Background/objectives Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial. Methods Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival. Results Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (>= 10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008). Conclusion We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients >= 10 years (especially those >= 15 years) when receiving asparaginase.

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 (<10(-4)) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS. Conclusions Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at as NCT00165087 and NCT01574274, respectively.

The application of next-generation sequencing (NGS) approaches to leukemia markedly expanded our understanding of the molecular landscape of pediatric acute lymphoblastic leukemia (ALL), but NGS integration into clinical care and therapeutic decision making is still limited. The prognostic impact of discovered mutations in uniformly treated patients with newly diagnosed B-ALL is not well characterized, and there is no consensus regarding the clinical significance of many of these findings. We investigated the frequency of mutations affecting common molecular pathways in pediatric B-ALL that are potentially druggable with targeted therapies, to define the prognostic role of these mutations, as measured by end-induction minimal residual disease (MRD) and event-free survival (EFS). We analyzed 159 patients (median age 6 years, range 1-18) with newly diagnosed Ph-negative B-ALL treated between 2005-2015 according to the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 05-001 and 11-001. Diagnostic leukemia samples were sequenced using a validated clinical NGS panel. We focused on mutations affecting the following pathways: Ras (NRAS, KRAS, PTPN11, NF1 and BRAF), cell cycle regulation (CCND3, CDKN2A/B and RB1), PI3K signaling (PTEN, PIK3CA, PIK3R1, PIK3C2B, MTOR, TSC1 and TSC2), Polycomb repressive complex 2 (PRC2) (EED, EZH2 and SUZ12), and JAK/STAT signaling (CRLF2, JAK2, JAK3, MPL, SH2B3 and SOCS1). Additionally, we analyzed mutations affecting CREBBP, FLT3, PAX5, SETD2 and TP53. Mutations occurring in the ExAC database at a frequency greater than 0.01% were excluded. A Fisher exact test and Wilcoxon rank sum test were used for categorical and continuous variables. High end-induction MRD, defined as > 10-3, was assessed by an Ig-TCR PCR assay. EFS was estimated using Kaplan and Meier method and tested between groups using a log-rank test. Induction death/failure, relapse or death were considered as events. Overall, 108 of the 159 patients (68%) carried at least one mutation in the studied genes. Most common mutations were in the Ras pathway (47%), CREBBP (9%), JAK pathway (8%), FLT3 (8%), PI3K pathway (5%), PAX5 (4%), SETD2 (4%), TP53 (4%), cell cycle regulation (3%) and PRC2 complex (3%). We investigated the distribution of mutations among common cytogenetic groups: ETV6-RUNX1, high hyperdiploidy (HHD) (51-65 chromosomes), hypodiploidy (<45 chromosomes), KMT2A-rearranged, TCF3-PBX1, and intra-amplification chromosome 21 (iAMP21). There was a strong association between TP53 and hypodiploidy (43% vs 2%; p=0.001). Ras pathway and FLT3 mutations were enriched in HHD (67% vs 39%; p=0.004) and (17% vs 4%; p=0.016), respectively. FLT3 mutations were mutually exclusive with ETV6-RUNX1 (12% vs. 0%, p=0.038), and Ras pathway mutations were rare in this subgroup (p=0.018). PAX5 mutations were enriched in children >10 years of age (p=0.035). There were no associations with sex. Ras pathway mutations were associated with high end-induction MRD (68% vs 42%; p=0.045), and this association was stronger for clonal (variant allele frequency (VAF) >25%) mutations (n=33) (63% vs 19%; p=0.0002). Focusing on HHD, CREBBP mutations frequently co-occurred with clonal Ras pathway mutations (83% vs 17%; p=0.032). Among HHD patients with evaluable MRD (n=33), 7 patients had high MRD, and 3 of these had CREBBP mutations (p=0.052). The analyzed cohort was enriched for higher risk ALL disease (Table 1). The 5-year EFS was 80%±3% among these 159 patients. Overall, no EFS difference was observed based on Ras pathway (p=0.35). Among HHD ALL, the presence of CREBBP or clonal Ras pathway mutations was significantly associated with inferior 5-yr EFS (50%±20% vs 97%±3%; p=0.0006, Figure 1) and (70%±13% vs 100%; p=0.007, Figure 2), respectively. In conclusion, our findings provide insight into the prognostic significance of the most common mutations in pediatric HHD B-ALL in a uniformly treated cohort of patients as part of the DFCI ALL Consortium. The presence of CREBBP and clonal Ras pathway mutations may be associated with upfront chemotherapy resistance as demonstrated by high end-induction MRD. Further analysis of Ras pathway mutations segregated by VAF is warranted. Future trials may integrate these findings into risk stratification of HHD ALL. With prospective continued clinical use of NGS assays, we will further clarify the role of mutations and their contribution to disease outcomes in B-ALL. Disclosures Mar: Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Stegmaier:Novartis: Research Funding; Auron Therapeutics: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

