DFCI Acute Lymphoblastic Leukemia Research Articles

Oral Chemotherapy Adherence in Pediatric Acute Lymphoblastic Leukemia (ALL): A Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001

Background: Successful treatment of pediatric acute lymphoblastic leukemia (ALL) requires 2 years of risk-directed therapy, much of which is built on a backbone of oral chemotherapy including 6-mercaptopurine (6MP) and dexamethasone (DEX). Studies conducted in the Children's Oncology Group (COG) demonstrate that poor adherence to 6MP during the maintenance phase confers increased relapse risk; however, little is known about the rates of 6MP adherence in non-COG ALL regimens. DFCI ALL Consortium protocols utilize 3-week cycles including 14-day pulses of 6MP with weekly intravenous or intramuscular methotrexate. This treatment approach requires more frequent contact between families and healthcare providers and reduces the number of oral chemotherapy agents prescribed. Whether this higher-touch regimen might reduce the frequency of non-adherence as compared to published COG data is not known. Additionally, there remains a paucity of data investigating incidence of non-adherence to DEX, 6MP, and to any medications during the first year of therapy. Methods: Oral chemotherapy adherence was prospectively evaluated as an embedded ancillary study on the DFCI ALL Consortium Protocol 16-001. Eligible participants included English-, Spanish-, or French-speaking caregivers of patients (<22 years) receiving 6MP and DEX (both liquid and tablet formations) and did not utilize a pillbox. Adherence to 6MP and DEX were measured using Medication Event Monitoring Systems (MEMS) caps, which record the date and time of medicine bottle opening. MEMS caps were used to measure adherence for three consecutive cycles during the first year of therapy, and again for three consecutive cycles during the second year of therapy. Caregivers completed surveys reporting sociodemographic determinants of health (SDOH), medication-taking behaviors, and chemotherapy comprehension. MEMS-based medication adherence rates were calculated as a percentage based upon the ratio of the number of days with MEMS cap openings to the number of days 6MP and/or DEX were prescribed. Adherent patients were defined as those with ≥95% adherence based on prior COG trials that observed an excess risk of relapse below this threshold (Bhatia JAMA Onc 2015). Results: Between 2018 - 2022, 252/429 (59%) eligible patients consented to study participation, and adherence data was successfully collected for 207 (82%). Sixty-six (26%) participants were enrolled from Canadian hospital centers, and 186 (74%) participants were enrolled from US hospital centers. Participant age included 159 (77%) <10 years of age, 31 (15%) 10 - 14 years, and 17 (8%) 15 - 21 years (see Table 1). Thirty-four (16%) patients identified as Hispanic, 13 (6%) non-Hispanic Black, 18 (9%) non-Hispanic Other, and 142 (69%) non-Hispanic White. 57 (31%) patients relied on public insurance at time of diagnosis, 61 (34%) patients reported a primary household language other than English, and 36 (20%) patients lived in lone-parent households. A third, 61 (34%) and 62 (34%), of caregivers reported being unsure of what would happen if their child stopped taking 6MP or DEX, respectively. Over the course of six cycles, MEMS-measured adherence rates to 6MP (N = 180) and DEX (N = 195) were 73% (range 21 - 100) and 86% (range 10 - 100), respectively. Preliminary data suggest that adherence rates to 6MP improved during year 2 of treatment (cycles 4-6 of monitoring) (Table 2). In unadjusted analyses, there was a non-significant association between patient age and likelihood of adherence to oral medication: adherence to 6MP was 71% in those <10 years, 80% in those 10 - 14 years, and 71% in those 15 years or older (Jonckheere-Terpstra test p = 0.66). Conclusion: Among a diverse cohort of patients treated with a DFCI ALL Consortium regimen, adherence to oral chemotherapy is suboptimal with rates of 73% to 6MP and 86% to DEX. This finding recapitulates published data from COG ALL trials, suggesting more frequent contact with healthcare providers in the DFCI Consortium protocol does not mitigate non-adherence. Numerical differences between age groups suggest patients ages 10 - 14 years (N=31) have higher adherence compared to patients both younger and older. These preliminary findings suggest that there may be a behavioral component when it comes to medication adherence - with barriers among young children differing from those in both younger and older adolescents.

Updated Results on a Multicenter Phase II Study of a Dose Intensified Pediatric Regimen in Adults with Acute Lymphoblastic Leukemia: The 06-254 DFCI ALL Consortium Trial

