Children's Oncology Group's 2023 blueprint for research: Hodgkin lymphoma.

The goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event-free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high-risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early-stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL.

Disparities in parental distress in a multicenter clinical trial for pediatric acute lymphoblastic leukemia.

BACKGROUND: Parent psychological distress during childhood cancer treatment has short- and long-term implications for parent, child, and family well-being. Identifying targetable predictors of parental distress is essential to inform interventions. We investigated the association between household material hardship (HMH), a modifiable poverty-exposure defined as housing, food, or utility insecurity, and severe psychological distress among parents of children aged 1-17 years with acute lymphoblastic leukemia (ALL) enrolled on the multicenter Dana-Farber ALL Consortium Trial 16-001. METHODS: This was a secondary analysis of parent-reported data. Parents completed an HMH survey within 32 days of clinical trial enrollment (T0) and again at 6 months into therapy (T1). The primary exposure was HMH at T0 and primary outcome was severe parental distress at T0 and T1, defined as a score greater than or equal to 13 on the Kessler-6 Psychological Distress Scale. Multivariable models were adjusted for ALL risk group and single parent status. RESULTS: Among 375 evaluable parents, one-third (32%; n = 120/375) reported HMH at T0. In multivariable analyses, T0 HMH was associated with over twice the odds of severe psychological distress at T0 and T1 HMH was associated with over 5 times the odds of severe distress at T1. CONCLUSIONS: Despite uniform clinical trial treatment of their children at well-resourced pediatric centers, HMH-exposed parents-compared with unexposed parents-experienced statistically significantly increased odds of severe psychological distress at the time of their child's leukemia diagnosis, which worsened 6 months into therapy. These data identify a high-risk parental population who may benefit from early psychosocial and HMH-targeted interventions to mitigate disparities in well-being.

Implementation of Systematic Financial Screening in an Outpatient Breast Oncology Setting.

PURPOSE: Implementation of routine financial screening is a critical step toward mitigating financial toxicity. We evaluated the feasibility, sustainability, and acceptability of systematic financial screening in the outpatient breast oncology clinic at a large, urban cancer center. METHODS: We developed and implemented a stakeholder-informed process to systematically screen for financial hardship and worry. A 2-item assessment in English or Spanish was administered to patients through the electronic medical record portal or using paper forms. We evaluated completion rates and mode of completion. Through feedback from patients, clinicians, and staff, we identified strategies to improve completion rates and acceptability. RESULTS: From March, 2021, to February, 2022, 3,500 patients were seen in the breast oncology clinic. Of them, 39% (n = 1,349) responded to the screening items, either by paper or portal, 12% (n = 437) preferred not to answer, and the remaining 49% (n = 1,714) did not have data in their electronic health record, meaning they were not offered screening or did not complete the paper forms. Young adults (18-39 years) were more likely to respond compared with patients 70 years or older (61% v 30%, P < .01). English-preferring patients were more likely to complete the screening compared with those who preferred Spanish (46% v 28%, P < .01). Non-Hispanic White patients were more likely to respond compared with Non-Hispanic Black patients and with Hispanic patients (46% v 39% v 32%, P < .01). Strategies to improve completion rates included partnering with staff to facilitate paper form administration, optimizing patient engagement with the portal, and clearly communicating the purpose of the screening. CONCLUSION: Systematic financial screening is feasible, and electronic data capture facilitates successful implementation. However, inclusive procedures that address language and technology preferences are needed to optimize screening.

Oral Mercaptopurine Adherence in Pediatric Acute Lymphoblastic Leukemia: A Survey Study From the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium.

Background: Oral chemotherapy nonadherence is a challenge in clinical oncology. During therapy for acute lymphoblastic leukemia (ALL), poor adherence to 6-mercaptopurine (6MP) increases relapse risk. Clinically significant nonadherence is reported in 30% of children treated for ALL on Children's Oncology Group (COG) trials. Whether nonadherence rates vary across regimens with different treatment schedules and modes of administration is unknown. Methods: We conducted an exploratory, cross-sectional survey study on parents of children (1-18 years) receiving continuation therapy on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001. Treatment required weekly visits to the clinic and 14 days of oral 6MP every 3 weeks. Survey assessed self-reported sociodemographics, medication-taking, chemotherapy comprehension, and 6MP adherence; adherence survey items were developed from published surveys. Patients were grouped as nonadherent if they endorsed missing one 6MP dose during the last cycle, or more than one dose during prior cycles, for nonmedical reasons. Results: Sixty-two families completed the surveys, all of whom had evaluable adherence data. In total, 25% of patients met the study definition of nonadherence. Twenty-three percent reported that it was "not easy" to follow administration guidelines around the dairy intake and 57% requested more teaching and educational resources. Conclusion: Self-reported nonadherence to oral 6MP in the DFCI ALL Consortium is high, with rates similar to those observed in the COG. This suggests that the additional contact during weekly infusions on the DFCI is insufficient to address barriers affecting oral chemotherapy adherence.

Feasibility of oncology clinical trial-embedded evaluation of social determinants of health.

Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is virtually absent from oncology clinical trials. Trial-based SDoH data are essential to ensure representation of marginalized populations, contextualize outcome disparities, and identify health-equity intervention opportunities. We report the feasibility of a pediatric oncology multicenter therapeutic trial-embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted-in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (88.9-93.1%) over 24 months. Trial-embedded SDoH data collection is feasible and acceptable and must be consistently included within future oncology trials.

New persistent opioid use among adolescents and young adults with sarcoma.

BACKGROUND: Adolescents and young adults (AYA) with sarcoma experience both acute and chronic pain related to their disease and treatment. Studies in older adults have reported a high risk of persistent opioid use after cancer therapy among previously opioid-naive patients; however, few studies have evaluated posttreatment opioid use among AYAs. This article describes patterns of new persistent opioid use among AYAs in the year after treatment for sarcoma. METHODS: Opioid-naive patients who were 10 to 26 years old and diagnosed with sarcoma (2008-2016) were identified with the IBM Marketscan Database. Included subjects had an International Classification of Diseases code for sarcoma (ninth or tenth revision), received anticancer therapy (chemotherapy, surgery, and/or radiation) within 30 days of the first diagnosis code, and had continuous insurance coverage (commercial or Medicaid) for more than 12 months both before the diagnosis and after the last therapy. The primary outcome was new persistent opioid use, which was defined as at least 2 opioid prescriptions in the 12 months following treatment completion. Covariates included age, sex, insurance, tumor type, surgical procedure, mental health (MH) or substance use diagnoses before or during therapy, and concomitant lorazepam use. RESULTS: In total, 938 patients met the inclusion criteria; 521 (56%) were male, and 578 (62%) were younger than 18 years. In total, 727 (78%) had commercial insurance, and 273 (29%) had an MH diagnosis either before or during the treatment period. Of the total group, 464 (49%) used opioids during treatment only. Of those who used opioids during treatment, 135 (23%) received at least 2 prescriptions in the year after therapy. In a multivariable analysis, Medicaid versus commercial insurance (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.15-2.64) and non-soft tissue sarcoma (OR for Ewing sarcoma, 3.23; 95% CI, 1.81-5.78; OR for osteosarcoma, 2.05; 95% CI, 1.36-3.09) conferred a higher likelihood of new persistent use. CONCLUSIONS: In this cohort of AYAs treated for sarcoma, 64% of the patients received opioid prescriptions during treatment, and 23% of these patients became new persistent users. Because of the risks associated with persistent opioid use, studies of novel pain management strategies along with age-appropriate education and anticipatory guidance are urgently needed. LAY SUMMARY: Using an insurance claims database, we conducted a study to determine the rate of new persistent opioid use among adolescents and young adults treated for sarcoma. We found that 64% of adolescents and young adults treated for sarcoma received opioid prescriptions during treatment, and 23% of these patients met the criteria for new persistent opioid use. These findings support the need for age-appropriate education and novel pain management strategies in this vulnerable population.

Second primary malignancy risk after Hodgkin lymphoma treatment among HIV-uninfected and HIV-infected survivors.