PURPOSE The benefits and risks of supplementation with antioxidants during cancer therapy have been a controversial area. Few studies have systematically evaluated dietary intake of antioxidants with toxicity and survival in childhood cancer. We sought to determine the role of dietary intake of antioxidants on rates of infections, mucositis, relapse, and disease-free survival during induction and postinduction phases of therapy among children and adolescents with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We enrolled 794 children in a prospective clinical trial for treatment of ALL. Dietary intake was prospectively evaluated by a food frequency questionnaire. The association between dietary intake of antioxidants and treatment-related toxicities and survival were evaluated with the Benjamini-Hochberg false discovery rate (q) and logistic regression and the Kaplan-Meier method, respectively. RESULTS Dietary surveys were available for analysis from 614 (77%), and 561 (71%) participants at diagnosis and at end of induction, respectively. Of 513 participants who completed the dietary surveys at both time points, 120 (23%) and 87 (16%) experienced a bacterial infection and 22 (4%) and 55 (10%) experienced mucositis during the induction or postinduction phases of treatment, respectively. Increased intake of dietary antioxidants was associated with significantly lower rates of infection and mucositis. No association with relapse or disease-free survival was observed. Supplementation was not associated with toxicity, relapse, or survival. CONCLUSION Consumption of antioxidants through dietary intake was associated with reduced rates of infection or mucositis, with no increased risk of relapse or reduced survival. Dietary counseling on a well-balanced diet that includes an array of antioxidants from food sources alone may confer a benefit from infections and mucositis during treatment of childhood ALL.

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutritional morbidities are a persistent problem facing pediatric patients during and after treatment and age-gender groups that are at risk for nutritional conditions have not been clearly identified. Therapy is a contributing factor; however, the role of dietary intake remains largely unknown. Prior to conduct of interventional trials, an understanding of the effects of treatment on fluctuations in dietary intake is necessary. Methods: We enrolled 794 children with ALL in a prospective clinical trial. Dietary intake was collected with a food frequency questionnaire at diagnosis and throughout the course of treatment for pediatric ALL. Reported values were compared to the Dietary Recommended Intake (DRI), and normative values (NHANES). Hierarchical linear models and multilevel mixed-effects ordered logistic regression models were used to evaluate longitudinal changes in dietary intake; independent samples t-test with Bonferroni correction was performed to compare to NHANES. Results: Of the evaluable participants at each time-point, dietary intake was obtained on 81% (n = 640), 74% (n = 580) and 74% (n = 558) at diagnosis, end of induction phase of treatment, and continuation, respectively. Despite exposure to corticosteroids, caloric intake decreased over therapy for most age-gender groups. Predictive models of excess intake found reduced odds of over-consuming calories (OR 0.738, P < 0.05); however, increased odds of over-consuming fat (OR 6.971, P < 0.001). When compared to NHANES, we consistently found that >= 1/3 of children were consuming calories in excess of values. For select micronutrients, a small proportion of participants were above or below the DRI at each time evaluated. Conclusions: Our study suggests that dietary intake fluctuates during treatment for ALL as compared to age-gender recommended and normative values. Improving our understanding of nutrient fluctuations and dietary quality will facilitate subsequent analyses addressing relationships of dietary intake, toxicity, and survival. Crown Copyright (C) 2019 Published by Elsevier Ltd. All rights reserved.

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.

PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission (P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase (P = .65). CONCLUSION Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.

Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (ETV6-ABL1: n = 1; FOXP1-ABL1: n = 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1-altered patients, irrespective of the presence of a kinase-activating fusion.

Key Points Childhood B-ALL patients, including those with VHR features, had favorable outcomes on DFCI 05-001 risk-stratified therapy. IKZF1 deletion was an independent predictor of inferior outcome, including among patients with low end-induction MRD.

Cardiac signaling proteins regulate the intrinsic cardioprotective and repair response to doxorubicin cardiotoxicity. We estimated the relationship between these proteins, serum biomarkers of cardiac status and imaging in doxorubicin-treated children with ALL. Concentrations of the proteins

Children and adolescents with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are reported to have increased relapse rates and therapy‐related mortality (TRM). Treatment regimens for DS‐ALL patients often include therapy modifications. Dana‐Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk‐stratified treatment for patients with and without DS.

To the Editor: We thank Dr. Saxena, Dr. Jain, and Dr. Gupta for their Letter to the Editor1 regarding our paper entitled “Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia”.2 Saxena et al. point out that continuous improvement in supportive care and availability of more potent antibiotics could have contributed to the decreased incidence of bacteremia during induction chemotherapy for acute lymphoblastic leukemia (ALL) observed on Dana–Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001 compared to the predecessor, DFCI 05-001. We certainly concur with this comment and recognize that the use of historical controls limits our ability to draw a definitive conclusion on the role of fluoroquinolone prophylaxis during induction chemotherapy. However, we had previously observed that rates of bacterial and fungal infections during induction chemotherapy remained constant across different DFCI ALL trials conducted between 2000 and 2011, despite changes in the intensity of chemotherapy and presumed improvement in supporting care; we believe that this observation supports that uniform use of antibiotics during induction chemotherapy is the main cause of the decreased incidence of bacteremia noted in Protocol 11-001. Dr. Saxena et al. suggest that the increase in fungal infections observed in Protocol 11-001 could be related to the prolonged exposure to fluoroquinolones and that the use of routine antifungal prophylaxis adopted by two institutions could have falsely decreased the incidence of fungemia. We absolutely concur with the authors that prolonged antibacterial prophylaxis represents a risk factor for the development of fungal infections; fortunately, we did not observe a significant increase in the incidence of invasive fungal infection in 11-001, compared to 05-001 (4.8% vs. 3.6%, P = 0.34); additionally, the same two institutions used antifungal prophylaxis during induction chemotherapy in 05-001 and 11-001. Saxena et al. suggest that obtaining blood cultures routinely prior to initiation of antibacterial prophylaxis in afebrile patients could have identified bacteremias eventually suppressed by the use of prophylactic antibiotics. We believe that routine blood cultures in patients with no signs or symptoms of infection could generate a significant rate of false positive results and lead to subsequent unnecessary investigations and use of antibiotics; we would therefore discourage this practice. Lastly, Dr. Saxena et al. suggest that additional clinical information regarding the children with ALL who received antibacterial prophylaxis would have been useful, such as the number of febrile days and the severity of the infections.We thank the authors for this comment and agree that more detailed clinical informationwould havebeenuseful for the reader; in ourmanuscript,wedo provide information on the severity of the infections in patients who received fluoroquinolone prophylaxis (n = 66), noting that six (9.1%) developed bacteremia and one (1.5%) developed a fungal infection and bacteremia, of which six were Grade 3 and onewas Grade 4. In summary, we concur with Saxena et al. that large, randomized, and controlled trials are needed to confirm the efficacy of antibacterial prophylaxis during induction chemotherapy for childrenwith ALL.

Background Thromboembolism (TE) is a serious complication in pediatric patients with ALL associated with significant morbidity, mortality and therapy alterations. Thromboprophylaxis, though effective in preventing TE in patients at high risk for TE, is associated with increased risk of bleeding. Hence it is important to identify the population at the highest risk for TE for whom preventive strategies may be warranted. However, predictors of TE in pediatric patients with ALL remain uncertain and the role of inherited thrombophilia is ill defined. Adult studies of non-cancer patients and our prior smaller pilot study of pediatric ALL patients showed higher rates of TE with non-O blood types. Aim To identify variables at the time of ALL diagnosis that are associated with increased risk of TE in children and adolescents treated on DFCI ALL 05-001 trial. Design/Methods Eligible and consenting patients (1 to ≤18 yrs. of age) with newly diagnosedALL were enrolled on the DFCI 05-001 trial between 2005-2011 at 11 participating institutions in the USA and Canada. Risk categorization and protocol therapy have previously been described (Lancet Oncol 2015;16:1677-90). Treatment included one dose of pegaspargase (2500 IU/m2) during remission induction and 30 consecutive weeks of L-asparaginase during post-induction therapy (either pegaspargase 2500 IU/m2 every 2-weeks or native E.coli L-asparaginase 25000 IU/m2 weekly). Baseline clinical and laboratory data as well as all TE events requiring intervention (Grade 2 or higher) were prospectively collected. Genomic DNA was isolated from peripheral blood or bone marrow obtained at the time of complete remission in participants who consented for the collection of research samples. Single nucleotide polymorphisms (SNP) were detected using PCR-based allelic discrimination assays for prothrombin (PT)gene G20210A (rs1799963) and Factor V G1691A (rs6025) (Factor V Leiden, FVL) (Applied Biosystems, Carlsbad CA). The cumulative incidence of TE was estimated with induction failure, relapse and death considered as competing events. Effect of clinical [age, gender, body mass index (BMI) ALL immunophenotype, risk-group] and laboratory variables [presenting leukocyte count, blood group, SNPs for PT and FVL] at ALL diagnosis on the cumulative incidence of TE was evaluated in univariate and multivariable competing risk regression models. The impact of TE on ALL outcome (event free and overall survival) was further explored using a time-varying covariate in Cox regression modelling. Results Of 794 enrolled patients [median age 4.97 (range 1.04 -17.96) yrs.; males 441], 100 developed TE; the 25-month cumulative incidence was 13.0% (95%CI 10.7,15.5). Twenty-one patients had 21 events during induction (3 with CNS TE) and 79 patients had 88 events post-induction (16 CNS TE). Table 1 provides the cumulative incidence of the time to first event of TE by patient characteristics and is compared using Gray test. Sex, BMI and thrombophilia SNPs had no detectable impact on the incidence of TE. There was no difference in incidence of TE by asparaginase type (data not shown). In the final competing risk multivariable regression model older age group and non-O blood group were each significantly associated with TE (Table 2). Figure 1 depicts the effect of blood group type on the incidence of TE within each age group; the cumulative incidence of TE was significantly higher for non-O blood group only for patients Conclusion Older age and non-O blood group are significant predictors of TE during ALL therapy. The effect of non-O blood group is more pronounced in younger age patients. Polymorphisms of FVL and PT gene had no impact on the risk of TE. We recommend further evaluation of these risk factors and recommend thromboprophylaxis for pediatric patients with ALL over 10 years of age (and especially those 15 years or older) receiving asparaginase-intensive regimens, and consideration of thromboprophylaxis in younger patients with non-O blood group. Download : Download high-res image (161KB) Download : Download full-size image Disclosures Neuberg: Synta Pharmaceuticals: Other: Stock shares.

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.

PurposeThis 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 methodsSecondary analysis of prospectively collected data from a phase III multicenter study in children and adolescents of 1-18 years with previously untreated ALL. ResultsBetween 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<0.001) and osteonecrosis (ON; P=0.047). In multivariable risk regression, the risk of ON was significantly lower in Hispanic patients 10 years (HR 0.23; P=0.006). Hispanic patients had significantly lower 5-year event-free survival (EFS) (79.4%; 95% CI: 71.6-85.2) and overall survival (OS) (89.2%; 95% CI: 82.7-93.4) than non-Hispanic patients (EFS: 87.5%; 95% CI: 84.5-90.0, P=0.004; OS: 92.7%; 95% CI: 90.2-94.6, P=0.006). Exploratory analyses revealed differences between Hispanic and non-Hispanic patients in the frequency of common variants in genes related to toxicity or ALL outcome. ConclusionHispanic children treated for ALL on DFCI 05-001 had fewer bone-related toxicities and inferior survival than non-Hispanic patients. While disease biology is one explanatory variable for outcome disparities, these findings suggest that biologic and non-biologic mechanisms affecting drug delivery and exposure in this population may be important contributing factors as well.