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have good outcomes when treated with pediatric regimens (DeAngelo Leukemia 2014; Stock Blood 2019). Here we update our multi-center Phase II study (06-254) applying the DFCI pediatric regimen to young adults, as well as our post-trial experience. The 06-254 protocol is based on the very high-risk arm of the DFCI Pediatric Protocol 05-001. This report focuses on Philadelphia negative (Ph-) pts. Methods: Pts between 18-50 years (yrs) with de novo ALL were eligible. The primary objective was to determine the feasibility of a single dose of pegylated-asparaginase (PEG-ASP) during induction followed by a 30 week PEG-ASP consolidation. Induction chemotherapy included doxorubicin, prednisone, vincristine, PEG-ASP, and intra-thecal chemotherapy (IT). Consolidation I consisted of high-dose methotrexate (A), followed by a BFM-like intensification (B), and a course of high-dose cytarabine, etoposide and dexamethasone (C). Central nervous system prophylaxis included intrathecal therapy and cranial radiation. Intensification therapy consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-MP and 30 weeks of PEG-ASP. Dosing of PEG-ASP was initially 2500 IU/m2 every 2 weeks but due to toxicity was reduced to 2000 IU/m2 every 3 weeks and given concomitantly with consolidation. Body surface area was capped at 2.3m2 for PEG-ASP dosing. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate, and 6-MP until 2 yrs from complete remission (CR). Additional consecutive Ph- pts treated “as per” 06-254 (2009-2021) were identified; these pts received treatment following 06-254 including PEG-ASP 2000 IU/m2 every 3 weeks in consolidation. Median follow-up was calculated with the reverse Kaplan Meier indicator. The chi square test was used to compare categorical characteristics. Overall survival (OS) and event free survival (EFS) among groups were compared with the log rank test. Results: A total of 152 Ph- pts were treated from 2007 to 2021 (89 pts on protocol and 63 “as per”). Median follow up was 3.5 yrs for pts treated on protocol and 3.8 yrs for pts treated “as per.” Characteristics at diagnosis: Median age 27.9 yrs (82, 54% < 30 yrs); 39.5% female; 31.6% T-lineage; 53.3% overweight/obese BMI per CDC criteria. Older pts (30-50 yrs) were more likely to be overweight/obese than younger (18-29y) pts (71.4% vs. 37.8%, p < 0.001) and were more frequently allografted in CR1 (21.4% vs. 9.8%, p = 0.045). CR was achieved by 142 (92.1%) pts. Among 81 (53.3%) pts with known end-induction measurable residual disease (MRD) status, 68 (84.0%) were MRD negative. In total, 88 (57.9%) pts completed all protocol treatment, 9 (5.9%) had induction failure, 3 (2.0%) died during treatment, 13 (8.6%) relapsed during treatment, 16 (10.5%) exited the protocol for other reasons, and 22 (15.1%) were consolidated with bone marrow transplant (BMT) in CR1. Among the 95 patients who remained on protocol for at least 1 year, 73 (76.8%) had ≥ 26 wks of asparagine depletion. Regarding toxicity: 21 pts (13.8%) had clinical pancreatitis, 98 (64.5%) experienced grade 3-4 laboratory hepatotoxicity, and 20 (13.1%) had allergic reactions to ASP. OS of the entire cohort was 84.4% (95% CI 77.4-89.3) at 3 yrs and 75.8% (95% CI 67.0-82.6) at 5 yrs. Pts aged 18-29 yrs had superior 5-yr OS to those aged 30-50 yrs (82.4% [95% CI 69.4-90.2] vs. 67.1% [95% CI 53.3-77.7], p = 0.004), and pts with a BMI < 25 at diagnosis had superior 5-yr OS than those with BMI ≥ 25 (87.1% [95% CI 73.5-94.0] vs. 66.5% [95% CI 53.9-76.5], p = 0.002). Patients with negative MRD at end of induction had a 5-yr OS of 80.7% (95% CI 66.7-89.3) and those with positive MRD 59.1% (95% CI 21.8-83.4) (p = 0.16). Pts treated “as per” had superior 5-yr OS to those treated on protocol (86.0% [95% CI 71.3-93.5] vs. 68.7% [95% CI 56.5-78.1], p = 0.012). EFS was 77.1% (95% CI 69.0-83.3) at 3 yrs and 70.6% (95% CI 61.4-78.0) at 5 yrs. Pts aged 18-29 yrs had superior 5-yr EFS compared to those aged 30-50 yrs (76.3% [95% CI 63.0-85.3] vs. 62.8% [95% CI 48.8-74.0], p = 0.033). Treatment on trial (compared to “as per”), BMI, and MRD status were not statistically associated with EFS. Conclusions: The administration of a pediatric regimen with dose intensified PEG-ASP to population between 18-50 is feasible and results in a high remission rate with 5-yr OS 75.8%.

Impairment of health-related quality of life for children with acute lymphoblastic leukemia over the first year of therapy: A report from the DFCI ALL Consortium.

Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL. Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue. Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy. This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase.

Vitamin A and association with asparaginase-associated pancreatitis in children with acute lymphocytic leukemia.

10021 Background: Asparaginase is a key component of treatment of acute lymphoblastic leukemia (ALL), which is the most common cancer in the pediatric population. However, asparaginase is associated with many toxicities, including pancreatitis, which is observed in up to 10% of patients and can lead to severe sequelae. Methods: We performed analysis of (1) transcriptomic data from (a) asparaginase-treated leukemic cells, and (b) the pancreas of mice that were induced with a chemical form of pancreatitis; (2) the US FDA Adverse Reporting System (FAERS) and electronic health records (TriNetX); (3) global plasma metabolomic screen and dietary intake evaluation from ALL patients; and (4) experimental animal studies to identify factors that impact asparaginase-associated pancreatitis (AAP). Results: Connectivity map analysis showed that asparaginase-induced gene signatures are potentially reversed by the retinoids (vitamin A and its natural and synthetic analogs). Analysis of TriNetX and FAERES demonstrated a 2-fold reduction in AAP risk with concomitant exposure to vitamin A. Further, we performed a case-control metabolomic study of 50 subjects with ALL enrolled in the Dana-Farber Cancer Institute DFCI ALL clinical trial protocols 05-001 (NCT00400946) and 11-001 (NCT01574274). All subjects were given a single dose of pegylated E. Coli asparaginase during induction therapy. Twenty-four subjects developed pancreatitis within 9 months from the start of induction therapy and were considered cases. The median time to develop pancreatitis among cases was 3.68 months (interquartile range: 3.58 months). Twenty-six control subjects were identified among patients who did not develop pancreatitis within the same evaluation period. The controls were matched for age, sex, and initial ALL risk. The screening revealed that the plasma levels of carotene diol isomers, from the start of induction to its end, were reduced by about 60% in the cases compared to the controls. A detailed 30-day dietary recall showed that the cases had received less dietary vitamin A than the controls during induction therapy. Notably, the median value for the composite intake of vitamin A constituents, termed the RAE (retinol activity equivalents) was 656.92 mcg per day among the controls, but was 34.6% lower among in the cases (median of 429.40 mcg per day, which is just above the recommended dietary allowance level of 400 mcg per day for the 4–8 year-old age group). In mice, asparaginase administration as a single agent was sufficient to reduce circulating and hepatic retinol levels. Conclusions: Based on these data, we propose that circulating retinoids maintain pancreatic health, that asparaginase reduces circulating retinoids, and AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach provides the impetus to examine the role of dietary vitamin A supplementation for preventing or treating AAP.

