Race and Ethnic Group Enrollment and Outcomes for Wilms Tumor: Analysis of the Current Era Children's Oncology Group Study, AREN03B2.

BACKGROUND: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. STUDY DESIGN: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. RESULTS: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. CONCLUSIONS: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.

Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children.

PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.

Treatment of children with favorable histology Wilms tumor with extrapulmonary metastases: A report from the COG studies AREN0533 and AREN03B2 and NWTSG study NWTS-5.

BACKGROUND: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD-4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS-5, were reviewed. METHODS: Combined outcomes for patients with EPM from NWTS-5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS-5. Prognostic factors were explored in the pooled cohort. RESULTS: Forty-seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS-5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4-year event-free survival (EFS) of 77.3% (95% CI, 70.8-84.4) and 4-year overall survival of 88.9% (95% CI, 83.9-94.2). Four-year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6-89.4) vs 64.9% (95% CI, 51.7-82.2) on NWTS-5; hazard ratio, 0.64, p = .26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort. CONCLUSIONS: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611.

Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy.

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Complete resolution of alopecia totalis following chemotherapy for B-cell acute lymphoblastic leukemia.

Alopecia totalis (AT) is a cosmetically debilitating chronic disease characterized by non-scarring hair loss of the entire scalp. The clinical course of AT is highly unpredictable, and effective durable treatment options are limited. The resolution of alopecia has been reported post-autologous and allogeneic hematopoietic stem cell transplantation; however, no cases of AT remission following chemotherapy alone have been described. Herein, we present a case of complete remission of AT following chemotherapy for B-cell acute lymphoblastic leukemia in a pediatric patient.

Impact of the First Generation of Children's Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor.

Refinements in surgery, radiation therapy, and chemotherapy since the mid-20th century have resulted in a survival rate exceeding 90% for patients with Wilms tumor (WT). Although this figure is remarkable, a significant proportion of patients continue to have event-free survival (EFS) estimates of <75%, and nearly 25% of survivors experience severe chronic medical conditions. The first-generation Children's Oncology Group (COG) renal tumor trials (AREN '0'), which opened to enrollment in 2006, focused on augmenting treatment regimens for WT subgroups with predicted EFS <75% to 80%, including those with the adverse prognostic marker of combined loss of heterozygosity (LOH) at chromosomes 1p/16q, pulmonary metastasis with incomplete lung nodule response after 6 weeks of chemotherapy, bilateral disease, and anaplastic histology. Conversely, therapy was reduced for patient subgroups with good outcomes and potential for long-term toxicity, such as those with lung metastasis with complete lung nodule response after 6 weeks of chemotherapy. This article summarizes the key findings of the first-generation COG renal tumor studies and their implications for clinical practice.

Association between in-line filtration and Type I hypersensitivity reactions in pediatric oncology patients receiving intravenous etoposide.

The objective of this study was to describe hypersensitivity reactions with and without the use of in-line filters during intravenous etoposide therapy in pediatric oncology patients. This was a retrospective review of all patients treated in the Division of Oncology/Hematology/Bone Marrow Transplant at British Columbia Children's Hospital with intravenous etoposide between December 1, 2013 and February 1, 2018. Hypersensitivity reactions and anaphylaxis associated with etoposide infusions were compared over time, including 12 months prior to, 27 months during the use of, and for 12 months after the discontinuation of in-line filtration. There were 192 patients (median age 6.0 (IQR 2.8-13.0) years treated with etoposide and 486 etoposide infusions including 137 (28%) before, 261 (54%) during and 88 (18%) after use of in-line filters at our center. Twenty-six of 486 (5%) and 13/486 (3%) of infusions resulted in a type I hypersensitivity reaction and anaphylaxis, respectively. There were 2/137 (1%), 36/261 (14%) and 1/88 (1%) infusion reactions prior to, during and after in-line filter use, respectively. Infusion reactions during the in-line filter period were higher than during the pre-filter (Z = 3.978; p < 0.001) and post-filter (Z = 3.335; p < 0.001) periods of the study. These data suggest that the use of in-line filtration may be associated with increased frequency of hypersensitivity reactions to etoposide in pediatric cancer patients.

Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report.

PURPOSE: In National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy. METHODS: Patients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies. RESULTS: LOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%). CONCLUSION: Augmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Impact of Vertebral Fractures and Glucocorticoid Exposure on Height Deficits in Children During Treatment of Leukemia.

Objective: To assess the effect of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL). Methods: Children with ALL treated without cranial radiation therapy (n = 160; median age, 5.1 years; 58.1% male) were followed prospectively for 6 years. Spinal deformity index (SDI) was used to quantify VF status. Results: Baseline height z score ± SD was 0.3 ± 1.2. It fell by 0.5 ± 0.4 in the first 6 months for boys and by 0.4 ± 0.4 in the first 12 months for girls (P < 0.01 for both) and then subsequently recovered. The prevalence of VF peaked at 1 year (17.6%). Among those with VF, median SDI rose from 2 [interquartile range (IQR): 1, 7] at baseline to 8 (IQR: 1, 8) at 1 year. A mixed model for repeated measures showed that height z score declined by 0.13 (95% CI: 0.02 to 0.24; P = 0.02) for each 5-unit increase in SDI during the previous 12 months. Every 10 mg/m2 increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height z score decrement of 0.26 (95% CI: 0.20 to 0.32; P < 0.01). Conclusions: GC likely plays a major role in the observed height decline during therapy for ALL. Because only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the subset with VF.

Bone Morbidity and Recovery in Children With Acute Lymphoblastic Leukemia: Results of a Six-Year Prospective Cohort Study.

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.

Treatment of Stage IV Favorable Histology Wilms Tumor With Lung Metastases: A Report From the Children's Oncology Group AREN0533 Study.

Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

Successful umbilical cord blood hematopoietic stem cell transplantation in pediatric patients with MDS/AML associated with underlying GATA2 mutations: two case reports and review of literature.

Germline GATA2 mutations have been associated with a vast array of clinical manifestations, as well as hematological deficiencies and a propensity to AML or MDS. We present two cases of pediatric AML/MDS with underlying GATA2 mutations who underwent a successful umbilical cord hematopoietic stem cell transplantation using two different conditioning regimens. These cases illustrate the importance of recognizing the clinical features associated with GATA2 mutations and performing the appropriate molecular testing. Diagnosis of heritable gene mutations associated with familial AML/MDS has significant clinical implication for the patients and affected families.

A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy.

BACKGROUND: Megestrol acetate (MA) is an appetite stimulant with efficacy in promoting weight gain in adults with cancer-associated anorexia-cachexia. Studies documenting MA efficacy in children, however, are limited. We present the first randomized, double-blind, placebo-controlled clinical trial of MA versus placebo in children with cancer and weight loss. METHODS: Subjects <18 years of age with weight loss (minimum 5% from highest previous weight; or %ideal body weight <90%) due to cancer and/or cancer therapy were randomized to either MA (7.5 mg/kg/day) or placebo for a planned study duration of 90 days. Primary outcome was the difference between groups in mean percent weight change from beginning to end of the study period. Secondary outcomes included effects on anthropometrics, body composition, need for tube feeding or parenteral nutrition, and toxicities. RESULTS: Twenty-six patients were randomly assigned (13 MA, 13 placebo). The MA group experienced a mean weight gain of +19.7% compared to a mean weight loss of -1.2% in the placebo group, for a difference of +20.9% (95%CI: +11.3% to +30.5%, P = 0.003) in favor of MA over placebo. MA subjects experienced significant increases in weight for age z-scores, body mass index z-scores, and mid upper arm circumference compared to placebo. DXA scanning suggested disproportionate increases in fat accrual. Adrenal suppression was the main toxicity of MA. CONCLUSION: In children with high-risk malignancies, MA resulted in significant increases in mean percent weight change compared to placebo. Further studies of MA should be pursued to better delineate the effect on nutritional status.

Children's Oncology Group's 2013 blueprint for research: renal tumors.

Renal malignancies are among the most prevalent pediatric cancers. The most common is favorable histology Wilms tumor (FHWT), which has 5-year overall survival exceeding 90%. Other pediatric renal malignancies, including anaplastic Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal cell carcinoma, have less favorable outcomes. Recent clinical trials have identified gain of chromosome 1q as a prognostic marker for FHWT. Upcoming studies will evaluate therapy adjustments based on this and other novel biomarkers. For high-risk renal tumors, new treatment regimens will incorporate biological therapies. A research blueprint, viewed from the perspective of the Children's Oncology Group, is presented.

Rasch analysis of the PedsQL: an increased understanding of the properties of a rating scale.

OBJECTIVE: Traditionally, measures have been developed using classical test theory (CTT). This study examines the psychometrics of the PedsQL 4.0 Generic Core Scales (parent report) using a modern psychometric approach (i.e., Rasch analysis) to determine if further insight regarding the behavior of the measure can be gained using a modern approach. STUDY DESIGN AND SETTING: Data from a Canadian study of 376 parents of children aged 2-17 years on active cancer treatment were analyzed using Rumm2030 software (RUMM Laboratory, Australia). RESULTS: Overall data did not fit the Rasch model and indicated important limitations in the PedsQL including disordered item thresholds, local dependency, and poor targeting. The internal consistency was higher using CTT (Cronbach's α=0.93) than Rasch (Person Separation Index=0.78). Rasch item curves showed that respondents did not discriminate between the five-point response categories and a three-point scale was easier to discriminate. CONCLUSIONS: The PedsQL is the most widely used generic measure of health-related quality of life in pediatrics. The use of Rasch allows detailed item-level evaluation and assists in identifying limitations of measures that could then be further explored. Studies are needed in other populations to better understand the behavior of the PedsQL from a modern psychometric perspective.

High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy.

PURPOSE: Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. PATIENT AND METHODS: We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures. RESULTS: Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006). CONCLUSION: Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.