B-Lymphoblastic Lymphoma in Children: A Case Series From a Single Institution.

BACKGROUND: Pediatric B-lymphoblastic lymphoma is an uncommon subtype of non-Hodgkin lymphoma. Studies regarding the biology, clinical course, and approach to relapse are limited. OBSERVATIONS: We present a series of children with B-lymphoblastic lymphoma to describe the clinical course at diagnosis and relapse as well as the role of tumor cytogenetics, immunotherapy, and hematopoietic stem cell transplant. CONCLUSIONS: The prognostic significance of cytogenetic changes in B-lymphoblastic lymphoma is not well described but may offer improved risk stratification. Immunotherapy may offer salvage options for relapsed disease and can serve as a bridge to transplant.

Outcomes of children treated for multiple Epstein-Barr virus-associated post-transplant tumors.

BACKGROUND: After solid organ transplantation, children are at risk for Epstein-Barr virus-associated post-transplant lymphoproliferative disorder and smooth muscle tumors. Little is known about the clinical course, Epstein-Barr viral load variations, and optimal treatment for such patients. We set forth to understand the course of repeated episodes of post-transplant lymphoproliferative disorder and smooth muscle tumors. METHODS: We performed a retrospective chart review of patients up to 21 years old with solid organ transplantation and post-transplant lymphoproliferative disorder at the Children's Hospital of Philadelphia from January 2003 through June 30, 2020. RESULTS: Six patients had multiple episodes of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder and smooth muscle tumors. When the second episode was discovered, only one patient was symptomatic. Histology differed from diagnosis in four patients. Treatment included viral-specific T-lymphocytes (2), rituximab (3), reduction in immunosuppression alone (1). Five patients had complete response, and one had stable disease, but three patients developed a subsequent tumor. Two patients developed Epstein-Barr virus-associated smooth muscle tumors. Of these six patients, four are alive. The deaths were not related to their tumors. CONCLUSIONS: Despite a complete response to initial therapy, children are at risk for repeated episodes of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder and smooth muscle tumors. Histology and location were not typically consistent with initial diagnosis, suggesting these are second primaries rather than recurrences. Disease may be managed with individualized treatment plans but EBV-specific T cells need further study in such tumors.

Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children's Oncology Group Trial ANHL12P1.

PURPOSE: Arm crizotinib (CZ) of the Children's Oncology Group trial ANHL12P1 (ClinicalTrials.gov identifier: NCT01979536) examined the efficacy and toxicity of adding CZ to standard chemotherapy for children with newly diagnosed, nonlocalized ALK+ CD30+ anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: Between 2013 and 2019, 66 enrolled children received CZ with chemotherapy. Patients received a 5-day prophase followed by six chemotherapy cycles at 21-day intervals with CZ administered twice daily during each 21-day cycle. The study was temporarily closed for two periods (total 12 months) to evaluate toxicity, during which CZ was discontinued. Measurements of NPM-ALK fusion transcripts in peripheral blood were performed at diagnosis for minimal disseminated disease (MDD). RESULTS: The 2-year event-free survival (EFS) is 76.8% (95% CI, 68.5 to 88.1) and the 2-year overall survival is 95.2% (95% CI, 85.7 to 98.4). Fifteen patients relapsed and one patient died; median time to relapse was 7.4 months from diagnosis, with relapses occurring after chemotherapy was complete. The 66 patients completed 384 cycles of chemotherapy. Thirteen of the 66 patients experienced a grade 2+ thromboembolic adverse event (19.7%; 95% CI, 11.1 to 31.3). In the 25 patients who received mandated prophylactic anticoagulation, there were two thromboembolic events (8.0%; 95% CI, 0.01 to 26). Patients with negative MDD had a superior outcome, with an EFS of 85.6% (95% CI, 68.6 to 93.8); positive MDD was associated with a lower EFS of 58.1% (95% CI, 33.4 to 76.4). CONCLUSION: Arm CZ of ANHL12P1 demonstrated that the addition of CZ to standard treatment prevented relapses during therapy for children with ALCL, MDD predicted EFS, and the addition of CZ resulted in unexpected thromboembolic events. Overall survival and EFS rates are consistent with the highest reported outcomes for children with ALCL.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Guideline for Children With Cancer Receiving General Anesthesia for Procedures and Imaging.

Children with cancer and those undergoing hematopoietic stem cell transplantation frequently require anesthesia for imaging as well as diagnostic and therapeutic procedures from diagnosis through follow-up. Due to their underlying disease and side effects of chemotherapy and radiation, they are at risk for complications during this time, yet no published guideline exists for preanesthesia preparation. A comprehensive literature review served as the basis for discussions among our multidisciplinary panel of oncologists, anesthesiologists, nurse practitioners, clinical pharmacists, pediatric psychologists, surgeons and child life specialists at the Children's Hospital of Philadelphia. Due to limited literature available, this panel created an expert consensus guideline addressing anesthesia preparation for this population.

Improving Guideline-Congruent Care for Chemotherapy-Induced Nausea and Vomiting Prophylaxis in Pediatric Oncology Patients.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a very common side effect of pediatric cancer therapy. High-quality, evidence-based, pediatric-specific guidelines for prophylaxis and treatment of CINV are available. At many centers, guideline-concordant care is uncommon. We formed a multidisciplinary quality improvement team to implement guideline-concordant care for CINV prophylaxis at our center. We present the results following the first year of our interventions. METHODS: We planned and implemented a multipronged approach in three key phases: (1) developing and publishing an acute CINV prophylaxis pathway, (2) education of providers, and (3) updating the computerized provider order entry system. We used iterative, sequential Plan-Do-Study-Act cycles and behavioral economic strategies to improve adherence to guideline-concordant CINV prophylaxis. We focused on aprepitant usage as a key area for improvement. RESULTS: At the beginning of the study period, < 50% of patients were receiving guideline-concordant CINV prophylaxis and < 15% of eligible patients were receiving aprepitant. After 1 year, more than 60% of patients were receiving guideline-concordant care and 50% of eligible patients were receiving aprepitant. CONCLUSION: We describe the development and implementation of a standardized pathway for prevention of acute CINV in pediatric oncology patients. With a multidisciplinary, multifaceted approach, we demonstrate significant improvements to guideline-congruent CINV prophylaxis.

Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1.

Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Complete resolution of primary cutaneous marginal zone B-cell lymphoma on the cheek of a 7-year-old boy with intralesional triamcinolone and tincture of time.

A 7-year-old healthy boy presented with an asymptomatic smooth, firm red plaque on the cheek. Histopathology, immunostaining, molecular testing and imaging confirmed a diagnosis of a primary cutaneous marginal zone B-cell lymphoma. The lesion was treated with intralesional triamcinolone, with complete clinical resolution achieved within one year. Intralesional steroid injection is an effective first-line modality for the treatment of patients with limited disease in cosmetically sensitive areas.

Creation of a pediatric mature B-cell non-Hodgkin lymphoma cohort within the Pediatric Health Information System Database.

Mature B-cell non-Hodgkin lymphoma (B-NHL) constitutes a collection of relatively rare pediatric malignancies. In order to utilize administrative data to perform large-scale epidemiologic studies within this population, a two-step process was used to assemble a 12-year cohort of B-NHL patients treated between 2004 and 2015 within the Pediatric Health Information System database. Patients were identified by ICD-9 codes, and their chemotherapy data were then manually reviewed against standard B-NHL treatment regimens. A total of 1,409 patients were eligible for cohort inclusion. This process was validated at a single center, utilizing both an institutional tumor registry and medical record review as the gold standards. The validation demonstrated appropriate sensitivity (91.5%) and positive predictive value (95.1%) to allow for the future use of this cohort for epidemiologic and comparative effectiveness research.

The impact of dexamethasone and prednisone on sleep in children with acute lymphoblastic leukemia.

PURPOSE: Corticosteroids can affect sleep patterns, mood, and behavior. Two of the most commonly prescribed corticosteroids in acute lymphoblastic leukemia (ALL), dexamethasone and prednisone, may impact sleep differently, but no research has compared these medications in children. The current study tested the hypothesis that dexamethasone and prednisone differentially affect sleep in children with ALL to understand how these medications contribute to health-related quality of life (HRQL). METHODS: Parents of 81 children 3-12 years old in maintenance therapy for ALL completed a baseline measure of child sleep (dexamethasone n = 55, prednisone n = 26), and 61 parents returned 28 days of child sleep diaries starting the first day of a 5-day steroid course (dexamethasone n = 43, prednisone n = 18). Parents also completed measures of HRQL and fatigue on the last day of steroids and the last day of the month. RESULTS: At baseline, parents reported more sleep disturbances in children taking dexamethasone than prednisone. Across the month, children taking dexamethasone experienced poorer sleep quality compared to children taking prednisone. During corticosteroid treatment, children taking dexamethasone also experienced more night awakenings than children taking prednisone. Sleep variables accounted for almost half of the variance in HRQL during time off steroids and also significantly contributed to fatigue during the corticosteroids course and time off corticosteroids. CONCLUSIONS: Sleep is an essential component of HRQL in children taking corticosteroids, and the impact on sleep is more pronounced in children taking dexamethasone compared to prednisone. Screening for sleep disturbances and offering brief interventions to manage steroid-related sleep disruptions may improve HRQL.

Quality improvement initiative to increase influenza vaccination in pediatric cancer patients.

BACKGROUND: Pediatric patients with cancer face more severe complications of influenza than healthy children. Although Centers for Disease Control and Prevention guidelines recommend yearly vaccination in these patients, in our large academic center, <60% of oncology patients receiving chemotherapy were immunized at baseline. Our objective was to increase this rate through a multifaceted quality improvement initiative. METHODS: Eligible patients were >6 months old, within 1 year of receiving chemotherapy, >100 days from stem cell transplant, and had ≥ 1 outpatient oncology visit between September 1, 2012, and March 31, 2013. Five interventions were instituted concomitantly: (1) family education: influenza/vaccine handouts were provided to families in clinic waiting rooms; (2) health informatics: daily lists of outpatients due for immunization were generated from the electronic medical record and sent automatically to triage staff and nurses; (3) outpatient clinic: patients due for vaccination were given colored wristbands during triage to alert providers; (4) inpatient: vaccine order was built into admission order set; and (5) provider education: staff education was provided at conferences on screening of patients, vaccine ordering, and documentation of refusals/contraindications. RESULTS: The complete influenza immunization rate increased by 20.1% to 64.5%, and the proportion of patients receiving ≥ 1 dose of vaccination increased by 22.9% to 77.7%. Similar changes were noted across all cancer types, with highest rates of immunization in leukemia/lymphoma patients (86.8%) and lowest in patients after stem cell transplant (66.7%). CONCLUSIONS: Technology, education, and multidisciplinary clinical process changes increased influenza vaccination rates. Ongoing efforts are targeting subgroups with lowest rates of immunization.

Association of weekend admission with hospital length of stay, time to chemotherapy, and risk for respiratory failure in pediatric patients with newly diagnosed leukemia at freestanding US children's hospitals.

IMPORTANCE: In adult patients with leukemia, weekend admission is associated with increased inpatient mortality. It is unknown whether weekend diagnostic admissions in pediatric patients with leukemia demonstrate similar adverse outcomes. OBJECTIVE: To estimate adverse clinical outcomes associated with weekend admission in the first hospitalization of pediatric patients with newly diagnosed leukemia. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study from 1999 to 2011 featured index hospital admissions identified from the Pediatric Health Information System database. Participants were children with newly diagnosed acute lymphoid leukemia or acute myeloid leukemia. EXPOSURES: Weekend (Saturday and Sunday) or weekday index admission. MAIN OUTCOMES AND MEASURES: Inpatient mortality, length of inpatient stay, time to chemotherapy, and organ-system failure in index admission. RESULTS: A total of 10 720 patients with acute lymphoid leukemia and 1323 patients with acute myeloid leukemia were identified; 2009 patients (16.7%) were admitted on the weekend. While the total daily number of patients receiving intensive care unit-level care was constant regardless of the day of admission, these patients represented a larger percentage of total admissions on weekends. In adjusted analyses, patients admitted on the weekend did not have an increased rate of mortality during the first admission (odds ratio, 1.0; 95% CI, 0.8-1.6). Patients whose initial admission for leukemia occurred during a weekend had a significantly increased length of stay (1.4-day increase; 95% CI, 0.7-2.1), time to initiation of chemotherapy (0.36-day increase; 95% CI, 0.3-0.5), and risk for respiratory failure (odds ratio, 1.5; 95% CI, 1.2-1.7) after adjusting for demographics, severity of illness, and hospital-level factors. CONCLUSIONS AND RELEVANCE: While pediatric patients with newly diagnosed leukemia admitted on weekends do not have higher mortality rates, they have a prolonged length of stay, increased time to chemotherapy, and higher risk for respiratory failure. Patients who are severely ill at presentation represent a higher proportion of weekend index admissions. Optimizing weekend resources by increasing staffing and access to diagnostic and therapeutic resources may help to reduce hospital length of stay across all weekend admissions and may also ensure the availability of comprehensive care for those weekend admissions with higher acuity.