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A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated hypersensitivity (14.8%), hyperbilirubinemia (9.7%), venous thromboembolism (VTE, 9.7%), and pancreatitis (5.3%). Odds ratios (OR) and 95% confidence intervals (CI) evaluated associations between clinical factors and each toxicity, cumulative number of toxicities, and toxicity clusters identified using k-mode analysis. Most (68.9%) did not experience any toxicity, 24.6% experienced one toxicity, and 6.3% two or more. Age10 years was associated with hyperbilirubinemia (OR = 3.83; 95% CI: 1.64-8.95), pancreatitis (OR = 3.72; 95% CI: 1.29-10.68), VTE (OR = 4.65; 95% CI: 1.96-11.02), and cumulative toxicity burden (OR = 3.28, 95% CI: 1.97-5.47); high-risk therapy with hypersensitivity (OR 2.25; 95% CI 1.25-4.05); and overweight with cumulative toxicity burden (OR = 1.76, 95% CI: 1.20-2.57). Eight unique toxicity profiles were identified. Older age, overweight, and treatment intensity contribute to pegaspargase-associated toxicities.

Objectives This systematic review provides an overview of the effect of malnutrition on the pharmacokinetics of chemotherapy in children with cancer. Methods PubMed, Embase and Cochrane were searched to identify eligible studies. Malnutrition was referred to as undernutrition, as defined by the World Health Organisation and the Gomez Criteria. Results Four studies with a total of 668 children with cancer were included and n=121 (18%) were malnourished. In vincristine, the differences in pharmacokinetic parameters were statistically significant where clearance rates were commonly lower and area under the curve was increased in malnourished children. Conclusion The results are suggestive for pharmacokinetic alterations of chemotherapy in malnourished children with cancer. However, the data is scarce, groups are small, and most studies have been performed in high-income countries. Pharmacokinetic research among (severely) malnourished children with cancer is needed in order to improve their outcome, directed by sub-group and ultimately individualized drug dosing.

Background The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective. Methods A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs. Results Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices. Conclusions Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions. Lay summary Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.

High-dose methotrexate (HD-MTX) with rigorous supportive care is essential to the treatment of pediatric non-Hodgkin lymphomas (NHL). We describe the safety and tolerability of HD-MTX in patients with NHL treated at our center. In our cohort of 46 patients, the majority had at least one course of delayed clearance and/or creatinine elevation. Additionally, more than one-third of patients experienced an episode of grade ≥3 mucositis. Creatinine elevations and delayed clearance were independently associated with subsequent grade ≥3 mucositis. We advocate for greater availability of methotrexate monitoring to allow dose escalation of this essential modality around the world.

The overall survival of children with acute lymphoblastic leukemia (ALL) is over 90%. Much of this success comes from the daily use of 6-mercaptopurine (6-MP) during maintenance therapy [1]. Mercap...

The Oncology Pharmacy Team (OPT), consisting of specialty-trained pharmacists and/or pharmacy technicians, is an integral component of the multidisciplinary healthcare team (MHT) involved with all aspects of cancer patient care. The OPT fosters quality patient care, safety, and local regulatory compliance. The International Society of Oncology Pharmacy Practitioners (ISOPP) developed this position statement to provide guidance on five key areas: 1) oncology pharmacy practice as a pharmacy specialty; 2) contributions to patient care; 3) oncology pharmacy practice management; 4) education and training; and 5) contributions to oncology research and quality initiatives to involve the OPT. This position statement advocates that: 1) the OPT be fully incorporated into the MHT to optimize patient care; 2) educational and healthcare institutions develop programs to continually educate OPT members; and 3) regulatory authorities develop certification programs to recognize the unique contributions of the OPT in cancer patient care.

Background Carboxypeptidase G2 (CPDG2 ; glucarpidase) is a rescue drug for patients at risk for kidney injury from high-dose methotrexate (MTX). As there are no strategies for predicting patients who will require CDPG2 , we evaluated the role of demographic, clinical, and genetic factors for CPDG2 use. Procedure Cases who received CPDG2 and controls who did not were identified by chart review of acute lymphoblastic leukemia (ALL) patients who received MTX doses between 1000 and 5000 mg/m2 between 2010 and 2017. We used multivariable Bayesian logistic regression to evaluate the association of CPDG2 use with demographic and clinical variables and, on a subset of patients, with genetic ancestry and 49 single nucleotide variants previously associated with MTX toxicity. Results We identified 423 patients who received 1592 doses of MTX. Of the 18 patients who received CPDG2 , 17 (94%) were Hispanic. No patients who received 1000 or 2000 mg/m2 of MTX received CPDG2 . Hispanic ethnicity (odds ratio: 4.68; 95% compatibility interval: 1.63-15.06) and older age (1.87 [1.17-3.17]) were associated with receiving CPDG2 . Of the 177 patients in the genomic cohort, 11 received CPDG2 . Each additional G allele of rs7317112 in ABCC4 increased the odds of requiring CPDG2 (3.10 [1.12-6.75]). Six other loci (NTRK1/rs10908521, TSG1/rs9345389, STT3B/rs1353327, SCLO1B1/rs4149056, GATA3/rs3824662, ARID5B/rs10821936) demonstrated probabilities of association between 88% and 97%. Conclusion We demonstrated that demographic characteristics, including Hispanic ethnicity and age, are associated with CPDG2 use. Additionally, we provide evidence that inherited genetic variation is associated with risk of requiring CPDG2 . If validated in independent populations, this information could be leveraged to develop targeted toxicity prevention strategies for children with ALL.