Impact of Age, Body Surface Area, and Body Mass Index on Pegaspargase Toxicity and Pharmacokinetics: A Report from the DFCI ALL Consortium

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 <19 years (DFCI 05-001) or 1 to <22 years (DFCI 11-001) with newly diagnosed ALL were eligible for enrollment. Those who received PEG (2500 IU/m 2) were included in this analysis. Pts received 1 dose of IV PEG on day 7 of Induction and every 2 weeks for 15 doses post-induction. Serum asparaginase activity (SAA), considered therapeutic at >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 (<1.5 m 2, 1.5 to <2.0 m 2, ≥2.0 m 2, p= 0.007) with increased toxicity in those with BSA ≥2.0m 2 (22.7% vs. 6.8% for those <2.0 m 2, p = 0.016) (Figure 1b). Age was highly correlated with BSA (Pearson r = 0.93, p <0.0001). There was numerically higher toxicity in the BMI category of overweight vs. those underweight or normal weight (11.3% vs 6.5%) however this did not extend to the obese category, and overall, increasing BMI was not associated with statistically higher toxicity (p= 0.13, Figure 1c).Post-Induction, age ≥15 years was associated with increased asparaginase toxicity (57.1% vs 21%, p<0.0001) (Figure 1d). Toxicity differed significantly across BSA categories (p<0.0001) but was similar between BMI categories (p=0.19, Figure 1e-f). The impact of BSA was observed when dichotomized at thresholds of 1.5m 2 (54% vs. 19%, p<0.0001) and 2.0m 2 (70% vs. 23%, p=0.003) (Figure 1e). Considering only those ≥10 years of age, trends for BSA/BMI and toxicity were similar. There was no significant association between BMI or BSA and allergy. In multivariable analysis, BSA was a significant predictor of Post-Induction toxicity (OR 4.21, p<0.0001). Age was significant in the univariate setting (OR 1.14, p<0.0001) however due to high correlation with BSA, was not included with BSA in the multivariable model.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 <1.5m 2 (Figure 2a-d).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. [Display omitted] DisclosuresNeuberg: 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.

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.

Genetic Ancestry and Skeletal Toxicities Among Childhood Acute Lymphoblastic Leukemia Patients in the DFCI 05-001 Cohort

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.

2699. Pneumococcal Vaccination During Chemotherapy in Children Treated for Acute Lymphoblastic Leukemia

BackgroundChildren undergoing therapy for acute lymphoblastic leukemia (ALL) are at high risk of invasive pneumococcal disease (IPD). Immunization with conjugated vaccines following chemotherapy is recommended for pediatric patients. In an attempt to provide an earlier protection against invasive pneumococcal infection, we aimed to assess immunity to S. pneumoniae among children vaccinated during chemotherapy for ALL.MethodsWe retrospectively analyzed the rate of seroprotection among ALL children treated in our institution in accordance with the DFCI ALL Consortium protocol between 2007 and 2014. A pneumococcal conjugate vaccine (PCV) booster was given to all subjects after the end of chemotherapy (groups 1 and 2). In group 2, a PCV dose was also administered during the maintenance phase. Clinical characteristics as well as individual immunization records were collected from our local immunization database. All children were up to date with their vaccination schedule at diagnosis. Serum samples were obtained on a routine follow-up visit, after the end of chemotherapy and after the PCV vaccine booster to measure serotype-specific IgG pneumococcal antibodies. Antibody level ≥0.35µg/mL was considered protective. Patients with seroprotective antibodies level for ≥ 50% of serotypes contained in vaccines were defined as seroprotected.Results62 children [34 girls (54.8%)] were included in the analysis. Median age at diagnosis was 45 months (range:12–160). At the end of chemotherapy, 34.2% of children in group 1 (13/38) and 79.2% in group 2 (19/24) were seroprotected (P < 0.01). Median interval of time between the end of chemotherapy and the PCV booster vaccination was 6 months (range: 2–64 months). After PCV-13 booster, the rate of seroprotection raised to 100% (38/38) in group 1 and 91.7% in group 2 (22/24).ConclusionRates of pneumococcal seroprotected children treated for ALL are low at the end of chemotherapy. However, PCV booster during chemotherapy could be useful to increase the level of seroprotection and shorten the period of susceptibility to IPD. After chemotherapy for ALL, children benefit from a PCV booster to enhance seroprotection. Disclosures All authors: No reported disclosures.

Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia/lymphoma: Results of DFCI 11-001.

10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calaspargase pegol (SC-PEG), a novel pegylated asparaginase (ASP) formulation with longer half-life, compared with standard pegaspargase (SS-PEG). Methods: Patients (pts) aged 1-21 years with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) were eligible. At study entry, pts were randomly assigned to receive either intravenous SS-PEG or SC-PEG, 2500 IU/m2/dose. Pts received 1 dose during the first treatment month. Beginning week 7, SS-PEG was administered every 2 weeks for 15 doses, SC-PEG every 3 weeks for 10 doses (30 weeks). Serum asparaginase activity (SAA) (considered therapeutic at ≥ 0.1 IU/mL) was assessed 4, 11, 18, and 25 days after the induction dose and before each post-induction dose. End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCR PCR. Results: Between 2012-2015, 239 eligible pts enrolled (230 ALL, 9 LL); 120 assigned to SS-PEG, 119 to SC-PEG. After dose 1, SAA remained ≥ 0.1 IU/mL in ≥ 95% of pts on both arms through day 18. Median SAA was higher (0.319 IU/mL vs 0.056 IU/mL) and more pts had therapeutic SAA (88% vs 17%, p˂0.001) with SC-PEG vs SS-PEG 25 days after dose 1. Post-induction, median nadir SAA (NSAA) were similar ( &gt; 1.0 IU/mL) for both arms. There was no difference in rates of ASP-allergy, pancreatitis, thrombosis, hyperbilirubinemia, osteonecrosis, or infection. Of 230 evaluable pts, 99% of SS-PEG and 95% of SC-PEG pts achieved complete remission (p = 0.12). For B ALL pts, there was no difference in frequency of high end-induction MRD (10.3% SS-PEG, 9.5% SC-PEG, p = 1.0). With 4-year median follow-up, 4-year event-free survival (EFS) (90% confidence interval) for SS-PEG was 90.2% (84.3, 93.9), 87.7% (81.5, 91.9) for SC-PEG (p = 0.78); overall survival (OS) was 95.6% (91.0, 97.9) for SS-PEG, 94.8% (90.0, 97.3) for SC-PEG (p = 0.74). Conclusions: Every 3-week SC-PEG had similar EFS, OS, safety profile, and NSAA compared with every 2-week SS-PEG. The high NSAA observed for both preparations suggest dosing strategies can be further optimized. These data informed FDA approval of SC-PEG for pediatric pts. Clinical trial information: NCT01574274.

Feasibility and safety of delivering full-dose anticoagulation therapy in children treated according to Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium therapy protocols.

