: Among 258 families with evaluable data, 34% reported baseline HMH. Families were predominantly English-speaking (54%) dual parent households (71%). Children were a median of 5.7 years (IQR 1.0-17.99) at diagnosis and predominantly non-Hispanic white (66%) with expected disease distribution by immunophenotype (84% B-cell). HMH (odds ratio (OR) 2.18, 95% confidence interval (CI) 1.0-4.31, p = 0.025) and VHR initial risk group (OR 2.32; 95% CI 1.06-5.06, p = 0.035) were independently associated with baseline severe psychological distress. Only HMH was independently associated with 6-mos severe psychological distress (OR 4.93, 95% CI 1.80-13.48, p = 0.002). Future analyses will investigate race and ethnicity associations with parental distress pending trial accrual for statistical power. Conclusions: HMH, a modifiable poverty exposure, is significantly associated with severe parent psychological distress at diagnosis that persists 6-months into pediatric ALL therapy. These findings identify a cohort at high risk of inferior mental health outcomes, and affirm the need for HMH-targeted interventions to support children and parents during cancer treatment to reduce poverty-associated outcome disparities in survivorship.