Introduction: While end-induction minimal residual disease (MRD) is the strongest prognostic factor for relapsed ALL, approximately half of all relapses occur in children who are MRD negative. Latino ethnicity is also a risk factor for relapse. To further explore these associations, we conducted an interim analysis of risk factors for relapse in a large multi-ethnic population of children diagnosed with ALL. Methods: The REDIAL Consortium includes patients diagnosed with ALL at six major pediatric cancer centers in the Southwestern U.S. The study period was 2004 to 2018, and we included individuals who were 1-23 years of age when diagnosed with ALL. Time to relapse was defined as time from ALL diagnosis to the initial relapse event, with individuals censored at date of death, last follow-up, or bone marrow transplant. Demographic and clinical factors evaluated included race/ethnicity (Latino, non-Latino Black, non-Latino White, non-Latino other), sex, age at diagnosis (1-5, 6-10, 11-15, >15 years), ALL immunophenotype (B-cell, T-cell), National Cancer Institute (NCI) risk group, central nervous system involvement, enrollment on a Children’s Oncology Group clinical trial, end-induction disease failure, and end-induction bone marrow flow cytometric MRD. Cox proportional hazards models were used to calculate adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). Analyses were further stratified based on end-induction MRD status (positive ≥0.01%, negative Results: Overall, there were 1,710 ALL patients with a median age at diagnosis of 5 years (interquartile range: 3-11 years). The majority of patients were Latino (60.1%) and male (56.9%). Of the 379 MRD-positive patients, 74 (19.5%) relapsed, compared to 138 of 1,233 (11.2%) MRD-negative patients (p15 vs. 1-5 years, HR=1.98, 95% CI: 1.19-3.29), and NCI high-risk group (HR=1.74, 95% CI: 1.20-2.52), while patients enrolled on a clinical trial were less likely to relapse (HR=0.76, 95% CI: 0.57-0.99). Among MRD-positive patients, Latinos were less likely to relapse (HR=0.60, 95% CI: 0.33-0.99) compared to non-Latino Whites, whereas Latinos who were MRD negative were more likely to relapse (HR=1.68, 95% CI: 1.09-2.59). Conclusion: In a large contemporary multi-ethnic cohort of >1,700 children with ALL, we observed significant disparities in relapse by MRD status, age at diagnosis, NCI risk group, clinical trial enrollment, and race/ethnicity. Notably, nearly 65% of relapse events occurred in MRD-negative patients. Further analyses are ongoing in REDIAL to evaluate the impact of other factors including cytogenetics and novel biomarkers of relapse. Citation Format: Pagna Sok, Austin L. Brown, Olga A. Taylor, M. Brooke Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Laura Klesse, Kathleen Ludwig, Sandi L. Pruitt, Karen R. Rabin, Michael E. Scheurer, Philip J. Lupo. Disparities in relapse among a large multi-ethnic population of children diagnosed with acute lymphoblastic leukemia (ALL): A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3633.

e15081 Background: Methotrexate (MTX) is a cornerstone of therapy for several types of cancer. HDMTX-induced mucositis can impact quality of life and delay subsequent chemotherapy. Objective: The objective of this study was to understand the factors increasing risk for mucositis in patients receiving HDMTX in a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric and young adult patients ages 0-32 years at diagnosis who received at least one dose of HDMTX (>500 mg/m2) at Children’s Healthcare of Atlanta or Cincinnati Children’s Hospital Medical Center from January 2010 through December 2020. Demographic and clinical variables were manually abstracted, while medications and lab values were electronically pulled from the electronic medical record. Common Terminology Criteria for Adverse Events v5 was used to identify the presence and grade of mucositis after HDMTX administration. Institutional review board approval was obtained at each site. Chi-square and t-tests, as appropriate, were calculated using GraphPad Prism v9. MTX concentrations were fit to a published pharmacokinetic model to estimate clearance using NONMEM. Results: The cohort is described in Table. The rate of mucositis was highest after the first HDMTX administration (54.6%), when the MTX clearance is slowest (30.1%2 and albumin was lowest (14.3%2 (OR 1.75 (CI: 1.503 to 2.028), p

Background/objectives Standard supportive care during induction therapy for high-risk neuroblastoma (HR-NBL) includes primary prophylactic granulocyte colony-stimulating factor (G-CSF) aimed at limiting duration of neutropenia, reducing infection risk, and minimizing treatment delays. Preclinical models suggest that G-CSF promotes maintenance of neuroblastoma cancer stem cells and may reduce the efficacy of chemotherapy. This study's objective was to determine the safety and feasibility of administering induction chemotherapy without routine use of prophylactic G-CSF. Design/methods Children with newly diagnosed HR-NBL received six-cycle induction chemotherapy regimen without prophylactic G-CSF in four cycles. G-CSF was administered for stem cell mobilization after cycle 3 and granulocyte-monocyte colony-stimulating factor after cycle 5 prior to surgical resection of primary disease. The primary outcome measure was the incidence of grade 3 or higher infection. We hypothesized that the per patient infection rate would be comparable to our institutional baseline rate of 58% in patients with HR-NBL receiving induction chemotherapy with prophylactic growth factor support. The trial used an A'Hern single-stage design. Results Twelve patients with HR-NBL received 58 cycles of chemotherapy on study. Three patients completed the entire six-cycle regimen with no infections. Nine patients experienced grade 3 infections (bacteremia four, urinary tract infection two, skin/soft tissue infection three). No patients experienced grade 4 infections or required intensive care treatment for infection. Conclusion A greater than expected number of serious bacterial infections were observed during administration of induction chemotherapy for HR-NBL without primary prophylactic G-CSF. These results support continued prophylactic administration growth factor during induction chemotherapy.

The scarcity of adequate pediatric drug labeling information has long been problematic in the pediatric population, which may place children at risk for adverse drug effects. The ontogeny of infants, children, and adolescents over the course of the first two decades of life pose complex pharmacokinetic, dosing, administration, effectiveness, and toxicity-related questions that require specific investigation. Here, we review the history that led to the passage of the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA), and provide commentary on issues relevant to pediatric oncology now and in the future.

BACKGROUND National drug shortages of essential medications for childhood cancer have increasingly posed a challenge in the treatment of patients. The efficacy of standardized supportive care practices to avoid treatment-related toxicities may be limited during these drug shortages. High-dose methotrexate (HDMTX) plays a critical role in modern treatment protocols for acute lymphoblastic leukemia and requires stringent supportive care measures to mitigate toxicity. As the result of a national intravenous (IV) sodium bicarbonate shortage, institutional standard HDMTX supportive care guidelines had to be modified. We describe the unanticipated consequences on HDMTX clearance. METHODS We performed a retrospective chart review assessing the impact of alternative compositions of IV fluids on the mean 24-h methotrexate levels (Cpss ) of 25 patients receiving 76 total HDMTX infusions at Texas Children's Hospital Cancer Center from March to October 2017. During the sodium bicarbonate drug shortage, all patients received IV hydration consisting of either dextrose 5%, 0.45% normal saline (D5 ½ NS-Group A) or dextrose 5%, 0.2% normal saline (D5 ¼ NS-Group B). RESULTS Patients receiving a higher total sodium dose demonstrated significantly lower Cpss (25.36 ± 16.6 μMol) compared to patients receiving less sodium (53.9 ± 37.9 μMol; P

INTRODUCTION: Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited. Therefore, we conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF. METHODS: Fatigue in pediatric ALL patients (2012–2017) was assessed during post-induction therapy approximately 6-months post-diagnosis. Post-induction CSF was collected on 171 participants, comprising discovery (n=86) and replication (n=85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall’s rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate (FDR) was used to account for multiple comparisons. RESULTS: Participants were 56% male and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (p

PURPOSE: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention. METHODS: Pediatric patients with ALL (age 2–18 years) and/or their primary caregivers completed symptom surveys at: end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between symptom clusters, individual symptoms and subsequent relapse were calculated using multivariable Cox proportional hazards models, adjusting for clinical and demographic factors. RESULTS: Eligible patients (n=208) were followed an average of 2.6 years for the incidence of relapse (n = 22). Associations between relapse and symptoms were identified for fatigue at DI (HR = 1.83, 95%CI: 1.23–2.73) and MC1 (HR = 2.14, 95%CI: 1.62–2.84), pain at DI (HR = 1.80, 95%CI: 1.19–2.72), nausea at end induction (HR=1.19, 95%CI: 1.01–1.39), and sleep disturbances at end induction (HR=2.00, 95%CI: 1.11–3.62), DI (HR = 1.73, 95%CI: 1.01–2.96), and MC1 (HR = 2.19, 95%CI: 1.10–4.35). Symptom clusters comprised of individuals with a higher average symptom burden at DI were significantly (p < 0.05) associated with relapse. CONCLUSION: Patient-reported symptoms may provide prognostic information to aid in the identification of pediatric ALL patients at increased risk of relapse.

The overall survival for children with cancer in high income countries is excellent. However, there are many disparities that may negatively affect survival, which are particularly problematic in low income countries, such as nutritional status at diagnosis and throughout therapy. Nutritional status as well as concomitant foods, supplements, and medications may play a role in overall exposure and response to chemotherapy. Emerging science around the microbiome may also play a role and should be further explored as a contributor to disease progression and therapeutic response. This article highlights some of these issues and proposes additional areas of research relevant to nutritional status and pharmacology that are needed in pediatric oncology.

High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities. We developed a simple algorithm to individualize HDMTX infusions with 0–2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study; eligible patients were identified and referred by their oncologist. Fifty-four evaluable cycles of HDMTX (5 g/m2 over 24 h) were administered to 22 patients. Blood samples were obtained in 21 patients to examine single nucleotide polymorphisms (SNPs) related to methotrexate disposition. Twelve (54.5%) subjects had a history of previous HDMTX toxicities including seven (31.8%) who previously required glucarpidase rescue and seven (31.8%) with an entry glomerular filtration rate Grade 1 acute kidney injury. This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. NCT02076997.

Background Liposomal bupivacaine may be an option for reducing opioid utilization in pediatric scoliosis surgery. The use of liposomal bupivacaine in this patient population has not been previously described. Methods Patients who underwent posterior spinal fusion surgery at our institution from 2011-2016 were identified. We performed a retrospective matched cohort study, matching patients who received intraoperative liposomal bupivacaine by age, gender, and extent of surgery to patients who did not. The primary endpoint was the use of morphine equivalents in the first 72 hours after surgery. Data collection included demographic and surgical data, pain medication utilization, and pain scores. Area under the curve (AUC) for pain scores was calculated. Descriptive statistical methods and univariable analysis were used to compare patients who received liposomal bupivacaine to patients who did not. Results One hundred and forty-one patients met study criteria; 47 patients who received liposomal bupivacaine were matched to 94 control patients who did not receive liposomal bupivacaine. No significant differences were noted in the patient population with the patients requiring a median of 11 segments (range 10-13 segments) fused. Patients received a mean of 56.6 ± 37.4 mg/kg of intravenous acetaminophen, a mean of 3.4 ± 2.1 mg/kg of intravenous ketorolac, and 1.9 ± 0.93 mg/kg of morphine equivalents in the first 72 hours after surgery. On univariable analysis, no differences were noted in intravenous acetaminophen use, pain score AUC, intravenous ketorolac use, or morphine equivalents (2.0 ± 98 vs 1.8 ± 0.82) in patients who did not receive liposomal bupivacaine as compared to those patient who did received liposomal bupivacaine. Conclusion Liposomal bupivacaine was not associated with reductions in postoperative opioid use in pediatric spinal surgery.

Background: Methotrexate (MTX) is a cornerstone of therapy for pediatric patients with acute lymphoblastic leukemia (ALL). Administration of high dose (HD) MTX requires hospitalization and concurrent intravenous fluids and leucovorin while awaiting drug excretion. HDMTX has been associated with acute adverse events (AEs), such as mucositis, neurotoxicity, and myelosuppression, that can impact quality of life and ability to administer subsequent chemotherapy. There are limited data evaluating differences in AEs after HDMTX among demographic groups. Objective: The objective of this study was to describe AEs for patients receiving HDMTX (defined as >500 mg/m2 to account for dose reductions from protocol dosing) and to compare rates by age, race, ethnicity and dose number using a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric ALL patients ages 0-21 years at diagnosis who received at least one dose of HDMTX at Children's Healthcare of Atlanta or Cincinnati Children's Hospital Medical Center from January 2010 through December 2020. Demographic (age, sex, race, ethnicity) and clinical (vital status, Down Syndrome, HDMTX doses) variables were manually abstracted from the electronic medical record. Algorithms were developed a priori based on Common Terminology Criteria for Adverse Events v5 to identify the presence and grade of targeted AEs after HDMTX administration. The following AEs were abstracted for the time period from each HDMTX dose until the next HDMTX or other chemotherapy administration: mucositis, neurotoxicity, neutropenia, and thrombocytopenia. Only grade 4 neutropenia and grades 3-4 thrombocytopenia were collected. Institutional review board approval was obtained at each site. Descriptive and inferential statistics, including chi-square, Fisher's exact test, and generalized estimating equations (GEE) as appropriate, were calculated to evaluate differences in AEs by dichotomized age ( Results: Across sites, 543 patients with ALL patients received HDMTX (2064 administrations). The median age at first HDMTX was 8.0 years (0.1-21.0); 230 (42.4%) were female, 381 (70.2%) were White, and 441 (81.2%) were Non-Hispanic or Latino (Table 1). The median number of HDMTX administrations was 4.0 (Range 1-10). In total, 469 (86.4%) patients had at least one AE. Mucositis occurred in 386 (71.1%) patients, grade 4 neutropenia occurred in 243 (50.1%) and grade 3-4 thrombocytopenia occurred in 156 (32.2%, Table 2). Mucositis, neurotoxicity, and thrombocytopenia were significantly more likely in patients 10+ years (p=0.02, p Conclusion: AEs after administration of HDMTX are common, with 86% of patients experiencing at least one AE after receipt of HDMTX and half of administrations leading to at least one AE. Greater than half of patients experienced mucositis and neutropenia. Older patients experienced significantly more mucositis, neurotoxicity, and thrombocytopenia. Unsurprisingly, we found that overall the rate of AEs was highest after the first HDMTX administration and decreased significantly across doses, which is likely due to dose reductions in HDMTX or concurrent antimetabolite therapy and to increased supportive care (hydration and leucovorin) after experience of an AE. Chart abstraction is ongoing at a third hospital that will increase the sample size of patients, particularly those of Hispanic/Latino ethnicity, to delineate potential differences by race and ethnicity. In addition, current analyses are evaluating the impact of supportive care and dosing changes between administrations on the burden of HDMTX-related AEs and differences by age. The results of this study will provide valuable data regarding who is at highest risk for AEs and can be used to tailor supportive care during this potentially toxic chemotherapy. Figure 1 Figure 1. Disclosures Bernhardt: Bristol Myers Squibb: Research Funding; BTG International: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharmaceuticals: Consultancy; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Ramsey: BTG Specialty Pharmaceuticals: Honoraria, Research Funding.

Background: Children with acute leukemia (AL) are at risk for relapse, treatment toxicity, second neoplasms, and death. Understanding host and tumor response to therapy is necessary to achieve high survival rates and minimize adverse effects. Metabolomics, the characterization of small molecules in a biological system, may be useful for monitoring treatment response. In support of this, we previously identified metabolites in bone marrow (BM) plasma associated with end-induction minimal residual disease (MRD) and in cerebrospinal fluid (CSF) associated with fatigue. Because procedures for obtaining BM and CSF are invasive and subject patients to risk, we sought to determine whether the BM and CSF metabolomes of children undergoing therapy for AL were correlated with the blood metabolome. Methods: Blood plasma, BM, and CSF were collected at the end-induction from 11 patients with newly diagnosed AL treated at Texas Children's Hospital (Houston, TX). Global metabolomic profiling was performed by Metabolon (Durham, NC), using liquid chromatography-tandem mass spectrometry according to published methods. We assessed the number and type (e.g. lipid, amino acid) of metabolites in each sample. For each metabolite identified in ≥2 samples from ≥2 patients, we computed Spearman rank correlation coefficients to estimate the pairwise correlations between blood, BM, and CSF. Results: Patients were predominantly male (N=7) and Latino (N=9). Ten were diagnosed with B-cell acute lymphoblastic leukemia and one with mixed phenotype acute leukemia. Among 670 metabolites detected in ≥2 blood and BM plasma samples, 370 (58%) demonstrated moderate to strong correlations (Spearman's rho ≥0.5) and 317 (47%) were significant at p Conclusions: There is substantial correlation between the blood and BM plasma metabolomes at end-induction among children with ALL, including metabolites putatively associated with early treatment response. Correlations between CSF and blood or BM plasma are weaker, implying that the CSF metabolome is distinct. The blood plasma metabolome may approximate the BM but not CSF metabolome in children with ALL. Citation Format: Jeremy M. Schraw, J.P. Woodhouse, Melanie B. Bernhardt, Olga A. Taylor, Terzah M. Horton, Michael E. Scheurer, Mehmet F. Okcu, Karen R. Rabin, Philip J. Lupo, Austin L. Brown. Comparison of the blood, bone marrow, and cerebrospinal fluid metabolomes in children with acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2349.

OBJECTIVETo investigate an outbreak ofBurkholderia cepaciacomplex and describe the measures that revealed the source.SETTINGA 629-bed, tertiary-care, pediatric hospital in Houston, Texas.PATIENTSPediatric patients without cystic fibrosis (CF) hospitalized in the pediatric and cardiovascular intensive care units.METHODSWe investigated an outbreak ofB. cepaciacomplex from February through July 2016. Isolates were evaluated for molecular relatedness with repetitive extragenic palindromic polymerase chain reaction (rep-PCR); specific species identification and genotyping were performed at an independent laboratory. The investigation included a detailed review of all cases, direct observation of clinical practices, and respiratory surveillance cultures. Environmental and product cultures were performed at an accredited reference environmental microbiology laboratory.RESULTSOverall, 18 respiratory tract cultures, 5 blood cultures, 4 urine cultures, and 3 stool cultures were positive in 24 patients. Among the 24 patients, 17 had symptomatic infections and 7 were colonized. The median age of the patients was 22.5 months (range, 2–148 months). Rep-PCR typing showed that 21 of 24 cases represented the same strain, which was identified as a novel species within theB. cepaciacomplex. Product cultures of liquid docusate were positive with an identical strain ofB. cepaciacomplex. Local and state health departments, as well as the CDC and FDA, were notified, prompting a multistate investigation.CONCLUSIONSOur investigation revealed an outbreak of a unique strain ofB. cepaciacomplex isolated in clinical specimens from non-CF pediatric patients and from liquid docusate. This resulted in a national alert and voluntary recall by the manufacturer.Infect Control Hosp Epidemiol2017;38:567–573

We developed a bedside algorithm for individually adjusting the high-dose methotrexate (HDMTX) dose (5 g/m) given to patients with acute lymphoblastic leukemia at high risk for methotrexate toxicity. Data were reviewed for 8 patients receiving 21 cycles of HDMTX as per our algorithm. Eleven cycles began with 5 g/m, 10 cycles began with a preinfusion 20% to 25% dose reduction. Neither mean MTX AUC (2320.5±179.1 vs. 2080.4±161.7 μmol×h/L), mean Cpss (64.3±7.9 vs. 60.8±6.1 μM), nor toxicities were statistically different between groups. Our algorithm allowed the safe administration of HDMTX to patients at risk of MTX toxicities and obviated the need for preinfusion dose reduction.

High-dose methotrexate (HD-MTX; 12 g/m2 ) is part of standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. We investigated the association between peak MTX levels (four-hour) and delayed MTX clearance or treatment toxicity. Information was retrieved from electronic medical records of 33 OS patients treated with HD-MTX at Texas Children's Hospital from 2008 to 2015. We found that the four-hour MTX level did not contribute to toxicity or delayed MTX clearance. We demonstrated that certain demographic characteristics are associated with delayed clearance and increased toxicity.

Objective: To describe the prescription of hydrocodone-containing products (HCPs) and codeine-containing products (CCPs) by patient and provider race and ethnicity at two pediatric emergency departments (EDs) before and after the US Drug Enforcement Administration (DEA) rescheduling of HCPs in 2014. Design and setting: The authors performed a secondary analysis of data describing the prescription of HCPs and CCPs for 6 months before and after the DEA rescheduling of HCPs in two academic, urban pediatric EDs. Patients, participants: The authors included all children for whom race and ethnicity data were available and who were prescribed HCPs or CCPs at the time of discharge from the ED during a 12-month period (n = 1,246). The authors sent a three-question survey soliciting name, race, and ethnicity to all providers who prescribed an HCP or a CCP during the study period. Main outcome measures: Chi-square comparisons were made between the number of HCP and CCP prescriptions for primary ED diagnosis and patient ethnicity or race. The number of HCP and CCP prescriptions before and after the DEA rescheduling were compared to patient and provider race and ethnicity using the Breslow-Day test for homogeneity. Results: There were no significant differences in the number of HCP and CCP prescriptions between the pre- and post-DEA rescheduling periods across all racial and ethnic groups. When comparing the number of HCP and CCP prescriptions to patient race, Caucasian patients (84.4 percent) were prescribed more HCPs and CCPs than African Americans (15.6 percent) for abdominal pain (p value = 0.02). Non-Hispanic providers prescribed CCPs more often (n = 38, 55.2 percent) than Hispanic providers (n = 0, 0.0 percent) after DEA rescheduling (Breslow-Day p value = 0.01). Providers of all races wrote similar numbers of HCP and CCP prescriptions before and after the DEA rescheduling (Breslow-Day p value = 0.99). Conclusions: Pediatric patients of all races and ethnicities received fewer HCP prescriptions after the 2014 DEA rescheduling of HCPs. However, Caucasian patients were prescribed HCPs and CCPs for abdominal pain more frequently than African American patients. There were no significant differences in the number of prescriptions of HCPs and CCPs by provider race.

Purpose of study: To identify factors related to the increased risk of neurotoxicity in children with acute lymphoblastic leukemia (ALL) after treatment with the antifolate agent methotrexate (MTX), a critical component of curative protocols. Methods: We analyzed the incidence of and factors associated with acute MTX neurotoxicity (neurologic episode within 14d of dose that resulted in treatment modification) in a multi-site study of 280 (48% Latino) newly diagnosed (between 2012–2017) patients treated on recent pediatric ALL protocols. We examined the effects of genetic ancestry and single nucleotide variants in a subset of 190 patients with genotype data. Results: MTX neurotoxicity occurred in 22% of Latino compared to 7% of non- Latino patients; a nearly 2.5-fold increased risk after accounting for other clinical and demographic factors. Patients with neurotoxicity received fewer total MTX doses, and their risk for relapse was 2-fold higher than patients who did not experience neurotoxicity. We also found that 42% of our Latino patients who experienced a first neurotoxic event went on to have additional events, compared to only 21% of non-Latino patients. The proportion of genetic variation that co-segregates with Native American ancestry was overrepresented in individuals with MTX-related neurotoxicity (mean = 35%) vs without neurotoxicity (mean = 23%, p = 0.025). In multivariable models accounting for sex, age at diagnosis, and treatment risk group, every 10% increase in the proportion of Native American genetic ancestry was associated with a 16% increase in neurotoxicity incidence (HR = 1.16; 95% CI: 1.02–1.32). Our data also suggest that Latinos are at higher risk for first (OR = 3.51, p = 0.02) and subsequent (OR = 6.10, p = 0.04) neurotoxic events associated with a missense variant in TCF12, which is more common in admixed Latino (23%) compared to European (3%) or African (

Importance Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. Objective To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. Design, setting, and participants This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). Interventions All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. Main outcome and measures The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P Results Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. Conclusions and relevance Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. Trial registration ClinicalTrials.gov Identifier: NCT02101853.

Key Points Question Is the use of rituximab for young people associated with short- or long-term adverse events? Findings This cohort study identified 468 patients younger than 21 years receiving rituximab for more than 25 indications, among whom infectious and noninfectious adverse events were common. The majority of these events were mild, but a small population experienced prolonged immune suppression and severe infections following even single courses of rituximab. Meaning Findings suggest that rituximab appears to be well tolerated among young people, but the observed frequent infections and prolonged recovery of B lymphocyte numbers highlight the need for better strategies to mitigate infection risk in this population., Importance Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children. Objective To describe the use of rituximab and to assess whether its use is associated with short- or long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people. Design, Setting, and Participants This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children’s Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020. Exposure One or more doses of rituximab. Main Outcomes and Measures Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events. Results We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19+ or CD20+ cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-for-age B cell counts. Recovery of CD27+ memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM. Conclusions and Relevance Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued., This cohort study conducted at a large pediatric referral hospital assesses whether the use of rituximab for many diverse indications is associated with short- or long-term adverse events among patients younger than 21 years.

Background Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. Procedure Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. Results Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1 737) mg/m2 . Conclusions Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.

Background Oncology drug shortage is associated with increased patient adverse events and decreased enrollment on clinical trials for adult patients; however, the impact of oncology drug shortages has not been well studied in children with cancer. Procedure The Children's Oncology Group (COG) distributed a 5-item survey to 226 COG site-specific principal investigators (PI's) and 14-item survey to 161 COG pharmacists to gather data the impact of chemotherapeutic shortages on clinical trials and patient care. Results The response rate was 66.4% (150/226) for PI's and 29.8% (48/161) for pharmacists. COG PI's reported daunorubicin (73%), methotrexate (56%), asparaginase/PEG-asparaginase (42%), doxorubicin (26%), thiotepa (21%), and cytarabine (20%) were most commonly in shortage, while COG pharmacists reported daunorubicin (80%), methotrexate (66%), vincristine (21%), thiotepa (41%), asparaginase/PEG-asparaginase (34%), and cytarabine (34%) were most commonly in shortage over the past two years. Pharmacists were twice as likely to report a shortage compared with PI's (OR 2.1, 95% CI: 1.6–2.7, P

Purpose Institutional prescribing trends of hydrocodone-containing products (HCPs) before and after the Drug Enforcement Administration’s rescheduling of HCPs were evaluated. Methods A retrospective evaluation was performed on 6 oral opioid analgesics on the hospital formulary that were prescribed to patients treated at Texas Children’s Hospital and Pavilion for Women for the 6 months before and after the rescheduling of HCPs on October 6, 2014. Patients were eligible for inclusion if they were prescribed any of the following oral agents: HCPs (e.g., hydrocodone with acetaminophen), codeine-containing products (e.g., codeine, codeine with acetaminophen), morphine, hydromorphone, oxycodone-containing products (e.g., oxycodone, oxycodone with acetaminophen), and tramadol. Results During the 12-month study period, a total of 38,928 inpatient orders and outpatient prescriptions were processed for the studied agents in both locations; the majority were orders for inpatients. An overall reduction in the total number of opioid prescriptions was observed after the rescheduling of HCPs. Substantial increases in the proportional use of codeine were observed in all 4 settings after HCP rescheduling. Data for each of the agents revealed a shift in prescribing patterns centered along the HCP rescheduling date of October 6, 2014, and revealed a decrease in HCP use across all areas with an accompanying increase in codeine-containing products, oxycodone-containing products, and tramadol. Conclusion The rescheduling of HCPs resulted in a reduction in HCP prescriptions but was accompanied by increases in the use of codeine-containing products and tramadol in all settings.

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, has been described following treatment of acute lymphoblastic leukemia (ALL) with the anti-metabolite 6-thioguanine (6-TG). Previous studies incorporating daily 6-TG into maintenance chemotherapy demonstrated a high incidence of SOS, typically presenting after prolonged exposures to 6-TG. 6-TG continues to be used as a single, 14-day burst during intensification; however, SOS associated with brief courses of 6-TG is poorly described. We aim to describe this rare though clinically significant phenomenon. Children with 6-TG-related SOS were retrospectively identified from 680 de novo patients with ALL at Texas Children’s Cancer Center over 8 years. Clinical characteristics and outcomes are described. Ten (1.5%) patients were identified with SOS. No predominant sex, ethnicity, or race was noted. SOS was diagnosed 16.5 (6–42) days from starting 6-TG. Isolated thrombocytopenia (IT) was noted in 9/10 patients and presented a median of 5 days prior to SOS. Refractoriness to platelet transfusions was noted in 8/10 patients, presenting a median of 2 days prior to SOS. Most patients were otherwise clinically stable outpatients upon presenting with IT or transfusion refractoriness. Fever was noted in 7/10 patients at diagnosis and 6/10 had documented or suspected infection within 14 days of SOS. Two patients died, while eight fully recovered. Intermediate thiopurine methyltransferase genotype was noted in 5/8 patients with data available. SOS following short courses of 6-TG in DI is clinically distinct from SOS following prolonged courses of 6-TG in maintenance, particularly in its early presentation and outcomes.

Traditional administration of rituximab requires careful titration and may involve many hours to minimize the risk of reactions. The objective of this study was to evaluate the safety of rapid infusions of rituximab in a pilot group of children with hematologic, oncologic, and rheumatologic disorders, and to determine the incidence of rate-related infusion reactions. Twenty patients enrolled in the study. All patients tolerated the rapid infusion of rituximab and no patient had an infusion-related reaction. We conclude that rapid infusions of rituximab are well tolerated and safe in our pilot group of patients.

Background To determine the MTD of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors. Patients (≥3–≤21 years) with neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features were eligible. Procedure Part A (single dose of NTX-010) enrolled 13 patients at three dose levels (1 × 109 viral particles (vp)/kg [n = 6], 1 × 1010 vp/kg [n = 3], 1 × 1011 vp/kg [n = 4]). Diagnoses included neuroblastoma (n = 9), rhabdomyosarcoma (n = 2), carcinoid tumor (n = 1), and adrenocorticocarcinoma (n = 1). Part B added cyclophosphamide (CTX) (oral CTX (25 mg/m2/day) days 1–14 and IV CTX (750 mg/m2) days 8 and 29) to two doses of NTX-010 (1 × 1011 vp/kg, days 8 and 29). Nine patients enrolled to Part B. Diagnoses included neuroblastoma (n = 3), rhabdomyosarcoma (n = 1), Wilms tumor (n = 3), and adrenocorticocarcinoma (n = 2). Results Twelve patients on Part A were evaluable for toxicity. There was a single DLT (grade 3 pain) at dose level 1. Additional grade ≥3 related adverse events (AEs) included leukopenia (n = 1), neutropenia (n = 3), lymphopenia (n = 3), and tumor pain (n = 1). No DLTs occurred on part B. Other grade ≥3 related AEs on Part B included: Leukopenia (n = 3), nausea (n = 1), emesis (n = 1), anemia (n = 1), neutropenia (n = 4), platelets (n = 1), alanine aminotransferase (n = 1), and lymphopenia (n = 2). All patients cleared NTX-010 from blood and stool by 3 weeks with 17/18 patients developing neutralizing antibodies. Conclusion NTX-010 is feasible and tolerable at the dose levels tested in pediatric patients with relapsed/refractory solid tumors either alone or in combination with cyclophosphamide. However, despite the addition of cyclophosphamide, neutralizing antibodies appeared to limit applicability. Pediatr Blood Cancer 2015;62:743–750. © 2014 Wiley Periodicals, Inc.

Background Glomerular filtration is an important route of elimination for many types of chemotherapy. Accurate estimation of glomerular filtration at the bedside is essential in the management of children with cancer. Bedside formulae for the estimation of glomerular filtration have not been validated in children with cancer. We investigated the accuracy of three formulae (the original Schwartz, Counahan-Barratt, and revised Schwartz equations) against measurement of the glomerular filtration rate (GFR) in a cohort of children with cancer. Procedure This was a retrospective review of existing data from a single institution. The electronic medical record was queried for subjects meeting inclusion criteria during a 3.5 year time frame. Bland-Altman analyses were used to assess agreement among current formulae and estimating the GFR compared to the measured, or index GFR. Logistic regression was performed to identify potential variables with an effect on the estimation of GFR. Results None of the three estimation formulae provided a reliable estimate of the index GFR. The mean difference was lowest between the revised Schwartz and the index GFR compared to the other two formulae and the index GFR. For the original Schwartz equation, age and prior receipt of chemotherapy were significant predictors of under- and overestimation. For the revised Schwartz equation, one age group (6–12 years) and a diagnosis of neuroblastoma actively receiving chemotherapy were positive risk factors for overestimation of the GFR. Conclusion Currently available estimation formulae for GFR may not be appropriate for children with cancer. Pediatr Blood Cancer 2015;62:80–84. © 2014 Wiley Periodicals, Inc.

INTRODUCTION Intravenous iron therapy in children with iron deficiency anemia (IDA) has previously been limited to those with severe or refractory anemia. However, increased availability of intravenous iron preparations with improved safety profiles has increased its utilization in both the adult and pediatric patient populations. Ferric carboxymaltose (FCM) was approved for adult patients by the Food and Drug Administration (FDA) in 2014 and has lower rates of severe allergic reactions. However, literature on adult patients has reported the development hypophosphatemia in up 50% of those receiving the drug. In early stages, hypophosphatemia can lead to abnormal bone mineral metabolism and hypercalciuria. Rickets and osteomalacia can result after prolonged hypophosphatemia. Severe, prolonged hypophosphatemia ( METHODS This was a single center retrospective cohort study of all children who received FCM over the initial 2.5 year period for which the drug was added to our institution's formulary (November 1, 2016 through April 30, 2019). Pharmacy records of all FCM infusions administered over this period were obtained. Medical record numbers of all patients who received an infusion were then searched for any available phosphorus testing. Patients were included in the review if they had phosphorus laboratory results available from 1 to 6 weeks post-receipt of FCM and were less than 21 years of age at the time of infusion. Hypophosphatemia was defined as a phosphorus level below the lower limit of normal for age as delineated by our institution's central laboratory. Changes in phosphorus levels were calculated in those patients in whom pre-infusion phosphorus levels were also available within the 4 weeks prior to drug infusion. When multiple phosphorus levels were available within the post-infusion window, the lowest value was selected to calculate changes in levels. The electronic medical record (EMR) was reviewed in all patients in whom hypophosphatemia was identified to assess for administration of supplemental phosphorus, as well as other clinical factors that may affect phosphorus levels such as the administration of total parental nutrition (TPN) and/or renal medications (i.e. furosemide), as these are known risk factors for hypophosphatemia. RESULTS From November 1, 2016 through April 30, 2019, 1,081 infusions of FCM were administered in 656 patients. Post-infusion phosphorus testing was available in 165 patients in whom 247 infusions were administered (range 1 to 6). Patients' median age was 4.6 years (range 4 months to 20.6 years) and 56% (n=92) were female. Hypophosphatemia occurred after 36 (15%) infusions in 32 unique patients (19%). Six patients (19%) received potassium phosphorus supplementation (Table). In the 23 patients in whom phosphorus testing was available at 6 weeks, 15 (65%) continued to have phosphorus levels below the normal value for age. Of the entire cohort, pre- and post-infusion phosphorus levels were available relative to 197 infusions (80%) in 136 unique patients (82%). The median change in phosphorus was -0.6 mg/dL (IQR -0.1, -1.6). CONCLUSIONS The assessment of serum chemistries, including phosphorus, is not routinely performed in otherwise healthy children with iron deficiency. While over 650 children received over 1000 infusions of FCM during a 2.5 year period, only 165 patients had phosphorus testing available during the stated time frame of the infusion. In those in whom testing was available, and in which hypophosphatemia occurred, the majority were patients admitted to the hospital with co-morbid conditions or complex clinical care for which phosphorus levels may be affected. Our center has developed a clinical protocol to obtain baseline phosphorus levels in all children in whom intravenous FCM is being considered. Post FCM therapy, phosphorus monitoring is being performed to better identify those patients who may be at risk for hypophosphatemia and in whom phosphorus supplementation may be indicated. OffLabel Disclosure: Ferric carboxymaltose is FDA approved for treatment of iron deficiency in adults. This presentation will discuss the use of ferric carboxymaltose to treat iron deficiency in pediatric patients.

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL.

Drug shortages require clinical teams to decide how to allocate drugs in limited supply among their patients. Ethical frameworks are invaluable for promoting rational approaches to drug distribution, but gaps remain between ethical theory and clinical application. The goal of this work was to explore how decision modeling could supplement ethical frameworks to inform drug distribution from the perspective of a clinical team.We created a hypothetical pediatric oncology clinic with a limited supply of 50,000 mg of methotrexate (MTX) and 21 patients due for treatment on one of six regimens. We constructed a simple decision analytic model to compare the effectiveness of MTX in milligrams per life year saved for each regimen. The robustness of the model was tested under various conditions including alternative drug effectiveness and time horizons. Effects on outcomes and distribution by substituting alternative dosing were explored for each regimen.Prescribed therapy for this group of patients required 108,791 mg MTX. Two regimens for three patients required ≥20,000 mg/mIn this hypothetical drug shortage, no allocation scenario exists that does not result in a worse outcome for some patients. Evidence of drug efficacy affected the decisions to substitute alternative treatments. First-come-first-served allocation resulted in fewer patients receiving treatment than allocation based on efficiency.

The Drug Enforcement Administration (DEA) changed hydrocodone-containing products (HCPs) from Schedule III to II status on October 6, 2014, making codeine-containing products (CCPs) the only non-Schedule II oral opioid agents.We sought to describe prescribing patterns of oral opioid agents in the pediatric emergency department before and after the 2014 DEA rescheduling of HCPs.We performed a cross-sectional study evaluating prescribing patterns in the pediatric emergency department at an urban, academic, quaternary care children's hospital system for 6 months before and 6 months after the DEA rescheduling of HCPs. Differences in patient demographics, provider type, and diagnoses were assessed during the two time periods using Pearson's chi-squared test. The Breslow-Day statistic was used to assess differences in prescribing patterns by provider type.There were 1256 prescriptions for HCPs and CCPs in our pediatric emergency department during the study period, and only 36 prescriptions for alternate oral opioid medications. Prescriptions of all opioid pain medications decreased by 55% after rescheduling. The odds of prescribing HCPs were reduced by 60% after the DEA rescheduling (odds ratio 0.40 [95% confidence interval {CI} 0.30-0.54]; p 0.001). There was no difference between monthly ordering frequencies for CCPs before or after the DEA rescheduling (p = 0.75).The period after rescheduling of HCPs was associated with a lower odds of HCP prescriptions in our emergency department without an increase in the prescription of CCPs.

Healthcare for children with cancer costs significantly more than other children. Cost reduction efforts aimed toward relatively small populations of patients that use a disproportionate amount of care, like childhood cancer, could have a dramatic impact on healthcare spending. The aims of this review are to provide stakeholders with an overview of the drivers of financial costs of childhood cancer and to identify possible directions to curb or decrease these costs. Costs are incurred throughout the spectrum of care. Recent trends in pharmaceutical costs, evidence identifying the contribution of administration costs, and overuse of surveillance studies are described. Awareness of cost and value, i.e., the outcome achieved per dollar or burden spent, in delivery of care and research is necessary to bend the cost curve. Incorporation of these dimensions of care requires methodology development, prioritization, and ethical balance.

Shortages of life-saving chemotherapy and supportive care agents for children with cancer are frequent. These shortages directly affect patients' lives, compromise both standard of care therapies and clinical research, and create substantial ethical challenges. Efforts to prevent drug shortages have yet to gain traction, and existing prioritization frameworks lack concrete guidance clinicians need when faced with difficult prioritization decisions among equally deserving children with cancer. The ethical framework proposed in this Commentary is based upon multidisciplinary expert opinion, further strengthened by an independent panel of peer consultants. The two-step allocation process includes strategies to mitigate existing shortages by minimizing waste and addresses actual prioritization across and within diseases according to a modified utilitarian model that maximizes total benefit while respecting limited constraints on differential treatment of individuals. The framework provides reasoning for explicit decision-making in the face of an actual drug shortage. Moreover, it minimizes bias that might occur when individual clinicians or institutions are forced to make bedside rationing and prioritization decisions and addresses the challenge that individual clinicians face when confronted with bedside decisions regarding allocation. Whenever possible, allocation decisions should be supported by evidence-based recommendations. "Curability," prognosis, and the incremental importance of a particular drug to a given patient's outcome are the critical factors to consider when deciding how to allocate scarce life-saving cancer drugs.

Background We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Methods Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Results Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m2 /day. At 40 mg/m2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). Conclusions A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m2 /day. A phase 2 study of cabozantinib is being conducted.

Approximately 18% of the United States' gross domestic product is attributed to healthcare expenditures. Several studies have illustrated that shifting healthcare from the inpatient to the outpatient setting is more cost effective, in addition to improving patient satisfaction. Vincristine, dactinomycin, and cyclophosphamide (VAC) are used together to treat children with solid tumors. Our traditional treatment approach included a two day inpatient admission. The purpose of this project was to establish a process for the administration of VAC in the outpatient setting to improve satisfaction, and reduce costs.We aimed to benchmark practice standards with other institutions, revised our treatment approach to permit outpatient administration, and implemented the new protocol in a stepwise manner. We collected caregiver satisfaction metrics through the use of surveys. Costs of encounters were obtained from administrative data. Total costs and costs by service type were compared using descriptive and mean comparisons.Seven patients received a total of 31 cycles of VAC in the outpatient setting. The time to achieve an appropriate pre-chemotherapy specific gravity was reduced by a median of 120 min. In addition, time spent in the hospital setting was reduced by a mean of 27.2 hr. Adverse effects were minimal and all caregivers reported greater satisfaction with the outpatient regimen. Outpatient administration of VAC was $3,300 less on average compared to the inpatient administration.Outpatient VAC provides a safe alternative for administration that reduces healthcare costs, reduces healthcare utilization, and improves patient satisfaction.

Background Chemotherapy-induced nausea and vomiting (CINV) negatively impacts patients' quality of life. The emetogenicity of high-dose methotrexate in children and adolescents with cancer is incompletely characterized. At our institution, a number of patients with acute lymphoblastic leukemia (ALL) have received aprepitant with courses of high-dose methotrexate after poor CINV control with prior courses. Procedure We conducted a retrospective cohort analysis on patients with ALL who received methotrexate 5 g/m2 /dose with and without concomitant aprepitant at Texas. Children's Hospital between October 1, 2010 and January 31, 2016. Results We identified 16 patients who received a total of 69 courses of methotrexate. An enhanced antiemetic regimen containing aprepitant was administered with 42 methotrexate courses and resulted in a 54% reduction in the use of as-needed antiemetics (P = 0.002, 95% CI: 21-89%). There were no statistically significant differences in methotrexate area under the curve values (2,209 μM⋅hr/l ± 151 vs. 2,051 μM⋅hr/l ± 94, P = 0.355) or end-infusion methotrexate concentrations (80.5 μM ± 5.6 vs. 74.7 μM ± 3.2, P = 0.335) in patients receiving a standard versus an enhanced antiemetic regimen. Conclusions The addition of aprepitant reduces both CINV and the use of rescue antiemetics. Aprepitant does not appear to affect the pharmacokinetics of methotrexate. Granisetron was prescribed more frequently than ondansetron, but selection of secondary and tertiary agents, if any, was highly variable.