The literature is void of an evidence-based anticoagulation therapy (ACT) management strategy in the context of thrombocytopenia. We examined the impact of thrombocytopenia on low-molecular-weight heparin (LMWH) dosing and incidence of bleeding in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) who developed thromboembolism (TE) during therapy according to DFCI ALL protocols. Patient records from our tertiary care center were reviewed for demographics, details of diagnoses and therapy of ALL/LL and TE diagnoses, platelet counts during ACT, LMWH dosing, and bleeding episodes. Thirty-nine TEs were diagnosed in 33 patients [mean age 9 years (range, 2.5-18); 16 males and 31 with ALL] during the study period. A majority (85%) of patients were diagnosed with TE in the consolidation phase with mean time to TE 5.75 months from ALL/LL diagnosis. All patients received LMWH, and the median duration of ACT was 5.9 months (range, 1-11 months). Platelets were measured weekly. On 29 occasions, platelet nadir was<50×109 /L, and twice it was<20×109 /L. One (3%) patient had major bleeding episode while on ACT. Platelet count at the time of bleeding was 222×109 /L. Ninety-two procedures [83 lumbar punctures (LPs), 9 central venous line (CVL) insertion/revision] were completed without bleeding complications. Asparaginase was held temporarily with TE diagnosis in 48% of patients; most (88%) patients completed all scheduled doses as per protocol. Ability to administer full-dose LMWH, expected bleeding rate, and completion of asparaginase doses while on ACT suggest full-dose ACT is feasible and safe in children with ALL/LL who develop TE during DFCI ALL consortium therapy protocols.

Asparaginase May Affect Mercaptopurine Tolerability in the Context of Multi-Agent Therapy for Acute Lymphoblastic Leukemia

▪Background: Mercaptopurine (MP) and asparaginase (ASP) are critical components in the treatment of acute lymphoblastic leukemia (ALL). Dose-limiting toxicities of the two drugs are common, resulting in therapy interruption, which has been associated with inferior treatment outcome in some studies. However, the interaction between these drugs has not been clearly identified. Merryman et al (Pediatr Blood Cancer 2012) reported that in DFCI ALL 05-01, patients had lower blood counts and more dosage reductions of MP during consolidation therapy (with concomitant ASP treatment) than during continuation therapy (identical treatment without concomitant ASP). Among groups of homogeneously treated patients with ALL, variability in ASP exposure due to inactivating antibodies can affect ASP pharmacodynamics: we have reported that ASP antibodies were associated with lower plasma ASP activity and higher dexamethasone (DEX) clearance, leading to a lower risk of osteonecrosis and a higher risk of CNS relapse (Liu, Leukemia 2012; Kawedia, Blood 2012). Here we studied the possible effect of ASP antibodies on MP tolerability in St. Jude Children's Research Hospital Total XV, a clinical trial featured intensive ASP treatment.Methods: A total of 390 children with ALL treated on St. Jude Total XV protocol were evaluable. TPMT genotype was used to guide starting doses of MP. During maintenance treatment, planned MP doses were higher on the low-risk arm (LR; n = 202) than on the standard/high-risk arm (SHR; n = 188). MP dose intensity was estimated as (prescribed dose)/(protocol dose) for weeks 1-146 (boys) or 1-120 (girls) for patients on the LR and SHR arms of maintenance therapy.Native E.coli-ASP (Elspar) was administered intramuscularly at 10000 U/m2 thrice weekly for 6 or 9 doses during remission induction. During maintenance therapy, patients on the LR arm received ASP only during reinductions I (weeks 7-9) and II (weeks 17-19), whereas those on the SHR arm received 19 weekly doses at 25000 U/m2 during weeks 1-19. Patients were tested for serum anti-Elspar antibodies at days 5, 19, 34 of remission induction, day 1 of reinduction I and day 1 of reinduction II, and were grouped based on whether they were ever positive for antibodies at any time during therapy or not. The area under the antibody concentration-time curve (AUC) for the entire period up to week 19 was also estimated in 360 patients.Result: Overall MP dose intensity was higher in those with vs without ASP antibodies in patients on the LR (median 83 vs 75%, P = 0.003) and SHR arms (median 86 vs 76%, P = 3.3 × 10-5; Figure 1A), and MP dose intensity was correlated with ASP antibody AUC in patients on both treatment arms (LR, P = 7.7 × 10-3 and SHR, P = 2.4 × 10-4; Figure 1B). In a multivariate model including age, sex, risk arm, ancestry, TPMT status, NUDT15 genotype and ASP antibody status, TPMT genotype was the strongest determinant of MP dose intensity (-17% in heterozygotes, P = 1.9 × 10-8), followed by ASP antibody positivity (+8.9% dose intensity in those with antibodies, P = 5.8 × 10-6). The model also confirmed previously identified associations of higher MP dose intensity with higher African ancestry (Bhatia et al. Blood 2014) (P = 1.8 × 10-4) and lower Asian ancestry (P = 0.05) (Yang et al. J Clin Oncol 2015).Conclusion: Interindividual differences in ASP systemic exposure, as reflected by ASP antibodies, had a strong impact on MP tolerance, especially in patients on the SHR arm who received intensive ASP therapy. We have previously shown that patients who are positive for ASP antibodies not only have lower exposure to ASP but also to dexamethasone (Kawedia, Blood 2012; Liu, Leukemia 2012). These data further emphasize the capacity for variation in ASP exposure to impact yet another critical component of ALL therapy. [Display omitted] DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Ikaros Gene Deletion Significantly Predicts Relapse in Pediatric B-ALL Patients with Low End-Induction Minimal Residual Disease

