Adrenal Suppression in Children During the Treatment for Acute Lymphoblastic Leukemia Beyond Induction.

BACKGROUND: Adrenal suppression (AS) is an iatrogenic, life-threatening condition that can occur after glucocorticoid exposure. Despite recognition that AS occurs after induction phase treatment in children with acute lymphoblastic leukemia (ALL), the risk of AS in phases beyond induction is unknown. We conducted a pilot study in pediatric patients with ALL to ascertain whether the risk of AS persists in post-induction phases of treatment. PROCEDURE: Patients diagnosed between 12 months to younger than 18 years with B or T-ALL and starting any new phase of treatment were eligible for the study. Relapsed or infant ALL were excluded. Low dose ACTH stimulation testing (LDST), measurement of albumin and cortisol binding globulin were performed in all patients. Screening for symptoms of AS was done. RESULTS: Twenty-four patients enrolled in the study. One was diagnosed with clear AS. Five others had a borderline cortisol peak, representing possible mild AS. Symptoms were nonspecific and did not help distinguish patients with normal LDST from those with borderline or abnormal results. CONCLUSION: Patients on treatment for ALL continue to be at risk of AS beyond induction treatment. Although this risk appears small, physicians must be vigilant as patients may be asymptomatic but could develop adrenal crisis during treatment.

Hypoglycemia Associated With PEG-asparaginase and 6-MP Therapy During Treatment of Acute Lymphoblastic Leukemia in Pediatric Patients: A Case Series.

BACKGROUND: Asparaginases are a mainstay treatment for pediatric acute lymphoblastic leukemia (ALL). Recent reports identified hypoglycemia associated with asparaginases. Other reports describe hypoglycemia associated with 6-mercaptopurine (6-MP), another fundamental ALL therapy. Little is known about the risk of hypoglycemia associated with ALL therapy, an adverse event that puts children at risk of decreased level of consciousness, seizures, and possibly negative neurocognitive sequelae. METHODS: We performed a retrospective chart review of 6 children with hypoglycemia during ALL treatment in our institution from May 2016 to August 2019. Timing and duration of hypoglycemia relative to polyethylene glycol (PEG)-asparaginase, 6-MP, and corticosteroids were determined. Laboratory values of the critical sample were collected. RESULTS: The median age was 2.75 (interquartile range: 1.88 to 3.63) years. Three patients had trisomy 21. The onset of hypoglycemia was 5 to 19 days after the most recent PEG-asparaginase administration or 6 to 7 months after initiating daily 6-MP. Sixteen hypoglycemic events were documented, and 9/16 had a critical sample drawn. Six events were hypoketotic, associated with PEG-asparaginase. Three were ketotic, associated with 6-MP. Two patients required treatment with diazoxide and cornstarch. CONCLUSIONS: Hypoglycemia associated with PEG-asparaginase occurred later and lasted longer than previous reports with l-asparaginase, with the likely mechanism being hyperinsulinism. 6-MP was associated with ketotic hypoglycemia.

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.

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.

Treatment of Sinusoidal Obstruction Syndrome With Defibrotide in Pediatric Cancer Patients Following Nontransplant-associated Chemotherapy: A Case Report and Review of the Literature.

Sinusoidal obstruction syndrome (SOS), formerly veno-occlusive disease (VOD), in pediatric cancer patients often presents as a complication of hematopoietic stem cell transplantation, and less commonly secondary to nontransplant-associated chemotherapy. Therapy with defibrotide is well-described as standard care for transplant-associated SOS/VOD, but the treatment of nontransplant-associated SOS/VOD is less clear. We report a 3-year-old with relapsed Wilms tumor and recurrent SOS/VOD, with successful use of defibrotide during chemotherapy. A review of pediatric cancer patients with nontransplant-associated SOS/VOD treated with defibrotide revealed 83 patients, and 66 were in remission. This review supports early treatment with defibrotide in patients with nontransplant-associated SOS/VOD.

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.

Pediatric Oncology Clinic Care Model: Achieving Better Continuity of Care for Patients in a Medium-sized Program.

Providing the best care in both the inpatient and outpatient settings to pediatric oncology patients is all programs goal. Using continuous improvement methodologies, we changed from a solely team-based physician care model to a hybrid model. All patients were assigned a dedicated oncologist. There would then be 2 types of weeks of outpatient clinical service. A "Doc of the Day" week where each oncologist would have a specific day in clinic when their assigned patients would be scheduled, and then a "Doc of the Week" week where one physician would cover clinic for the week. Patient satisfaction surveys done before and 14 months after changing the model of care showed that patients were very satisfied with the care they received in both models. A questionnaire to staff 14 months after changing showed that the biggest effect was increased continuity of care, followed by more efficient clinic workflow and increased consistency of care. Staff felt it provided better planning and delivery of care. A hybrid model of care with a primary physician for each patient and assigned clinic days, alternating with weeks of single physician coverage is a feasible model of care for a medium-sized pediatric oncology program.

The Spectrum of Recovery From Fracture-Induced Vertebral Deformity in Pediatric Leukemia.

Vertebral fractures (VF) are a frequent complication of acute lymphoblastic leukemia. Some children with VF undergo vertebral body reshaping to the point of complete restoration of normal vertebral dimensions. Others are left with permanent vertebral deformity if the degree of reshaping has been incomplete by the time of final adult height attainment. In this report, we describe three children with painful VF at leukemia diagnosis or during chemotherapy. Each patient highlights different clinical trajectories in their recovery from VF and underscores the need for osteoporosis intervention trials with the goal to prevent permanent vertebral deformity in selected patients.

A longitudinal analysis of early lung function trajectory in survivors of childhood Hodgkin lymphoma.

BACKGROUND: Childhood Hodgkin lymphoma survivors suffer from long-term effects decades after treatment completion with a prevalence of pulmonary dysfunction of up to 65.2%. AIMS: This study explored the early trajectory of pulmonary function in pediatric cancer patients with Hodgkin lymphoma who received pulmonary toxic therapy. METHODS AND RESULTS: In this single-center, 20-year retrospective cohort study, we included patients who were <18 years old at diagnosis of Hodgkin lymphoma between January 1994 and December 2014, and received bleomycin or thoracic radiation. We measured pulmonary function and reported on percent predicted values for forced expiratory volume in 1 s, total lung capacity, and diffusing capacity of the lungs. We used linear mixed models to identify the association of clinical factors with longitudinal changes in lung function at time points before and after treatment completion. Of 80 children who met inclusion criteria, all were treated with bleomycin, and 83.8% received thoracic radiation. More than half (51.2%) of patients had any abnormalities in lung function measures during the study observation period which averaged 24.2 months (±31.1SD). Females, younger age at diagnosis and treatment with radiation were associated with lower lung function measurements at various time points. While the majority of children experienced a recovery of their lung function within 1-2 years after treatment completion, some children with these risk factors did not. CONCLUSION: Pulmonary function abnormalities begin early in children treated for Hodgkin lymphoma. While the majority of children demonstrate a slow and continuous improvement in lung function back to baseline over time, we recommend routine asymptomatic screening of pulmonary function in certain childhood cancer survivors, particularly females, those diagnosed young and patients who received radiation therapy.

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.

Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932.

PURPOSE: AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL). METHODS: AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m2 (MTX20) or 40 mg/m2 (MTX40). RESULTS: Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) v 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively (P = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) v 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively (P = .92 and .89). CONCLUSIONS: The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m2/week did not improve outcomes when compared with 20 mg/m2/week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors.

BACKGROUND: Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES: This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS: Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10-15). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS: Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778).

Ecthyma Gangrenosum: Vulvar Ulcers, Pseudomonas, and Pancytopenia: A Case Report of an 18-Month-Old Female Toddler.

BACKGROUND: An 18-month-old female toddler presented with severe vulvar ulcers and pancytopenia with investigations revealing Pseudomonas aeruginosa bacteremia. CASE: A previously healthy 18-month-old female toddler presented with 6 days of fevers, vulvar rash, and ulcers. Vulvar cultures showed Staphylococcus aureus and P aeruginosa. Bloodwork showed pancytopenia and P aeruginosa bacteremia. She started receiving broad-spectrum antibiotics. Bone marrow aspirate revealed a hypocellular marrow with erythroid dysplasia. Vulvar ulcers progressed rapidly, therefore magnetic resonance imaging was performed to rule out necrotizing fasciitis. She was diagnosed with ecthyma gangrenosum (EG). Three months after initial presentation, she was diagnosed with precursor B-cell acute lymphoblastic leukemia. SUMMARY AND CONCLUSION: This case highlights that health care providers should suspect EG when severe vulvar ulcers are present with P aeruginosa infection and neutropenia. Because EG poses significant morbidity and mortality, its presence should prompt aggressive antimicrobial therapy and mobilization of a multidisciplinary team to initiate workup for an underlying immunodeficiency syndrome or malignancy. This case also illustrates that surgical debridement might be avoided in certain patients with EG as long as meticulous wound care and close monitoring with a multidisciplinary team are in place.

Delayed diagnosis in an adolescent with a malignant testicular tumour.

Feelings of embarrassment and fear in adolescents may contribute substantially to a delay in the diagnosis of malignant tumours arising from the genital region, with subsequent increase in morbidity and mortality. A case of a 15-year-old boy who had multiple visits to physicians with complaints of recurrent lower abdominal and back pain is presented in the current case report. He refused examination of his genital area during all visits, stating that there were no problems. The patient was admitted to the hospital with a working diagnosis of lymphoma after finding an abdominal mass and a neck mass. During bone marrow aspiration, while the patient was sedated, a large testicular mass was discovered. Each time the patient had been examined, he refused a genital examination and denied any change in the genital region.

Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

PURPOSE: To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer. PATIENTS AND METHODS: Subsequent malignant neoplasm history was determined in 13,136 participants (surviving > or = 5 years postmalignancy, diagnosed from 1970 to 1986 at age < 21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data. RESULTS: In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkin's lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9). CONCLUSION: Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to risk.

Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952.

BACKGROUND: Patients with Down syndrome (DS) and standard risk (SR) acute lymphoblastic leukemia (ALL-DS) are reported to have inferior event free (EFS) and overall survival (OS) compared to patients without DS (ALL-NDS). PROCEDURE: We compared the prevalence of favorable and unfavorable clinical and biologic features, toxicity and outcome within the ALL-DS and ALL-NDS cohorts of 2,174 eligible patients with SR-ALL enrolled on CCG-1952. RESULTS: Fifty-nine patients (3%) had ALL-DS. DS patients were less likely to have either favorable (hyperdiploidy, triple trisomy of chromosomes 4, 10, and 17, TEL-AML1 rearrangement) or unfavorable (T-cell ALL, hypodiploidy, adverse translocations) biologic features. Toxicity occurred significantly more often and number of days hospitalized was significantly greater in ALL-DS than in ALL-NDS. ALL-DS patients had an inferior 4-year EFS compared to the NDS cohort. However, EFS was equivalent when the comparison excluded ALL-NDS with favorable biologic features. OS was significantly inferior for ALL-DS. CONCLUSIONS: The absence of favorable biologic features within ALL-DS contributes to the difference in EFS previously observed between DS and NDS SR-ALL cohorts.