Kenneth M. Heym

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.

Figure S1 shows a cross-validation plot to determine ‘k’ number of populations for the REDIAL dataset. Note the elbow of the scree plot at k = 4. This indicates that the genetic structure of the dataset is best explained by four ancestral populations, as adding more populations provides diminishing returns in reducing cross-validation error.

Supplementary Table S2 shows demographics and clinical characteristics of the 593 genetically analyzed REDIAL patients.

Figure S2 shows correlation matrices of (A) inferred global genetic ancestry within each ancestry cluster defined by K-means classification (AFR, EUR, AS, AMR), and (B) inferred genetic ancestry by self-reported racial/ethnic categories.

Supplementary Table S3 shows mean genetic ancestry by self-reported race/ethnicity.

Supplementary Table S1 shows mean genetic ancestry by k-means clustering of inferred global genetic ancestry.

Background: Pediatric acute lymphoblastic leukemia (ALL) is the most common cancer in children, and its incidence and outcomes vary by race and ethnicity. Methods: The Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium has assembled a cohort of patients <25 years at diagnosis to examine genetic and neighborhood-level factors influencing ALL. As the cohort is ongoing, for this report, we examined sociodemographic and cytogenetic factors that might be associated with ALL outcome disparities. Results: Among 2,512 patients diagnosed between 2005 and 2020, we observed distinct patterns of genetic ancestry and residential characteristics across self-reported race and ethnicity. Latino children, who comprised 55.3% of the cohort, had a mean Amerindigenous ancestry proportion of 50.9%, whereas non-Latino White children exhibited a predominantly European ancestry (mean = 78%). Neighborhood-level analysis revealed significant socioeconomic and geographic differences by race/ethnicity, with Latino children more frequently residing in Latino enclaves or economically disadvantaged neighborhoods. Cytogenetic profiling of 551 patients showed that favorable subtypes (double trisomies and ETV6::RUNX1) predominated overall, but ETV6::RUNX1 was significantly less common in Latino than in non-Latino White children; conversely, CRLF2 overexpression and immunoglobulin heavy chain (IGH) rearrangements were more frequent among Latino children. Conclusions: This first REDIAL cohort analysis reveals how genetic ancestry and neighborhood-level factors jointly shape the distribution of ALL cytogenetic subtypes, advancing our understanding of contributors to disparities in ALL outcomes. Impact: This analysis offers insights into factors underlying disparities in ALL outcomes that may be targeted for mitigation, ultimately guiding more equitable approaches to risk stratification and intervention.

INTRODUCTION: Vincristine sulfate liposome injection (VSLI), a liposomal formulation of vincristine, may be better tolerated than standard aqueous vincristine and enable dose intensification. PROCEDURES: Based on single‐agent tolerability, activity, and FDA approval in adults with acute lymphoblastic leukemia (ALL), we tested the safety and feasibility of VSLI as replacement for standard vincristine in the UK ALL R3 mitoxantrone‐based four‐drug induction (Cohort A), a three‐drug anthracycline‐free induction (Cohort B), and maintenance chemotherapy (Cohort C) in children and young adults with relapsed/refractory B‐cell ALL. RESULTS: Among 29 participants with a median age of 12.4 years (range: 1.8–19.6 years), 16 received Cohort A, eight received Cohort B, and five received Cohort C therapy. Dose level 1 (DL1): 1.5 mg/m ² and dose level 2 (DL2): 2 mg/m ² of VSLI, each without a dose cap, were tested. Collectively, the median VSLI dose administered was 1.9 mg (range: 0.71–4.06 mg), and 13 (44.8%) received a dose above the standard 2 mg vincristine dose cap. Dose‐limiting toxicities (DLTs) at DL2 were seen in three patients, two in Cohort A and one in Cohort B, prompting further evaluation at DL1 for both cohorts. No DLTs were experienced at DL1. Only DL2 was tested in Cohort C—without DLT. Complete remissions were seen in 14 of 16 (87.5%) participants in Cohort A; three of eight (37.5%) in Cohort B; and one (20%) in Cohort C. VSLI with combination chemotherapy at DL1 was generally well tolerated. CONCLUSION: Based on the promising response signal in this heavily pretreated population, further study of VSLI is warranted. (ClinicalTrials.gov NCT02879643)

Purpose:Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML.Experimental Design:ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens.Results:Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23–0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19–0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05–3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96–4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score–based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002).Conclusions:Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.