Faculty Bibliography

Asparaginase-associated toxicities (AAT) often compromise therapy for acute lymphoblastic leukemia (ALL), impacting relapse risk and survival. There are conflicting data on the contributions of older age, obesity by body mass index (BMI), and/or large body surface area (BSA) to AAT. We examined the association of these risk factors with AAT and the impact of AAT on disease response. Induction data were examined from 4,925 patients ages 1-30 years enrolled in the Children's Oncology Group ALL trials AALL0232 and AALL0434, which included a single dose of pegaspargase (2,500 IU/m2) without a maximum dose. The associations of age, BMI, and BSA with hyperbilirubinemia, elevated alanine aminotransferase (ALT), thrombosis, and pancreatitis were evaluated. The impact of AAT on minimal residual disease (MRD) positivity (≥0.01%) at the end of induction (EOI) was assessed. Increased risk for developing at least one AAT was observed in patients ≥10 years (p=0.002) and in those with obesity and high BSA (p<0.0001), but not with high BSA alone. Risks for hyperbilirubinemia, ALT elevations, and thrombosis were all increased in patients with obesity and high BSA (Odds ratio [OR] 3.5 [95% confidence interval [CI] 2.2-5.7], OR 3.3 [95%CI 1.7-6.6], and OR 3.1 [95%CI 1.5-6.5], respectively). AATs were not associated with EOI MRD positivity. To our knowledge, we report the largest dataset of AAT in children, adolescents, and young adults. Preventive strategies are indicated for older patients and for those with obesity and high BSA but not with high BSA alone. NCT00075725, NCT00408005.

The identification of molecular subgroups of pediatric B-cell acute lymphocytic leukemia (B-ALL) has proven to be a powerful tool in understanding disease pathogenesis and treatment stratification. Studies have suggested aberrant transcription factor function and epigenetic regulation can explain differences between B-ALL subtypes, however, the impact of 3D genome re-organization remains unclear. Here we used in situ Hi-C and RNA-seq to profile the chromatin architectural landscape in healthy B-cell progenitors and B-ALL patient samples harboring prognostically relevant structural variations, including ETV6::RUNX1, KMT2A::AFF1, and BCR::ABL. We showed that B-ALLs undergo subtype-specific changes that, in part, reflect the differentiation stage of the disease, and that they acquire aberrant chromatin configurations that allow expression of oncogenic drivers. One such driver, ERG, displayed increased interactivity and expression in ETV6::RUNX1 B-ALL, and evidence suggests it plays a role in regulating survival and differentiation. Overall, these results underscore the essential role of 3D nuclear organization in acute leukemia.

By integrating short-read WGS and RNA-seq data with long-read RNA sequencing, we dissect the complex genomic architecture of PAX5 intragenic tandem multiplication (PAX5-ITM), revealing that these complex rearrangements result in in-frame transcripts that likely encode proteins with altered domains.

BACKGROUND:Quality of life (QOL) is impacted in children treated for leukemia. AALL0932 randomized reduction in vincristine/dexamethasone (VCR/DEX) pulses every 4 versus 12 weeks during maintenance in the average-risk subset of NCI standard risk B-ALL (NCI-SR AR B-ALL). We longitudinally assessed physical and emotional QOL, behavioral health, and school services by randomization. PROCEDURE/METHODS:NCI-SR AR B-ALL English-speaking patients aged ≥4 years were evaluated at T1-T5 (∼2, 9, 18, 26 months [females treatment end], and 38 [males only] months from diagnosis) with parent-report. The Pediatric Quality of Life Inventory-4.0 and school services survey were administered longitudinally, and the Behavior Assessment Scale for Children-2 at therapy end. RESULTS:Data were obtained from 420 consented and randomized participants (mean 6.0±1.6 years, 45.7% female). Impairment among randomized participants at T2 and T4, respectively, was 11.3% and 12.5% for physical, and 12.2% and 9.8% for emotional function. In longitudinal models adjusting for race/ethnicity, time, and baseline impairment, pulse frequency was not associated with impairment (physical odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.5-1.8; emotional OR = 0.9, 95% CI = 0.5-1.7). T2 impairment was associated with increased risk of post-randomization impairment for physical (OR = 4.3, 95% CI: 1.9-9.9) and emotional (OR = 4.9, CI: 2.3-10.5) function. Approximately 73.8% reported one or more school-based service during treatment: special education/accommodations (67.6%) and physical/occupational therapy (8.8%). Depression (20%) and anxiety (19%) did not differ by pulse frequency. DISCUSSION/CONCLUSIONS:Children with NCI-SR AR B-ALL experience diminished QOL, despite reduced frequency of VCR/DEX maintenance pulses. Impairment begins early during ALL therapy and persists; interventions should commence early and continue throughout and after therapy.

Despite extensive studies of the error profiles of SNVs, those of insertions/deletions (indels)/structural variants (SVs) remain elusive. Using ultra-deep sequencing, we show that the error rates of indel/SVs are >100-fold lower than those of SNVs, although repeat indels have high error rates of 1%. We validated this pattern in a cohort of 103 patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We analyzed repeat indels in 339 cancer driver genes and demonstrated that the number of repeat units is highly predictive of the error rate. We then analyzed minimal residual disease samples from 72 patients with relapsed B-ALL and demonstrated that our approach had positive detections in 61% of cases, outperforming clinical flow cytometry (51% detection). Overall, we established indel and SV error profiles in deep next-generation sequencing (NGS) data, enabling superior tumor detection at very low burdens, which has a significant impact on the clinical diagnosis and monitoring of human cancers and other diseases.

Pediatric Hispanic and Black patients with newly diagnosed B-acute lymphoblastic leukemia (B-ALL) experience worse overall survival (OS). We hypothesized that differential outcomes by race and ethnicity following relapse may contribute to disparities. We examined 2,053 patients with ALL enrolled on frontline Children's Oncology Group trials from 1996-2014 who relapsed. We assessed association of race and ethnicity, disease characteristics, and socioeconomic status with relapse survival predictors and post-relapse OS. For non-infant B-ALL, post-relapse OS (p=0.002) and disease-related prognosticators such as time-to-relapse (p=0.0002) differed by race and ethnicity. After adjusting for disease and patient characteristics, the OS association with overall race and ethnicity was attenuated, and lost statistical significance; Hispanic ethnicity specifically remained associated with worse OS (hazard ratio, HR=1.19, 95% confidence interval, CI 1.01-1.41). Patients from highest annual median household income ZIP codes (>$85,000, ~highest quartile of patients) had better 5-year OS compared to those from the lowest (<$50,000, HR=0.79, 95%CI 0.63-0.99). Non-Hispanic Black and Hispanic patients more commonly lived in lower income ZIP codes. For T-ALL, race, ethnicity and socioeconomic status were not associated with OS. Worse post-relapse outcomes among racial and ethnic minority patients are largely driven by prevalence of adverse disease-related factors at time of relapse, with a persistent disparity observed in Hispanic patients. The greatest impact in decreasing racial and ethnic B-ALL outcome disparities may come through targeting frontline treatment interventions to address increased relapse among Black and Hispanic patients, as well as developing and enabling equitable access to effective relapse treatments such as novel immunotherapies. (CCG 1991, POG 9404, POG 9407, POG 9904, POG 9905, POG 9906, COG AALL0232, COG AALL0331, COG AALL0434, COG AALL0631, COG AALL07P4, COG AALL08P1).

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.