Development and validation of thromboembolism diagnostic algorithms in children with cancer from real-world data.

OBJECTIVE: To evaluate the accuracy of diagnostic algorithms developed using the International Classification of Diseases (ICD-9-CM and ICD-10-CA) diagnostic codes and physician billing codes for thromboembolism (TE) from health administrative data compared to chart review diagnoses of TE in children with cancer. METHODS: Using data linkage between the Pediatric Oncology Group of Ontario Network Information System (Ontario pediatric cancer registry) and various administrative data housed at ICES, eight algorithms were developed including a single reference to one of the billing codes, multiple references with varying time intervals, and combinations of various billing codes during primary cancer therapy for the whole cohort and, for early (<04/2002) and later (≥04/2002, solely ICD-10 codes) periods. Reference standard was chart review data from prior studies (from 1990 to 2016) among children (≤19 years) with cancer and radiologically confirmed TE. RESULTS: Records of 2056 patients diagnosed with cancer at two participating sites during study period were reviewed; 112 had radiologically confirmed TE. The algorithm with addition of anticoagulation utilization codes was the best performing algorithm (sensitivity = 0.76;specificity = 0.85). With use of ICD-10 only codes, sensitivity of the same algorithm improved to 0.84 with specificity of 0.80. CONCLUSION: This study provides a valid approach for ascertaining pediatric TE using real-world data. IMPACT: Research in pediatric thrombosis, especially cancer-related thrombosis, is limited mainly due to small-sized studies. Real-world data provide ready access to large and diverse populations. However, there are no validated algorithms for identifying thrombosis in real-world data for children. An algorithm based on combination of thrombosis and anticoagulation utilization codes had 76% sensitivity and 85% specificity to identify diagnosis of thrombosis in children in administrative data. This study provides a valid approach for ascertaining pediatric thrombosis using real-world data and offers a good avenue to advance pediatric thrombosis research.

Risk factors and clinical impact of thrombosis during induction chemotherapy for pediatric acute lymphoblastic leukemia: A report from CYP-C.

Thromboembolism (TE) is associated with reduced survival in pediatric acute lymphoblastic leukemia (ALL). It has been hypothesized that TE might signal leukemic aggressiveness. The objective was to determine risk factors for TE during ALL induction (TEind ) therapy and whether TEind is associated with treatment refractoriness. This retrospective cohort study using the population-based Cancer in Young People Canada (CYP-C) registry included children <15 years of age diagnosed with ALL (2000-2019) and treated at one of 12 Canadian pediatric centers outside of Ontario. Univariate and multivariable logistic regression models were used to determine risk factors for TEind and whether TEind predicted induction failure and ALL treatment intensification. The impact of TEind on overall and event-free survival was estimated using Cox proportional hazard regression models. The study included 2589 children, of which 45 (1.7%) developed a TEind . Age (<1 year and ≥10 years vs. 1-<10 years), T-cell phenotype, high-risk ALL, and central nervous system involvement were all associated with TEind in univariate analysis. Age and T-cell phenotype remained independent predictors of TEind in multivariable analysis. Induction failure occurred in 53 patients (2.1%). TEind was not associated with induction failure (OR: not estimable) or treatment intensification (adjusted OR [95% CI]: 0.66 [0.26-1.69]). TEind was independently associated with overall survival (adjusted HR [95% CI]: 2.54 [1.20-5.03]) but not event-free survival (adjusted HR [95% CI] 1.86 [0.98-3.51]). In this population-based study of children treated with contemporary chemotherapy protocols, TEind was associated with age and T-cell phenotype and mortality but did not predict induction failure.

Rates and predictors of visits to primary care physicians during and after treatment of childhood acute lymphoblastic leukemia: A population-based cohort study.

INTRODUCTION: Patient re-engagement with primary care physicians (PCPs) after cancer treatment is essential to facilitate survivorship care and to meet non-oncology primary care needs. We identified rates and predictors of PCP visits both during and after treatment among a population-based cohort of children with acute lymphoblastic leukemia (ALL). METHODS: Children of age less than 18 years at ALL diagnosis in Ontario between 2002 and 2012 were linked to administrative data and matched to controls without cancer. PCPs at diagnosis were identified and PCP visit rates during treatment compared between patients and controls. Post-treatment PCP visit rates were also calculated. Predictors included demographic-, disease-, and PCP-related variables. RESULTS: A total of 743/793 (94%) patients and 3112/3947 (79%) controls had a PCP at diagnosis. Almost half of patients (361/743, 45%) did not visit their PCP during treatment. Visit rate during treatment was 0.64 per person per year (PPPY) versus 1.4 PPPY among controls (adjusted rate ratio [aRR] 0.47, 95th confidence interval [95CI]: 0.40-0.54; p < .0001). No disease- or PCP-related factors were associated with visit rates. Total 711 patients completed frontline therapy; 287 (40.4%) did not have a PCP visit after treatment. Nonetheless, survivors overall visited PCPs post treatment more often than controls (aRR 1.4, 95CI: 1.2-1.6; p < .0001). Survivors who saw their PCP during treatment had post-treatment visit rates twice that of other survivors (aRR 2.0, 95CI: 1.6-2.5; p < .0001). CONCLUSIONS: Only a portion of children with ALL see their PCPs during treatment and return to PCP care following treatment completion. Post-treatment engagement with PCPs may be improved by PCP involvement during ALL treatment.

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

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

Safety and Efficacy of Alendronate to Treat Osteopenia in Children During Therapy for Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of Sequential Outcomes.

BACKGROUND: Low bone mineral density is encountered in children with acute lymphoblastic leukemia (ALL) before, during, and after treatment. Prior experience with alendronate, an oral bisphosphonate, demonstrated high tolerability and evident clinical efficacy. However, concerns have been expressed about the long-term safety and utility of such agents in children. PROCEDURE: Sixty-nine children with ALL received alendronate for a mean of 87 weeks after dual-energy radiograph absorptiometry. Dual-energy radiograph absorptiometry was repeated following the completion of alendronate, and 5 to 9 years later in a subgroup of 32 children. Lumbar spine areal bone mineral density (LS aBMD) Z scores were obtained. RESULTS: The mean LS aBMD Z score rose from -1.78 to-0.47 ( P <0.0001). There was a modest median loss of LS aBMD subsequently in the 32 subjects on long-term follow-up. Almost 80% (N=172) of the children remain in continuous complete remission at a mean of 14.5 years from diagnosis. Of those who received alendronate, which was almost uniformly well tolerated, 7/69 (10.3%) relapsed compared with 19/89 (21.3%) who did not receive the drug. DISCUSSION: Alendronate appears to be well tolerated and moderately effective in osteopenic children with ALL. Whether it offers protection against relapse of leukemia needs further study.

An exploratory analysis of the impact of the COVID-19 pandemic on pediatric type 1 diabetes mellitus patient outcomes: A single-center study.

Background: The COVID-19 pandemic led to substantial shifts in pediatric diabetes care delivery to virtual and hybrid models. It is unclear if these changes in care delivery impacted short-term patient outcomes. Objectives: We aimed to explore glycemic control and other diabetes-related outcomes in children living with Type 1 Diabetes Mellitus (T1DM) during the first year of the COVID-19 pandemic at a tertiary pediatric academic center in Canada. Subjects: Patients <18 years of age with a confirmed diagnosis of T1DM for at least one year were included. Methods: This was a retrospective chart review. We compared data from two years pre-pandemic (March 15, 2018-March 14, 2020) to the first year of the pandemic (March 15, 2020-March 14, 2021). The data assessed included glycemic control [Hemoglobin A1c (HbA1c)], diabetic ketoacidosis (DKA), hospital attendance and hospitalizations, hypoglycemia, and hyperglycemia. The generalized estimating equation (GEE) analysis was used to model potential factors affecting the HbA1c and diabetes-related morbidities. Multiple imputations were conducted as a sensitivity analysis. Results: There were 346 eligible patients included in the study. The HbA1c remained stable during the pandemic compared to the pre-pandemic phase (MD-0.14, 95% CI, -0.28, 0.01; p = 0.058). The pandemic saw an increase in the number of newly diagnosed patients (X2 = 16.52, p < 0.001) and a higher number of newly diagnosed patients presenting in DKA (X2 = 12.94, p < 0.001). In patients with established diabetes, there was an increase in hyperglycemia (OR1.38, 95% CI, 1.12,1.71; p = 0.003) and reduced DKA (OR 0.30, 95% CI, 0.12,0.73; p = 0.009) during the pandemic compared to the pre-pandemic phase. Stable rates of hospitalization (OR0.57, 95% CI, 0.31,1.04, p = 0.068) and hypoglycemia (OR1.11, 95% CI, 0.83,1.49; p = 0.484) were noted. These results were retained in the sensitivity analysis. Conclusions: Glycemic control in children with T1DM remained stable during the first year of the pandemic. There were more newly diagnosed patients during the pandemic compared to the pre-pandemic phase, and more of these new patients presented in DKA. The latter presentation was reduced in those with established diabetes during the same period.Further studies are needed to assess the ongoing impact of the COVID-19 pandemic on T1DM care pathways and outcomes to allow children, families, and diabetes teams to personalize choices of care models.

Prognostic factors and outcomes of infant acute lymphoblastic leukemia (ALL), hypodiploid ALL, and mixed-phenotype acute leukemia (MPAL) in Canada: a report from CYP-C.

The epidemiology of infant acute lymphoblastic leukemia (ALL), hypodiploid ALL, and mixed-phenotype acute leukemia (MPAL) in Canada is unknown. The main objective was to describe the prevalence, prognostic factors, and outcomes of three rare and high-risk ALL subtypes in Canada. This is a retrospective study using the Cancer in Young People-Canada (CYP-C) database. Event-free survival (EFS) and overall survival (OS) were described by the Kaplan-Meier method and compared using the log-rank test. Among 2626 children aged 0-14 years diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) between 2001 and 2018, 227 (8.6%) patients were identified to be infant ALL (n = 139), hypodiploid ALL (n = 43), or MPAL (n = 45). The 5-year EFS/OS was significantly worse in the infant ALL subgroup compared to that of hypodiploid ALL and MPAL. For the entire cohort, presenting White blood cells (WBCs) ≥50 × 109/L was independently associated with worse EFS/OS.

Healthcare utilization and costs associated with acute lymphoblastic leukemia in children with and without Down syndrome.

BACKGROUND: Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are at increased risk of treatment-related morbidity and mortality compared to non-DS-ALL, requiring increased supportive care. We examined the healthcare utilization and costs in DS-ALL patients to inform future evaluations of novel therapies. METHODS: A provincial registry identified all children (1-17 years) diagnosed with B-lineage ALL in Ontario, Canada between 2002 and 2012. Detailed demographic, disease, treatment, and outcome data were abstracted. Linkage to population-based health services databases identified all outpatient and emergency department (ED) visits, hospitalizations, and physician billings. Healthcare utilization costs were available for patients diagnosed during 2006-2012 using validated algorithms (2018 Canadian dollars). Healthcare utilization rates and costs were compared between DS and non-DS patients using regression models, adjusting for all covariates. RESULTS: Of 711 patients, 28 (3.9%) had DS. Adjusting for all covariates, children with DS-ALL experienced substantially higher rates of ED visits (rate ratio [RR] 1.5, 95% confidence interval [95% CI]: 1.2-2.0; p = .001) and inpatient days (RR 2.5, 95% CI: 1.4-4.5; p = .002) compared to non-DS children. Outpatient visit rates were similar (RR 1.1, 95% CI: 0.9-1.3; p = .41). Among patients with available cost data (N = 533, DS = 19), median 5-year healthcare utilization cost was $247,700 among DS patients (interquartile range [IQR]: 200,900-354,500) and $196,200 among non-DS patients (IQR: 148,900-280,300; p = .02). In adjusted analyses, DS-associated costs were 50% higher (RR 1.5, 95% CI: 1.2-1.9; p < .002). CONCLUSIONS: Healthcare utilization and treatment costs of DS-ALL patients are substantially higher than those of non-DS-ALL. Our data provide a baseline for future DS-specific cost-effectiveness studies.

The Influence of Body Composition on Bone Health in Long-term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence: Analyses by Dual-energy Radiograph Absorptiometry and Peripheral Quantitative Computed Tomography.

BACKGROUND: The normal interrelationship of body composition with bone health is less clear in the context of disease. Survivors of acute lymphoblastic leukemia (ALL) exhibit sarcopenic obesity and osteopenia. The impact of body composition on bone health in such survivors was examined. SUBJECTS AND METHODS: Survivors of ALL (N=74), >10 years from diagnosis, underwent dual-energy radiograph absorptiometry and peripheral quantitative computed tomography. RESULTS: Whole-body bone mineral content (WB BMC) Z scores were greater in males than females, but WB BMC indices (WB BMC/height 2 ) were comparable (0.74±0.125 and 0.72±0.069, respectively). WB BMC index (I) and fat-free mass index correlated significantly with trabecular bone mineral density, only in males. Fat mass index and appendicular lean mass index showed no such correlations. WB BMCI and fat-free mass index also correlated, again predominantly in males, with measures of strength in both trabecular and cortical bone. WB BMCI also correlated strongly with trabecular number, thickness, and hole size, also only in males. CONCLUSIONS: The results point to the need for enhancing muscle mass, measured by appendicular lean mass index, while reducing fat mass and maintaining good bone mineralization in long-term survivors of ALL to ensure the integrity of healthy bones.

Predictors of thrombosis in children receiving therapy for acute lymphoblastic leukemia: Results from Dana-Farber Cancer Institute ALL Consortium trial 05-001.

BACKGROUND/OBJECTIVES: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial. METHODS: Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival. RESULTS: Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008). CONCLUSION: We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase.

Impact of virtual care on health-related quality of life in children with diabetes mellitus: a systematic review protocol.

INTRODUCTION: Diabetes mellitus is the most common endocrine disorder in children, and the prevalence of paediatric type 1 and type 2 diabetes continue to rise globally. Diabetes clinical care programs pivoted to virtual care with the COVID-19 pandemic-driven social distancing measures. Yet, the impact of virtual care on health-related quality of life in children living with diabetes remains unclear. This protocol reports on the methods that will be implemented to conduct a systematic review to assess the health-related quality of life and metabolic health impacts of virtual diabetes care. METHODS AND ANALYSIS: We will search MEDLINE, Embase, EMCare, PsycInfo, Web of Science, and the grey literature for eligible studies. We will screen title, abstract, and full-text papers for potential inclusion and assess the risk of bias and the overall confidence in the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis will be conducted if two studies report similar populations, study designs, methods, and outcomes.This systematic review will summarise the health-related quality of life outcomes for virtual diabetes care delivery models. ETHICS AND DISSEMINATION: No ethics approval is required for this systematic review protocol as it does not include patient data. The systematic review will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42021235646.

Desmoplastic Small Round Cell Tumor With Ascending Intraspinal Metastasis at Recurrence: Case Report and Review of the Literature.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy commonly involving the abdomen and/or pelvic peritoneum. Despite aggressive therapy, the prognosis remains poor. Central nervous system relapse is rare in abdominal/pelvic primary DSRCT. OBSERVATION: We report a case of a 10-year-old female with a large pelvic DSRCT and involvement of the rectosigmoid colon and liver. Following treatment with chemotherapy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy an initial response was noted. With progressive lower limb weakness, recurrence with perineural invasion in the lumbosacral nerve root involving the conus was noted 2.5 years from diagnosis. Cerebrospinal fluid showed tumor cells with a molecular confirmation. CONCLUSIONS: Perineural invasion and ascending paralysis secondary to primary abdominal DSRCT has not been previously reported to our knowledge. We recommend a high index of suspicion for early and accurate diagnosis of this rare presentation.

Bone health in long-term survivors of pediatric acute lymphoblastic leukemia. An assessment by peripheral quantitative computed tomography.

BACKGROUND: Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may be encountered long into survivorship. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. METHODS: A sample of 74 subjects, ages 13.5-38.3 years more than 10 years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density, and architecture. RESULTS: Average values in multiple metrics were similar to those in healthy individuals, but deficits in both trabecular and cortical bones were revealed by lower Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard-risk ALL had greater connectivity in and more compact trabecular bone than high-risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation, or use of a bisphosphonate. CONCLUSIONS: These long-term survivors of ALL have somewhat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.

Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001.

PURPOSE: Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS: Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS: Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission (P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase (P = .65). CONCLUSION: Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.

Health care utilisation and costs associated with different treatment protocols for newly diagnosed childhood acute lymphoblastic leukaemia: A population-based study in Ontario, Canada.

BACKGROUND: Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared. METHODS: Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002-2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment. FINDINGS: Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1-1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5-1.7, p < 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5-1.9; p < 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase-treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients). INTERPRETATION: COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols. FUNDING: C17 Research Network.

Phase-specific risks of outpatient visits, emergency visits, and hospitalizations during Children's Oncology Group-based treatment for childhood acute lymphoblastic leukemia: A population-based study.

BACKGROUND: Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with substantial health care utilization and burden on families. Little is known about health care utilization during specific treatment phases. PROCEDURES: We identified children with ALL diagnosed during 2002-2012 in Ontario, Canada and treated according to Children's Oncology Group (COG) protocols. Disease and treatment data were chart abstracted. Population-based health care databases identified all outpatient visits, emergency department (ED) visits, and hospitalizations. In addition to comparing standard and intensified versions of treatment phases, we compared patients receiving different steroids (dexamethasone vs. prednisone) and different versions of interim maintenance (IM) (Capizzi vs. high-dose methotrexate [HD-MTX]). RESULTS: Six hundred thirty-seven children met inclusion criteria. During intensified consolidation, 76.2% of patients were hospitalized at least once, compared to only 32.3% of patients receiving standard consolidation (p < .0001). Similarly, 72.9% of patients receiving intensified delayed intensification (DI) were hospitalized during this phase compared to 50.3% of patients receiving standard DI (p < .0001). Among patients receiving a four-drug induction, those receiving dexamethasone had an 85% higher rate of ED visits (adjusted rate ratio [aRR] 1.85, 95th confidence interval [95CI] 1.14-3.00; p = .01) and a 44% higher rate of hospitalization (aRR 1.44, 95CI 1.24-1.68) compared to those receiving prednisone. Among high-risk B-ALL and T-ALL patients in IM, Capizzi MTX was not associated with an increased rate of ED visits versus HD-MTX. CONCLUSIONS: These results can be used to inform anticipatory guidance for families, particularly those undergoing intensified therapy. Our results also suggest that increased toxicity rates associated with dexamethasone during Induction seen in clinical trials reflect real-world practice.

Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP-C.

There are conflicting data about whether the development of cancer-associated thrombo-embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population-based retrospective cohort study using the Cancer in Young People-Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000-2016). The primary exposure variable was radiologically-confirmed thrombo-embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo-embolism on survival, where TE was time-dependent. We included 2006 children (median age: 4 years, 88.5% precursor B-cell ALL). Thrombo-embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35-184 days) after ALL diagnosis. Among standard/low-risk patients, 41/1165 (3.5%) developed TE while among high/very high-risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62-4.22, p < 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35-3.05, p = 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high-risk ALL (aHR of death: 2.90, 95% CI: 1.79-4.72, p < 0.001; aHR of an event: 2.02, 95% CI: 1.30-3.12, p = 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high-risk leukemia.

Genetic ancestry and skeletal toxicities among childhood acute lymphoblastic leukemia patients in the DFCI 05-001 cohort.

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms.