Faculty Bibliography

Patients with central nervous system (CNS) disease at diagnosis on Children's Oncology Group (COG) B-acute lymphoblastic leukemia (B-ALL) trials AALL0331 and AALL0232 had inferior outcomes, largely secondary to CNS relapse. In response, for patients with newly diagnosed B-ALL enrolled on COG studies AALL0932 and AALL1131, therapy was adjusted to incorporate additional intrathecal cytarabine during induction for patients with low level CNS involvement (CNS2). We evaluated the impact of this intervention. Event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were compared among CNS2 patients pre- versus post-amendment, stratified by receipt of a 3-drug (SR) or 4-drug (HR) induction. Multivariable models were constructed to adjust for demographic and disease variables. When stratified by trial, pre- and post-amendment patients with CNS2 status did not differ significantly by demographic or disease factors. Additional intrathecal cytarabine doses during induction did not improve outcomes for patients with B-ALL. Multivariable analyses adjusting for disease prognosticators, race/ethnicity, and leukemia cytogenetics did not identify any subpopulation that significantly benefited from additional intrathecal cytarabine. Additional intrathecal cytarabine during induction for CNS2 patients did not improve outcomes or mitigate the adverse prognostic impact of CNS2 status in B-ALL. Future COG B-ALL studies will not include additional intrathecal cytarabine in induction for patients with CNS2 disease. Alternative treatment strategies are needed for patients with CNS2 disease.

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.

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.

Children's Oncology Group AALL1331 utilized an intensive chemotherapy induction (Block 1) based on UK ALLR3 induction for children, adolescents, and young adults with acute lymphoblastic leukemia in first relapse, followed by risk-stratified therapy. High/intermediate-risk patients were subsequently randomized to receive two blocks of chemotherapy or two blocks of blinatumomab followed by a hematopoietic stem cell transplant. Low-risk patients were randomized to chemotherapy or chemotherapy cycles intercalated with three blinatumomab blocks. Patients who had early treatment failure were eligible to receive blinatumomab for up to two salvage cycles. We reviewed Block 1 responses, risk stratification, randomization rates, adverse events, event-free survival and overall survival for all enrolled patients. AALL1331 enrolled 661 patients: 24 died during Block 1 and 42 experienced early treatment failure. Overall, 531/661 (80.3%) attained complete remission with 586 risk-assigned and only 471 were randomized. Of 532 patients with bone marrow involvement, 290 (54.5%) were positive for minimal residual disease (≥0.01%) after Block 1. Grade 3, 4 or 5 adverse events occurred in Block 1 in 44.9%, 24.1%, and 3.6% of patients, respectively, with febrile neutropenia, infections, and sepsis being most frequent. Notably, 190 enrolled patients (28.7%) did not proceed with post-induction therapy, including 115 (17.4%) risk-stratified but not randomized. These patients had dismal survival. More effective and less toxic reinduction strategies are needed for B-cell acute lymphoblastic leukemia in first relapse. Trial registration number: NCT02101853.

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).

Methotrexate (MTX) has improved survival for children with acute lymphoblastic leukemia, but is associated with a 3%-7% incidence of neurotoxicity. This retrospective study showed a higher incidence of MTX neurotoxicity (11.3%) with the classic presentations of stroke-like syndrome (17/19), seizures (2/19), and the majority (14/19) showing characteristic radiographic findings. Most cases occurred during the consolidation phase, a median of 6 days after MTX exposure. Older age, Hispanic ethnicity, greater body mass index, and National Cancer Institute high-risk status were predictors of neurotoxicity, with only ethnicity remaining significant in adjusted analyses. Prophylactic leucovorin after repeated intrathecal MTX doses may be protective.

BACKGROUND:Treatment of pediatric B-acute lymphoblastic leukemia (B-ALL) impacts both patients and their caregivers. An understanding of family functioning during therapy can inform family-centered care. We aimed to prospectively identify negative and positive changes in family life as perceived by caregivers throughout ALL therapy. METHODS:Caregivers of children aged ≥4 years with average-risk B-ALL enrolled on the Children's Oncology Group trial AALL0932 who consented to an ancillary study were asked: "How has family life changed since your child's diagnosis of leukemia for the better or for the worse?" Written free responses were collected at approximately 2, 8, 17, 26 (end of therapy for females), and 38 (end of therapy for males) months post-diagnosis. Inductive content analysis was used to create codes, subcategories, and categories. Descriptive statistics were used to characterize the sample and frequencies of reported codes. RESULTS:Overall, 994 responses were collected from caregivers of 468 children across all timepoints. Twenty-seven individual codes were identified, categorized by negative changes (reported by 89% of caregivers) and positive changes (reported by 58% of caregivers). Subcategories of negative changes, including changes in daily routines, work and finance, patient health and care needs, effects on other family members, and emotional changes, were identified across all timepoints, but were most prevalent early in therapy. Importantly, positive changes were also identified, including family support, community support, and changes in outlook. CONCLUSION/CONCLUSIONS:This study identifies negative and positive family changes perceived by caregivers of children undergoing B-ALL therapy that can inform future interventions to better support families.