We compared secondary primary malignancy risk (SPM) in HIV-uninfected and HIV-infected Hodgkin lymphoma (HL) survivors. We used data from the California Cancer Registry on patients diagnosed with HL from 1990 to 2015 (all ages included), and standardized incidence ratios (SIRs) and multivariable competing risk models for analyses. Of 19,667 survivors, 735 were HIV-infected. Compared with the general population, the risk of SPM was increased by 2.66-fold in HIV-infected and 1.92-fold in HIV-uninfected survivors. Among HIV-infected survivors, median time to development of SPM was shorter (5.4 years) than in HIV-uninfected patients (8.1 years). Additionally, the highest risk of SPM was observed <2 years after diagnosis in HIV-infected survivors (SIR = 4.47), whereas risk was highest ≥20 years after diagnosis (SIR = 2.39) in HIV-uninfected survivors. The risk of SPMs persisted for decades and was higher among HIV-infected survivors, suggesting that these patients should benefit from long-term surveillance and cancer prevention practices.

Improving Health Equity and Reducing Pediatric Cancer Disparities: The Role of the Medical Home.

The advances in pediatric cancer outcomes over the last quarter century are some of the most successful in modern medicine. Improved diagnostics and novel therapies have led to continued increases in the survival rates of most patients; however, not all populations have benefitted equally. Compared to White children, Black, Indigenous, People of Color patients with cancer more often present with advanced stage illness, less frequently participate in clinical trials, and are more likely to be lost to follow-up once therapy is complete. Proposed hypotheses for these disparities include both biologic and nonbiologic factors, and a growing body of research suggests that barriers influencing care from diagnosis through survivorship are important. In this article, we consider how primary pediatricians can help reduce disparities over the cancer continuum by identifying vulnerable populations, considering potential diagnoses, referring to cancer centers, and following up with patients through survivorship in partnership with the oncology team. [Pediatr Ann. 2022;51(1):e22-e26.].

Racial Disparities in Children, Adolescents, and Young Adults with Hodgkin Lymphoma Enrolled in the New York State Medicaid Program.

Background: We examined the impact of race/ethnicity and age on survival in a publicly insured cohort of children and adolescent/young adults (AYA; 15-39 years) with Hodgkin lymphoma, adjusting for chemotherapy using linked Medicaid claims. Materials and Methods: We identified 1231 Medicaid-insured patients <1-39 years diagnosed with classical Hodgkin lymphoma between 2005 and 2015, in the New York State Cancer Registry. Chemotherapy regimens were based on contemporary therapeutic regimens. Cox proportional hazards regression models quantified associations of patient, disease, and treatment variables with overall survival (OS) and disease-specific survival (DSS), and are presented as hazard ratios (HR) with confidence intervals (95% CIs). Results: At median follow-up of 6.6 years, N = 1108 (90%) patients were alive; 5-year OS was 92% in children <15 years. In multivariable models, Black (vs. White) patients had 1.6-fold increased risk of death (HR: 1.58, 95% CI: 1.02-2.46; p = 0.042). Stage III/IV (vs. I/II) was associated with 1.9-fold increased risk of death (HR: 1.86, 95% CI: 1.25-2.78; p = 0.002) and treatment at a non-National Cancer Institute (NCI) affiliate was associated with worse DSS (HR: 2.71, 95% CI: 1.47-4.98; p = 0.001). Conclusions: In this Medicaid-insured cohort of children and AYAs with Hodgkin lymphoma, Black race/ethnicity remained associated with inferior OS in multivariable models adjusted for disease, demographic, and treatment data. Further work is needed to identify dimensions of health care access not mediated by insurance, as findings suggest additional factors are contributing to observed cancer disparities in vulnerable pediatric and AYA populations.

Use of Communication Technology to Improve Clinical Trial Participation in Adolescents and Young Adults With Cancer: Consensus Statement From the Children's Oncology Group Adolescent and Young Adult Responsible Investigator Network.

Adolescents and young adults (AYAs; age 15-39 years) with cancer are under-represented in cancer clinical trials because of patient, provider, and institutional barriers. Health care technology is increasingly available to and highly used among AYAs and has the potential to improve cancer care delivery. The COVID-19 pandemic forced institutions to rapidly adopt novel approaches for enrollment and monitoring of patients on cancer clinical trials, many of which have the potential for improving AYA trial participation overall. This consensus statement from the Children's Oncology Group AYA Oncology Discipline Committee reviews opportunities to use technology to optimize AYA trial enrollment and study conduct, as well as considerations for widespread implementation of these practices. The use of remote patient eligibility screening, electronic informed consent, virtual tumor boards, remote study visits, and remote patient monitoring are recommended to increase AYA access to trials and decrease the burden of participation. Widespread adoption of these strategies will require new policies focusing on reimbursement for telehealth, license portability, facile communication between electronic health record systems and advanced safeguards to maintain patient privacy and security. Studies are needed to determine optimal approaches to further incorporate technology at every stage of the clinical trial process, from enrollment through study completion.

Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001.

The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030.

Survival by age in paediatric and adolescent patients with Hodgkin lymphoma: a retrospective pooled analysis of children's oncology group trials.

BACKGROUND: Adolescents with Hodgkin lymphoma have worse disease outcomes than children. Whether these differences persist within clinical trials is unknown. We examined survival, by age, in patients receiving response-adapted therapy for Hodgkin lymphoma on Children's Oncology Group (COG) trials. METHODS: Patients (aged 1-21 years) diagnosed with classical Hodgkin lymphoma and enrolled between Sept 23, 2002, and Jan 19, 2012, on one of three phase 3 COG trials in the USA and Canada were eligible for inclusion. The three COG trials were defined by risk group according to Ann Arbor stage, B-symptoms, and bulk (AHOD0431 [low risk; NCT00302003], AHOD0031 [intermediate risk; NCT00025259], or AHOD0831 [high risk; NCT01026220]). The outcomes of this study were event-free survival (death, relapse, or subsequent neoplasm) and overall survival. Cox proportional hazards models estimated survival, adjusting for disease and treatment factors both overall and in patients with mixed cellularity or non-mixed cellularity (nodular sclerosing and not-otherwise-specified) disease. FINDINGS: Of 2155 patients enrolled on the three trials, 1907 (88·4%; 968 [50·8%] male and 939 [49·2%] female; 1227 [64·3%] non-Hispanic White) were included in this analysis. After a median follow-up of 7·4 years (IQR 4·3-10·2), older patients (aged ≥15 years) had worse unadjusted 5-year event-free survival (80% [95% CI 78-83]) than did younger patients (aged <15 years; 86% [83-88]; HR 1·38 [1·11-1·71]; p=0·0038). Older patients also had worse unadjusted 5-year overall survival than did younger patients (96% [95% CI 95-97] vs 99% [98-99]; HR 2·50 [1·41-4·45]; p=0·0012). In patients with non-mixed cellularity histology, older patients had a significantly increased risk of having an event than did younger patients with the same histology (HR 1·32 [1·03-1·68]; p=0·027). Older patients with mixed cellularity had significantly worse 5-year event-free survival than did younger patients in unadjusted (77% [95% CI 65-86] for older patients vs 94% [88-97] for younger patients; HR 2·93 [1·37-6·29]; p=0·0039) and multivariable models (HR 3·72 [1·56-8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49-6·39]; p=0·0025). INTERPRETATION: Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (<15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum. FUNDING: National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

Initial cancer treatment and survival in children, adolescents, and young adults with Hodgkin lymphoma: A population-based study.

BACKGROUND: Hodgkin lymphoma (HL) is a treatable tumor affecting children, adolescents and young adults (AYAs; 15-39 years old). Population-based studies report worse survival for non-White children and AYAs but have limited data on individual therapeutic exposures. This study examined overall and HL-specific survival in a population-based cohort of patients while adjusting for sociodemographic factors and treatment. METHODS: Data for 4807 patients younger than 40 years with HL (2007-2017) were obtained from the California Cancer Registry. Individual treatment information was extracted from text fields; chemotherapy regimens were defined by standard approaches for pediatric and adult HL. Multivariable Cox models examined the influence of patient and treatment factors on survival. RESULTS: At a median follow-up of 4.4 years, 95% of the patients were alive. Chemotherapy differed by age, with 70% of 22- to 39-year-olds and 41% of <22-year-olds receiving doxorubicin, bleomycin, vinblastine, and dacarbazine (P < .001). In multivariable models, older patients (22-39 vs < 21 y; hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11-2.10), Black (vs White patients); HR, 1.90; 95% CI, 1.25-2.88), and Hispanic patients (HR, 1.45; 95% CI, 1.06-1.99) experienced worse survival; among those < 21 y, Black race was associated with a 3.3-fold increased risk of death (HR, 3.26; 95% CI, 1.43-7.42). CONCLUSIONS: In children and AYAs with HL, older age and non-White race/ethnicity predicted worse survival after adjustments for treatment data. Further work is needed to identify the biological and nonbiological factors driving disparities in these at-risk populations.

