Serum cytokine panels in pediatric clinical practice.

Background: Cytokines are soluble signaling proteins that regulate inflammation and coordinate immune responses. Serum cytokine panels are increasingly used in medical practice, yet our understanding of cytokines as biomarkers for disease remains limited.

Objective: We sought to analyze real-world single-center use of a multiplexed cytokine panel, correlate its results with diagnosis and severity, and explore its use in pediatric practice.

INSPIRED Symposium Part 5: Expanding the Use of CAR T Cells in Children and Young Adults.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy in relapsed/refractory (r/r) B cell malignancies, including in pediatric patients with acute lymphoblastic leukemia (ALL). Expanding this success to other hematologic and solid malignancies is an area of active research and, although challenges remain, novel solutions have led to significant progress over the past decade. Ongoing clinical trials for CAR T cell therapy for T cell malignancies and acute myeloid leukemia (AML) have highlighted challenges, including antigen specificity with off-tumor toxicity and persistence concerns.

Clinical Trials on Cellular Therapy for Children and Adolescents With Cancer: A 15-Year Trend in the United States.

Introduction: Cellular therapies are frequently studied in clinical trials for pediatric patients with malignant disease. Characteristics of ongoing and completed cellular therapy clinical trials in the U.S.

INSPIRED Symposium Part 3: Prevention and Management of Pediatric Chimeric Antigen Receptor T Cell-Associated Emergent Toxicities.

Chimeric antigen receptor (CAR) T cell (CAR-T) therapy has emerged as a revolutionary cancer treatment modality, particularly in children and young adults with B cell malignancies. Through clinical trials and real-world experience, much has been learned about the unique toxicity profile of CAR-T therapy. The past decade brought advances in identifying risk factors for severe inflammatory toxicities, investigating preventive measures to mitigate these toxicities, and exploring novel strategies to manage refractory and newly described toxicities, infectious risks, and delayed effects, such as cytopenias.

Practice Preferences for Consolidative Hematopoietic Stem Cell Transplantation Following Tisagenlecleucel in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia.

Treatment with tisagenlecleucel (tisa-cel) achieves excellent complete remission rates in children and young adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), but approximately 50% maintain long-term remission. Consolidative hematopoietic stem cell transplantation (cHSCT) is a potential strategy to reduce relapse risk, but it carries substantial short- and long-term toxicities. Additionally, several strategies for management of B cell recovery (BCR) and next-generation sequencing (NGS) positivity post-tisa-cel exist, without an accepted standard.

HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL.

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs.

SARS-CoV-2 infections in pediatric and young adult recipients of chimeric antigen receptor T-cell therapy: an international registry report.

Background: Immunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%-40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited.

Acute Left Ventricular Dysfunction Following Gemtuzumab Ozogamicin in Two Pediatric AML Patients.

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-tumor antibiotic conjugate with proven efficacy in pediatric and adult patients with CD33+ acute myeloid leukemia. Adverse effects commonly associated with GO include hyperbilirubinemia, elevated transaminases, and sinusoidal obstruction syndrome. Cardiotoxicity has not been a commonly described adverse event.

Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy.

Here we review the pathophysiology and management of cytokine release syndrome (CRS) secondary to immunotherapy, and potential options for CRS refractory to IL6 inhibition and glucocorticoids, for which there are no proven treatments. To illustrate, we describe a patient with B-cell acute lymphoblastic leukemia who developed refractory grade 4 CRS following CD19-directed chimeric antigen receptor T-cell therapy, treated with tocilizumab, methylprednisolone, siltuximab, and the IFNγ inhibitor emapalumab, with complete remission from leukemia for 12 months. See related article by Bailey et al.

Proteomic Profiling of MIS-C Patients Reveals Heterogeneity Relating to Interferon Gamma Dysregulation and Vascular Endothelial Dysfunction.

Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms.

Xenograft models for pediatric cancer therapies.

The prognosis for childhood cancer has improved considerably over the past 50 years. This improvement is attributed to well-designed clinical trials which have incorporated chemotherapy, surgery, and radiation. With an increased understanding of cancer biology and genetics, we have entered an era of precision medicine and immunotherapy that provides potential for improved cure rates.

Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood.

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients.

Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) Antibody Responses in Children With Multisystem Inflammatory Syndrome in Children (MIS-C) and Mild and Severe Coronavirus Disease 2019 (COVID-19).

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike immunoglobulin G (IgG) titers compared with those with severe coronavirus disease 2019, likely reflecting a longer time since the onset of infection in MIS-C patients.

Deep Immune Profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood.

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome.

SARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-19.

SARS-CoV-2 antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients.

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.

Enhancing Neuroblastoma Immunotherapies by Engaging iNKT and NK Cells.

Neuroblastoma (NB) is the most common extracranial solid tumor in children and, in the high-risk group, has a 5-year mortality rate of ~50%. The high mortality rate and significant treatment-related morbidities associated with current standard of care therapies belie the critical need for more tolerable and effective treatments for this disease. While the monoclonal antibody dinutuximab has demonstrated the potential for immunotherapy to improve overall NB outcomes, the 5-year overall survival of high-risk patients has not yet substantially changed.

Sinusoidal Obstruction Syndrome During Maintenance Therapy for Acute Lymphoblastic Leukemia With 6-Mercaptopurine and Methotrexate: A Pediatric Case Report.

We report a case of a child with pre-B cell acute lymphoblastic leukemia undergoing maintenance chemotherapy with 6-mercaptopurine and methotrexate (MTX) who developed sinusoidal obstruction syndrome after being treated with ciprofloxacin for BK viremia. This case represents a rare complication of maintenance therapy with MTX and 6-mercaptopurine, and suggests a drug interaction between ciprofloxacin and MTX.