Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Research Articles

Venous Thromboembolism in Adolescents and Young Adults with Acute Lymphoblastic Leukemia Treated on a Pediatric-Inspired Regimen

Introduction Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) can be effectively treated with pediatric-inspired ALL regimens which incorporate asparaginase (ASP). Asparaginase is associated with increased venous thromboembolic (VTE) complications. We examined the incidence of and risk factors for VTE events as well as the impact of VTE events on outcomes of AYA pts treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols. Methods We identified pts aged 15-50 years diagnosed with Philadelphia chromosome negative (Ph-neg) ALL treated on 4 multicenter DFCI Consortium protocols (Pediatric 00-001, Pediatric 05-001, Adult 01-175, and Adult 06-254), or treated as per these protocols between 2000-2021. All regimens included an ASP containing induction, 30 weeks of continuous ASP exposure during consolidation and a continuation phase without ASP. The use of a pegylated vs non-pegylated ASP formulation varied between protocols. As ASP exposure is associated with both VTE and survival, it may confound the association between VTE and survival; thus, to ameliorate confounding, all survival associated outcomes were conducted on pts who remained on protocol for at least 1 year (encompassing ASP exposure). Overall survival (OS) and event free survival (EFS) were presented with Kaplan Meier curves and comparisons were made by the log-rank test. Cumulative incidence of VTE, relapse (CIR) and non-relapse mortality (NRM) were estimated by the cumulative incidence method with the appropriate competing risks, and comparisons were made by the Gray test. Cox regression analysis was fit to evaluate the effect of covariates on OS and EFS. Results Among 341 Ph-neg AYA ALL pts aged 15-50 years, 109 (32%) experienced one or more VTE events. The baseline characteristics did not differ between pts who experienced a VTE and those who did not experience a VTE, except for a higher rate of VTE among overweight/obese pts (BMI≥25 kg/m 2, n=56, 38%) vs normal BMI (n=53, 27%, p=0.04) and a lower rate of VTE in patients with hyperdiploid vs non-hyperdiploid karyotype (n=4, 12% vs n=105, 34%, p<0.01). Of the 109 pts with VTE, 9 (8%) experienced sinus vein thrombosis (2.6% in the overall cohort) and 19 (17%) experienced at least one additional VTE. Most initial VTE events occurred during consolidation (n=78, 72%), followed by induction (n=22, 20%), and continuation/follow-up (n=9, 8%). The 2-yr cumulative incidence of VTE was 32% (95% CI, 27%-37%) and was similar between patients who were treated with non-pegylated ASP vs. pegylated ASP (n=43, 30% vs n=65, 35%, p=0.35). The 2-yr cumulative incidence of VTE was higher in the BMI ≥ 25 kg/m 2 group compared to those with normal BMI (38% vs 28%, p=0.035, Figure 1) and was the only covariate associated with increased VTE risk in the univariate regression model (HR 1.49, 95% CI, 1.03-2.17). Among pts who completed ≥ 1 year of protocol therapy (n=220), the 4-year OS was 92%, and did not differ between pts who experienced VTE vs. not (94% vs 90%, p=0.99, Figure 2). Similarly, there were no differences in 4-year CIR (14% vs 11%, p=0.50), NRM (0% vs 3%, p=0.37), and EFS (86% vs 86%, p=0.79). In univariate analysis for OS, obese BMI (>30 kg/m 2), higher WBC, B-cell immunophenotype, and fewer weeks on ASP therapy were associated with worse OS; all remained predictive in the multivariable model. In the uni- and multivariable analysis for EFS, higher WBC and B-cell immunophenotype were associated with worse EFS. Notably, VTE was not associated with worse OS or EFS in all regression analyses. Conclusion Among AYAs treated on DFCI ALL Consortium protocols, VTE events were frequent, occurred mostly during consolidation phase and were more common among pts with overweight/obese BMI vs normal BMI. Sinus vein thrombosis was rare. VTE incidence did not impact CIR, NRM, EFS or OS, suggesting that VTE is a manageable toxicity.

Feasibility of serial neurocognitive assessment using Cogstate during and after therapy for childhood leukemia.

Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline. In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001; NCT01574274). Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests. Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment.

Children with Acute Lymphoblastic Leukemia and Early Thrombosis Have Dysregulated Coagulation-Related Genes and Pathways

Introduction Thrombo-embolic events (TE) are a frequent complication of childhood acute lymphoblastic leukemia (ALL). Disease-specific mechanistic insights governing the development of TE in this disease remain unclear. Overexpression of coagulation-related genes (coagulome) and pathways have been identified in cancer-induced TE. We investigate whether coagulome dysregulation in newly-diagnosed children with ALL is associated with TE development. Methods We included patients aged 1-21 years old with newly-diagnosed ALL from September 3, 2015, to June 30, 2021, with available RNA-sequencing (RNAseq) data at diagnosis, either enrolled on the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001 or treated following the DFCI 11-001 protocol. RNAseq was performed through an optional study performed as part of the DFCI 16-001 clinical trial for patients who consented to it, or through the research oncogenomic program of the province of Quebec. The primary outcome was the occurrence of TE during ALL therapy requiring medical intervention (grade ≥2 as per the CTCAE version 5). TE were classified as early thrombosis (ET) if they occurred within 6 weeks from treatment start. Patients' characteristics were compared using Chi-Square or Fisher's exact test. Differential gene expression (DE) was performed to compare children with and without TE, adjusted for ALL phenotype (B- or T-cell lineage). The dysregulated genes were compared to a customized panel of 174 genes known to be implicated in cancer-related TE (coagulome and podoplanin) and in coagulation pathways. A secondary analysis, determined a priori, stratified children between ET and no TE, based on the hypothesis that the leukemia environment might predominantly affect early complications. Gene set enrichment analyses (GSEA) were performed on KEGG and gene ontology (GO) databases from the molecular signatures database (MSigDB). DE was considered for absolute fold change (FC) ≥2, and benjamini-Hochberg adjusted p-values (adj p) <0.05. Results We included 274 ALL patients (median age: 6.7 years [interquartile range, IQR: 3.7-12.0 years], 54% male, 81% B-ALL) of whom 49 (17.9%) experienced a TE (including 21 ET) at a median of 76 days (IQR: 27-155 days) following ALL diagnosis. Patients with TE were more likely to be ≥10 years old (57.1% vs. 31.6%, p<0.001) compared to those without TE. Sex, immunophenotype, mediastinal mass, central nervous system disease (CNS) involvement at diagnosis and risk status were otherwise not significantly different among the two groups. Three coagulation pathway-related genes were dysregulated in children with TE compared to those without TE. Glycoprotein 9 (GP9) and platelet factor 4 (PF4), implicated in von Willebrand-dependent platelet adhesion and platelet aggregation, were upregulated (log2FC = 2.1 and 1.5, respectively). Metalloproteinase-2 (MMP2), involved in collagenolysis and thrombus degradation, was downregulated (log2FC = -1.9). The KEGG olfactory transduction pathway was downregulated in the group with TE (normalized enrichment score (NES) = 1.55, adj p<0.001). In the secondary analysis stratified by timing of TE, patients with early TE were more likely to be ≥10 years (80.9% vs. 31.6%, p<0.001), have T-ALL (38.1% vs. 16.9%, p=0.002) and be CNS-positive at diagnosis (52.4% vs. 22.7%, p=0.004). Patients with ET showed overexpression of the GP9, PF4, integrin subunit beta 3 (ITGB3) and clusterin (CLU) genes involved in platelet aggregation and adhesion (log2FC = 3.3, 3.7, 2.7 and 1.6, respectively). The following GO pathways were significantly upregulated: blood coagulation (NES=1.73, adj p<0.001), platelet activation (NES=2.21, adj p<0.01), and platelet alpha granules (NES=2.48, adj p<0.001) while the KEGG olfactory transduction pathway was downregulated (NES=-1.70, adj p<0.001). Dysregulation of the olfactory transduction pathway has previously been described in cancer-associated TE in adults. Conclusion Our study identified coagulation-related genes and pathways that might be drivers of leukemia-induced thrombosis. Early TEs in childhood ALL were associated with significant upregulation of coagulation and platelet activation pathways, suggesting a role of the leukemia microenvironment in TE development. Additional studies are required to validate these observations that could be incorporated in future algorithms to predict TE risk in children with ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adolescent and Young Adults with ALL Who Complete Therapy on DFCI Consortium ALL Trials Have Excellent Long-Term Overall Survival

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) have good outcomes when treated on pediatric regimens but still face worse survival compared to younger children (Siegel JAMA Onc 2018). Pediatric patients who do not complete ALL treatment, particularly planned asparaginase (ASP), have inferior oncologic outcomes (Silverman Blood 1997). In the CALBG 10403 trial of a pediatric-inspired regimen in AYAs 17-39 years (yrs), only 39% of pts completed planned treatment (Stock Blood 2019). We aimed to describe the prevalence of treatment failure, reasons for treatment non-completion, and their effect on survival among patients treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: We identified Philadelphia chromosome negative (Ph-) pts aged 1-49 yrs treated on 4 sequential multi-center DFCI Consortium protocols between 2000 and 2018 (00-001, 05-001, 01-175, 06-254). Additional consecutive Ph- pts treated as per these protocols were identified by chart review. All pts were intended to receive 30 continuous weeks (wks) of ASP during consolidation. Treatment failure was defined as induction failure, induction death, relapse/progression on therapy, and remission death on therapy. Treatment non-completion was defined as transplant in first complete remission (CR), withdrawal due to toxicity or other reasons, loss to follow up, and ineligible status. Treatment completion was defined as no exit from treatment protocol before its completion, approximately 2 yrs from complete remission (CR). Per protocol, no patients were recommended for allogeneic hematopoietic stem cell transplant (HSCT) in CR1. ASP completion was defined as receiving at least 26 wks of ASP during consolidation (Silverman, Blood 2001). The protocols allowed for truncation of ASP for toxicity without exit from protocol. Median follow-up time was calculated using the reverse Kaplan Meier indicator. The chi square test was used to compare proportions between groups. Overall survival (OS) among groups was compared using the log rank test. Results: A total of 1,480 pts were identified: 1,149 children (< 15 yrs, median age 4.5 yrs) and 331 AYAs (15-49 yrs, median age 24 yrs). Median follow-up was 7.9 yrs. Treatment completion rate was lower among AYAs than children (61.3% vs. 89.9%, p < 0.001) (Table 1). This was driven by higher treatment failure rates among AYAs than children (19.9% vs. 5.5%) as well as higher treatment non-completion rates (19.0% vs. 4.6%), primarily driven by transplants in CR1 among AYAs. Treatment completion rates were lower among older (30-49 yrs) AYAs compared to younger (15-29 yrs) AYAs (50.5% vs. 65.7%, p = 0.009). Among 1235 pts who completed treatment, 1086 (87.9%) received ³26 weeks of ASP. ASP completion rate was lower among AYAs vs. children (79.2% vs. 89.6%, p < 0.001). A higher percentage of AYAs discontinued ASP because of toxicity than children (11.9% vs. 5.5%, p = 0.01). In a landmark analysis of patients who survived and had follow-up for at least 2 years from diagnosis, AYAs who completed treatment (with or without ASP completion) had an estimated 5-year OS of 92.7% (95% Confidence Interval (CI): 87.5%, 95.8%), while children who completed treatment had a 5-year OS of 97.9% (95% CI: 96.7%, 98.6%) (Log-rank test p = 0.002) (Figure 1). Patients alive at 2 years who failed or did not complete treatment had worse survival outcomes with a 5-year OS of 70.5% (95% CI: 53.9%, 82.1%) among AYAs and 76.1% (95% CI: 62.2%, 85.5%) among children (Log-rank test p = 0.598) Conclusions: AYAs in our cohort completed protocol treatment at higher rates than previously reported trials. Among AYAs who completed treatment protocol, oncologic outcomes were excellent (5-year OS above 90%) and comparable to (although statistically lower than) those of children. AYAs had higher treatment failure rates, likely due to more aggressive disease biology. AYAs had lower ASP completion rates and higher ASP discontinuation rates due to toxicity compared to children; the etiology and impact of that on survival will need to be further investigated. Introduction of novel agents to improve remission induction rates and prevent early relapse in AYAs might help further improve oncologic outcomes for this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

Ocular abnormalities at diagnosis and after the completion of treatment in children and adolescents with newly diagnosed acute lymphoblastic leukemia.

Ocular abnormalities (OA) in pediatric patients with acute lymphoblastic leukemia (ALL) are common findings both at diagnosis and later in follow-up. The frequency, predictors, and prognostic impact of OA in the context of recent ALL protocols are not well characterized. Single-center retrospective analysis of the medical records of 224 patients with ALL enrolled on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. Overall, 217 (98%) patients had at least one ophthalmic exam. Retinal hemorrhages were the most frequent abnormalities at diagnosis (11%) and cataracts at later time points (13%). OA at diagnosis were associated with age ≥10years and with the severity of anemia and thrombocytopenia; they were also univariately associated with lower 5-year event-free survival (EFS) (high risk [HR]=3.09 [95% CI: 1.38-6.94]; p=.006), but not in a disease-free survival (DFS) model adjusted for end-induction minimal residual disease (p=.82). The cumulative incidence of cataract was 13.1% ± 2.8% at 43months from diagnosis; its development was associated with high presenting white blood cell count (≥50,000/μl) (p=.010), male sex (p=.036), higher risk group (p=.025), and cranial radiation (p=.004). Cataract was associated with decreased visual acuity. OA at diagnosis, present in 12% of patients, were associated with older age, anemia, and thrombocytopenia and did not carry a significant prognostic impact. Cataracts were detected in over 10% of patients and were associated with decreased visual acuity, thus supporting routine screening after completion of therapy, especially for those treated with high-risk protocols.

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

AbstractThe 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.

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials

AbstractAdolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

Dietary Antioxidant Micronutrient Intake and Toxicity during Remission Induction in Children with Acute Lymphoblastic Leukemia (ALL): Results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 05-001

Introduction: Treatment related toxicities are a major contributor to morbidity during induction therapy in childhood ALL. Our prior study in 103 children with ALL suggested that low intakes of antioxidant micronutrients were associated with toxicity and delays in chemotherapy administration (Am J Clin Nutr 79:1029, 2004). The objective of this study was to examine whether inadequate antioxidant micronutrient dietary intake in children with ALL is associated with episodes of infection or ≥grade 3 mucositis during Remission Induction.Methods: Assessment of dietary intake was collected in patients (pts) ages 1-17.9 years enrolled on the DFCI ALL Consortium Protocol 05-001 from 2005-2011. Institutional review board approval was obtained by each of the 9 participating centers. Grade 3 or higher (NCI CTCAEvs) mucositis, culture positive bacteremia and fungemia, and radiographic invasive fungal disease were prospectively collected. Dietary intake was assessed with the Harvard Service Food Frequency Questionnaire (FFQ) for children ages 1-5 years and the Youth and Adolescent Harvard FFQ for children ages 5-18 years and queried about intake in the past 30 days at the end of induction. Dietary antioxidant intake from food sources ± supplementation was examined by comparing consumption above and below recommended intake for age and sex as per the Dietary Reference Intake (DRI). Micronutrient intake was summarized with descriptive statistics and plotted by the presence/absence of a given toxicity in induction. Categorical and continuous variables were compared between group with the Fisher's exact test and the Wilcoxon rank sum test respectively. Logistic regression was used to model the probability of a given toxicity univariately and with a multivariable adjustment for sex and age.Results: Among 794 eligible pts, 561 (71%) had analyzable FFQs. The sample with dietary surveys responses was marginally younger (p=0.06) and more often classified as initial standard risk (p=0.01) than those with no end of induction survey. DRI recommendations were not met for vitamin C (18%), vitamin E (67%) and zinc (12%); 39% of pts reported zinc overconsumption. 141 (25%) of pts with dietary data had ≥1 bacterial and/or fungal infection, 131 (23%) had ≥1 bacterial infection, and 19 (3%) had ≥1 fungal infection. 24 (4%) pts experienced at least 1 event of ≥grade 3 mucositis. Female sex was associated with overall and bacterial infection (p=0.02) and marginally with mucositis (p=0.06). The proportion of patients with ≥Grade 3 mucositis was marginally higher (p=0.06) for those not meeting the vitamin C recommendation (OR=2.3; 95% CI 1.0-5.5), but was not significant (p=0.10) in a multivariable model. Supplementation was reported by 88 (16%) for zinc, vitamins C, E, and A in combination, 16 (3%) for β-carotene and total carotene, and 87 (15%) for vitamin E alone. Intake levels of vitamins C, E, and A, zinc and total carotenoids from food sources and total (food + supplementation) were compared for pts with and without infection and mucositis (unadjusted for age/sex) (Figure 1). Bacterial infection was associated with low intake from food only of zinc (p=0.02), vitamin A (p=0.01), and vitamin E (p=0.049). Mucositis was associated with the following: low intakes of vitamin C from food (p=0.04), vitamin E from food (p=0.03), total lycopene (p=0.03), total α-carotene (p=0.01), total β-carotene (p=0.007) and from food (p=0.008), total carotene (p=0.005) and carotene from food (p=0.006), and total vitamin A (p=0.01) and vitamin A from food (p=0.004). Females age <10 had higher rates of bacterial infection with low β-carotene (p=0.05) and vitamin A from food (p=0.004). In males age ≥10, low vitamin E from food was observed in those with bacterial infections (p=0.05). Supplementation did not confer an added benefit for most nutrients.Conclusions: Confirming our pilot study, data from a large prospective cohort show that low dietary intakes of antioxidant vitamins, carotenoids and zinc primarily from food sources predict risk for bacterial infection or mucositis during induction therapy for childhood ALL. Dietary supplementation for most vitamins and minerals did not confer an added benefit for prevention of infection or mucositis over levels obtained from food. Our results suggest a possible modifiable dietary intervention to reduce toxicity during induction therapy for ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Age and ABO Blood Group Are Significant Predictors of Thrombosis in Children with Acute Lymphoblastic Leukemia (ALL): Results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 05-001

BackgroundThromboembolism (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.AimTo 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/MethodsEligible 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.ResultsOf 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 <5 years of age (p=0.01). There was no difference in the event free or overall survival between patients with or without TE.ConclusionOlder 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. [Display omitted] DisclosuresNeuberg:Synta Pharmaceuticals: Other: Stock shares.

Household material hardship and parental distress in a multicenter clinical trial for pediatric acute lymphoblastic leukemia.

10025 Background: Poverty is associated with inferior psychosocial function among parents of children with cancer. Severe parental distress during treatment predicts future poor mental health for both parents and children. It is also associated with impaired parental cognitive bandwidth and executive function, which may have implications for treatment adherence. Efforts to identify poverty-exposures amenable to intervention are essential to improving survivorship quality of life for the &gt; 90% of children with acute lymphoblastic leukemia (ALL) who will be long-term survivors. Household material hardship (HMH) is a targetable poverty exposure defined as at least 1 of 3 unmet basic needs including food, housing, or utilities. Dana-Farber Cancer Institute (DFCI) ALL Consortium trial 16-001 is the first pediatric oncology clinical trial to systematically evaluate HMH. We investigated the hypothesis that HMH exposure independently predicts severe parent psychological distress during ALL therapy. Methods: Patients with newly diagnosed ALL ages 1-17 years were enrolled on the DFCI 16-001 embedded HMH cohort study at 8 U.S. and Canadian centers. Secondary interim analyses used baseline (within 32-days of trial enrollment) and 6-mos parent-reported sociodemographic data, the Kessler-6 (K6) Psychological Distress scale, and trial-collected child and disease data. Severe psychological distress was defined as a K6 &gt; = 13. Multivariable cox regression evaluated baseline HMH-exposure and parent distress at baseline and 6-mos adjusting for child’s initial ALL risk group (Very High Risk (VHR) vs other) and marital status (single vs dual parent). Results: Among 258 families with evaluable data, 34% reported baseline HMH. Families were predominantly English-speaking (54%) dual parent households (71%). Children were a median of 5.7 years (IQR 1.0-17.99) at diagnosis and predominantly non-Hispanic white (66%) with expected disease distribution by immunophenotype (84% B-cell). HMH (odds ratio (OR) 2.18, 95% confidence interval (CI) 1.0-4.31, p = 0.025) and VHR initial risk group (OR 2.32; 95% CI 1.06-5.06, p = 0.035) were independently associated with baseline severe psychological distress. Only HMH was independently associated with 6-mos severe psychological distress (OR 4.93, 95% CI 1.80-13.48, p = 0.002). Future analyses will investigate race and ethnicity associations with parental distress pending trial accrual for statistical power. Conclusions: HMH, a modifiable poverty exposure, is significantly associated with severe parent psychological distress at diagnosis that persists 6-months into pediatric ALL therapy. These findings identify a cohort at high risk of inferior mental health outcomes, and affirm the need for HMH-targeted interventions to support children and parents during cancer treatment to reduce poverty-associated outcome disparities in survivorship.

Frequency and Prognostic Significance of Recurrent Gene Mutations in Pediatric B-ALL: Report from the DFCI ALL Consortium

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 &amp;gt; 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 (&amp;lt;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 &amp;gt;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) &amp;gt;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.

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: A prospective evaluation.

Children with acute lymphoblastic leukemia (ALL) have increased risk of thromboembolism (TE). However, the predictors of ALL-associated TE are as yet uncertain. This exploratory, prospective cohort study evaluated the effects of clinical (age, gender, ALL risk group) and laboratory variables (hematological parameters, ABO blood group, inherited and acquired prothrombotic defects [PDs]) at diagnosis on the development of symptomatic TE (sTE) in children (aged 1 to ≤18) treated on the Dana-Farber Cancer Institute ALL 05-001 study. Samples collected prior to the start of ALL therapy were evaluated for genetic and acquired PDs (proteins C and S, antithrombin, procoagulant factors VIII (FVIII:C), IX, XI and von Willebrand factor antigen levels, gene polymorphisms of factor V G1691A, prothrombin gene G20210A and methylene tetrahydrofolate reductase C677T, anticardiolipin antibodies, fasting lipoprotein(a), and homocysteine). Of 131 enrolled patients (mean age [range] 6.4 [1-17] years) 70 were male patients and 20 patients (15%) developed sTE. Acquired or inherited PD had no impact on the risk of sTE. Multivariable analyses identified older age (odds ratio [OR] 1.13; 95% confidence interval [CI]: 1.01, 1.26) and non-O blood group (OR 3.64, 95% CI: 1.06, 12.51) as independent predictors for development of sTE. Patients with circulating blasts had higher odds of developing sTE (OR 6.66; 95% CI: 0.82, 53.85). Older age, non-O blood group, and presence of circulating blasts, but not PDs, predicted the risk of sTE during ALL therapy. We recommend evaluation of these novel risk factors in the development of ALL-associated TE. If confirmed, these easily accessible variables at diagnosis can help develop a risk-prediction model for ALL-associated TE.

Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia

Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols. Two-year cumulative incidence of symptomatic ON was 10.6%. Two BCL2L11 polymorphisms, the 891T>G (rs2241843) in all QcALL patients and 29201C>T (rs724710) in high-risk group were significantly associated with ON, P = 0.009 and P = 0.003, respectively. The association remained significant in multivariate model (HR891TT = 2.4, 95% CI 1.2-4.8, P = 0.01 and HR29201CC = 5.7, 95% CI 1.6-20.9, P = 0.008). Both polymorphisms influenced viability of dexamethasone treated lymphoblastoid cell lines (P ≤ 0.03). The 891T>G influenced Bim gamma isoform levels (0.03) and its association with ON was also confirmed in replication DFCI cohort (N = 168, P = 0.03). QcALL children had a high incidence of ON during therapy, which was highly associated with BCL2L11 polymorphisms.

The use of prophylactic anticoagulation during induction and consolidation chemotherapy in adults with acute lymphoblastic leukemia.

Treatment for acute lymphoblastic leukemia (ALL) in adults confers a high risk of venous thromboembolic (VTE) complications. We describe the implementation and results of prophylactic anticoagulation guidelines in adults (18-50years) treated on a Dana-Farber Cancer Institute ALL pediatric inspired consortium protocol from 2007 to 2013. A high rate of asparaginase related toxicity events, including thrombosis, resulted in a protocol amendment adding guidelines for prophylactic anticoagulation and a modified asparaginase dose and schedule. After excluding patients with Philadelphia positive ALL, a cohort of 36 patients were treated after the protocol amendment with prophylactic anticoagulation and compared to 49 patients who received no prophylactic anticoagulation. Bleeding complications were not significantly different in those treated with prophylactic anticoagulation compared with those enrolled prior to the amendment (p = 0.26). No patients on prophylactic anticoagulation had grade ≥ 3 bleeding. Prior to the amendment, the 2year cumulative incidence of VTE post-induction was 41% compared to 28% while on prophylactic anticoagulation (p = 0.32). The 2year cumulative incidence pulmonary embolus pre-amendment was 16% compared with 8% post-amendment (p = 0.34). Prophylactic anticoagulation can be safely administered to adults with ALL without increasing the number or severity of bleeding events and, in addition to modifications in the asparaginase regimen, resulted in a reduction in the cumulative incidence of VTE.

Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study

BackgroundThromboembolism (TE) is a serious complication in children with acute lymphoblastic leukemia (ALL). The incidence of symptomatic thromboembolism is as high as 14% and case fatality rate of ~15%. Further, development of thromboembolism interferes with the scheduled chemotherapy with potential impact on cure rates. The exact pathogenesis of ALL-associated thromboembolism is unknown. Concomitant administration of asparaginase and steroids, two important anti-leukemic agents, is shown to increase the risk of ALL-associated TE. Dana-Farber Cancer Institute (DFCI) ALL studies reported ~10% incidence of thrombosis with significantly increased risk in older children (≥10 yrs.) and those with high-risk ALL. The majority (90%) of thromboembolic events occurred in the Consolidation phase of therapy with concomitant asparaginase and steroids when high-risk patients (including all older patients) receive higher dose steroids. Certain inherited and acquired prothrombotic defects are known to contribute to the development of TE. German investigators documented ~50% incidence of TE during therapy with concomitant asparaginase and steroids, in children with at least one prothrombotic defect. However, current evidence regarding the role of prothrombotic defects in the development of ALL-associated TE is contradictory. Although thromboprophylaxis can prevent thromboembolism, ALL and it’s therapy can increase the risk of bleeding. For judicious use of thromboprophylaxis, identifying a population at high risk for TE is important. The risk factors, including prothrombotic defects, predisposing to thrombosis in children with ALL have not been defined.MethodsThis prospective, observational cohort study aims to evaluate the prevalence of inherited prothrombotic defects in children with ALL treated on DFCI 05–01 protocol and the causal relationship of prothrombotic defects in combination with patient and disease-related factors to the development of TE. We hypothesize that the combination of prothrombotic defects and the intensive therapy with concomitant high dose steroids and asparaginase increases the risk of TE in older patients and patients with high-risk ALL.DiscussionThe results of the proposed study will help design studies of prophylactic anticoagulant therapy. Thromboprophylaxis given to a targeted population will likely reduce the incidence of TE in children with ALL and ultimately improve their quality of life and prospects for cure.

Excellent Outcome of Children with Down Syndrome (DS) and Acute Lymphoblastic Leukemia (ALL) Treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 00-001 and 05-001

▪BackgroundChildren with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are shown to have increased therapy-related morbidity and mortality. Hence, therapy modifications and/or dose-reductions are common treatment strategies for this patient (pt) population. Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk-stratified treatment for children with and without DS and ALL.Aim:To define the toxicity profile and outcome of children with DS and de novo ALL treated on DFCI ALL Consortium therapy protocols 00-001 and 05-001 using therapy identical to non-DS patients.Methods:Demographic, clinical and outcome data of DS and non-DS patients enrolled on the DFCI ALL protocols 00-001 (2000-2004) and 05-001 (2005-2011) were analyzed. Risk categorization and protocol therapy have previously been described (J Clin Oncol 2013; 31:1202-10; Lancet Oncol 2015;16:1677-90). On both protocols, DS ALL pts were treated identically to non-DS pts without any dose reduction or modification, except for the option for DS ALL pts to receive 3 doses of leucovorin after IT methotrexate. Fisher’s exact test was used to compare toxicities in the DS and non-DS pts and Gray test was used to compare the cumulative incidence of fracture and osteonecrosis. Overall survival (OS) was defined as time from registration to death. Event-free survival (EFS) was defined as time from registration to first event (defined as induction failure, relapse, second malignant neoplasm (SMN) or death due to any cause). Induction failure and induction death were included as events at time zero. Disease-free survival (DFS) was defined as time from complete remission (CR) to relapse, SMN or death. Pts without an event were censored at the last known follow-up. The Kaplan-Meier method was used for survival estimation and Greenwood’s formula for calculation of 95% confidence interval (CI) of survival estimates. Outcome of DS patients was also examined using Ponte di Legno (PdL) risk group [Low risk (LR) was defined as age at diagnosis ≤ 6 yr. and white cell count < 10X109/L and, remainder as high risk (HR)].(Blood 2014;123:70-7). Two-sided p values <0.05 were considered significant.Results:Of 1286 eligible pts aged 1-18 yrs. with de novo ALL enrolled on protocols 00-001 and 05-001, 38 (3%) had DS. There was no difference in demographic or presenting clinical features between DS and non-DS ALL pts except immunophenotype (absence of T-ALL in DS vs 11.7% in non-DS, p=0.017) and presence of high hyperdiploidy (51-65 chromosomes) (8.8% in DS vs 25.1% in non-DS, p=0.027) (Table 1). Two DS-ALL pts withdrew from the study after achieving CR. There was no difference in the CR rates (DS: 100% vs non-DS: 95.2%, p=0.47) or proportion of pts with low end of induction minimal residual disease (MRD) between DS and non-DS groups (p=0.73). Toxicities were comparable except DS pts had significantly higher rates of ≥Grade 3 mucositis (data available for protocol 05-001 only) (DS: 52.0% vs. non-DS: 12.0%, p<0.001), non-CNS thrombosis/bleed (18.4% vs. 8.2%; p=0.036), and seizure (15.8% vs. 4.7%, p=0.010). DS pts also had marginally higher rate of bacterial and fungal infections (55.3% vs. 41.3%, p=0.096) (Table 2). All 38 DS pts achieved a CR and there were 4 relapses with 1 death due to disease. There were no treatment-related deaths in DS-ALL pts. With a median follow-up of 6.2 yrs. the 5-yr EFS, DFS, and OS of DS pts were similar to non-DS pts (90.7% [81.1-100.0] vs. 83.7% [81.7-85.9]; 90.7% [81.1-100.0] vs. 87.4% [85.5-89.3]; 97.1% [91.8-100.0] vs. 91.4% [89.8-93.0]), with the 95% CI overlapping for each comparison (Figures 1a and 1b). There was no difference in outcomes of DS-ALL PdL LR pts (n=13) compared to PdL HR pts (n=25) (5-yr EFS 90.0% [73.2-100.0]. vs. 91.0% [79.9-100.0]; 5-yr OS 100.0% [100.0-100.0] vs. 95.8% [88.2-100.0]).Conclusion:DS pts treated on DFCI ALL Consortium protocols without dose reduction or modifications achieved similar outcomes to non-DS pts. DS pts had a higher frequency of mucositis, infection, and seizures, but did not experience any treatment-related deaths. Other than a higher risk of thrombotic complications, they did not develop excessive toxicity to asparaginase. The low rates of relapse and toxicity-related mortality support the approach of unified therapy protocol for DS and non-DS ALL pts with emphasis on supportive care interventions to prevent toxicities. [Display omitted] [Display omitted] [Display omitted] DisclosuresAsselin:Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy.

Randomized Study of Pegasparagase (SS-PEG) and Calaspargase Pegol (SC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001

▪Background: E.coli L-asparaginase (L-ASP) is an important component of treatment for childhood acute lymphoblastic leukemia (ALL), but the optimal preparation and dosing remain to be determined. Pegaspargase (SS-PEG) is a pegylated L-ASP formulation commonly used in frontline therapy. Calaspargase pegol (SC-PEG) is a novel formulation that uses the same ASP enzyme and PEG moiety as SS-PEG but a different linker molecule that is more hydrolytically stable, leading to a longer half-life. On Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols, patients (pts) typically receive a single dose SS-PEG during induction, and then 15 doses every 2-weeks (wks) during post-induction in order to maintain therapeutic serum asparaginase activity (SAA), defined as ≥ 0.1 IU/mL, for 30 consecutive wks. We hypothesized that SC-PEG could be administered less frequently than SS-PEG during post-induction therapy with a similar SAA and toxicity profile.Methods: Between 2012-2015, pts aged 1-21 years with newly diagnosed ALL or lymphoblastic lymphoma (LL) were eligible to enroll on DFCI ALL Consortium Protocol 11-001. Pts were randomized at study entry to receive either SS-PEG (N=120) or SC-PEG (N=119), each given intravenously (IV) at a dose of 2500 IU/m2. Both groups received a single dose during multi-agent remission induction. Post-induction, pts assigned to SS-PEG received 15 doses every 2-wks and those assigned to SC-PEG received 10 doses every 3-wks along with other risk-stratified chemotherapy. Serum samples were obtained 4, 11, 18 and 25 days after the induction dose to determine SAA and prior to each post-induction dose (2 wks after each SS-PEG and 3 wks after each SC-PEG dose) to determine nadir SAA (NSAA) by a validated biochemical assay. Pts were switched to Erwinia asparaginase for Grade 2 or higher allergy or for silent inactivation (defined as 2 consecutive non-detectable NSAA). Asparaginase was permanently discontinued for pancreatitis and held for thrombosis (but re-started once the clot improved). End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCRPCR assay, with low MRD defined as < 0.001.Results: 239 eligible pts were enrolled (230 ALL and 9 LL). There were no significant differences in presenting characteristics between randomized arms. SAA during induction and NSAA during post-induction are displayed in Figure 1. SAA was similar for the two preparations at 4, 11 and 18 days after the induction dose, with SAA ≥ 0.1 IU/mL in ≥ 95% of pts at these time points on both arms. 25 days after the induction dose, SAA was higher with SC-PEG (median 0.298 IU/mL vs 0.056 for SS-PEG), with significantly more pts on SC-PEG arm with SAA ≥ 0.1 IU/mL (88% vs 15%, p<0.0001). Post-induction NSAA was similar between arms, with median NSAA ≥ 1.0 IU/mL (10-times higher than goal NSAA) at 7, 13, 19 and 25 wks after beginning the 30-wk post-induction asparaginase treatment. NSAA was ≥ 0.1 IU/mL in ≥ 98% of pts on both arms at each time point. Two pts on the SC-PEG arm (1.7%) and none on the SS-PEG arm met criteria for silent inactivation. There was no significant difference in rates of ASP-related allergy (p=1.00), pancreatitis (p=1.00), thrombosis (p=0.22) or infections (p=0.86) during induction or post-induction treatment (Table 1). Of 230 evaluable pts, 97% achieved CR, with no difference in proportion of pts with low end-induction MRD by randomized arm (91% SC-PEG vs 90% SS-PEG, p=1.00).Conclusion: During remission induction, a single dose of SC-PEG (2500 IU/m2) leads to more sustained SAA without excess toxicity or significant difference in the proportion of pts with low end-induction MRD. During post-induction therapy, SC-PEG can be given less frequently (every 3-wks) than SS-PEG (every 2-wks) with similar NSAA and toxicity. The high NSAA observed during post-induction therapy with each preparation suggests that a longer dosing interval and/or reduced dose may be feasible while still maintaining NSAA ≥ 0.1 IU/mL. Longer follow-up is necessary to determine event-free survival by randomized arm. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dietary intake and childhood leukemia: The Diet and Acute Lymphoblastic Leukemia Treatment (DALLT) cohort study

ObjectiveChildren with acute lymphoblastic leukemia (ALL) are at elevated risk for nutrition-related morbidity both during and after therapy. We present the demographic characteristics and nutrient intake at study entry of a prospective cohort in which evaluating dietary intake in children diagnosed with ALL was investigated. MethodsDietary intake data were collected for participants enrolled on the Dana-Farber Cancer Institute ALL Consortium Protocol. Dietary intake was assessed with a food frequency questionnaire and was compared with the dietary reference intake by ALL risk group (standard and high risk). ResultsDietary intake data were collected from 81% of participants (n = 640). We found that 27% of participants were overweight/obese. Intake of total calories and other nutrients exceeded the dietary reference intake in up to 79% of children. This was evident in both risk groups and was pronounced among younger children. For micronutrients, dietary intake of calcium, vitamin D (females only), and zinc differed significantly between patients with standard-risk and those with high-risk ALL. ConclusionsThis study was successful in collecting dietary intake data at the time of cancer diagnosis in a multicenter setting in a pediatric population at high-risk for nutrition-related morbidity. We identified “at-risk” dietary intakes, which vary by sex and ALL risk group; such patients may benefit from future dietary interventions.