Patterns of National Cancer Institute-Sponsored Clinical Trial Enrollment in Black Adolescents and Young Adults.

BACKGROUND: Both adolescent and young adult (AYA) and Black or African American (hereafter referred to as Black) cancer patients are historically under-enrolled in cancer treatment trials (CTT). The purpose of this study was to quantify enrollment of Black AYAs in National Cancer Institute (NCI)-sponsored CTTs overall and by age, sex, and cancer diagnosis during 2000-2015. METHODS: Utilizing data from NCI's Cancer Therapy Evaluation Program and the Surveillance, Epidemiology and End Results (SEER) Program, we assessed CTT enrollment in Black patients with cancer and measured changes in enrollment over time between the study periods 2000-2007 and 2008-2015. Enrollment patterns were compared across age groups (≤14 years [y], 15-19y, 20-29y, 30-39y and 40+ years), sex, and cancer diagnosis. RESULTS: From 2000 through 2015, <3% of Black AYAs (20-39y) enrolled on CTTs. While AYAs had significantly higher cancer incidence than children, 20.5% fewer Black AYAs enrolled on CTTs. Enrollment was lowest among Black males 20-29y, with a mean of 18 enrolling in CTTs annually. The proportion of AYA enrollees who were Black did not change significantly over time periods (2000-2007 vs 2008-2015). CONCLUSIONS: Few Black AYAs enroll in CTTs each year. Given known benefits of clinical trial participation and the well-documented racial and age-related differences in cancer outcomes, addressing barriers to enrollment in these patients may, in turn, reduce disparities. Targeted interventions aimed at increasing the CTT enrollment of Black cancer patients, particularly young Black men, are urgently needed. PRECIS: This study documents that compared with Black children, Black adolescent, and young adult (AYA) patients were less likely to enroll in NCI-sponsored CTTs from 2000 to 2015. Black AYA male enrollment decreased with increasing age, highlighting disparities among this specific population in CTT enrollment.

Improving Health Equity and Reducing Disparities in Pediatric and Adolescent/Young Adult Oncology: In Support of Clinical Practice Guidelines.

Despite extraordinary strides in cancer therapy over the past 30 years, racial/ethnic, socioeconomic, and age-related survival disparities persist. Hodgkin lymphoma offers an excellent paradigm to understand these disparities because successful approaches are well established in both the up-front and relapsed treatment settings. The following review, which accompanies the 2021 NCCN Guidelines for Pediatric Hodgkin Lymphoma, suggests that systemic inequities in cancer care disproportionately affect minority and low-income children, adolescents, and young adults, and directly contribute to observed disparities in cancer-related outcomes. It proposes that the first step toward reducing disparities is large-scale dissemination of guidelines, because equity is best achieved when treatment approaches are clear, comprehensive, and standardized across all clinical practice settings.

Severe Vincristine-related Neurotoxicity in 5 Patients With Pediatric Acute Lymphoblastic Leukemia Requiring Discontinuation of Vincristine: A Description of Long-term Outcome.

Vincristine, a key agent in the treatment of many pediatric malignancies, causes sensory, motor and autonomic neuropathy. We report the clinical courses of 5 patients who required cessation of vincristine after developing severe neurotoxicity during treatment for acute lymphoblastic leukemia. All 5 patients lost the ability to ambulate and 3 had additional severe neurotoxic side effects including vision loss and vocal cord dysfunction. Although prior literature reports poor outcomes for children in whom vincristine was discontinued during acute lymphoblastic leukemia therapy, all 5 patients described here achieved and have maintained complete continuous remission.

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.

Genetic ancestry and skeletal toxicities among childhood acute lymphoblastic leukemia patients in the DFCI 05-001 cohort.

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms.