Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries.

OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

Impact of the COVID-19 pandemic on utilization and cost for care of pediatric and young adult ALL.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and among the most common malignancies in young adults and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood and young adult ALL in regard to utilization and cost of care among commercially insured individuals in the United States. RESULTS: Utilizing a commercial insurance claims database, 529 pediatric and young adult patients were identified who were diagnosed with ALL between January 2016 and March 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost during the initial 8 months of therapy. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric and young adult ALL was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic's impact on health equity and access to care, especially in vulnerable pediatric and young adult populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric and young adult cancer.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

MRD at the end of induction and EFS in T-cell lymphoblastic lymphoma: Children's Oncology Group trial AALL1231.

ABSTRACT: Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children's Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

HLH Syndrome in a Community Hospital: The Challenge of an Early Diagnosis.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory cytokine storm. It can be secondary to infections, malignancies, autoimmune diseases, or the manifestation of genetic disorders, including primary immune deficiency. HLH requires a high index of suspicion and is challenging for community hospitals. Methods: Medical records of children with HLH admitted to the Meir Medical Center in Israel between 2014 and 2017 were reviewed. Results: Nine children met ≥5/8 HLH-2004 criteria. The median age was 1.1 year, and 78% of the patients were aged <2 years. All patients had prolonged fever, cytopenia, and elevated soluble interleukin-2 receptor, and 89% had elevated ferritin levels. Of three children who underwent gene panel evaluation, one had heterozygote genetic variants of UNC13D and STXBP2 of unclear significance, whereas the other two had no variants. Infection was identified in 8 of 9 patients: adenovirus, HHV6, EBV, and Streptococcus Group A. Only 2 patients received HLH-2004 therapy (dexamethasone, etoposide, cyclosporin-A) and the others received dexamethasone and/or intravenous gamma globulins (IVIG), with rapid resolution of fever (median 2 days). One patient (11%) died of Pseudomonas septicemia and multiorgan failure. At a median follow-up of 7 years (range 2.6-8.1 years), all others (8/9) are long-term survivors with no recurrent HLH, but 2 patients developed adenovirus-related bronchiolitis obliterans. Conclusion: Children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin, triglycerides, and fibrinogen levels which indicate possible HLH. Early intervention with corticosteroids and/or IVIG may prevent deterioration, spare them from chemotherapy and provide time for more elaborate testing to identify true HLH. Unfortunately, mortality remains a significant risk for these children.

In the emergency department, children with common infections may have a severe complication called Hemophagocytic Lymphohistiocytosis or HLH. HLH can be life threatening if not rapidly recognized. HLH is rare and challenging for doctors in community hospitals. We describe nine patients who presented to a community hospital who were later diagnosed with HLH, posing a dilemma for physicians. Most (78%) were less than 2 years, all had prolonged fever, abnormal blood counts, elevated marker of HLH called soluble interleukin­2 receptor and 8 of 9 had elevated ferritin, which can be a marker of HLH. HLH could be genetic therefore three children had genetic studies, with one having minor abnormalities, but the contribution to HLH is unclear. Infection as cause for HLH was identified in 8 of 9 patients. Chemotherapy that is used for severe HLH was required for 2 patients and the others received steroids and/or intravenous gamma globulin with rapid improvement. One patient who received chemotherapy and had suppressed immunity died of a severe bacterial infection. Others (8 of 9) are long-term survivors with no evidence of recurrent HLH. Two patients developed a pulmonary complication from adenovirus known as bronchiolitis obliterans. We conclude that children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin and other markers of possible HLH. Early intervention may prevent deterioration, may spare them from chemotherapy, and allow further assessment of true HLH. However, the death of one (11%), demonstrates the significant risks to these children.

Healthcare cost and utilization for chimeric antigen receptor (CAR) T-cell therapy in the treatment of pediatric acute lymphoblastic leukemia: A commercial insurance claims database analysis.

BACKGROUND: B-lineage acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. With the introduction of novel cellular therapies, cost of care is a critical component and the financial burden experienced by patients and society requires evaluation. AIMS: This study aims to assess the utilization and cost of care for chimeric antigen receptor T-cell (CAR-T) therapy for pediatric ALL patients with commercial insurance coverage in the United States. METHODS AND RESULTS: Using de-identified commercial insurance data from the OptumLabs® Data Warehouse, a cohort of 37 patients, aged 1-25 years, with B-ALL treated with CAR-T therapy between Oct 2016 and Dec 2021 in the United States was identified. Cost was evaluated for a 90 day period encompassing CAR-T infusion and by administration and complication characteristics. Among the 37 identified B-ALL patients that received a CAR-T product infusion, 14 patients were female, median age at administration was 13 years. The median 90-day total cost was $620,500 (Mean: $589,108). Inpatient cost accounted for approximately 71% of the total cost with an average of 28 inpatient days per patient. Although inpatient cost was slightly higher in the older age group (aged 10-25 years) and in patients with a code for cytokine release syndrome (CRS), these differences were not statistically significant. CONCLUSION: This real-world cost analysis shows for the first time the encompassing cost of CAR-T therapy for pediatric B-ALL patients in the US with commercial insurance. This study provides a valuable benchmark that can be used to analyze the financial implications of CAR-T therapy for pediatric B-ALL therapy on health systems.

Assessing the role of positron emission tomography and bone scintigraphy in imaging of pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography (PET) and bone scintigraphy (bone scans) in diagnostic evaluation and surveillance has not been documented to date. Available PET and bone scan data are presented in this study. PROCEDURES: Patients with PPB enrolled in the International PPB/DICER1 Registry and available PET imaging and/or bone scan reports were retrospectively abstracted. RESULTS: On retrospective analysis, 133 patients with type II and III (advanced) PPB were identified with available report(s) (PET scan only = 34, bone scan only = 83, and both bone scan and PET = 16). All advanced primary PPB (n = 11) and recurrent (n = 8) tumors prior to treatment presented with 18 F-fluorodeoxyglucose (FDG)-avid lesions, with median maximum standardized uptake values of 7.4 and 6.7, respectively. False positive FDG uptake in the thorax was noted during surveillance (specificity: 59%). Bone metastases were FDG-avid prior to treatment. Central nervous system metastases were not discernable on PET imaging. Sensitivity and specificity of bone scans for metastatic bone disease were 89% and 92%, respectively. Bone scans had a negative predictive value of 99%, although positive predictive value was 53%. Four patients with distant bone metastases had concordant true positive bone scan and PET. CONCLUSION: Primary, recurrent, and/or extracranial metastatic PPB presents with an FDG-avid lesion on PET imaging. Additional prospective studies are needed to fully assess the utility of nuclear medicine imaging in surveillance for patients with advanced PPB.

Utilization and Cost of Outpatient Rehabilitation Services for Pediatric Patients Treated for Acute Lymphoblastic Leukemia Using a Commercial Claims Database.

OBJECTIVE: To investigate the temporal trends and factors associated with outpatient rehabilitation utilization and costs for pediatric acute lymphoblastic leukemia (ALL). DESIGN: Deidentified administrative claims data and longitudinal health information on patients representing a mixture of ages, ethnicities, and geographic regions across the United States were accessed using Optum Labs Data Warehouse. Regression models were constructed to assess associations of outpatient rehabilitation with age, sex, race and ethnicity, year of diagnosis, and region. SETTING: Outpatient rehabilitation. PARTICIPANTS: 1000 Patients aged 1-30 years with a new diagnosis of ALL between 1993 and 2017 and continuous insurance coverage (N=1000). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Outpatient rehabilitation service utilization and cost based on reimbursed charge codes, summarized over 36 months after cancer diagnosis. RESULTS: In 1000 patients, utilization of outpatient rehabilitation services increased from 20% in 1993-2002 to 55% in 2013-2017. In the earliest era examined, physical and/or occupational therapy was provided to 18% and increased to 54% in the latest years. Speech service utilization remained between 5%-8% across timepoints. Inflation-adjusted cost for provision of services did not change significantly across time and remained low, accounting for a median of 1.3% (Q1, Q3 0.3, 3.4) of total treatment cost in 1993-2002 and decreasing to a median 0.4% (Q1, Q3, 0.1, 1.0) in 2013-2017. Age 1 to 5 years at ALL diagnosis was associated with increased rehabilitation visit number and cost, and treatment in the Midwest was associated with increased likelihood of outpatient rehabilitation service utilization compared to other geographic regions. CONCLUSIONS: Outpatient rehabilitation services are being increasingly provided to patients with ALL at a relatively low cost per patient, yet geographic variability in care utilization is evident. These services do not add excessively to the overall cost of leukemia care and thus cost containment should not be an excuse to limit access.

Health-related quality of life in children and adolescents with pleuropulmonary blastoma: A report from the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood and is associated with germline DICER1 variants. Type I and Ir PPB are cystic lesions treated surgically, with a subset of children with type I receiving chemotherapy. Type II and III are more aggressive lesions, treated with surgery, intensive chemotherapy and potentially radiation. We sought to assess health-related quality of life (HRQoL) in children with PPB and known germline DICER1 variants. METHODS: Children with a diagnosis of PPB or germline DICER1 pathogenic variant without history of PPB or other DICER1-related neoplasm (DICER1+ only) were enrolled in the International PPB/DICER1 Registry. Parent reports for participants aged 2-17 years for the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 were collected. Fatigue, physical, and psychosocial function scores were compared. RESULTS: Analysis included 84 participants (PPB type Ir = 20, type I = 15, type II/III = 27, DICER1+ only = 22). Total fatigue scores of participants with type I and II/III PPB were lower compared to DICER1+ only, with effect size larger in type II/III (-0.82 vs. -0.40). Total psychosocial and physical functioning scores were lower in participants with type I and type II/III PPB compared to DICER1+ only, with larger effects noted in type II/III. Female sex was suggestive of worse HRQoL for both type I/Ir and type II/III cohorts. CONCLUSIONS: These data demonstrate the importance of regular HRQoL assessment in patients with a history of PPB as well as the importance and feasibility of studying HRQoL in children with rare tumors.

Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. CONCLUSIONS: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.

Effect of Prearrival Orders on Time to Antibiotics for Immunocompromised Oncology Patients Presenting to the Emergency Department With Fever.

OBJECTIVE: Pediatric cancer patients with fever are at risk for invasive bacterial infection. The administration of antibiotics to these patients within the first hour of evaluation is viewed as a quality of care metric with potential to improve outcome. We sought to evaluate the impact of prearrival patient orders on the timeliness of antibiotic administration for this patient population presenting to the emergency department (ED) because of fever. METHODS: A single-site pediatric ED intervention study was performed. Four hundred thirty-nine consecutively referred febrile immunocompromised pediatric oncology patients were included in the study. The intervention used structured monthly messages sent to oncology and emergency medicine providers highlighting specific roles in prehospital communication and in ED-based care emphasizing the use of standardized, prearrival order (PAO) sets. Primary outcome measures were time to antibiotic administration (TTA) and the proportions of patients receiving PAO placement and antibiotics within 60 minutes of ED arrival. Results were analyzed for the preintervention (September 2016-July 2017), intervention (August 2017-February 2018), and postintervention (March-December 2018) periods. RESULTS: Improvements occurred across the study periods in the proportion of patients with PAO placement (preintervention, 68%; intervention, 82%; postintervention, 87%; P = 0.001) as well as in the percentages of patients receiving antibiotics in less than 60 minutes (preintervention, 73%; intervention, 84%; postintervention, 85%; P = 0.02). Median TTA decreased from 48 to 40 minutes ( P = 0.018). Linear regression with TTA as a dependent variable revealed that PAO placement predicted a shorter TTA, decreasing by more than 15 minutes ( B = -15.90; [95% confidence interval, -20.03--11.78]; P < 0.001). CONCLUSIONS: Standardizing elements of prehospital communication and ED-based care using PAO sets resulted in significant improvements in time to antibiotics and in the proportion of febrile immunocompromised oncology patients receiving antibiotics within 60 minutes of ED arrival.

Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy: A Report From the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS: Patients with known or suspected PPB were enrolled in the International PPB/DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

Impact of the COVID-19 Pandemic on Utilization and Cost for Care of Pediatric ALL.

Objective: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood ALL in regard to utilization and cost of care. Results: Utilizing a commercial insurance claims database, 529 pediatric patients were identified who were diagnosed with ALL and completed their initial 8 months of treatment between January 2016 and December 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric ALL is largely inflexible and was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic's impact on health equity and access to care, especially in vulnerable pediatric populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric cancer.

Real-World Cost of Pediatric Acute Lymphoblastic Leukemia Care Among Commercially Insured Individuals in the United States: Effect of Era and Age at Diagnosis.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Five-year survival is approaching 90%. In efforts to further improve outcomes, it is critical to consider the cost of ALL care. MATERIALS AND METHODS: Commercial insurance data from OptumLabs Data Warehouse were used to identify patients with ALL, age 1-30 years, diagnosed in 1993-2017 in the United States, with 36 months of continuous insurance coverage. Patients treated with hematopoietic cell transplantation were excluded. Inpatient and outpatient utilization and cumulative reimbursements (inflation-adjusted to December 2020) were computed 8 and 36 months from diagnosis and stratified by age (1-9, 10-12, and ≥ 13 years) as proxies for National Cancer Institute risk groups. Regression models were constructed to assess associations with demographic and clinical characteristics. RESULTS: Among 927 patients (median age, 6 years; interquartile range, 3-12 years; 43% female), individuals age ≥ 10 years had 23-25 more inpatient days and 22 more outpatient encounters compared with younger patients. The 36-month median cost was $394,000 (USD) (interquartile range, $256,000-$695,000 [USD]), and 64% of the total cost was incurred during the initial 8 months. The 36-month cost was 1.5-fold higher for those age 10-12 years and 1.7-fold higher for those age ≥ 13 years compared with 1-9 years. The cost for those diagnosed in 2013-2017 was 70% higher compared with 1993-2002, and was not different on the basis of sex, race, or ethnicity. CONCLUSION: Older age was associated with higher utilization and cost, and the cost of treatment increased significantly over time. These data provide valuable benchmarks for future studies examining the cost-benefit of ALL therapy modifications.

Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR).

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m2 /day and cyclophosphamide at 330-400 mg/m2 /day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3 weeks, were nelarabine 650 mg/m2 /day, etoposide 100 mg/m2 /day, and cyclophosphamide 400 mg/m2 /day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.

Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.

PURPOSE: To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS: Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS: AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600). CONCLUSION: Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

A natural history study of nitrous oxide versus propofol-assisted intrathecal therapy in the treatment of acute lymphoblastic leukemia.

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) treatment requires numerous lumbar punctures (LPs) with intrathecal (IT) chemotherapy to prevent and treat central nervous system disease. Historically, LPs in this setting are performed using propofol sedation at most institutions. At our center, LPs are often alternatively performed under nitrous oxide (N2 O). To date, there have been no large-scale assessments comparing these sedation methods for this purpose. PROCEDURES: Retrospective cohort study of patients aged 0-31 years with ALL treated between January 1, 2013 and December 31, 2018 at the Children's Minnesota Cancer and Blood Disorders Center, including all therapeutic LPs performed in the clinic setting under either propofol or N2 O. RESULTS: Among 215 patients and 2677 therapeutic LPs, 56.6% (n = 1515) occurred under N2 O, with 43.3% (n = 93) of patients using exclusively N2 O with all LPs. The incidence of traumatic LPs (red blood cell [RBC] ≥10 cells/µl) was similar between both treatments (27.3% vs. 30.2%). Successful IT chemotherapy delivery (99.7% N2 O vs. 99.8% propofol) did not differ between sedation types. Experiencing a traumatic LP under N2 O was associated with a sedation switch for the subsequent LP (adjusted odds ratio [aOR] 2.40, p = .002), whereas older age (aOR 1.08, p < .0001) and higher body mass index (BMI) percentile (aOR 1.01, p = .009) were associated with increased likelihood for undergoing a traumatic LP. CONCLUSION: N2 O is an effective sedation option for therapeutic LPs in children with ALL with noninferiority to propofol in terms of IT chemotherapy administration and traumatic LP incidence. For many patients, N2 O can effectively replace propofol during LP procedures, which has important safety and quality-of-life implications.

Thoracic Sertoli-Leydig cell tumor: An alternative type of pleuropulmonary blastoma associated with DICER1 variation.

A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl.