Faculty Bibliography

OBJECTIVE:NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant genetic disorder characterized by the development of schwannomas, meningiomas, and spinal ependymomas. Treatment with bevacizumab, a monoclonal antibody against VEGF, has been shown to result in decreased vestibular schwannoma size and hearing improvement in ~50% of NF2-SWN patients. It is unknown whether the same degree of benefit is seen in younger patients compared with older patients. The objective of this study is to determine the association between age and bevacizumab treatment outcomes in NF2-SWN. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Thirty-seven patients with NF2-SWN. INTERVENTIONS/METHODS:Bevacizumab. MAIN OUTCOME MEASURES/METHODS:Change in tumor size of 20% or more. RESULTS:This study includes 37 patients with NF2-SWN who were treated with bevacizumab at our institution between 2014 and 2024. They were divided into 2 groups: 22 adults over the age of 25 (26 to 71 y) and 15 adolescent and young adult (AYA) patients under the age of 25 (12 to 24 y). The median treatment duration was 2.1 years. A significantly higher proportion of AYA schwannomas (37.5%, n=9) exhibited radiographic tumor progression during the treatment period compared with those of the older patient group (11.9%, n=5) (P=0.026), despite similar pre-treatment growth rates. There was no significant difference in the proportion of older and younger patients with hearing decline, improvement, or stability (P>0.05). CONCLUSIONS:AYA patients were significantly more likely to exhibit progression of tumor growth during bevacizumab treatment compared with older patients, though no significant differences were detected in hearing outcomes.

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.

While the physical manifestations of NF2-related schwannomatosis (NF2-SWN) have been well documented, there are a limited number of qualitative studies on health-related quality of life in NF2-SWN. The present study sought to explore the cumulative impact of symptoms, treatments, and healthcare on the quality of life of individuals with NF2-SWN. We interviewed 16 adolescent and adult patients with NF2-SWN enrolled in the INTUITT-NF2 clinical trial and 10 clinicians with NF2-SWN expertise from the United States, United Kingdom, and Australia. Analysis of patient and clinician interviews yielded five overall themes: (1) impacts on daily living, (2) impacts on life roles, (3) impacts on relationships and social integration, (4) impacts on psychological and emotional wellbeing, and (5) burden of treatment and healthcare. Multiple symptom areas contributed to impairments in quality of life across each theme. These findings reveal that quality of life in NF2-SWN is shaped not only by individual symptoms, but by their complex, cumulative impact-highlighting the urgent need for disease-specific tools and holistic care approaches that reflect the lived realities of patients across the lifespan.

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.

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.