Ashley Chavana

Background: Neurotoxicity is a rare, often dose‐limiting adverse effect of methotrexate (MTX) therapy that disproportionally affects Latino children. Factors contributing to the observed disparity are not well understood. This study leveraged admixture mapping to identify genetic regions associated with MTX‐related neurotoxicity susceptibility among Latino children undergoing therapy for pediatric acute lymphoblastic leukemia (ALL). Procedure: The study cohort was composed of 429 self‐identifying Latino children diagnosed with ALL (2005–2019) between the ages of 2 and 20 years treated at one of six US pediatric cancer treatment centers. MTX‐related neurotoxicity was defined as neurologic episodes (e.g., seizures, stroke‐like symptoms, altered mental status, and tremors) occurring within 21 days of intravenous (IV) and/or intrathecal (IT) MTX that were documented by magnetic resonance imaging (MRI) abnormalities and/or clinical symptoms. Among the 429 patients, we identified 46 (10.7%) Latino children with neurotoxicity. Admixture mapping was used to identify local genomic regions that are associated with the risk of MTX‐related neurotoxicity among Latino children with ALL. Conclusions: Ultimately, this study identified 11 genomic regions carrying suggestive associations with MTX‐neurotoxicity risk among Latino children with ALL. Review of biological plausibility of the loci within these regions revealed associations with areas of the brain or downstream regulatory functions. Results from this study may guide future work to further interrogate these regions through fine‐mapping to identify genetic variants associated with increased risk of MTX‐related neurotoxicity among Latino children with ALL.

Purpose. High-dose-rate interstitial brachytherapy (HDR-IBT) is an essential component of curative treatment for locally advanced cervical cancer, but it is invasive and resource-intensive. Alternative boost techniques are needed when brachytherapy is not feasible. This study compares the dosimetric performance of stereotactic body radiotherapy (SBRT) and Syed-based HDR-IBT to evaluate the potential role of SBRT as a non-invasive boost modality. Materials and Methods. Eighteen patients with stage III–IV cervical cancer previously treated with external beam radiotherapy (EBRT) (45 Gy/25 fx ± nodal boost) followed by Syed HDR-IBT (28 Gy/4 fx) in our clinic were retrospectively analyzed. For each patient, SBRT plans prescribing 28 Gy in 4 fractions were generated on EBRT computed tomography images using fused Syed contours. Dosimetric parameters for targets and organs-at-risk (OARs), such as D ₉₈ , D ₉₀ , mean dose, maximum dose, D _2cc , D _1cc , were compared using the Wilcoxon signed-rank test. Results. For the high-risk clinical target volume (CTV_HR), HDR-IBT provided significantly superior coverage: mean 27 Gy D ₉₈ and 32 Gy D ₉₀ (Syed) vs. mean 25 Gy D ₉₈ and 29 Gy D ₉₀ (SBRT) ( p = 0.04 and p < 0.001). For the intermediate-risk CTV, SBRT plans achieved significantly better coverage: mean 18 Gy D ₉₈ and 22 Gy D ₉₀ (SBRT) vs. mean 14 Gy D ₉₈ and 18 Gy D ₉₀ (Syed) ( p < 0.001 for both). OAR doses were largely comparable between the two modalities, except that HDR-IBT resulted in significantly lower mean bladder dose and improved bowel sparing, whereas SBRT yielded significantly lower bladder maximum dose and reduced rectum D _2cc . Overall, SBRT exhibited greater low-dose spread to surrounding tissues, while HDR-IBT produced higher intratumoral dose hot spots. Conclusion. HDR-IBT remains superior for CTV_HR dose escalation, but SBRT can achieve acceptable target coverage and OAR sparing when brachytherapy is not feasible. SBRT may serve as a practical alternative for selected patients who are medically inoperable, anatomically unsuitable, or lack access to brachytherapy services. Prospective studies are needed to optimize SBRT planning strategies and define appropriate patient selection criteria.

Hepatotoxicity is a well-documented complication of induction chemotherapy for acute lymphoblastic leukemia (ALL), but our understanding of its biological mechanisms is limited. We identified 314 patients with ALL (aged 1-19 years) treated at Texas Children’s Hospital (2008-2019) with diagnostic bone marrow plasma available for metabolomic profiling: 234 for discovery and 80 for replication. Hepatotoxicity during induction was defined as follows: (1) transaminitis: grade ≥3 aspartate aminotransferase or alanine aminotransferase or (2) conjugated hyperbilirubinemia: conjugated bilirubin (c.bili) >3 mg/dL. Untargeted profiling detected 519 metabolites. Adjusted odds ratios (aORs) for each metabolite were calculated with logistic regression, accounting for sex, age, body mass index, race/ethnicity, and treatment intensity. The population was 56% Latino, 57% male, 92% B-ALL, 25% overweight/obese, and 57% National Cancer Institute standard-risk at a median age of 5 years. Transaminitis was observed in 34% of the discovery and 24% of the replication cohort. Seven instances of c.bili >3 mg/dL were observed in the discovery cohort, with none in the replication cohort. Furthermore, 12 metabolites were associated with transaminitis (P < .05) in the discovery cohort, including 2 that replicated (P < .05): 1,2-dipalmitoyl-glycerophosphocholine (GPC) (aOR combined = 1.88 [95% confidence interval [CI], 1.26-2.79], P = .002) and 1-(1-enyl-palmitoyl)-2-palmitoleoyl-GPC (aOR combined = 1.56 [95% CI: 1.17-2.09], P = .003). In the discovery cohort, 34 metabolites were associated with c.bili >3 mg/dL, including the top association of 1,2-dipalmitoyl-GPC (aOR = 5.76 [95% CI: 2.20-23.16], P = .002). We observed and replicated associations between phosphatidylcholine metabolites at ALL diagnosis and hepatotoxicity during induction therapy, suggesting a potential role for lipid dysregulation in the development of hepatotoxicity.

High‐dose methotrexate dosage and infusion durations differ across treatment protocols for pediatric leukemia, lymphoma, and osteosarcoma. Supportive care interventions are dependent on a patient's elimination of methotrexate (MTX). Therefore, it is important to establish the expected MTX elimination across protocols. Using modeling and simulation of real‐world data, we determined the expected MTX concentrations at common time points from the start of infusion (24, 36, 42, 48, 60, and 72 hours) and the time that each patient would reach a typical discharge threshold (0.4, 0.2, 0.15, and 0.10 µM). These data provide a reference for MTX concentrations for common pediatric protocols.

Background: Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate‐related neurotoxicity.Methods: This study included children (aged 2–20 years) diagnosed with ALL (2005–2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance therapy were independently reviewed by at least two pediatric oncologists. Germline DNA was genotyped and 97 methotrexate pharmacogenomic variants of interest with at least grade 3 evidence were identified using the Pharmacogenomics Knowledge Base. Associations between variants and neurotoxicity were assessed by logistic regression. Data were randomly split (80/20) and random forest was constructed to estimate the ability of the variants to correctly classify neurotoxicity.Results: Of the 763 patients included in the study, 8.2% (n = 63) developed methotrexate‐associated neurotoxicity. In logistic models, none of the 97 available pharmacogenomic variants reached adjusted statistical significance. However, two variants, rs17222723 (odds ratio [OR] = 2.83 [ref. = T allele], 95% confidence interval [CI]: 1.20–6.15) in ABCC2 and rs1045642 (OR = 0.66 [ref. = minor A allele], 95% CI: 0.44–0.98) in ABCB1, were nominally associated (p‐value < 0.05) with neurotoxicity susceptibility. The addition of pharmacogenomic variants did not improve the predictive performance of random forest model (AUC = 0.73) compared to clinical information alone (AUC = 0.74).Conclusion: Overall, our results suggest that associations between neurotoxicity susceptibility and methotrexate pharmacogenomic variants are generally modest and these variants do not significantly improve neurotoxicity risk stratification among children with ALL.

Background: Delayed excretion of high‐dose methotrexate (HD‐MTX) in pediatric acute lymphoblastic leukemia (ALL) can result in significant morbidity. While methotrexate is primarily renally excreted, HD‐MTX may overwhelm renal excretion and increase reliance on fecal elimination. This study evaluated the association between laxative use for constipation and delayed excretion of HD‐MTX.Methods: This multisite chart review included pediatric patients with ALL (2010–2020) who received HD‐MTX (5 g/m²). Delayed excretion was defined as a serum MTX concentration greater than 0.4 µM at Hour 48. We identified use of laxative medications after each HD‐MTX infusion, with receipt of two or more doses considered a proxy for constipation. Multilevel logistic regression models evaluated associations between clinical factors and delayed HD‐MTX excretion to account for multiple MTX cycles per individual.Results: A total of 533 eligible patients received 1875 HD‐MTX infusions. Patients were mostly male (59.8%), Hispanic (56.7%), with a median age of 9.5 years. Delayed excretion was observed following 42.7% of HD‐MTX infusions, and patients received two or more laxative doses during 19.9% of infusions. Independent of other factors, individuals who received two or more laxative doses were nearly 60% (odds ratio 1.58; 95% confidence interval: 1.19–2.09; p = .002) more likely to experience delayed excretion compared to those receiving fewer than two laxative doses.Conclusion: Receipt of at least two laxative doses was independently associated with delayed methotrexate excretion in pediatric patients with ALL. Future prospective studies are needed to confirm the secondary effects of constipation and confirm the association with constipation and identify clinical benefits that optimize drug excretion.

High‐dose methotrexate (HD‐MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD‐MTX (4.6–13.5 g/m²) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010–2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2–3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3–4 thrombocytopenia in 58%. No neurotoxicity was observed. HD‐MTX can be safely used with supportive care and monitoring.