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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.

VAF concordance

Supplementary Data file including supplementary methods and clinical case vignettes.

Reasons for not using recommended targeted therapy.

Patient sequencing data, by patient number and diagnosis.

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

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.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.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 (aged15 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).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.National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

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, 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.

BackgroundHodgkin 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.MethodsData 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.ResultsAt 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

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.

Background Food insecurity (FI) is an adverse social determinant of health (SDoH) prevalent among pediatric cancer patients and associated with poorer health outcomes in general pediatrics. Receipt of federal SNAP benefits reduces FI in general pediatrics, and is thus a marker of appropriate resource support to mitigate adverse SDoH. Dana-Farber Cancer Institute (DFCI) Acute Lymphoblastic Leukemia (ALL) Consortium Trial 16-001 is the first pediatric oncology clinical trial to prospectively collect parent-reported SDoH, including income, SNAP receipt, and FI. We investigated whether income-eligible pediatric ALL families were successfully receiving SNAP benefits, and whether SNAP receipt was associated with FI. Methods Secondary analysis of children aged 1-17 years with de novo ALL enrolled on the DFCI 16-001-embedded SDoH cohort study at 6 US centers from 2017-2022. We utilized parent-reported SDoH data at diagnosis (T0) and 6-mos (T1) into therapy to identify families as (1) SNAP-eligible, proxied as household income Citation Format: Rahela Aziz-Bose, Yael Flamand, Puja J. Umaretiya, Lenka Ilcisin, Ariana Valenzuela, Peter D. Cole, Lisa M. Gennarini, Justine M. Kahn, Kara M. Kelly, Bruno Michon, Thai-Hoa Tran, Jennifer J. G. Welch, Lewis B. Silverman, Kira Bona. Food insecurity and receipt of Supplemental Nutrition Assistance Program (SNAP) benefits among income-eligible US pediatric acute lymphoblastic leukemia patients enrolled on a multi-center clinical trial [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B096.

Introduction Second primary malignancy (SPM) is one of the most devastating late complications following Hodgkin lymphoma (HL) treatment. Historically, the most common SPMs in patients treated for HL are solid tumors, which are largely related to radiation exposure during initial therapy. For the last three decades, efforts to address the risk of SPM after HL therapy have focused on reducing exposure to radiation, as well as refining the approach for patients where radiation is indicated. To date, few population-based studies in the United States have quantified the burden of SPMs and evaluated the potential effect of changes in therapeutic management over time. Additionally, to our knowledge, no study has compared SPM risk between human immunodeficiency virus (HIV)-infected and HIV-uninfected HL survivors. Methods We used data from the California Cancer Registry on 21,043 patients diagnosed with primary HL between 1988 and 2015 with follow-up through 2017. We calculated standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) and absolute excess risks (AERs) to compare SPM incidence in our HL cohort with the expected number of first primary cancer incidence in the general California population, based on patient's age at diagnosis (5-year categories), sex, calendar year (3-year intervals), cancer site, and race/ethnicity. SIRs are presented by HIV status, SPM latency, treatment era, and cancer type. P-values for trends were used to examine whether SPM risk changed over time. Findings Among 20,303 HIV-uninfected patients (median follow-up of 14.1 years), overall SPM risk was increased 1.95-fold compared with the general population (SIR=1.95, 95% CI 1.86-2.04). In 740 HIV-infected patients (median follow-up of 11.7 years), overall risk was increased 2.68-fold compared with the general population (SIR=2.68, 95% CI 2.0-3.40), translating to an 37% higher incidence of SPM in HIV-infected vs. HIV-uninfected patients. The AER (per 10,000 person-years) of SPM was 43.1 in HIV-uninfected and 76.5 in HIV-infected patients, resulting in a 33.4 excess SPM per 10,000 person-years in HL survivors with HIV. Malignancies that contributed the most to overall AER were non-Hodgkin lymphoma (NHL), female breast and lung cancers in HIV-uninfected patients; and Kaposi sarcoma, NHL, anorectal and head & neck (HNC) cancers in HIV-infected patients. Notably, among HIV-uninfected patients, the highest overall risk of SPM occurred ≥20 years after diagnosis (SIR= 2.27, 95% CI 1.99-2.58) (Figure). In contrast, the highest overall risk in HIV-infected patients was observed Conclusion Compared with the general population, the risk of developing a SPM following HL treatment was significantly higher among both HIV-uninfected and HIV-infected patients, with the absolute excess risk greater for those with HIV infection. There were different temporal patterns and types of SPM between HIV-uninfected and HIV-infected patients. These findings prompt the question on whether earlier and/or more intensive cancer screening should be pursued for HIV-infected survivors. The trend towards decreased risk for selected solid SPMs among HIV-uninfected patients, especially lung and female breast cancers, suggest that strategies to reduce radiation in HL survivors may be working. Despite promising trends in this group, the observation that SPM risk was highest ≥20 years after initial therapy further highlights the need for long-term surveillance and survivorship care in this at-risk population. Disclosures Rosenberg: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Wun:Glycomimetics, Inc.: Consultancy.

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening condition associated with endothelial cell damage due to hematopoiet...

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.

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

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.

Poor adherence to 6-mercaptopurine during acute lymphoblastic leukemia (ALL) therapy increases relapse risk. Clinically-significant non-adherence has been documented in up to 30% of children treated for ALL on Children’s Oncology Group trials. Whether non-adherence rates vary across regimens with different chemotherapy schedules and modes of administration is not known. In a cross-sectional survey study of N= 61 children treated on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001, 25% (95% CI 14 – 37%) of respondents self-reported non-adherence to 6MP, suggesting that the frequency of non-adherence may be similar across different Consortia regimens.

Identifying which patients are at high risk for transplant-related mortality, prior to allogeneic hematopoietic cell transplantation (alloHCT), is crucial both to guide decision making with patients and families and to inform the alloHCT approach. There is a paucity of data evaluating the utility of the HCT comorbidity index (HCT-CI) in pediatric patients. We performed a retrospective cohort study of 188 patients who underwent alloHCT between January 2008 and October 2016 and assessed pretransplant comorbidities defined and weighted by the HCT-CI. The primary endpoint of our study was overall survival (OS). Kaplan-Meier method was used to assess survival estimates at 1-year post-transplant and did not differ based on HCT-CI scores: 78.7% (SE 6.69%) for HCT-CI = 0, 74.7% (SE 6.33%) for HCT-CI = 1 to 2, and 77.3% (SE 4.17%) for HCT-CI ≥3. Multivariable Cox proportional hazards analysis did not show HCT-CI having an effect on OS: hazard ratio (HR) of 0.633 (95% confidence interval [CI], 0.297 to 1.347) for HCT-CI scores 1 to 2 and HR of 0.935 (95% CI, 0.456 to 1.918) for HCT-CI scores ≥3 compared to scores of 0. The most frequent comorbidities observed were hepatic disease (mild in 29%, severe in 23%) and pulmonary disease (moderate in 15% and severe in 29%). However, only 55% were able to complete pulmonary function testing. Hepatic disease was based on transaminitis in 48% and by bilirubin alone in 26% of patients; 46% of patients with hepatic dysfunction had an underlying hemoglobinopathy and hyperbilirubinemia related to ongoing hemolysis. This study evaluates HCT-CI comorbidities in greater detail than has been performed previously in children undergoing alloHCT. We identify challenges with the HCT-CI in the pediatric population and highlight the comorbidities that may benefit from adjustments to their definition to create an improved risk assessment tool for children.

BACKGROUND/OBJECTIVES While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range

To ensure optimal clinical outcomes for patients while retaining adequate protection for donors, the National Marrow Donor Program developed guidelines specifying that up to 20 mL/kg of bone marrow can be harvested from donors. These guidelines, originally developed for unrelated adult donors, are followed in children as well. We studied the impact of granulocyte colony-stimulating factor (G-CSF) priming on the cellular composition of harvested bone marrow, sought to develop an algorithm to optimize bone marrow harvest volume from pediatric matched sibling donors, and studied the impact of CD34+ cell dose on clinical outcomes. We analyzed data from 92 bone marrow harvests and clinical outcomes for 69 sibling recipient-donor duos, The mean age of recipients was 9.85 ± 5.90 years, and that of donors was 11.85 ± 6.36 years. G-CSF priming was not associated with higher yield of CD34+ cells/µL. The median CD34+ cell count obtained from donors was 700 cells/µL (range, 400-1700 cells/µL) in donors age 12 years (P

Introduction: Allogeneic hematopoietic cell transplantation (HSCT) is a curative treatment option for children and adolescents with non-malignant disorders. Continued advances in HSCT have led to a growing population of long-term survivors. For these survivors, late occurring chronic health conditions or so-called "late effects" remain a challenge. We examined the cumulative incidence of selected late effects at 5- and 10-years post-HSCT in pediatric and adolescent patients transplanted for non-malignant diseases. Methods: A retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database was performed. Eligible patients (1 - 20 years) underwent HSCT between 1995 and 2012 for treatment of non-malignant disorders including marrow failure, red cell disorders, and immunodeficiencies (Table). Late effects evaluated were: avascular necrosis (AVN), cataracts, diabetes, growth hormone deficiency, hypothyroidism, gonadal dysfunction, renal failure requiring dialysis, and neurologic events (stroke and seizure). The cumulative incidence of each late effect was calculated at 5-years and 10-years from date of first report post-HSCT. Results: Median follow up was 94.1 months. A total of 5,858 patients from 230 centers were included. Median age at HSCT was 5.5 years. The majority (65%) of the patients were White race/ethnicity and 9% were Black, 60% were male. Diagnoses included: Marrow failure disorders, hemoglobinopathies, immunodeficiencies and immune-dysregulation syndromes (Table). The majority (62%) of the cohort received myeloablative conditioning (MAC), and a minority (16%) received total body irradiation (TBI). Among all patients, 19% had chronic graft-versus-host-disease (GVHD). Cumulative incidence estimates at 5- and 10-years post-HSCT are presented in the Table. One-third (28%) of patients had at least one late effect. Cumulative incidence estimates at 10 years included stroke/seizures (11.2%), renal failure (7.7%), growth hormone deficiency/disturbance (7.6%), gonadal dysfunction (4.2%), hypothyroidism (4.1%), cataracts (2.9%), and AVN (1.4%). For AVN, renal failure, and stroke or seizures, incidence was stable between 5 and 10 years. For endocrine-associated late effects, incidence increased over time, nearly doubling from 5 to 10 years (Table). Across the cohort, the probability of growth hormone deficiency increased from 3.7% at 5-years, to 6.5% at 10-years. Similarly, hypothyroidism increased from 2.7% at 5-years, to 4.5% at 10 years. The cumulative incidence of treatment-associated diabetes was 3.1%, with most cases occurring in the first-year post-transplant. Finally, the probability of cataracts at 10 years was 2.9%, which was double the incidence at 5 years. Conclusions Among children and adolescents undergoing HSCT for non-malignant diseases, cumulative incidence of late effects was overall low, and did not exceed 12% at 10 years. The timing of late effect development differed, with the cumulative incidence of AVN, diabetes, renal failure, and seizure/stroke staying fairly stable after 5-years. Diabetes occurred most frequently in the first year, which may be a reflection of steroids or other medications to manage graft-versus-host-disease during the early-post transplant period. In contrast, the incidence of endocrine-associated late effects including growth disturbance, hypothyroidism, gonadal dysfunction and cataracts nearly doubled between 5 and 10-years post-transplant. Findings from this work further emphasize the need for long-term follow-up and screening for late effects, particularly diabetes, renal disease and neurologic symptoms early post-transplant, and cataracts and endocrinopathies over time. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Schoemans: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: personal fees , Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants and personal fees; Gilead: Other: travel grants; CIBMTR: Consultancy, Other: travel grants; Janssen: Membership on an entity's Board of Directors or advisory committees; BHS: Membership on an entity's Board of Directors or advisory committees, Other: travel grants and personal fees , Research Funding; Jazz Pharmaceuticals: Other: personal fees; Takeda: Other: personal fees. Phelan: Amgen Pharmaceuticals: Research Funding.

Introduction: Increased toxicity with pegaspargase (PEG) in older and higher body mass index (BMI) patients (pts) with acute lymphoblastic leukemia (ALL) has recently led to dose capping practices. We assessed the influence of age, body surface area (BSA), and BMI on PEG-related toxicity and pharmacokinetics from two consecutive DFCI ALL Consortium trials without dose capping. Methods: Patient (pts) aged 1 to 0.1 IU/mL, was assessed 4, 11, 18, and 25 days after the Induction dose and nadir SAA was assessed before each Post-Induction dose. Asparaginase-related toxicities were prospectively assessed and graded by CTCAE version 3.0 (DFCI 05-001) or 4.0 (DFCI 11-001). Asparaginase toxicity for this analysis was defined as ≥1 of the following: pancreatitis, thrombosis, ≥grade 4 hyperbilirubinemia, ≥grade 4 hypertriglyceridemia. Allergy was analyzed separately (due to presumed dose independence). Height and weight at diagnosis were used for analyses. BMI categories were assigned using standard percentile ranges based on gender specific 2000 CDC growth charts. BSA was calculated using the Mosteller formula. Univariate analyses evaluated the relationship of age, BMI, and BSA with asparaginase toxicity. Comparisons of toxicity across BMI and BSA categories were performed using a Jonckheere-Terpstra test. Categorical comparisons for dichotomized BMI and BSA utilized a Fisher's exact test or chi square test. The relationships between BMI and BSA with toxicity were explored using multivariable models. Results: Between 4/2005-12/2011 802 pts enrolled on DFCI 05-001 and between 6/2012-6/2015 240 pts enrolled on DFCI 11-001. Both trials included random assignment of asparaginase formulation. In total 911 patients received pegaspargase during Induction and 351 during Post-Induction. During Induction, pts ≥15 years of age had higher asparaginase toxicity rates (17.1% vs 6.2%, p=0.0003) (Figure 1a). Toxicity differed significantly across BSA categories ( Post-Induction, age ≥15 years was associated with increased asparaginase toxicity (57.1% vs 21%, p Post-Induction, median nadir SAA levels were ≥0.1IU/mL for all BSA and age categories. Median SAA was similar or lower at all time-points for those ≥15 years of age compared with younger children. Median SAA for pts with BSA ≥1.5m 2 were similar or lower compared to those with BSA Conclusion: Age ≥15 years and BSA ≥2m 2 were each associated with significantly increased asparaginase toxicity. Older patients and those with higher BSA had similar or lower median SAA levels at all time-points. These results suggest that the differential toxicity seen in older patients and those with higher BSA is not explained by these patients having higher SAA levels. Prospective exploration of interventions to decrease toxicity in older patients and those with high BSA are needed. Figure 1 Figure 1. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Introduction: Assessment of minimal residual disease (MRD) in a sensitive and timely manner is an essential component of risk stratification in childhood acute lymphoblastic leukemia (ALL). Next generation sequencing (NGS) assays utilize unique genetic sequences created by VDJ rearrangements in leukemia cells to detect MRD at the level of 1 leukemic cell in 1 million cells (Wood et al., 2018). Here we report our experience using NGS MRD for risk group assignment of children and adolescents with newly diagnosed ALL enrolled on the Dana Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001. Methods: Patients (pts) ages 1-21 years with B- or T-ALL were eligible for enrollment from 8 centers across the US and Canada. Initial risk status was assigned based on age, presenting leukocyte count, central nervous system (CNS) leukemia status, immunophenotype, and disease biology (Table 1). All patients underwent bone marrow evaluation at diagnosis and again upon completion of remission induction approximately four weeks later (Induction 1a, timepoint 1 (TP1)), with samples evaluated by flow cytometry (FCM) and NGS. NGS was primarily used for MRD-based risk determination, with FCM as a back-up test. Patients with high TP1 MRD (≥10 -4) received intensified therapy and underwent additional MRD assessments at 10 and 20 weeks of therapy. Multiparametric FCM was conducted locally for 7 of 8 sites in accordance with local CLIA certified lab practices. One site used centralized FCM. NGS MRD was assessed at Adaptive Biotechnologies Corporation, Seattle, WA using the commercially available assay ClonoSEQ ®. Clonality was evaluated at the immunoglobulin (Ig) heavy and light chain (IgH and IgL) and T cell receptor beta and gamma (TCR-B and TCR-G) loci with the maximal sequence used for MRD determination. Results: NGS evaluation of MRD is feasible A total of 317 patients enrolled on 16-001 between 2017 and 2020 were included in this analysis. Among this cohort, NGS identified unique trackable sequences in 98% of pts (N=310). Of the 7 pts without trackable sequences, 57% were pts with early T precursor (ETP) T-ALL (36% of all ETP pts tested). NGS detected trackable sequences in all non-ETP T-ALL pts (N=40), and 99% of B-ALL pts (N=263). Locus used for MRD determination Patients with B-ALL had a median of 5 trackable sequences (range 0-14) with 92% having at least one IgH and 64% having at least one TCR-G. For B-ALL, the highest MRD value at TP1 was determined by IGH locus in 44% (N=115) of pts and by TCR-G in 41% (N=109). The IgL or TCR-B locus yielded the highest TP1 MRD value in 15% (N=39). In contrast, pts with T-ALL had fewer trackable sequences with a median of 3 (range 0-8). While 28% (N=13) had at least one Ig sequence, the TCR locus was used for MRD determination in nearly all (98%, N=46) with 94% using TCR-G. Comparison of NGS and FCM MRD results NGS and FCM MRD values for 309 pts with results from both assays at TP1 are displayed in Figures 1a-d. Correlation was high between the two modalities for patients with detectable disease by both NGS and FCM (Pearson r=0.87, p For B-ALL pts with high MRD (N=70), 43% (N=30) were high by NGS (≥10 -4) when FCM was low ( Eight pts, all with B-ALL, had low NGS MRD when FCM was above the threshold of 10 -4. One patient had undetectable NGS MRD and the remaining 7 had NGS MRD in the range of 10 -6 to Conclusions: Delivery of risk adapted therapy for newly diagnosed pediatric pts with ALL utilizing an NGS MRD assay is feasible with evaluable MRD for 98% of patients in our cohort. Importantly, NGS identified more cases as having high MRD than FCM, with the majority of discrepant cases just above the FCM limit of detection (10 -4). NGS provided improved resolution in the range of 10 -6 to Figure 1 Figure 1. Disclosures Kirsch: Adaptive Biotechnologies: Current Employment, Current holder of stock options in a privately-held company. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If < 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

Introduction While 5-year event-free (EFS) and overall survival (OS) in Hodgkin lymphoma (HL) generally exceed 85% and 95%, respectively, outcomes may not be as favorable in adolescents and young adults (15 - 39 years [y]) compared to children. Small clinical trials have reported better outcomes for pediatric but not adult patients with mixed cellularity (MC) vs. nodular sclerosing (NS) histology, suggesting the possibility of biologic differences across the age-spectrum in HL. We examined survival by age and histology in patients receiving risk-based, response-adapted therapy for de novo HL on contemporary Children's Oncology Group (COG) trials. Methods This was a pooled analysis of individual-level data from 1,907 patients enrolled on three Phase 3 COG clinical trials for treatment of low-risk (AHOD0431), intermediate risk (AHOD0031) and high-risk (AHOD0831) HL between 2002 and 2012. Histologic subgroups included MC, NS and classical HL, not-otherwise-specified (cHL, NOS). Five-year cumulative incidence of relapse, EFS and OS were compared by age group ( Results Between 2002 and 2012, N= 2155 patients 1 - 21 y enrolled on three COG trials, 1,907 (88%) of whom were included in this analysis. Mean age of the cohort was 14.6 y (± 3.5) with N= 871 (46%) Survival: Median follow up was 6.9 years. In unadjusted analyses, 5-year EFS and OS were 83% and 97%, respectively. The 5-year EFS was lower for patients ≥15 y vs. The effect of age on EFS varied by histologic subgroup. Among those with non-MC histology, cumulative incidence of relapse did not significantly differ by age in unadjusted models (Figure A), however 5-year EFS was significantly worse in the older group (Figure B). In multivariable analyses, age ≥15 y (vs. younger) was associated with a 1.3-fold increased risk of EFS (HR: 1.3; 1.03 - 1.7, p= 0.03) (Table). Among patients with MC histology, age ≥15 y (vs. younger) was associated with significantly higher relapse rate (22% vs. 5%, p< 0.01) (Figure C) and significantly worse 5-year EFS (75% vs. 94%, p< 0.01) (Figure D). This remained significant in multivariable models: patients with MC histology who were ≥15 y (vs. younger) had a 3.7-fold increased risk of EFS (HR: 3.7, 95% CI: 1.6, 8.9, p< 0.01) (Table). Conclusion In patients receiving response-adapted therapy for de novo HL on contemporary COG trials, adolescents ≥15 y had worse EFS and OS compared to younger groups. The magnitude of the effect of age was higher in patients with MC disease. Although recent pediatric trials in HL have indicated better survival for some children with MC histology, alternative approaches or novel therapies should be considered for older adolescents with MC disease, whose outcomes appear more like adults. Disclosures No relevant conflicts of interest to declare.

Introduction Survival disparities by race/ethnicity and socioeconomic status (SES) have been observed in a wide range of pediatric treatment settings. Few studies have examined the effects of ethnicity and SES in pediatric allogeneic hematopoietic cell transplantation (alloHCT). Objectives We explored whether survival differed by ethnicity or SES in children receiving alloHCT for non-malignant conditions at a single institution serving a diverse patient population. Methods The Kaplan-Meier method was used to estimate overall survival (OS) with the logrank test for between-group comparisons. Cox proportional hazards models were used for adjusted analyses of OS. Results Of 133 subjects from Conclusion Our findings suggest that in patients undergoing alloHCT for non-malignant conditions, treatment at a tertiary care center with a multidisciplinary approach may mitigate the health disparities seen in other treatment settings. Future research should include larger multicenter studies investigating the complex interrelationships among race/ethnicity, SES, and clinical outcomes in this understudied patient population. Occurrence of aGVHD was the only factor associated with inferior OS, emphasizing a need for better prevention and treatment strategies in children with non-malignant diseases.

Introduction: Hodgkin lymphoma (HL) is one of the most treatable cancers affecting adolescent and young adult (AYA) patients (15 - 39 years), however optimal therapy for de novo disease in this population remains a subject of debate. Population-based studies in HL consistently report a survival disadvantage for AYAs when compared with younger patients. Though the etiology of these disparities is unclear, analyses of clinical trials data suggest that observed survival differences may relate to treatment, rather than to age. Because registry analyses are often limited by lack of information about clinical characteristics and therapeutic exposures, the independent effect of age on HL-outcome outside of the cooperative group setting is unknown. To address this gap in the literature, we: (1) examined initial treatment regimen and patterns of care in a population-based cohort of AYAs compared to children with de novo HL, and (2) examined the impact of sociodemographic and clinical variables on overall survival (OS) and disease-specific survival (DSS) by age, after adjusting for therapy. Methods: Data for 4,426 patients aged 0 - 39 years diagnosed with classical HL between 2007 and 2016 were obtained from the California Cancer Registry (CCR). Detailed treatment information for each patient was extracted from unstructured free-text fields in the CCR database. Chemotherapy regimens were classified based on standard treatment approaches for adult and pediatric HL (Table). Multivariable cox proportional hazards regression models were used to examine the influence of sociodemographic and clinical variables on OS and DSS, overall and by age group, and are presented as adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Models were adjusted for race/ethnicity, sex, insurance, neighborhood socioeconomic status, histology, stage, B symptoms, treatment location at a NCI (National Cancer Institute)-designated cancer center, and radiation therapy (RT). Results: Of the 4,426 patients in this cohort, 33% were Conclusion: In this large, population-based cohort of children and AYAs with HL, we observed that initial therapy varies, but that the majority of AYAs receive ABVD. Variation in therapy was largely insufficient to explain observed survival disparities, as older age, NHB and Hispanic race/ethnicity, and public or no insurance each conferred increased risk of death, even after adjustment for chemotherapy regimen. Further analyses examining comorbidities, treatment-related toxicities, and cause of death are ongoing. Disclosures No relevant conflicts of interest to declare.

PURPOSE Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite—non-Hispanic black (NHB) and Hispanic—patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children’s Oncology Group trials. PATIENTS AND METHODS This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy. RESULTS At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% ( P < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively. CONCLUSION In patients who were treated for de novo HL in contemporary Children’s Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.

Author(s): Kahn, Justine M; Keegan, Theresa HM; Tao, Li; Abrahao, Renata; Bleyer, Archie; Viny, Aaron D | Abstract: BackgroundRace-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time.MethodsUsing the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time.ResultsTrends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL.ConclusionsAlthough survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society.

Tacrolimus (FK506) is a calcineurin inhibitor and is an essential component of many immunosuppressive regimens. The oral bioavailability of tacrolimus may be affected by many factors, including patient age and gender, as well as by drug-drug interactions or genetic polymorphisms in drug metabolism. The dosing recommendations for pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients have been derived from tacrolimus use in adult solid-organ transplantation patients. Data describing the impact of conversion of i.v. tacrolimus to oral on the incidence of acute graft-versus-host disease (aGVHD) are limited in children after alloHCT. In this study, we describe the incidence of grades II to IV aGVHD after conversion from i.v. tacrolimus to oral tacrolimus and study the clinical factors associated with delayed achievement of therapeutic blood levels. In this retrospective analysis, 68 pediatric patients (median age, 6.7 years; range, .25 to 22 years), underwent alloHCT for malignant and nonmalignant diseases and received tacrolimus and mycophenolate mofetil for aGVHD prophylaxis. Among all patients, the median number of days to achieve therapeutic tacrolimus trough concentration (10 ng/mL to 20 ng/mL) was 7 days (range, 0 to 37 days). Twenty-two patients developed grades II to IV aGVHD and the cumulative incidence of grades II to IV aGVHD in all patients was 32.4% (standard error, .06). On multivariate analysis ethnicity (white versus others: odds ratio [OR], −4.5; 95% confidence interval [95% CI], 1.091 to 18.91; P = .038) and ≥ 10 days of subtherapeutic tacrolimus levels in first 30 days on i.v. (OR, −3.8; 95% CI, 1.276 to 11.43; P = .017) were significantly associated with delay in achieving therapeutic tacrolimus trough concentration. The impact of race/ethnicity on therapeutic tacrolimus trough concentration in pediatric alloHCT recipients should be further studied prospectively so that individualized dosing plans can be developed.

Medulloblastoma (MB) is the most common high-grade primary brain malignancy in children and accounts for 1% of adult brain tumors. Previous studies have compared survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database finding no difference. However, diagnostic subgroup analyses are limited. We examined survival in children (age 0–19) and adults (20–79) coded as MB in the 2018 SEER database (2000–2016), using Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI).). MB in SEER-18 is defined as ICD-O-3 histology codes 9470–9474 (n=1,728). ICD 9473, supratentorial PNET (sPNET, n=97) is biologically distinct so was analyzed separately. 5-year survival for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) and adults (n= 488, 79.1%) (HR=0.97, CI: 0.79 – 1.17, p=0.50). Subtype analyses showed no survival difference comparing adults and children with desmoplastic nodular MB (n=222, p=0.09), large cell MB (n=73, p=0.46), or MB NOS (n=1330, p=0.10). In contrast, children with sPNET had improved survival (n=65, 72.3%) compared to adults (n=29, 51.7%) (HR = 2.0, CI: 1.10 – 3.92; p=0.02,). In conclusion, 2018 SEER data for MB continue to show no survival difference between adults and children, suggesting adult patients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race, and treatment. Comparison of adults and children with MB and sPNET will be re-evaluated using the new 2016 World Health Organization classification.

Background: While survival in Hodgkin lymphoma (HL) is excellent, disparities by race/ethnicity have been described. Population-based and single-center studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in non-Hispanic black (NHB) and Hispanic (vs. non-Hispanic white [NHW]) patients (Grubb, Pediatr Blood Cancer 2016; Metzger, JCO 2008). These studies, though suggestive of a significant public health disparity, are often limited by lack of information about disease characteristics and therapeutic exposures. Thus, whether racial/ethnic disparities persist after adjustment for clinical and treatment-related variables remains a subject of debate. We examined event-free survival (EFS) and overall survival (OS) in NHW, NHB and Hispanic patients receiving risk-stratified, response-adapted therapy for de novo HL on contemporary Children’s Oncology Group (COG) trials. Methods: This was a pooled analysis of individual, patient-level data from 1,605 children and adolescents ( Results: Between 2002 and 2012, 2,155 patients enrolled on COG trials for the treatment of newly diagnosed HL; 1,605 (76%) were included in this study. Patients treated outside of the United States (N= 299), with lymphocyte predominant histology (N= 86), and who withdrew consent after one cycle (N= 37), were excluded. For the purpose of this study, analyses were restricted to patients who were NHW, NHB, and Hispanic. In total, N= 49 patients who were Asian/Pacific Islander and N= 79 patients who were other/mixed race were excluded. Sixty-seven percent of the study cohort (N= 1,083) was NHW. Among non-white patients (N= 522), 13% were NHB and 20% were Hispanic. Median age was 14.6 years (± 3.5 years). Approximately 16% of NHW patients vs. 41% and 44% of NHB and Hispanic patients had public or government insurance (P< 0.01). Non-white patients were also more to come from low-income households (P < 0.01). Compared with non-white patients, a higher proportion of NHW children had nodular sclerosing histology (P< 0.01). A higher proportion of non-white patients presented with stage III/IV (vs. I/II, P< 0.01) and bulky disease (P= 0.04); however, there was no difference in receipt of RT by race/ethnicity. At median follow-up of 6.9 years, cumulative incidence of relapse was 17% and did not significantly differ by race/ethnicity. Unadjusted 5-year EFS and OS were 83% (standard error [SE]: 1.2%) and 97% (SE: Conclusion: In the controlled setting of COG clinical trials, treatment with dose-dense, response-adapted therapy for newly diagnosed HL eliminates racial/ethnic differences in EFS. This observation suggests that current approaches to risk stratification with response-adapted regimens are highly effective for both NHW and non-white children with HL. Though there was no difference in EFS across NHW and non-white patients in our cohort, the striking difference in the risk of all-cause mortality lends weight to the possibility that differences in cancer therapy or supportive care outside of the cooperative group setting may be driving the disparities observed at the population level. Critical areas of future study to reduce racial disparities in HL should focus on improving health equity, expanding clinical trial participation, and dentifying drivers of racial/ethnic disparities in children with relapsed disease. Research support: This work was supported by the Children’s Oncology Group Chair Grant No. U10CA98543, the Children’s Oncology Group Statistics and Data Center Grant No. U10CA098413, the National Clinical Trials Network Operations Center Grant No. U10CA180886, and the National Clinical Trials Network Statistics and Data Center Grant No. U10CA180899. This work was also supported by the St. Baldrick’s Foundation, the Lymphoma Research Foundation, and by a KL2 Mentored Career Development Award Grant No. KL2-TR001874 from the Irving Institute for Clinical and Translational Research at Columbia University Irving Medical Center. Citation Format: Justine Kahn, Kara M. Kelly, Qinglin Pei, Rizvan Bush, Debra L. Friedman, Frank G. Keller, Smita Bhatia, Tara O. Henderson, Cindy L. Schwartz, Sharon M. Castellino. Survival by race and ethnicity in pediatric and adolescent patients with Hodgkin lymphoma: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA37.

In this population-based evaluation of adolescents and young adults (AYA) acute lymphoblastic leukemia (ALL), we describe patterns of care (POC) and outcomes regarding hematopoietic cell transplantation (HCT) in first complete remission (CR1). Data were abstracted from the 2013 United States Surveillance, Epidemiology, and End Results POC study; newly diagnosed AYA ALL were included. Multivariable logistic regression evaluated associations with HCT in CR1; Cox proportional hazards regression evaluated survival associations. Of 399 AYAs with ALL included, 102 (28.5%) underwent HCT in CR1. High-risk cytogenetics (odds ratio [OR] = 4.86, 95% confidence interval [CI] = 3.02-7.83) and hyper-cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) induction (OR = 1.84, 95% CI = 1.07-3.16) were associated with HCT in CR1. Two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI = 23.4-33.4), 69.3% (95% CI = 63.6-74.3%), and 84.1% (95% CI = 79.7-87.5), respectively. Two-year RFS was significantly higher in patients receiving CR1 HCT relative to chemotherapy (83.6%, 95% CI = 72.6-90.5% vs. 64.3%, 95% CI = 57.5-70.3), but no difference was seen in 2-year OS (88.9%, 95% CI = 80.8-93.7 vs. 82.5%, 95% CI = 77.2-86.7). Treatment at a nonteaching hospital was independently associated with inferior OS (hazard ratio = 2.15, 95% CI = 1.23-3.76). Although the ALL landscape is changing, these data provide a snapshot of the use and outcomes of HCT for AYA ALL across the United States.

Purpose This study compared the relative incidence of treatment-related toxicities and the event-free and overall survival between Hispanic and non-Hispanic children undergoing therapy for acute lymphoblastic leukemia (ALL) on Dana-Farber Cancer Institute ALL Consortium protocol 05-001. Patients and methods Secondary analysis of prospectively collected data from a phase III multicenter study in children and adolescents of 1–18 years with previously untreated ALL. Results Between 2005 and 2011, 794 eligible patients enrolled on DFCI 05-001, 730 of whom were included in this analysis (19% [N = 150] Hispanic, 73% [N = 580] non-Hispanic). Hispanic patients were more likely to be ≥10 years of age (32% vs. 24%, P = 0.045) at diagnosis. Toxicity analyses revealed that Hispanic patients had significantly lower cumulative incidence of bone fracture (P

Background: Despite outstanding cure rates of pediatric acute lymphoblastic leukemia (ALL), Blacks and Hispanics have inferior survival than Whites. We recently reported that among 794 children from DFCI ALL Consortium Protocol 05-001 trial, Hispanic patients had significantly lower rates of fracture and osteonecrosis, but higher risk of relapse and death compared with non-Hispanic Whites (PMID: 29090520). Studies from other groups have reported inferior ALL outcomes in children with Native American ancestry, however the association between genetic ancestry and skeletal toxicities has not been explored. We examined whether genetic inheritance could provide an explanation for the reduced incidence of skeletal toxicities in Hispanic patients in DFCI 05-001. Methods: A total of 576 DNA samples extracted from bone marrow samples or blood samples obtained during remission, including 2% blind duplicates, were genotyped using the Illumina OmniExpress Beadchip array. After data QC and cleaning, 449 ALL patients were retained in the final analysis. Estimates of global genetic ancestry were derived from STRUCTURE program, which was used to re-classify individuals with discordant clinical race/ethnicity as reported by study site, and to assign individuals with unknown race/ethnicity information to an ethnic group when possible. Regression model for the subdistribution hazard of the cumulative incidence function was used to relate clinical race/ethnicity, genetically reclassified race/ethnicity, and genetic ancestry respectively with risk of fracture and osteonecrosis, with death and recurrence as competing risk factors while controlling for age, gender and baseline clinical factors. Cox proportional regression models were used to test race/ethnicity and ancestry with overall survival (OS) and event-free survival (EFS). Results: Among the 449 patients analyzed, average age was 6.7 years; 26% of patients were ≥10 years and 44% were female. The demographic and clinical characteristics of patients with genotype data were similar to those of the overall cohort, although the proportion of Hispanics was slightly lower in the genotyped sub-cohort (17% vs. 21%), whereas the rates of fracture and osteonecrosis were higher (fracture: 25% vs. 18%; osteonecrosis: 10% vs. 8%). Based on clinical race/ethnicity, 66% of patients were non-Hispanic White, 17% were Hispanic, 5% were non-Hispanic Black, 3% were Asian, and 10% were reported as Other. Genetic ancestry analyses revealed that non-Hispanic White patients had a median of 96% European ancestry, non-Hispanic Black patients had a median of 76% African ancestry, and Asian patients had a median of 58% Asian ancestry. The genetic make-up of Hispanic patients in the 05-001 cohort was more admixed, with 23% Native American and 17% African ancestry, higher than the national average (18% and 6%, respectively). After genetic reassignment, racial/ethnic groups were as follows: 68% non-Hispanic White, 17% Hispanic, 9% non-Hispanic Black, 6% Asian, and 1% unassigned. In analysis of genetically reassigned race/ethnicity with skeletal toxicities, Hispanic and Black patients had significantly lower risk of fracture compared with white patients (Hispanic: subdistribution hazard ratio [SHR]=0.42, 95% confidence interval [CI]=0.22, 0.81; Black: HR=0.28, 95%CI=0.10, 0.75). These groups also had significantly less osteonecrosis (Hispanic: SHR=0.24, 95%CI=0.08, 0.78; Black: SHR=0.12, 95%CI=0.02, 0.93). Similar results were observed when using clinical race/ethnicity. Further analyses revealed that African genetic ancestry, but not Native American ancestry was associated with lower risk of fracture and osteonecrosis in a dose-dependent manner (Table 1). In analysis of death and recurrence, those with higher proportion of Native American ancestry had significantly higher risk of death/recurrence after adjustment (OS: hazard ratio [HR]=4.00, 95%CI=1.45, 11.02; EFS: HR=2.07, 95%CI=1.13, 3.79). Analysis of single variants and polygenic risk scores with skeletal toxicities and survival outcomes is ongoing. Conclusion: Hispanic children and adolescents from the DFCI 05-001 cohort, had highly heterogenous genetic ancestral make-up. Among Hispanic patients, the observed lower risk of skeletal toxicities might be driven by African ancestry, whereas poorer survival observed might be driven by Native American ancestry. Disclosures Silverman: Servier: Consultancy, Research Funding; Takeda: Consultancy.

e18138 Background: Patients diagnosed with leukemia and lymphoma typically present with nonspecific symptoms, making a timely diagnosis difficult. Little is known about factors associated with delays in diagnosis. We hypothesized that age, minority race/ethnicity, and low income are associated with greater time to diagnosis. Methods: Using the OptumLabs Data Warehouse, which includes claims data for privately insured enrollees in a large US health plan, we identified 17,536 pediatric (0-14 y), adolescent (15-21 y), and young adult (22-39 y) patients diagnosed with acute leukemia or lymphoma between 2001-17. Using this retrospective cohort, potential cancer-related symptoms occurring up to 6 months pre-diagnosis were identified. Delay was defined as > 3 months from symptom onset to diagnosis. Contingency table analysis with chi-squared tests and unconditional logistic regression were used to estimate the association between sociodemographic factors and delays in diagnosis. Results: Seventy-eight percent of patients had a diagnosis of a cancer-related symptom in the 6 months prior to diagnosis. The most common presenting symptoms were lymphadenopathy, fever, and cytopenias. The median days to diagnosis was longer in young adults (93) than children (86) or adolescents (81) (p = < 0.0001). For pediatric v. AYA patients, median days to diagnosis differed for those with constitutional symptoms (18 v. 37, p = < 0.001), infectious symptoms (93 v. 74, p = < 0.001), and cytopenias (11 v. 22, p = < 0.001). Multivariable analysis identified younger age, female sex, and low household income to be significantly associated with delays in diagnosis (table below). Conclusions: In this large cohort of privately insured patients, adolescents had the shortest time to diagnosis. We saw no disparities by race/ethnicity or education but observed that low income ( < $40K) and female patients had greater odds of delays in diagnosis. [Table: see text]

In pediatric patients with acute lymphoblastic leukemia, adherence to oral chemotherapy relies largely on a parent's comprehension of the drug's indication and administration guidelines. We assessed how pediatric oncology providers educate families about oral chemotherapy. We conducted a cross-sectional survey of 68 physicians and nurses from 9 institutions in the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium. The inter-individual approach to patient education is variable and may consist of handouts, treatment calendars, and discussions. The extent of teaching often varies depending on a provider's subjective assessment of a family's needs. Twenty-five percent of providers suggested standardizing patient teaching. When developing educational models, care teams should consider approaches that (a) objectively identify families in need of extensive teaching, (b) designate allotted teaching time by nursing staff during clinic visits, and (c) maintain the variation and dynamism that informs a successful provider-patient relationship.

In pediatric and adolescent patients undergoing allogeneic hematopoietic cell transplantation, treatment-related toxicities remain a clinical challenge. A paucity of data investigates the risks for and survival impact of treatment-related toxicities in this population. Here the authors assess the relative toxicity of myeloablative, reduced-toxicity, and reduced-intensity conditioning regimens; identify patient-related predictors of post-transplant toxicities; and investigate the impact of early post-transplant toxicities on transplant-related mortality (TRM). In this retrospective study, 164 patients (aged 1 to 22 years) underwent allogeneic stem cell transplantation after busulfan-based conditioning for malignant and nonmalignant diseases between 2000 and 2014. The number of grades III to IV toxicities between days 0 and +30 was calculated for each patient. TRM was calculated to 2 years. Median patient age was 9 years, and median number of toxicities was 3 (range, 0 to 17). The 100-person day incidence of post-transplant toxicities in myeloablative conditioning was not different from the incidence in reduced-toxicity conditioning (13.88 versus 13.59, P = .812). Reduced intensity was less toxic than both myeloablative and reduced toxicity (13.75 versus 8.41, P

Infectious complications, particularly viral infections, remain a significant cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT). Only a handful of studies in children have analyzed the risks for and impact of viremia on alloHCT-related outcomes. We conducted a retrospective study of 140 pediatric patients undergoing alloHCT to investigate the incidence of and risk factors for cytomegalovirus (CMV), adenovirus (ADV), and Epstein-Barr virus (EBV) viremia and viral disease after alloHCT. Furthermore, we assessed the impact of viremia on days of hospitalization and develop an algorithm for routine monitoring of viremia. Patients were monitored before alloHCT and then weekly for 180 days after alloHCT. Patients were considered to have viremia if CMV were > 600 copies/mL, EBV were > 1000 copies/mL, or ADV were > 1000 copies/mL on 2 consecutive PCRs. The overall incidences of viremia and viral disease in all patients from day 0 to +180 after alloHCT were 41.4% (n = 58) and 17% (n = 24), respectively. The overall survival for patients with viremia and viral disease was significantly lower compared with those without viremia (58% versus 74.2%, P = .03) and viral disease (48.2% versus 71.2%, P = .024). We identified that pretransplantation CMV risk status, pre-alloHCT viremia, and use of alemtuzumab were associated with the risk of post-alloHCT viremia. The average hospitalization days in patients with CMV risk (P = .011), viremia (P = .024), and viral disease (P = .002) were significantly higher. The algorithm developed from our data can potentially reduce viral PCR testing by 50% and is being studied prospectively at our center. Improved preventative treatment strategies for children at risk of viremia after alloHCT are needed.

Background: Hodgkin lymphoma (HL) is one of the most common, and one of the most curable cancers in adolescents and young adults (AYAs) (15-39 years). Despite excellent outcomes in the majority of patients, the burden of long-term morbidity and mortality persists. Prior analyses of patients treated for HL before the year 2000 have reported mortality rates as high as 30% by 20 years. Further, this mortality risk has historically differed across different racial and ethnic groups. Over the past decade, cooperative groups have expanded the use of risk-adapted, response-based treatment in an effort to maintain high cure rates, while simultaneously reducing the burden of late effects. We examined long-term survival in AYAs with HL treated after the year 2000. Methods: We used the National Cancer Institute Surveillance, Epidemiology, and End Results registry data for 18 regions in the United States (SEER18) to examine survival in AYAs with a confirmed diagnosis of HL between 2000 and 2015. We obtained overall and cause-specific survival estimates for each year after cancer diagnosis (up to 15 years) for each racial/ethnic group with corresponding 95% confidence intervals. From these yearly survival estimates, we calculated the percentage of deaths not attributed to HL at 10- and 15-years after cancer diagnosis. Results: The final analysis included 16,868 HL patients. Racial/ethnic subgroups included: non-Hispanic white (NHW; 11,016, 65%), Hispanic (2,753, 16%), non-Hispanic black (NHB; 2,131, 13%), and Asian/Pacific Islander (API; 968, 6%) AYAs with HL. Across the full cohort, the 10-year and 15-year overall survival probabilities were 90% (95% confidence interval [95%CI]: 89 - 91) and 87% (95% CI: 86 - 88), respectively. At 10- and 15-years, overall survival was highest for NHWs (10-year: 92%: 15-year: 88%) and APIs (91%; 86%) compared to Hispanics (87%; 85%) and NHBs (82%; 78%). Overall survival, cause-specific survival, and percentage of deaths not attributed to HL by race/ethnicity are presented in the Figure. In the first year after diagnosis, 22% of deaths were due to causes other than primary disease, with the percentage of deaths not attributed to HL higher in NHWs and APIs than Hispanics and NHBs. At most time points after cancer diagnosis, a higher proportion of NHW (vs. NHB, Hispanic and API) patients died from causes other than HL. By 10 years after diagnosis, 25% of NHW patients died due to causes other than HL, vs. 20% in API, 17% in NHB, and 15% in Hispanic patients. By 15 years, 33% of all deaths were not attributed to HL. This was observed most dramatically in the NHW cohort in whom 40% of all deaths were not HL-related, compared to 24% of deaths in the NHB cohort and 26% - 27% of deaths in the Hispanic and API groups. Conclusion: In AYAs diagnosed with HL between 2000 and 2015, NHB patients had worse survival compared with NHW and API patients. The higher probability of survival in NHW patients was accompanied by a consistently higher proportion of non-cancer related death in this cohort both 10- years and 15-years after diagnosis. Studies are needed to evaluate risk factors for both short- and long-term mortality in AYAs, and to examine how these risks differ across racial/ethnic groups. Findings also suggest that despite increasing use of response-adapted therapy over the past two decades, all AYAs with HL remain at risk of death in the decades following therapy, further highlighting the need for long-term follow-up of this at-risk patient population. Figure. Figure. Disclosures Muffly: Adaptive Biotechnologies: Research Funding; Shire Pharmaceuticals: Research Funding.

Background: The optimal role of allogeneic hematopoietic cell transplantation (HCT) for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) is an area of clinical debate. In this population-based evaluation of AYA ALL patients across the United States (US), we sought to describe recent patterns of care and outcomes regarding HCT in first complete remission (CR1) amongst AYAs with ALL. Methods: Data were abstracted from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Patterns of Care (POC) study focused on AYA cancers. AYAs (15-39 years) with ALL newly diagnosed between January 1, 2012 through December 31, 2013 and registered in the SEER program were included. Allogeneic HCT in CR1 was defined as occurrence of HCT without relapse/progression prior to the HCT date; HCT was considered a time-dependent variable in survival models. Multivariable logistic regression was used to evaluate associations with HCT in CR1; cox proportional hazards regression was used to evaluate associations with survival. Results: Three-hundred and ninety-nine AYAs (15-39 years) with newly diagnosed ALL between 2012-2013 were included; median follow-up for survival was 19 months (range, 0-35 months). The median age was 24 years; 85% had B-cell ALL, 27% had high risk ALL cytogenetics. One-third of AYA ALL patients received care from pediatric oncologists while two-thirds were treated by adult hematologist/oncologists; a majority (86%) received care at a teaching hospital. Fifty-eight percent received an asparaginase-containing ALL front-line regimen, 32% received hyperCVAD; 5.9% and 4.5% received another/unknown regimens, respectively. One-hundred and two (29%) AYAs underwent allogeneic HCT in CR1. Excluding patients with relapse/progression or death within three months of diagnosis (n=32), older age, high-risk ALL cytogenetics, treatment by an adult hematologist/oncologist, and front-line therapy with hyperCVAD were variables significantly associated (all P< 0.05) with increased odds of HCT in CR1 in univariate analysis, while Hispanic ethnicity and public or no/other insurance were associated with significantly lower odds of HCT in CR1. In multivariate adjusted analysis, only high-risk cytogenetics (odds ratio (OR) 4.84, 95% confidence interval (CI) 2.99-7.83) and receipt of hyperCVAD (OR 1.84, 95% CI 1.07-3.16) retained significant associations with HCT in CR1. The two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI 23.4%-33.4%), 69.3% (95% CI, 63.6%-74.3%), and 84.1% (95% CI 79.7%-87.5%), respectively. Two-year cumulative incidence of relapse was significantly lower in patients receiving HCT in CR1 as opposed to those not receiving HCT in CR1 (15.1%, 95% CI 8.1%-24.1% vs 32.8%, 95% CI 26.9%-38.9%). This translated into a significant improvement in 2-year RFS (83.6%, 95% CI 72.6%-90.5% vs 64.3%, 95% CI 57.5%-70.3%), but no statistically significant differences in 2-year OS (88.9%, 95% CI 80.8%-93.7% vs 82.5%, 95% CI 77.2%-86.7%). Among all patients, receipt of care at a non-teaching hospital (hazard ratio (HR) 2.14, 95% CI 1.22-3.75) and use of another/unknown regimen (HR 9.08, 95% CI, 4.83-17.06) were significantly associated with inferior OS. Conclusions: In the US, allogeneic HCT in CR1 is most commonly administered to AYA ALL with high risk cytogenetics and as consolidation therapy for those who receive front-line hyperCVAD, as opposed to asparaginase-containing ALL regimens. Consistent with prior studies, AYA ALL patients treated at non-teaching hospitals have inferior survival. Although the landscape of ALL therapy is changing, these data provide an important snapshot of the modern state of HCT in CR1 for AYA ALL. Disclosures Muffly: Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding.

Hodgkin lymphoma (HL) is one of the most common cancers in the adolescent and young adult (AYA) population (15 – 39 years). Despite continued improvements in HL outcomes, AYAs have not exhibited survival gains to the same extent as other age groups. At present, details about tumor biology, optimal therapeutic approaches, supportive care needs, and long-term toxicities in AYAs with HL remain understudied. Herein, we summarize the current state of the AYA population with HL, specifically focusing on how collaborations across the pediatric and medical oncology divide, coupled with multidisciplinary patient care can further optimize outcomes for this group of patients.

Race-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time.Using the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time.Trends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL.Although survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society.