bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variations in cytarabine pathway genes as determinants of outcome in acute myeloid leukemia.
Authors: Lamba Jatinder Kaur , Pounds Stanley , Cao Xueyuan , Crews Kristine Radomski , Raimondi Susana , Campana Dario , Baker Sharyn D. , Ribeiro Raul Correa , Rubnitz Jeffrey E. 
Published: March 2020

10005 Background: Cytarabine (ara-C), a key component of AML therapy, is a prodrug that requires activation to ara-CTP, which inhibits DNA/RNA synthesis and triggers leukemic cell death. Thus, cellular pathways involved in ara-CTP metabolism and/or cell death are likely to influence treatment response. Methods: In the present study, we used a pathway-directed approach to identify the genetic predictors of ara-C response in 187 pediatric patients enrolled in the St. Jude AML02 trial. Patients were randomized to receive the first course of remission induction therapy containing either high- or low-dose ara-C, combined with daunorubicin and etoposide. SNPs in 14 key ara-C pathway genes were genotyped and screened for association with multiple endpoints, such as in vitro ara-C LC50 in diagnostic leukemic cells, minimal residual disease levels (MRD), event-free survival (EFS), overall survival (OS), and rate of relapse. Because AML is a very heterogeneous disease with multiple clinical, cytogenetic, and molecular features that are associated with response, we also evaluated SNPs in ara-C PK genes in the context of prognostic factors of proven clinical utility. Results: Ara-C pathway SNPs were significantly associated with clinical outcome. Known variables such as treatment, core-binding factor leukemia, MRD after one course of therapy, age at diagnosis, 11q23 rearrangements, megakaryoblastic leukemia without t(1;22), and FLT3-ITD accounted for 18.7% of variability in EFS. Additional variation in EFS could be explained by individual SNPs or a combination of SNPs within ara-C pathway genes. For instance, our analysis showed that incorporation of a DCTD SNP into existing model could enhance the percent total variation in EFS explained from 18.7% to 22.9%. Inclusion of all DCTD SNPs in the model increased the percent total variation in EFS explained from 18.7% to 29.7% Conclusions: Overall our results indicate that genetic variation in the ara-C pathway genes had a prognostic relevance that was similar to that of well-known factors. Understanding this variation can provide additional insights into the factors influencing treatment response and could lead to the identification of new prognostic markers.
Autologous-collected anti-CD19 chimeric antigen receptor T cells (19CARTs) for pediatric acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL): Clinical activity and cytokine release without graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Lee Daniel Warnell , Shah Nirali , Stetler-Stevenson Maryalice , Sabatino Marianna , Richards Kelly , Delbrook Cindy , Kochenderfer James , Rosenberg Steven A. , Stroncek Dave , Mackall Crystal , Wayne Alan S. 
Published: March 2020

10008 Background: Despite intensive chemotherapy and HSCT, outcomes in relapsed/refractory pediatric B cell ALL and NHL are poor. To treat children with or without prior allogeneic-HSCT and quickly deliver therapy, we developed a Phase I trial of 19CARTs for both HSCT-naive and post-allo-HSCT patients where autologous-collected T cells are manufactured in 11 days. Methods: T cells collected on Day -11 by lymphopheresis were positively selected and activated using anti-CD3/CD28 beads then transduced with the CD19-CAR gene via retrovirus. Cells were infused after 7 additional days of expansion. Patients (Pt) received fludarabine and cyclophosphamide prior to receiving 1e6 19CARTs/kg. Results: A 59-65 fold expansion of 19CARTs with 39-65% transduction efficiency was achieved in Pt 1 and 3 (ALL, NHL). Pt 1 achieved a complete response (CR). Mild cytokine release syndrome was observed (Gr 3 fever, Gr 2 hypotension) correlating with mild elevation in IL6, GM-CSF, INFg and C reactive protein (CRP; Table). No other non-hematologic, CAR-related Gr ≥3 toxicities were observed. Pt 2 (ALL) received 2.8% of the targeted cell dose due to lack of cell expansion likely from recent prior chemotherapy but experienced a transient CR with significant 19CART expansion (15% blood, 5% marrow, 6% CSF). Importantly, 19CARTs were well tolerated without evidence of GVHD in these post-allo HSCT patients. Conclusions: Autologous-collected allogeneic derived 19CART cells can be rapidly manufactured and safely administered to children with ALL and NHL. Clinical activity can be achieved without GVHD despite inflammatory cytokine generation. 19CARTs offer a potentially effective strategy to treat post-HSCT relapse warranting further study. Clinical trial information: NCT01593696. [Table: see text]
Comprehensive profiling of cardiac dysfunction in asymptomatic childhood cancer survivors (CCS) treated with anthracyclines.
Authors: Armenian Saro , Gelehrter Sarah , Vase Tabitha , Venkatramani Rajkumar , Landier Wendy , Wilson Karla , Herrera Claudia , Reichman Leah , Menteer John David , Mascarenhas Leo , Freyer David Robert , Venkataraman Kalyanasundaram , Bhatia Smita 
Published: March 2020