Background:Deletions in the Ikaros gene (IKZF1) have been associated with a poor outcome in pediatric B-ALL, but the interaction of IKZF1 deletions with other established prognostic factors, such as minimal residual disease (MRD), is still under investigation. Here we report the IKZF1 deletion status of 405 patients (pts) with acute lymphoblastic leukemia (ALL) and its association with other presenting features, end-induction MRD, and outcome.Methods:Between 2005-2011, 794 eligible pts (aged 1-18 yrs) with newly diagnosed pediatric ALL (B-ALL: 697; T-ALL: 97) were enrolled on DFCI ALL Consortium Protocol 05-001. End-induction MRD was assessed prospectively on all pts by allele-specific oligonucleotide-PCR assay. DNA was extracted from archived diagnostic blood or bone marrow samples from 399 B-ALL and 6 T-ALL pts with sufficient available material. Using a commercially available kit (SALSA MLPA P202 IKZF1, MRC-Holland), IKZF1 deletion status was assessed by multiplex ligation-dependent probe amplification (MLPA). Event free survival (EFS) and relapse free survival (RFS) were estimated using the method of Kaplan and Meier.Results:IKZF1 deletion was detected in 69 (17%) of the 405 evaluated pts. IKZF1 deletion was more common in pts over 10 years old (p<0.0001), males (p=0.05), Hispanic/Latinos (p=0.002) and those with presenting white blood cell count (WBC) at diagnosis ≥ 50K/ul (p<0.0001). IKZF1 deletions were detected in 7 of 13 (54%) pts with the Philadelphia chromosome (Ph+). Significantly more IKZF1 pts experienced induction failure (7% vs 1%, p=0.009) and relapse (25% vs 7%, p<0.0001) than pts without IKZF1 deletions. There was no difference in rates of treatment-related mortality. With a median follow-up of 5.3 years, the 5-year event free survival (EFS) for patients without IKZF1 deletion was 87% and 61% for those with IKZF1 deletion (p<0.0001; Figure 1). There was no significant difference in EFS based on type of IKZF1 deletion: 1) deletions of exons 4-7 or 4-8 (42% of cases, 5-yr EFS 51%) or 2) whole gene (49% of cases, 5-yr EFS 69%) (p=0.23).315 Ph-negative B-ALL pts achieving complete remission (CR) had assessable end-induction MRD. Significantly more IKZF1 non-deleted pts had low MRD compared with IKZF1-deleted pts (95% vs 82%, p=0.006). For the 293 MRD-low pts, relapse occurred in 7% of IKZF1 non-deleted and 24% of IKZF1-deleted pts (p=0.004); for 22 MRD-high pts (all of whom received intensified therapy), there was no significant difference in relapse between IKZF1 non-deleted and IKZF1-deleted pts (21% vs 37%, p=0.62). The 5-yr relapse-free survival (RFS) was significantly worse for MRD-low pts with IKZF1 deletions versus those without these deletions (Figure 1). In multivariable analysis, IKZF1 status, but not MRD, was significantly associated with RFS for Ph-negative B-ALL pts. (Table 1)Conclusions:IKZF1 deletion is associated with higher rates of induction failure and relapse, and is a significant predictor of inferior outcome in pediatric B-ALL. IKZF1 deletion was associated with significantly higher rates of relapse in Ph-negative B-ALL patients with low end-induction MRD, and thus may be useful factor to consider when stratifying treatment intensity in this subset of pts. We conclude that IKZF1 deletion should be incorporated into risk stratification for pediatric B-ALL.Table 1Prognostic Factors for RFS for B-ALL, Ph-negative pts with evaluable end-induction MRDUnivariateMultivariableHR [95% CI]p-valueHR [95% CI]p-valueAge, ≥10 vs <101.40 [0.68-2.91]0.361.19 [0.56-2.51]0.65IKZF1, del vs. not3.23 [1.61-6.45]0.00092.53 [1.20-5.30]0.01MRD, high vs. low2.51 [1.04-6.03]0.041.63 [0.64-4.11]0.30WBC, ≥50 vs. <502.50 [1.27-4.94]0.0081.99 [0.98-4.03]0.06[HR=Hazard ratio] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effectiveness of Antibacterial Prophylaxis during Induction Chemotherapy in Children with Acute Lymphoblastic Leukemia

Background. Pediatric patients with newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk for developing bacterial infections, particularly during the induction treatment phase. Infections are the primary cause of treatment-related mortality during the induction phase, and also lead to prolonged hospitalization, as well as delays and dose modifications in planned chemotherapy. On DFCI ALL Consortium Protocol 05-001 (2005-2011), 26.6% of 794 enrolled patients (pts) experienced at least one infectious complication during induction. In the subsequent study, DFCI Protocol11-001, we studied whether the use of prophylactic fluoroquinolones during induction would decrease the incidence of bacterial infections.Patients and methods.Between 2012-2015, 229 pts with ALL (aged 1-21 years) were enrolled on Protocol 11-001 at 9 participating sites. Induction therapy, regardless of risk group, included vincristine, methylprednisolone, doxorubicin, low-dose methotrexate and pegylated L-asparaginase. Afebrile pts were started on fluoroquinolone prophylaxis at the time of initiation of therapy and continued until count recovery at the end of induction. Pts were switched to broad-spectrum antibiotics (eg, cefepime) for fever or documented infection. Pts with fever at presentation were started on broad spectrum antibiotics rather than fluoroquinolone, and either remained on broad-spectrum antibiotics or were switched to fluoroquinolone prophylaxis until count recovery per treating clinician. Antifungal prophylaxis was not required. All episodes of microbiologically documented bacterial infection, microbiologically and/or radiographically documented fungal infection, and Clostridium difficile (C. diff) enterocolitis were prospectively collected. Using a 1-sample binomial test, rates of infections on Protocol 11-001 were compared to those from the predecessor study, DFCI Protocol 05-001, which included nearly identical induction chemotherapy but did not include guidelines regarding antibiotic prophylaxis or duration during induction.Results. Of the 229 pts, 89% had B-ALL and 11% T-ALL. Median age was 5.1 yrs (range 1.0-20.9). Eighty-six afebrile pts (37.5%) were administered upfront antibiotic prophylaxis and 141 (61.6%) had fever at diagnosis and received broad-spectrum antibiotics; two afebrile patients did not receive antibiotic prophylaxis for unknown reasons. Of the 86 pts who began prophylaxis, 37 (43%) subsequently developed fever. Toxicity data was available for 222 pts. Thirty-eight episodes of infection occurred in 29 patients. Age, presenting white blood cell count and immunophenotype were not associated with the development of infection. The proportion of pts experiencing an infection on Protocol 11-001 (13.1%) was significantly lower than on Protocol 05-001 (26.6%, p<0.0001) [Figure 1]. The observed reduction was due to a decrease in the incidence of bacterial infection (9.9% vs 24.7%, p<0.0001). Of note, there were significantly fewer episodes of bacteremias due to Gram negative rods, S. aureus and S. viridans on Protocol 11-001 compared to 05-001. There was no significant difference in incidence of fungal infection between the two protocols (4.5% vs 3.9%, p=0.32). Twenty (9%) pts on 11-001 developed C. diff colitis during induction (16 Grade 2, 3 Grade 3, 1 Grade 4). The induction death rate on Protocol l 11-001 was 0.9% compared with 2% on Protocol 05-001 (p=0.24).Conclusion.The results of our prospective, multi-institutional non-randomized study indicate that treating newly diagnosed pediatric ALL pts with antibiotics throughout the induction phase (including the use of antibiotic prophylaxis for afebrile pts) is effective at reducing the incidence of bacterial infections, and does not result in an increase in fungal infections or a high incidence of C. diff colitis. Additional larger, randomized studies are necessary to confirm the safety and efficacy of this approach during the induction phase. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Polymorphisms in Genes Related to Oxidative Stress Are Associated with Inferior Cognitive Function after Therapy for Childhood ALL

Introduction: Outcome studies consistently document increased rates of neurocognitive deficits among survivors of childhood acute lymphoblastic leukemia (ALL). This study was conducted to test whether some of the observed interpatient variability in cognitive outcomes can be explained by inherited polymorphisms in genes related to the multifactorial pathophysiology of treatment-induced cognitive decline.Methods: Neurocognitive testing was conducted for 350 leukemia survivors, at a target of 5 years after completion of treatment. All patients had been enrolled on DFCI ALL Consortium Protocols 95-01 or 00-01, between 1995 and 2005. The median age at diagnosis was 4.5 years (range 1-18); 54% were male. Neurocognitive outcomes included Wechsler estimated IQ, Vocabulary and Digit Span and parent-reported Attention and Hyperactivity scores (BASC-2). Impaired performance for all measures was defined as ³1 standard deviation below the reference population mean. Genomic DNA was isolated from bone marrow collected at remission. Twenty-nine candidate polymorphisms were selected, targeting variants within genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or PCR-based allelic discrimination assays. The number of 28bp nucleotide repeats within the 5′ untranslated region of the gene for thymidylate synthase was assessed by PCR-product length analysis. Multivariable logistic regression models were calculated to estimate the effects of genotype on neurocognitive outcomes, adjusting for the effects of age at diagnosis, sex, risk group, race, CNS prophylaxis (radiation vs. intrathecal chemotherapy), corticosteroid (prednisone vs. dexamethasone), and socioeconomic status.Results: For all target genes, the distribution of genotypes was consistent with Hardy-Weinberg equilibrium. Minor allele frequencies were similar to published values. Inferior cognitive or behavioral outcomes were significantly associated with polymorphisms in four genes related to oxidative stress and/or neuroinflammation: endothelial nitric oxide synthase (NOS3), prostaglandin transporter (SLCO2A1), hemochromatosis (HFE), and catechol-O-methyltransferase (COMT). Lower mean IQ scores were observed among survivors homozygous for the NOS3 T allele (95.8; 95% CI, 89.9-101.7; n = 30 vs. 103.9; 95% CI, 102.1-105.8; n = 264; multivariable P=0.011) and among those with at least one SLCO2A1 G allele (100.4; 95% CI, 97.5-103.2; n=117 vs. 104.6; 95% CI 102.4-107; n=177; P =0.014).Conclusions: Inferior cognitive and behavioral outcomes among childhood leukemia survivors were associated with prevalent polymorphisms in four genes associated with susceptibility to oxidative stress. These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurotoxicity among children with leukemia. Furthermore, our results suggest that detecting these polymorphisms can identify those children with ALL who are at greatest risk for treatment-induced cognitive decline, and who would therefore benefit from a clinical trial testing a protective intervention.Abstract 856. TableGene symbol(Ref SNP)Target Genotype(observed prevalence)Associated Cognitive or Behavioral OutcomeMultivariable OR(95% CI)P-valueNOS3 (rs1799983)TT (10%)1. Estimated IQ (Wechsler)5.1 (1.8-14.3)0.0022. Vocabulary (Wechsler)4.0 (1.6-10.3)0.004SLCO2A1 (rs1051266)AG/GG (38.2%)1. Estimated IQ (Wechsler)2.7 (1.2-5.9)0.0162. Digit Span (Wechsler)2.6 (1.5-4.4)0.0013. Impaired Attention (BASC-2)2.0 (1.2-3.6)0.013COMT (rs4680)AA (17.3%)1. Impaired Attention (BASC-2)2.6 (1.4-5.5)0.0102. Hyperactivity (BASC-2)2.7 (1.2-6.3)0.021HFE (rs1800562)AG/AA (23.3%)Hyperactivity (BASC-2)2.9 (1.2-7.0)0.021HFE (rs1799945)CG/GG (8.9%)Hyperactivity (BASC-2)2.3 (1.1-4.7)0.022 DisclosuresNo relevant conflicts of interest to declare.

Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: Findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01

Dexamethasone is more efficacious than prednisone in the treatment of acute lymphoblastic leukemia (ALL), but has also been associated with greater toxicity. We compared neuropsychological outcomes for patients treated on DFCI ALL Consortium Protocol 00-01, which included a randomized comparison of the two steroid preparations during post-induction therapy in children and adolescents with ALL. Between 2000 and 2005, 408 children with standard-risk or high-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 00-01 were randomly assigned to prednisone or dexamethasone administered as 5-day pulses every 3 weeks for 2 years, beginning at week 7 of treatment. Blinded neuropsychological testing was completed for 170 randomized patients (prednisone, N = 76; dexamethasone, N = 94), all of whom were in continuous complete remission after completion of therapy. Outcomes were comparable for most variables, although patients on the dexamethasone arm performed more poorly on a measure of fluid reasoning (P = 0.02). They also tended to be more likely to be enrolled in special education (dexamethasone, 33% vs. prednisone, 20%, P = 0.09). Dexamethasone has well documented benefit in treatment of ALL. Although formal testing provided little indication of increased risk for neurotoxicity relative to prednisone, the somewhat greater utilization of special education services by patients treated with dexamethasone merits further investigation.

Variations in Energy and Nutrient Specific Consumption Over the Course of Therapy in Children with Acute Lymphoblastic Leukemia.

AbstractAbstract 2575 Introduction:Few research studies have investigated the nutritional status of children with acute lymphoblastic leukemia (ALL). Preliminary studies have found that malnutrition is associated with lower 5-year survival, increased relapse rates and more frequent reductions in chemotherapy dose. The extent of malnutrition has not been well characterized. Results of a prospective multi-institution study investigating dietary micronutrient intake over the course of treatmentfor ALL are reported. Methods:Assessment of dietary intake was collected for participants 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. Dietary intake was assessed at three timepoints in therapy: diagnosis (T1), Day 32 (end) of induction therapy (T2), and 15 months post-diagnosis (T3) (during maintenance therapy) with the Harvard Service Food Frequency Questionnaire for children ages 1–5 years and the Youth and Adolescent Harvard Food Frequency Questionnaire for children ages 5–18 years. Questionnaires were self-administered and were completed by parents or primary care takers when children were below age 6 years. Dietary intake was examined by comparing energy and nutrient specific consumption above and below recommended intake using age specific values for Dietary Reference Intake (DRI). Results:Among 794 patients with ALL registered on the 05-001 Protocol, dietary intake questionnaires were availablefor 622, 564, and 423 patients at T1, T2, and T3, respectively. Median age of participants at T1 was 5 yrs (range 1–17.9 yrs) and 272 (44%) were female, 350 (56%) were male. Initial leukemia risk classification included 363 standard risk (58%) and 259 (42%) high risk. At diagnosis, the majority of children reported consuming more than the age and gender specific DRI. For 388 children (62%), reported caloric intake was >25% the DRI, while another 81 (13%) reported caloric consumption >10% the DRI. In contrast, only 116 (19%) did not meet the DRI. At T2, similar findings were observed, despite administration of a 32 day prednisone course which would have been expected to result in a higher proportion of children exceeding recommended caloric intake. Of those responding at T2, 128 (23%) were not meeting the DRI, while 65 (12%) and 335 (59%) exceeded the recommended caloric intake by >10% and >25% respectively. During maintenance therapy (T3), total caloric intake declined with a greater proportion of participating children reporting intake below the DRI (30%) and a smaller proportion reporting intake >25%DRI (49%), while the proportion consuming recommended intake or >10% DRI remained stable. Distribution of children reporting nutrient consumption below, at, or above age and gender specific DRI values for key micronutrients is summarized in Figure 1. The majority of patients did not meet the DRI for vitamin E and vitamin D at all 3 time points, while nearly half the participants exceeded the DRI for zinc and folate. Conclusions:The majority of children with newly diagnosed ALL have evidence of overnutrition or malnutrition, as demonstrated by overconsumption of calories, or deficiency or overconsumption of key micronutrients, which may be associated with increased risk for treatment related toxicities. Increased consumption of folate during the maintenance phase in which methotrexate is a major component of treatment also needs further study. Additional analyses are underway to explore these relationships. [Display omitted] Below DRIAt DRIAbove DRI Disclosures:No relevant conflicts of interest to declare.

Asparaginase-Associated Myelosuppression and Effects on Dosing of Other Chemotherapeutic Agents In Children and Adolescents with Acute Lymphoblastic Leukemia

AbstractAbstract 3249 Background:L-asparaginase (ASP) is a universal component of treatment for childhood acute lymphoblastic leukemia (ALL). It is associated with multiple toxicities, including allergy, pancreatitis, and thrombosis. It is not thought to have a significant direct myelosuppressive effect, but its impact on the ability to tolerate other chemotherapeutic agents has not been well-characterized. Patients and Methods:Between 2005–2010, 61 patients (pts) were diagnosed with Standard Risk (SR) ALL at DFCI/Children's Hospital Boston and treated on DFCI ALL Consortium Protocol 05-01. SR pts met all of the following criteria: 1 to <10 years of age; highest pretreatment WBC < 50,000/mm3; absence of central nervous system leukemia (ie, CNS-1 or -2, only); absence of T-cell markers; absence of t(9;22), MLL gene rearrangements, and hypodiploidy; and low minimal residual disease (MRD) levels at the end of the first 4 weeks of treatment. Beginning at week 7, all SR pts began a 30-week (wk) Consolidation phase, consisting of every 21-day cycles of vincristine (day 1), dexamethasone (days 1–5), 6-mercaptopurine (6MP) (days 1–14), and methotrexate (MTX) (days 1, 8 and 15), and also including 30 consecutive wks of ASP (either weekly IM E.coli ASP 25000 IU/m2 or every 2-wk IV PEG ASP 2500 IU/m2). The Continuation phase followed Consolidation, and consisted of identical systemic and intrathecal (IT) chemotherapy, except without any ASP. Starting dose of 6MP was 50 mg/m2/day and of MTX was 30 mg/m2/dose. Doses were adjusted every 21 days to maintain absolute phagocyte (APC) nadirs > 500/mm3 and platelet nadirs > 75,000. Chemotherapy cycles were delayed until APC was ≥ 1000/mm3 or platelets were ≥ 100,000. Medical records of the 61 SR pts were reviewed to ascertain the dose modifications of MTX and 6MP made due to low or high blood counts (APC and/or platelets) and/or delays in starting cycles (defined as ≥25 day interval between cycles). 27 pts were randomized to receive IM E. coli ASP, 29 to IV PEG ASP, and 5 declined randomization (directly assigned to IM E.coli ASP). A total of 1780 chemotherapy cycles were evaluated longitudinally using generalized estimating equations, 498 during Consolidation (with ASP) and 1282 during Continuation (No ASP). Results:Median age was 3.9 years and 57% of pts were female. There was a higher proportion of cycles modified for low blood counts (ie, dose reduction of MTX and/or 6MP) during Consolidation (ASP given) compared to Continuation (No ASP) (24% vs 8%, Odds Ratio (OR) = 2.35 [95% CI 1.41, 3.94]; p < 0.01). There was a lower proportion of cycles modified due to high blood counts (ie, dose escalation of MTX and/or 6MP) during Consolidation (ASP given) compared to Continuation (No ASP) (20% vs 33%, OR =0.20 [95% CI 0.13, 0.30]; p < 0.01). Figures 1 and 2 summarize the dosing of MTX and 6-MP during Consolidation and Continuation. During Consolidation, the proportion of cycles in which pts received escalated doses of MTX (above the starting dose) was 21% compared to 62% during Continuation. Similarly, the proportion of cycles in which pts received escalated doses of 6-MP (above starting dose) was 10% in Consolidation compared to 59% in Continuation. 17% of Consolidation cycles were delayed because starting criteria were not met compared to 9% of Continuation cycles when pts were not receiving ASP (OR =2.08, 95% CI 1.18, 3.64; p=0.01). No difference in delays or dose modification for counts was detected between ASP randomization arms in either the Consolidation or Continuation phases. [Display omitted] [Display omitted] Conclusion:During Consolidation, when SR pts received ASP, blood counts were lower than during Continuation (no ASP), despite an otherwise identical schedule of other systemic and IT agents during these two phases. Because of low blood counts, pts received lower doses of MTX and 6MP when they were also receiving ASP, and delays in beginning chemotherapy cycles were more common. This suggests that ASP has a myelosuppressive effect, either direct (due to ASP) or secondary to ASP-induced changes in the levels or metabolism of other chemotherapeutic agents; further investigation is necessary to elucidate the precise mechanism. The myelosuppressive effect of ASP should be taken into consideration when designing regimens for pts with ALL which combine ASP with other agents to avoid excessive dose reductions and/or treatment delays. Disclosures:Sallan:Enzon Inc.: Honoraria, Research Funding. Silverman:EUSA Pharmaceuticals: Consultancy, Honoraria; Enzon Pharmaceuticals: Consultancy, Honoraria.

Increased Risk of Skeletal Toxicity and Infection in Children 10 Years or Older Treated for Acute Lymphoblastic Leukemia (ALL) with Dexamethasone: Results from the DFCI ALL Consortium.

BACKGROUND: Dexamethasone (dex) may be more efficacious but also more toxic than prednisone (pred) in the treatment of childhood ALL. In order to compare the relative toxicities of these 2 steroids, patients (pts) on DFCI ALL Consortium Protocol 00–01 were randomized to receive dex or pred during post-induction therapy.METHODS: Pts received 5-day steroid pulses every 3 weeks for 2 years (yrs) (pred 40mg/m2/day or dex 6 mg/m2/day) beginning at week 7 of therapy. High Risk (HR) pts received 3 times these doses during the Intensification Phase (approximately 6 months).RESULTS: Between 2000–2004, 425 pts (ages 1–18 yrs) were randomized; 423 had evaluable skeletal toxicity data, including 241 Standard Risk (SR) and 182 HR pts. 211 received dex and 212 received pred. Within 26 months of enrollment, 55 pts (13%) experienced at least 1 bony event: 45 pts (11%) with fracture and 17 (4%) with osteonecrosis (ON). Bony events were more common in children ≥10 yrs of age (11% of those <10 yrs vs. 18.5% ≥10 yrs, p=0.007). There was no overall difference in frequency of pts with skeletal toxicity based on steroid type (see table, p=0.89), including no difference in fractures (11% dex vs. 10% pred, p=0.88) or ON (5% dex vs. 3% pred, p=0.23). However, skeletal toxicity was more common in dex-treated older children (≥10 yrs) compared with pred-treated older children (25% vs. 11%, p=0.07) and compared with younger (< 10 yrs) dex-treated pts (25% vs. 9%, p=0.004). There was no difference in frequency of skeletal toxicity by age in pred-treated pts (p=0.31). There was no difference in frequency of skeletal toxicity by steroid type in SR pts (8% dex vs. 14% pred, p=0.22) or in younger HR pts (12% dex vs. 11% pred, p=1.0). In multivariable analysis, children ≥10 yrs treated with dex had 2.7 times the risk of developing skeletal toxicity compared with all other pts (p=0.006). Of 404 pts with evaluable infection data, 37/200 (18.5%) dex-treated pts developed at least 1 infection (bacteremia and/or invasive fungal disease) during intensification or continuation compared to 24/204 (11.8%) pred-treated pts (p=0.07). There was no difference in infection rate by steroid type for those <10 yrs of age (p=0.53). However, for those ≥10 yrs, there were more infections in dex-treated than in pred-treated pts (24% vs. 5%, p=0.01). At 2.8 yrs median follow-up, there was no statistically significant difference in event-free survival (EFS) comparing dex- vs. pred-treated pts (90% vs. 88%, p=0.31), although there was a suggestion of inferior EFS in HR pts randomized to pred.Skeletal Toxicity and Infection: Dexamethasone vs. Prednisone*DexamethasonePrednisoneP valueSkeletal ToxicityAll28/211 (13.3%)27/212 (12.7%)0.89Age < 10 yrs14/160 (9%)22/166 (13%)0.21Age ≥ 10 yrs13/51 (25%)5/46 (11%)0.07InfectionAll37/200 (18.5%)24/204 (11.8%)0.07Age < 10 yrs26/154 (17%)22/160 (14%)0.53Age ≥ 10 yrs11/46 (24%)2/44 (5%)0.01*Depicted are the numbers of pts with at least 1 toxicity event of all pts within particular subgroups.CONCLUSION: Dexamethasone was associated with increased risk of skeletal toxicity and infection in pts ≥10 yrs of age. Longer follow-up is needed to fully assess EFS differences between the randomized treatment groups.

Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01

AbstractIn a prospective trial in 284 children with B-lineage acute lymphoblastic leukemia (ALL), we assessed the clinical utility of real-time quantitative polymerase chain reaction analysis of antigen receptor gene rearrangements for detection of minimal residual disease (MRD) to identify children at high risk of relapse. At the end of induction therapy, the 5-year risk of relapse was 5% in 176 children with no detectable MRD and 44% in 108 children with detectable MRD (P < .001), with a linear association of the level of MRD and subsequent relapse. Recursive partitioning and clinical characteristics identified that the optimal cutoff level of MRD to predict outcome was 10−3. The 5-year risk of relapse was 12% for children with MRD less than one leukemia cell per 103 normal cells (low MRD) but 72% for children with MRD levels greater than this level (high MRD) (P < .001) and children with high MRD had a 10.5-fold greater risk of relapse. Based upon these results we have altered our treatment regimen for children with B-lineage ALL and children with MRD levels greater than or equal to 10−3 at the end of 4 weeks of multiagent induction chemotherapy now receive intensified treatment to attempt to decrease their risk of subsequent relapse.

Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

AbstractIn a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)–Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P = .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/AML1-negative patients (P = .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients.