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Purpose: Medication prior authorization (mPA) occurs commonly in US cancer care. While medical oncologists report potential harm resulting from this requirement, the impact of mPA in pediatric oncology is unknown. This study's primary aim was to test the feasibility of prospectively collecting multi-institutional data on mPA in pediatric oncology, while secondarily assessing for resultant delays in care., Methods: Pediatric patients with cancer were enrolled between September 2021 and December 2022 at three Children's Oncology Group institutions participating in the National Cancer Institute Community Oncology Research Program. Data collected for each mPA event included the name of the medication, indication, desired initiation date, and actual date administered., Results: Among 68 patients enrolled at three institutions, 38 (56%) were subject to at least one mPA. A total of 69 mPAs occurred in these 38 patients, with 36 (52%) for supportive care and 33 (48%) for treatment medications. Ultimately, 61 of 69 (88%) mPAs were approved as prescribed (33 of 33 treatment mPAs) with a range of 5-240 minutes of provider/staff time required to resolve. MPAs delayed care in 15 of 69 (22%) cases with a range of 1-21 days. Most providers reported minimal or no additional burden to characterizing mPA data., Conclusion: Despite the complexity and variability of institutional mPA processes, it is feasible to prospectively collect multi-institutional mPA data. No cancer treatment mPA request led to alterations in prescriptions. Delays in care because of mPA affect roughly one quarter of pediatric patients with cancer, the consequences of which remain unknown.

Purpose: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A -rearranged ( KMT2Ar ) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia., Methods: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1 ) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m 2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar . The separate NPM1 cohort of the trial is ongoing., Results: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease., Conclusion: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

Purpose: Unlike most childhood cancers, therapy for ALL includes a prolonged maintenance phase during which children typically resume regular activities. Physicians need data regarding the persistent impact of COVID-19 in this population to help guide families after the pandemic., Methods: The Pediatric Oncology COVID-19 Case Report (POCC) collects deidentified data (sociodemographics, clinical data [cancer, COVID-19 course]) on children, adolescents, and young adults with cancer and COVID-19 from 104 US pediatric oncology institutions. The analysis presented here compares children (≤21 years) with ALL in maintenance (ALL-MTN) with all other children with cancer and COVID-19. Multivariable analyses adjust for age, race/ethnicity, insurance, absolute neutrophil count at the time of infection, vaccination, and comorbidities., Results: Compared with other children reported to POCC (n = 1,190), those in ALL-MTN (n = 481) were less often hospitalized (23% v 29%, P = .01) or admitted to the intensive care unit (ICU: 3% v 5%, P = .01); these findings persisted in multivariable analysis (hospitalization: odds ratio [OR], 0.7 [95% CI, 0.6 to 0.9]; ICU: OR, 0.5 [95% CI, 0.2 to 0.8]). However, cancer-directed therapy was changed more often for children in ALL-MTN (50% v 33%, P ≤ .01; OR, 2.0 [95% CI, 1.6 to 2.5[). Vaccination was an independent prognostic factor in our multivariable model, decreasing odds of hospitalization (OR, 0.7 [95% CI, 0.5 to 0.9])., Conclusion: Children in ALL-MTN required fewer hospitalizations and ICU admissions but more therapy modifications than other children with cancer. Vaccination against COVID-19 reduced the odds of hospitalization.

Abstract: The association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in the context of antimetabolite adherence. Using Children's Oncology Group AALL03N1 data, we examined the association between high DI during the first 4 study months and (i) treatment-related toxicities during the subsequent 2 study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first 4 study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the 4 study months) and normal DI phenotype (all others). Only patients with wild-type TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and nonadherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95% confidence interval [CI] = 1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95% CI = 1.6-5.1); odds were comparable among nonadherers (2.1-fold; 95% CI = 0.4-10.1). Although high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR] = 1.4; 95% CI = 0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR = 2.4; 95% CI = 1.0-5.5) but not among nonadherent participants (aHR = 0.9; 95% CI = 0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Adolescents and young adults (ie, individuals aged 15-39 years, known as AYAs) with cancer face unique vulnerabilities yet remain underrepresented in clinical trials, including adult registries of COVID-19 in cancer (AYAs: 8%-12%). We used the Pediatric Oncology COVID-19 Case Report to examine the clinical course of COVID-19 among AYAs with cancer. The Pediatric Oncology COVID-19 Case Report collects deidentified clinical and sociodemographic data regarding individuals aged from birth to 39 years with cancer (37%) and COVID-19 from more than 100 institutions. Between April 1, 2020, and November 28, 2023, 191 older AYAs (individuals 22-39 years of age) and 640 younger AYAs (individuals 15-21 years of age) were captured. Older AYAs were less often hospitalized (P < .001), admitted to the intensive care unit (P = .02), and required respiratory support (P = .057). In multivariable analyses, older AYAs faced 80% lower odds of intensive care unit admission but 2.3-times greater odds of changes to cancer-directed therapy. Unvaccinated patients had 5.4-times higher odds of intensive care unit admission. Among AYAs with cancer, the COVID-19 course varies by age. These findings can inform oncology teams directing COVID-19 management and prevention in AYA patients with cancer., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In the era of evolving and emerging therapies, adolescents and young adults (AYAs) living with advanced cancer experience a high degree of uncertainty, making palliative care and end-of-life (PCEOL) discussions difficult. Clinical conversations determine values/preferences that guide shared decision-making and goals of treatment, including end-of-life care when cancer progresses. Initiating PCEOL conversations is challenging for clinicians., Objective: This study describes the development and validation of an instrument that measures AYA readiness to engage in PCEOL clinical conversations., Methods: A Ready-to-Talk Measure (R-T-M) was developed, guided by the revised conceptual model of readiness across 3 domains (awareness, acceptance, and willingness). Content experts evaluated validity, and 13 AYAs with advanced cancer participated in cognitive interviews. Acceptability (item applicability, clarity, interpretation, sensitivity, missingness) and experiences (benefit, burden) were analyzed., Results: The scale content validity index was ≥0.90 for each domain. Forty-two of the 55 R-T-M items were acceptable without any change. Three items were deleted. Ten items were modified, and 3 were added. Adolescents and young adults wanted more items about friends/siblings and about AYA unique qualities for clinicians to know them better. Adolescents and young adults acknowledged benefit through talking about difficult, relevant topics., Conclusion: Ready-to-Talk Measure validity was strengthened by deleting or modifying unclear or misinterpreted items and by adding items. Next steps include psychometric analysis to determine reliability/dimensionality and stakeholder input to make the R-T-M a clinically useful tool., Implications for Practice: Ready-to-Talk Measure assessment of readiness to engage in PCEOL conversations while identifying unique preferences of AYAs holds promise for facilitating ongoing discussions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Germline pathogenic loss-of-function (pLOF) variants in DICER1 are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common DICER1 pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of DICER1 -related cancers and cascade testing of family members. However, some patients with DICER1 -associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense DICER1 RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.

The association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528., (© 2023 by The American Society of Hematology.)

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function 1-3 . The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1) 4-6 . KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia 7,8 . Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes., (© 2023. The Author(s).)

Importance: Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL., Objective: To compare the prevalence of cCMV infection between ALL cases and matched controls., Design, Setting, and Participants: In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother's race and ethnicity. Data were analyzed from November to May 2022., Exposures: cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots., Main Outcomes and Measures: ALL diagnosed in children aged 0 to 14 years., Results: A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19)., Conclusions and Relevance: In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Background: Obesity at diagnosis of childhood acute lymphoblastic leukemia (ALL) is associated with greater risk of relapse; whether this association extends to obesity during maintenance is unstudied., Methods: This study used data from AALL03N1 to calculate median body mass index (BMI) for 676 children over 6 consecutive months during maintenance therapy; BMI percentile (BMI%ile) were operationalized as normal/underweight (<85%ile), overweight/obese (85%-98%ile), and extreme obesity (≥99%ile). Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression after adjusting for all relevant demographic and clinical predictors., Results: Median age at study enrollment was 6 years and median length of follow-up was 7.9 years. Overall, 43.3% of the cohort was underweight/normal weight, 44.8% was overweight/obese, and 11.8% had extreme obesity. Cumulative incidence of relapse at 4 years from study enrollment was higher among those with extreme obesity (13.6% ± 4.5%) compared to those with underweight/normal weight (9.0% ± 2.1%). Multivariable analysis revealed that children with extreme obesity had a 2.4-fold (95% confidence interval [CI], 1.1-5.0; p = .01) greater hazard of relapse compared to those who were underweight/normal weight. Overweight/obese patients were at comparable risk to those who were underweight/normal weight (hazard ratio, 0.8; 95% CI, 0.4-1.6). Erythrocyte thioguanine nucleotide (TGN) levels were significantly lower among children with extreme obesity compared to those with underweight/normal weight (141.6 vs. 168.8 pmol/8 × 10 8 erythrocytes; p = .0002), however, the difference in TGN levels did not explain the greater hazard of relapse among those with extreme obesity., Conclusions: Extreme obesity during maintenance therapy is associated with greater hazard of relapse in children with ALL. Underlying mechanisms of this association needs further investigation., Lay Summary: Findings from this study demonstrate that extreme obesity during maintenance therapy is associated with a greater hazard of relapse among children with acute lymphoblastic leukemia. We show that children with obesity have lower levels of erythrocyte thioguanine nucleotides even after adjusting for adherence to oral chemotherapy. However, these lower levels do not explain the greater hazard of relapse, paving the way for future studies to explore this association., (© 2022 American Cancer Society.)

Blood shortages remain an ongoing challenge, ameliorable by increasing blood donations. Choice architecture is an emerging concept in psychology dealing with the targeted presentation of options to encourage a desired decision. A pilot study was designed to test the feasibility of implementing six choice architecture strategies on a Midwest high-school blood drive. These include framing, conformity, mere measurement, availability heuristic, loss aversion and status quo bias. A pre-post interrupted time-series evaluation was performed to evaluate for an immediate impact on blood donations. All six of the intended choice architecture strategies were successfully implemented. The pre-intervention 5-year average number of blood donations per blood drive was 15 (4.3% of age eligible donors) whereas post intervention, the number of blood donors rose to 25 (7.1% of age eligible donors; p-value = .0013). The application of choice architecture to blood donor recruitment strategies is feasible and has the potential to reduce the burden of blood shortages.

Few studies have explored interventions to improve adolescent and young adult (AYA) cancer care delivery. While many AYAs receive cancer care at NCI Community Oncology Research Program (NCORP) sites, few enroll on clinical trials. Barriers and facilitators to pediatric oncologist activation of and enrollment on an AYA cross-network National Clinical Trials Network (NCTN) supportive care trial were assessed using a survey that was administered to 162 stakeholders representing all 47 children's oncology group (COG) institutions affiliated to an NCORP. Fifty-eight stakeholders participated representing 62% of all sites surveyed. Approximately half of participants (45%) were unaware of the trial. Seven sites had the study open and one enrolled a patient. Reasons for not opening and enrolling on the trial included limited research staff and resources, low anticipated accrual, and lower prioritization of the trial. Enrollment facilitators included having a local "AYA champion," improving communication between pediatric and medical oncology, and having site education on available AYA trials. Interventions focused on increasing site and provider awareness of AYA trials and decreasing local barriers to AYA enrollment are needed.

Purpose: The Pediatric Oncology COVID-19 Case Report registry supplies pediatric oncologists with data surrounding the clinical course and outcomes in children with cancer and SARS-CoV-2., Methods: This observational study captured clinical and sociodemographic characteristics for children (≤ 21 years) receiving cancer therapy and infected with SARS-CoV-2 from the pandemic onset through February 19, 2021. The demographic and clinical characteristics of the cohort were compared with population-level pediatric oncology data (SEER). Multivariable binomial regression models evaluated patient characteristics associated with hospitalization, intensive care unit (ICU) admission, and changes in cancer therapy., Results: Ninety-four institutions contributed details on 917 children with cancer and SARS-CoV-2. Median age at SARS-CoV-2 infection was 11 years (range, 0-21 years). Compared with SEER, there was an over-representation of Hispanics (43.6% v 29.7%, P < .01), publicly insured (59.3% v 33.5%, P < .01), and patients with hematologic malignancies (65.8% v 38.3%, P < .01) in our cohort. The majority (64.1%) were symptomatic; 31.2% were hospitalized, 10.9% required respiratory support, 9.2% were admitted to the ICU, and 1.6% died because of SARS-CoV-2. Cancer therapy was modified in 44.9%. Hispanic ethnicity was associated with changes in cancer-directed therapy (adjusted risk ratio [aRR] = 1.3; 95% CI, 1.1 to 1.6]). Presence of comorbidities was associated with hospitalization (aRR = 1.3; 95% CI, 1.1 to 1.6) and ICU admission (aRR = 2.3; 95% CI, 1.5 to 3.6). Hematologic malignancies were associated with hospitalization (aRR = 1.6; 95% CI, 1.3 to 2.1)., Conclusion: These findings provide critical information for decision making among pediatric oncologists, including inpatient versus outpatient management, cancer therapy modifications, consideration of monoclonal antibody therapy, and counseling families on infection risks in the setting of the SARS-CoV-2 pandemic. The over-representation of Hispanic and publicly insured patients in this national cohort suggests disparities that require attention., Competing Interests: Julienne BrackettResearch Funding: Bristol Myers Squibb Smita BhatiaThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript. Jennifer M. LevineStock and Other Ownership Interests: UMotifNo other potential conflicts of interest were reported.

Background: Sedation for lumbar punctures (LPs) in pediatric acute lymphoblastic leukemia (ALL) patients has been the standard for decades to reduce pain and anxiety. Recent studies on the potential long-term neurocognitive effects of cumulative propofol exposure have raised concerns about this practice. The recent pandemic introduced additional burdens to patients, with the requirement of a negative COVID-19 test prior to each sedated procedure., Procedure: These factors prompted a quality improvement intervention at our institution where we aimed to reduce postinduction sedated LPs by 50%. Our intervention included patient and family education, followed by a simulation of the procedure for selected patients. Those converted to unsedated LPs were queried for their preference. Comparative cost, clinical time, and LP success rates were collected for sedated and unsedated LPs., Results: Following the intervention, the percentage of LPs performed with sedation dropped from 100% to 48%. All LPs were successful using both techniques. Most patients who experienced the unsedated LP technique, and their guardians, strongly preferred this approach. Unsedated LPs significantly reduced clinical time (169 vs. 83 minutes) for families, decreased expenditures ($5736 reduction per procedure), and improved institutional opportunity cost due to a decrease in last-minute cancelations., Conclusion: We have shown that it is feasible to significantly reduce the use of sedation for LPs in patients with ALL, which has the potential to improve health and patient experience at a lower cost., (© 2021 Wiley Periodicals LLC.)

Hematopoietic stem cell transplant (HSCT) is a potentially curative treatment for hematopoietic malignancies, complicated by decreased performance status and quality of life. Exercise therapy improves outcomes in HSCT, but several barriers have prevented exercise from becoming routine clinical practice. Based on existing data that wearable technologies facilitate exercise participation in other sedentary and chronic illness populations, we propose the novel hypothesis that wearable technologies are a valuable tool in transcending barriers and developing exercise therapy programs for HSCT patients., (Copyright © 2021 by the American College of Sports Medicine.)

Purpose: Clinical trial participation leads to progress in cancer care. Principal investigators (PIs) and clinical research associates (CRAs) play key roles in the provision and maintenance of clinical trial portfolios at their sites. Previous studies have evaluated the educational and resource needs of adult oncology providers, but nothing to date has focused on providers of pediatric oncology care. We aimed to identify the educational needs and clinical trial participation barriers at National Cancer Institute Community Oncology Research Program (NCORP) Children's Oncology Group (COG) sites to improve the quality of site investigator engagement., Methods: Quality improvement surveys of pediatric clinical research staff at NCORP sites were performed. The first was a web-based inquiry of NCORP COG PIs and lead CRAs to assess their general understanding of NCORP organizational structure and needs. The second survey of COG PIs was conducted by one-on-one telephone interviews aimed at identifying specific barriers to physician engagement and patient enrollment in clinical trial research., Results: The majority of NCORP COG PIs and CRAs (63%) reported an incomplete understanding of NCORP structure, with approximately half expressing interest in developing stronger collaborations and engagement. Most NCORP COG PIs reported at least one shared barrier to clinical trial enrollment (78%), with inadequate protected time and research support (39% each) being the most frequently cited barriers., Conclusions: Contributions to pediatric cancer clinical research at COG NCORP sites could be enhanced through improved education, resources, and time allocation.

Timely medication access in pediatric oncology is important; yet barriers are poorly described. We surveyed pediatric oncology health care providers at National Cancer Institute Community Oncology Research Program sites on their experience with the impact of drug acquisition difficulties, prior authorization (PA) requests, insurance denials, and patient copays leading to deviations or delays from prescribed treatment for their pediatric/adolescent/young adult patients in calendar year 2016. PA requests, the most frequently cited issue, created a deviation or delay from planned chemotherapy and supportive care treatment in at least 61% of respondents. Half of the respondents believed that PA-induced delays had a negative impact on care. Two-thirds of respondents felt that delays in starting therapy due to barriers in medication access created psychologic or emotional distress for the patient or family. Pediatric cancer patients may be receiving inferior care as a result of barriers to medication access.

Background: Medication prior authorization (PA) is a commonly occurring requirement, particularly for medications used for rare conditions. Based on standard definitions, cancer and many blood disorders affecting children are rare. The study aims were to describe the relative frequency of PA requests and their association with payers and medications in order to identify opportunities to improve system efficiency., Procedure: Requests for medication PA were logged prospectively for patients seen at a single institution over a 7-month period. Period prevalence was used to estimate the relative frequency of PA requests. Descriptive statistics summarized the relationship among payers, medications, and approvals relative to the frequency of PA requests., Results: For the study duration of 150 clinic days, there were 5,583 patient visits. A total of 142 medication PA requests were received resulting in a period prevalence rate of 2.5% patient visits. Of the 137 medication PA requests with available outcome data, 135 (98.5%) were ultimately approved with additional provider efforts. The median clinic staff time spent per request was 46 min with an interquartile range of 25-80 min. There was striking process heterogeneity among different payers., Conclusion: Virtually no medication PA request in pediatric hematology and oncology (PHO) leads to alterations in care. Medication utilization management strategies in PHO fail to provide benefits reported in other areas of medicine and have unmeasured negative effects on timeliness of care and parenteral psychological/emotional health. There is opportunity for increasing efficiency through payer and provider collaboration on the creation of prescribing standards for PHO patients., (© 2016 Wiley Periodicals, Inc.)

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution., (© 2017 by The American Society of Hematology.)

Purpose: Stagnant outcomes for adolescents and young adults (AYAs; 15 to 39 years old) with cancer are partly attributed to poor enrollment onto clinical trials. The National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP) was developed to improve clinical trial participation in the community setting, where AYAs are most often treated. Further, many CCOP sites had pediatric and medical oncologists with collaborative potential for AYA recruitment and care. For these reasons, we hypothesized that CCOP sites enrolled proportionately more AYAs than non-CCOP sites onto Children's Oncology Group (COG) trials., Methods: For the 10-year period 2004 through 2013, the NCI Division of Cancer Prevention database was queried to evaluate enrollments into relevant COG studies. The proportional enrollment of AYAs at CCOP and non-CCOP sites was compared and the change in AYA enrollment patterns assessed. All sites were COG member institutions., Results: Although CCOP sites enrolled a higher proportion of patients in cancer control studies than non-CCOP sites (3.5% v 1.8%; P < .001), they enrolled a lower proportion of AYAs (24.1% v 28.2%, respectively; P < .001). Proportional AYA enrollment at CCOP sites decreased during the intervals 2004 through 2008 and 2009 through 2013 (26.7% v 21.7%; P < .001)., Conclusion: Despite oncology practice settings that might be expected to achieve otherwise, CCOP sites did not enroll a larger proportion of AYAs in clinical trials than traditional COG institutions. Our findings suggest that the CCOP (now the NCI Community Oncology Research Program) can be leveraged for developing targeted interventions for overcoming AYA enrollment barriers., (Copyright © 2016 by American Society of Clinical Oncology.)

Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP). Adherence to oral 6MP among Asian-American and African-American children with ALL is unknown. We enrolled 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites) receiving oral 6MP for the maintenance phase. Adherence was measured electronically for 39 803 person-days. Adherence declined from 95.0% (month 1) to 91.8% (month 5, P < .0001). Adherence rates were significantly (P < .0001) lower in Asian Americans (90.0% ± 4.9%) and African Americans (87.1% ± 4.4%), as compared with non-Hispanic whites (95.2% ± 1.3%). Race-specific sociodemographic characteristics helped explain poor adherence (African Americans: low maternal education [less than a college degree: 78.9%, vs at least college degree: 94.6%; P < .0001]; Asian Americans: low-income households [<$50 000: 84.5%, vs ≥$50 000: 96.7%; P = .04]; households without mothers as full-time caregivers [85.6%] vs households with mothers as full-time caregivers [97.2%; P = .05]). Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P = .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00268528., (© 2014 by The American Society of Hematology.)

Purpose: Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity., Patients and Methods: A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed., Results: After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites., Conclusion: Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence-an observation currently under investigation.

Background: Although pediatric hospice care is commonly accepted as a beneficial intervention, the incremental advantage over end-of-life care delivered without engaging hospice remains unknown. The primary objective of this study was to describe differences in pediatric end-of-life care when delivered with and without hospice support, as perceived by the medical provider., Procedure: A retrospective survey of medical providers was conducted in 2005 over a 2-month period at a single institution, the Helen DeVos Children's Hospital (HDVCH). Medical providers with self-determined experience in pediatric end-of-life care were asked to separately provide positive and negative comments about their experience with hospice. Additionally they were asked to describe differences between children under their supervision who died with and without hospice care. Medical provider comments and comparisons of experiences in caring for children dying with and without hospice involvement are described., Results: Out of 157 responders, 43 reported positive comments about the hospice intervention. Non-medical support and location of death were the most frequently cited benefits. Nineteen responders provided negative comments about hospice; all involving feelings of lost hope, intrusion, or distrust. When asked to directly compare deaths with and without hospice support, 44 of 51 (86%) responders favored hospice. The most cited reason for preferring hospice involvement was better provision of non-medical services., Conclusions: The majority of pediatric providers in this survey observed an advantage to utilizing hospice care for dying children as compared to providing end-of-life care without hospice involvement.

Background: Pediatric end-of-life care involves multiple decision-makers including the patient, the family, and the health care provider. Although some information exists on the role of patient and family values on decision making, little is known about what influences the health care provider's decisions and performance., Objective: A survey was conducted to collect data on health care providers who provide pediatric end-of-life care to determine what factors influence provider confidence in managing eleven different end-of-life care issues., Design: An electronic 34-question survey was circulated in 2005 at a single children's hospital in Western Michigan., Results: One hundred fifty-seven responses were received. Age had the highest association with confidence. Older responders reported more confidence than their younger colleagues (odds ratio [OR] 3.3-26.1 on eight issues). Other provider factors associated with higher confidence levels included male gender (OR 3.6-11.2 on five issues), experience (OR 2.7-4.6 on five issues) and not being religious (OR 3.1-3.4 on three issues). Responders who received formal education during training felt better prepared than those who did not (17.1% versus 3.8% felt at least well prepared, respectively)., Conclusions: Age and experience create confidence in managing pediatric end-of-life care issues. Other provider variables including gender and religious beliefs may also influence confidence on some issues. Although formal education helps providers feel better prepared to care for children with terminal conditions, the majority of providers still feel no more than adequately prepared by their training. More emphasis on experience-driven education delivered by seasoned educators may improve confidence in delivering pediatric end-of-life care.

The initiation and progression of cancer is dependent on factors both intrinsic and extrinsic to the malignant cells. Stromal, vascular endothelial, and inflammatory cells are the principal normal populations that support tumors by supplying factors and nutrients. The mononuclear phagocyte lineage, which includes monocytes, macrophages, and dendritic cells is of particular clinical interest because lineage members can enhance tumor angiogenesis and metastasis, or alternately contribute to tumor destruction. Thus therapies that regulate these cells represent an innovative approach for improving patient survival in childhood cancer.

The primary focus in the pathogenesis and treatment of human malignancies has been the tumor cell. However, the biologic properties of a malignancy are not all intrinsically determined. Interactions between heterogeneous cell populations influence the growth and survival of both normal and malignant cells. Studies defining the origin of endothelial cells involved in tumor angiogenesis first demonstrated the contributions of normal cellular environment. Recently, the mononuclear phagocyte lineage has been found to have biologically and clinically significant tumor enhancing and tumor suppressive effects. This article reviews the multiple roles of mononuclear phagocytes in cancer biology. A companion manuscript (J Pediatr Hematol Oncol. 2008, in press) describes the targeting of these cells for therapeutic benefit. Incorporating these strategies into future childhood cancer protocols could be an innovative approach for improving patient outcome.

Choroid plexus carcinoma (CPC) is an uncommon central nervous system tumor requiring complete surgical excision for favorable outcome. The authors report the successful treatment of a 2-year-old patient with widely disseminated CPC and Li-Fraumeni syndrome. Following a partial resection of the tumor the patient received chemotherapy consisting of cyclophosphamide, etoposide, and carboplatin. There were no additional surgical procedures and radiation was not administered. Remarkably, the patient remains without evidence of active disease more than 3 years from the completion of therapy. Additional studies are necessary to determine whether this treatment plan can be beneficial to other patients with CPC and whether the patient's p53 mutation had an effect on outcome.

Purpose: Sarcomas express cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity. COX-2 inhibition is efficacious against many cancer types but has not been tested for human sarcomas. Matrix metalloproteinase (MMP) inhibitors also possess antiproliferative activity. Because MMP inhibitor therapy induces COX-2 expression, the authors hypothesized that the combination of COX-2 and MMP inhibitors results in a synergistic antitumor effect., Methods: Human osteosarcoma or rhabdomyosarcoma cells were injected into athymic mice. Tumor development and growth were measured following treatment with a COX-2 inhibitor (celecoxib), an MMP inhibitor (doxycycline), or both. The tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels., Results: When treatment was started prior to tumor cell implantation, doxycycline inhibited osteosarcoma tumor growth alone and in combination with celecoxib (30% and 33% reduction, respectively). An effect on osteosarcoma tumor implantation rates was noted in mice receiving doxycycline alone and in combination with celecoxib (12.5% and 6.25% reduction, respectively). Established osteosarcoma and rhabdomyosarcoma tumors were inhibited only by combination therapy (36% and 55%, respectively). A higher proportion of osteosarcoma tumors in the combination therapy group had more than 50% necrosis (3/7) when compared with control tumors (0/8). Antitumor effects did not correlate with PGE2 levels, suggesting the observed interaction with doxycycline was due to previously described non-enzymatic effects of celecoxib., Conclusions: The authors' preclinical data suggest that the combination of inexpensive, nontoxic, oral COX-2 and MMP inhibitors may be useful for the treatment of some types of solid tumors.

Purpose: To determine if expression of cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity, correlates with outcome in pediatric sarcomas. COX-2 overexpression correlates with more aggressive disease in a variety of adult solid tumors., Methods: Archived human osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma tumors were retrospectively evaluated, blinded to outcome, for COX-2 expression by immunohistochemistry and correlated with patient characteristics and survival., Results: COX-2 expression was detected in 94 of 142 (66%) tumors (osteosarcoma, 66/99 [67%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 7/8 [88%]) and 51 of 85 (60%) diagnostic biopsies (osteosarcoma, 26/45 [58%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 4/5 [80%]). COX-2 expression did not vary with clinicopathologic features and was not predictive of prognosis in these cases., Conclusions: This study does not support the use of COX-2 expression as an upfront prognostic variable in patients with osteosarcoma or rhabdomyosarcoma. Results from the small number of patients studied with Ewing sarcoma suggest a similar lack of predictive value for COX-2 expression. However, COX-2 inhibitors are not entirely dependent upon enzyme expression for their antitumor effects; this study does not necessarily preclude the use of COX-2 inhibitors for the treatment of pediatric sarcomas.

Therapies for metastatic pediatric sarcomas have reached maximum tolerated doses, but continue to provide suboptimal cure rates. Additionally, these treatments are associated with numerous short- and long-term side effects. Therefore, the search for newer, less toxic therapeutic agents is warranted. Overexpression of the inducible enzyme, cyclooxygenase-2 (COX-2), has been discovered in a variety of adult solid tumors and numerous studies have shown COX-2 inhibitors to have significant antiproliferative effects. Therefore, we sought to determine the expression of COX-2 in pediatric sarcomas. We evaluated rhabdomyosarcoma (RMS), osteosarcoma (OS), and Ewing sarcoma (EWS) samples for COX-2 expression by immunohistochemical analysis as well as by cDNA microarray analysis. COX-2 expression was detected in 48/58 (82.8%) tumors by immunohistochemistry and in an additional 52/59 (88.1%) tumors tested by microarray gene analysis. There was a trend toward increased COX-2 expression in metastatic rhabdomyosarcoma and osteosarcoma, though it did not reach clinical significance. The degree of COX-2 immunoreactivity did not vary significantly with other clinicopathologic features such as age, gender, or histologic classification. We conclude that the majority of these pediatric sarcoma samples express COX-2 to varying degrees. Therefore, studies testing the efficacy of COX-2 inhibitors in the treatment of pediatric sarcomas are warranted.