10020 Background: Anthracyclines are associated with left ventricular (LV) dysfunction in CCS with inevitable progression to congestive heart failure (CHF). Use of ejection fraction (EF) to identify LV dysfunction precludes intervention, because EF decline is a late event in the progression to CHF. Further, better understanding of pathogenesis at the cellular level could facilitate development of targeted interventions. Methods: Study design: Cross-sectional; Biomarkers: Echocardiographic (echo), and blood biomarkers in asymptomatic individuals exposed to anthracyclines ≥300mg/m2 (high-risk [HR]: n=100) compared with: i) CCS exposed to <300 mg/m2 (low-risk [LR]: n=50): and ii) matched healthy controls (Con: n=50). Pathogenesis: Metabolomic analyses (351 plasma metabolites; 64 pathways). Results: Time from dx to study was comparable for HR (12.0y) vs. LR (13.2y, p=0.8). All CCS had EF≥50%. Echo: HR had lower LV chamber thickness-dimension (T-D) ratio (Z-score: -0.62) compared with LR (-0.03) and Con (-0.02; P<0.01) as well as increased LV wall stress ([ESWS] HR: 66 g/cm2, LR: 58 g/cm2, Con: 55 g/cm2, p<0.01) and higher myocardial performance index ([MPI] HR: 0.51, LR: 0.46, Con: 0.46; P<0.01). Blood biomarkers: HR had higher plasma NT-pro BNP (HR: 71 pg/dL, LR: 37 pg/dL, Con: 26 pg/dL; P<0.01); there were no differences in troponins, Galectin-3 or ST-2. Metabolomics:Individuals with LV dysfunction (>2 SD ESWS) had reduced plasma carnitine levels (relative ratio [RR]: 0.88, p<0.01) contributing to altered fatty acid β-oxidation and accumulation of cardiotoxic long-chain (docosadienoate [RR=1.26], adrenate [RR=1.29]; p<0.05) and essential fatty acid intermediates (dihomo-linolenate [RR=1.27], eicosapentaenoate [RR=1.23], docosapentaenoate [RR=1.46]; p<0.05). Conclusions: Comprehensive profiling of anthracycline-exposed CCS with preserved EF revealed dose-dependent echo (LV ESWS, T-D ratio, MPI) and blood (NT-ProBNP) abnormalities 10+years from dx; metabolomic studies demonstrated the role of carnitine in the pathogenesis of LV dysfunction. Taken together, these findings may facilitate early detection and targeted interventions in CCS at highest risk for CHF.
Global fitness in adult survivors of childhood acute lymphoblastic leukemia (ALL).
Authors: Ness Kirsten K. , Huang Sujuan , Smith Webb A , Pui Ching-Hon , Lanctot Jennifer , Howell Carrie R , Karlage Robyn , Shelton Kyla C , Robison Leslie L. , Hudson Melissa M. 
Published: March 2020

10022 Background: The extent to which adult survivors of childhood ALL may have impaired fitness has not been well documented. This study compared clinically assessed fitness between childhood ALL survivors and matched controls, and examined risk factors for impaired fitness among survivors. Methods: 365 survivors of childhood ALL diagnosed from 1980-2002, treated at St. Jude Children’s Research Hospital (SJCRH), 10+ years from diagnosis, and 18+ years old completed questionnaires, fitness testing and physical activity assessment (accelerometry). 365 friends/relatives of current SJCRH patients, frequency matched on age, race and sex, were recruited as controls. Data from fitness measures were combined into a composite (SJFIT) using factor analysis. Individual measures and SJFIT scores were compared between survivors and controls with two sample t-tests. Among survivors, associations between demographic, lifestyle, treatment variables and poor fitness, i.e. scoring in the lowest 10th percentile of controls on the SJFIT, were evaluated with logistic regression. Results: Survivors were 52% male (mean age 28±7 years, mean diagnosis age 6±5 years, mean survival 21±5 years), and scored lower than controls on individual fitness measures (Table) and the SJFIT composite. Female sex (OR 9.4, 95%CI 3.4-26.1) and fewer daily minutes of moderate and vigorous physical activity (OR 0.95, 95% CI 0.92-0.99) were associated with poor fitness after adjusting for diagnosis age, current age, cranial radiation, body fat and smoking. Conclusions: Childhood ALL survivors, particularly females, have fitness impairments when compared to matched controls. Poor fitness is associated with physical activity levels. Interventions to address impairments need to be tested and implemented. [Table: see text]
A phase I study of the anti-insulin like growth factor type 1 receptor (IGF-1R) antibody dalotuzumab in pediatric patients with advanced solid tumors.
Authors: Frappaz Didier , McGregor Lisa M. , Pearson Andrew DJ , Gore Lia , DuBois Steven G. , Aerts Isabelle , Iannone Robert , Geschwindt Ryan , Van Schanke Arne , Wang Ruixue , Geoerger Birgit 
Published: March 2020

10026 Background: Insulin-like growth factor signaling plays an important role in several pediatric cancers. Dalotuzumab is a highly specific, humanized IgG1 monoclonal antibody against IGF-1R. This multicenter phase 1 study explored the safety and pharmacokinetics (PK) of dalotuzumab in pediatric patients with advanced solid tumors. Methods: Dalotuzumab was administered intravenously every 3 weeks. Dose-escalation was performed according to a modified Toxicity Probability Interval (mTPI) design starting at 900 mg/m2. The PK profile of dalotuzumab was evaluated with the primary goal of confirming that the Day 22 mean serum trough concentration exceeded 25 μg/mL. Results: 24 patients were enrolled and 20 treated (median age, 10.5 years; range, 3–17 years). Six patients had recurrent Ewing sarcoma. Patients received a median of 2 cycles (range, 1-10). No dose-limiting toxicity was observed in any of the three dose levels explored (900, 1200 and 1500 mg/m2). Main treatment-related toxicities were Grade 3 elevated transaminases. PK data showed dose dependent increases in AUC0-∞ (105,000, 164,000 and 281,000 hr*mg/mL, for the 900, 1200 and 1500 mg/m2 dose levels, respectively), Ctrough (65.2, 71.6, 148 mg/mL) and Cmax (559, 643, 888 mg/mL). The mean half-life was 247, 394 and 376 hours respectively. The Cmax exhibited mild variability (4.8-35% Coefficient of Variation), whereas variability was moderate to high on the Ctrough (39-200%), apparent t1/2 (28-154%), AUC0-∞ (29-106%) and clearance (52-161%). Except for one patient at the 1200 mg/m2 dose level, all patients met the PK target, a Ctrough of 25 μg/mL, suggesting 900 mg/m2as the recommended phase 2 dose (RP2D). One patient with Ewing sarcoma had a confirmed partial response; 2 patients with Ewing sarcoma and one with nephroblastoma had stable disease for at least 7, 5 and 6 months, respectively. Conclusions: Dalotuzumab is well tolerated in pediatric patients with advanced malignancies. The RP2D of 900 mg/m2 was chosen based on tolerability and PK parameters. Preliminary data confirm prior reports suggesting activity in Ewing sarcoma. Clinical trial information: NCT01431547.
Weekly vinblastine in chemotherapy-naive children with unresectable or progressive low grade glioma: A Canadian cooperative study.
Authors: Bouffet Eric , Scheinemann Katrin , Zelcer Shayna M. , Hukin Juliette , Wilson Beverley , Jabado Nada , Carret Anne Sophie , Lafay Cousin Lucie , Larouche Valerie , Hawkins Cynthia , Pond Gregory Russell , Poskitt Ken , Bartels Ute Katharina , Tabori Uri 
Published: March 2020

10029 Background: Vinblastine has shown promising activity in a phase II study in children with recurrent/refractory LGG. The aim of this study was to assess the activity of vinblastine in chemotherapy naïve children. Methods: Patients < 18 years old with unresectable or progressive LGG were eligible if they had not received any previous treatment with chemotherapy or radiation. Vinblastine was administered weekly at a dose of 6 mg/m2over a period of 70 weeks. Patients who showed progression on 2 consecutive imaging studies or evidence of clinical progression were removed from treatment. Results: 54 patients (23 female) were enrolled between 2007 and 2010. Median age at inclusion was 7 years, 13 patients were < 3 years. 32 had chiasmatic/hypothalamic tumours, 6 had evidence of dissemination. 13 had neurofibromatosis type 1. Histology was pilocytic astrocytoma (25), pilomyxoid astrocytoma (4), low grade astrocytoma variant (8); 17 patients had no histological diagnosis. Treatment was well tolerated; however, only 14 patients received full dose for the duration of the study. Most common toxicity was haematological: 40 patients who experienced grade 3+ neutropenia. There were only 6 episodes of febrile neutropenia, 3 RBC transfusions and no toxic death. Best response to chemotherapy was assessed centrally by an independent radiologist: 1 CR, 10 PR, 3 MR, 28 SD, 12 PD, for a response rate of 24.5%. With a median follow-up of 2 years (9-48 months), progression-free survival at 2 years was 72.1% (95%CI: 58.1-82.2). One patient died of progression. Conclusions: Weekly vinblastine is well tolerated in paediatric LGG patients. Although the response rate appears inferior to other common LGG regimens, progression free survival at 2 years favourably compares to most currently used regimens. Supported by a grant from the Ontario Institute Cancer Research. Clinical trial information: 1000011227.
A phase II trial of radiation and cetuximab followed by irinotecan/cetuximab for children with newly diagnosed diffuse pontine tumors and high-grade astrocytomas.
Authors: Macy Margaret , Kieran Mark W. , Chi Susan N. , Cohen Kenneth J. , MacDonald Tobey , Smith Amy A. , Etzl Michael Matthew , Narendran Aru , Gore Lia , DiRenzo Jennifer , Trippett Tanya M. , Foreman Nicholas K. , Dunkel Ira J. 
Published: March 2020

10030 Background: Diffuse intrinsic pontine gliomas (DIPG) and high-grade astrocytomas (HGA) have dismal prognoses. We previously demonstrated in a phase 1 study that cetuximab and irinotecan was a safe and tolerable regimen. Consequently, we initiated this 2-strata phase 2 trial to investigate the safety and efficacy of weekly cetuximab given with involved field external beam radiation therapy followed by 10 cycles of cetuximab and irinotecan for DIPG and HGA as determined by the 1-year progression-free survival. Methods: Eligible patients aged 3-21 years with newly diagnosed HGA or DIPG were enrolled to parallel strata. All patients received radiation therapy (5940 cGy) with concurrent cetuximab at 250mg/m2 IV weekly for 6 weeks. Following radiation, patients received cetuximab (250mg/m2 IV) weekly and irinotecan (16mg/m2/day IV) daily x 5 for two weeks every 21 days for 30 weeks. Tumor, serum, and CSF samples were collected for correlative studies. Sera collected at the onset of rash were analyzed for inflammatory and immune-related cytokines. Results: Forty-eight patients (27 DIPG, 21 HGA) were enrolled and 45 were treated (median age 8 years; range: 3–19). Toxicities were manageable; the most common adverse events were fatigue, gastrointestinal complaints, neutropenia, rash, headache, electrolyte abnormalities, elevated ALT/AST, and fever. Grade 3-4 events in ≥10% of patients were hypokalemia and lymphopenia. 4 patients experienced cetuximab-related hypersensitivity reactions (2 grade 3 reactions). The median PFS was 9.5 months (95% CI: 7.0-12.2) for HGA and 7.8 months (7.0-8.6) for DIPG with a 1-year PFS±SE of 24±10% and 25%±10% respectively. The median OS for HGA was 17.7 months (95% CI: 14.1-18.0) and 11.5 months (8.8-14.2) for DIPG. Biological correlative studies will be presented. Conclusions: Cetuximab and radiation therapy followed by cetuximab and irinotecan is well tolerated in children. Based on the 1-year PFS, this regimen may deserve further investigation in patients with DIPG. Biological correlative studies will delineate the mechanisms of the rash and possible implications for EGFR-targeted therapeutics in such patients. Clinical trial information: NCT01012609.
Investigating the pharmacokinetics and dosing of anticancer drugs in infants and young children.
Authors: Veal Gareth J , Errington Julie , Malik Ghada , Hill Christopher R , Boddy Alan V 
Published: March 2020

10033 Background: Dosing regimens for anticancer drugs administered to infants and young children frequently differ between tumour types and protocols, with dosing based on body weight commonly implicated. We have recently highlighted a reduced exposure to 13-cis-retinoic acid in neuroblastoma patients <12kg dosed on body weight (Clin Cancer Res19:469-79,2013). Given the toxicity observed with many chemotherapeutics, it is appropriate to establish a pharmacological basis for dose adjustments implemented in younger patients. Methods: The pharmacokinetics of cyclophosphamide (CPA), actinomycin D (Act D), carboplatin and etoposide were investigated in children aged 0-6, 6-12 and 12-24 months. CPA was administered i.v. at a dose of 100-1,500 mg/m2, with infusion times up to 1.5h, Act D as a bolus i.v. infusion of 0.4-1.5mg/m2, carboplatin as an i.v. dose of 3.8-30mg/kg over 1-4h and etoposide as an i.v. dose of 3.5-14mg/kg over 1-6h. Eighty-six children were studied at 14 centres, with PK sampling carried out over 24h for CPA and Act D, 3h for carboplatin and up to 6h for etoposide. Plasma concentrations of CPA, Act D and etoposide were determined by LC-MS analysis, with carboplatin concentrations determined in plasma ultrafiltrate by AAS. PK parameters were calculated using WinNonlin or previously used PK models as appropriate. Results: Clearance values normalized to body weight ranged from 0.5-7.7 ml/min/kg for CPA, 1.7-17.4 for Act D, 1.6-10.5 for carboplatin and 0.2-1.7 for etoposide. No significant differences in normalized clearance were observed between the defined age cohorts of 0-6, 6-12 and 12-24 months and the data do not indicate clear differences in drug handling in infants and young children. However, when normalized clearance values were compared to data from older children, a greater degree of inter-patient variation was observed in patients <2 years than in children >2 years for all drugs. Conclusions: While normalized clearance values for the drugs studied do not support reduced dosing approaches, data suggest that individual drug clearance values may be more difficult to predict in younger patients. Further studies involving additional anticancer drugs may allow more rationale approaches to dosing. Clinical trial information: NCT00897871.
Computerized intervention for amelioration of cognitive late effects among childhood cancer survivors.
Authors: Conklin Heather M. , Ashford Jason M. , Clark Kellie N. , Martin-Elbahesh Karen , Hardy Kristina K. , Merchant Thomas E. , Ogg Robert J. , Jeha Sima , Wu Shengjie , Zhang Hui 
Published: March 2020

10034 Background: Children treated for cancer with CNS-directed therapy are at significant risk for attention and working memory (WM) problems. There is empirical support for pharmacotherapy and therapist-delivered cognitive rehabilitation; yet, the reach of these approaches is limited by medical contraindications, need for facility proximity and high resource utilization. A computer-based WM intervention has demonstrated efficacy for healthy individuals with attention disorders. We investigated this approach with childhood cancer survivors. Methods: Sixty-eight survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) with identified WM deficits were randomly assigned to a computerized WM intervention (18 males/16 females, 23 ALL/11 BT, age= 12.21±2.47) or a wait-list control group (18 males/16 females, 24 ALL/10 BT, age= 11.82±2.42). Participants in the intervention group were asked to complete 25 training sessions at home with weekly, phone-based coaching support. Cognitive assessments were completed pre- and post-intervention. Results: Among 34 participants randomized to intervention, 30 (88%) were adherent while 4 were removed from intervention because they failed to complete training in the allotted time. Survivors who completed the intervention demonstrated significantly greater improvements than controls on measures of attention (e.g., WISC-IV Spatial Span Forward 3.30±3.87 vs 1.33±2.20, p= .02, ES= .63), WM (e.g., WISC-IV Spatial Span Backward 3.13±3.19 vs 0.80±2.46, p= .002, ES= .82) and processing speed (e.g., Conners’ CPT Hit Reaction Time -2.10±8.04 vs 2.36±6.68, p= .02, ES=.60), and showed greater reductions in parent reported executive dysfunction (e.g., Conners’ Parent Rating Scale, III -6.73±8.25 vs .13±8.86, p= .003, ES= .80). No group differences in academic fluency were found (e.g., Woodcock Johnson III Math Fluency 0.90±4.59 vs 1.90±7.18, p= .52, ES= .17). Conclusions: Study results suggest computerized intervention is feasible and efficacious for childhood cancer survivors, with some evidence for generalized benefits. Computerized training may offer a safer, less time intensive and more portable alternative to existing interventions. Clinical trial information: NCT01217996.