Central venous access device adverse events in pediatric patients with cancer: a systematic review and meta-analysis.

PURPOSE: To systematically review the proportion and incidence of CVAD-associated complications in pediatric patients with cancer. METHODS: PubMed, Embase, and the Cumulative Index of Nursing and Allied Health Literature were searched from 2012 to 2022. Cohort studies and the control arm of randomized controlled trials, which reported CVAD-associated complications in pediatric patients aged 0-18 years, were included. CVAD complications were defined as CVAD failure, central line-associated bloodstream infection (CLABSI), local infection, occlusion, CVAD-associated venous thromboembolism, dislodgement/migration, breakage/rupture, and dehiscence. The pooled proportion and incidence rate (IR) for each CVAD-associated complication were reported. RESULTS: Of 40 included studies, there was mixed quality of methods and reporting. Approximately 31.4% (95% confidence interval [CI] 22.5-41.1; 6920 devices) of devices experienced a CVAD-associated complication, and 14.8% (95% CI 10.2-20.1; 24 studies; 11,762 devices) of CVADs failed before treatment completion (incidence rate (IR) of 0.5 per 1000 catheter days (95% CI 0.3-0.8; 12 studies; 798,000 catheter days)). Overall, 21.2% (95% CI 14.3-28.9; 26 studies; 5054 devices) of CVADs developed a CLABSI, with an IR of 0.9 per 1000 catheter days (95% CI 0.6-1.3; 12 studies; 798,094 catheter days). Tunneled central venous catheters (TCVC) and peripherally inserted central catheters (PICCs) were associated with increased complications in comparison to totally implanted venous access devices (TIVADs). CONCLUSION: CVAD complication rates in this population remain high. TCVCs and PICCs are associated with increased complications relative to TIVADs. Insufficient evidence exists to guide device selection in this cohort, necessitating further research to determine the role of PICCs in pediatric cancer care. PROSPERO: CRD42022359467. Date of registration: 22 September 2022.

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia.

BACKGROUND: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is transforming care for pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). There are limited pediatric-specific data concerning the infection risks associated with CD19 CAR-T therapy and the adequacy of current antimicrobial prophylaxis guidelines for these patients. METHODS: We describe the antimicrobial prophylaxis used and the types of infectious occurring in the first 100 days following CAR-T therapy for relapsed or refractory B-cell ALL in children and adolescents (≤18 years) at our centre. RESULTS: Twenty-seven patients received their first CAR-T infusion (CTI) during the study period. Almost all patients (96%) had a comprehensive Infectious Diseases review prior to CTI, which informed a personalised prophylaxis or fever/sepsis plan in six (22%). Overall, six (22%) patients had one or more infections during the study period including five (19%, 0.9 per 100 days-at-risk) from days 0-30 and three (n = 20, 15%, 0.6 per 100 days-at-risk) from days 31-100. Bacterial blood stream infections were the most common type of infection encountered during both time periods, and one patient had probable pulmonary aspergillosis. There were no infection-related deaths. CONCLUSION: Our study contributes important information on the spectrum of infections encountered in pediatric patients with B-ALL post CAR-T therapy. Overall, the burden of infectious complications post CAR-T therapy in our cohort is lower than previously reported in the literature. Results suggest that our prophylaxis recommendations are effective in this population.

Density of antibiotic use and infectious complications in pediatric allogeneic hematopoietic cell transplantation.

BACKGROUND: Antibiotics, while an essential component of supportive care in allogeneic hematopoietic cell transplantation (allo-HCT), can have adverse effects and select for antibiotic resistance. Understanding of patterns of use will inform antimicrobial stewardship (AMS) interventions. METHODS: Retrospective, single-center cohort of children undergoing first allo-HCT (n = 125). Antibiotic prescription and infection data were included from the date conditioning was commenced until 30 days post allo-HCT. Antibiotic use was reported as length of therapy (LOT) (number of days a patient received an antibiotic) and days of therapy DOT (aggregating all antibiotics prescribed per day). Infections were classified as microbiologically documented infection (MDI) or clinically documented infections. RESULTS: At least one course of antibiotics was administered to 124 (99%) patients. The LOT was 636 per 1000 patient days and DOT was 959 per 1000 patient days. The median duration of cumulative antibiotic exposure per patient was 24 days (interquartile range [IQR] 20-30 days). There were 131 days of fever per 1000 patient days with patients febrile for a median of 4 days (IQR 1-7 days). Piperacillin-tazobactam was used for 116 (94%) of patients with an LOT of 532 per 1000 patient days. A total of 119 MDI episodes occurred in 74 (59%) patients, including blood stream infection in 30 (24%) and a proven/probable invasive fungal infection in 4 (3%). CONCLUSION: Pediatric HCT patients receive prolonged courses of broad-spectrum antibiotics relative to the frequency of fever and bacterial infections. This study has identified opportunities for AMS intervention to improve outcomes for our HCT patients.

Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.

Novel approaches to the prediction and diagnosis of pulmonary complications in the paediatric haematopoietic stem cell transplant patient.

PURPOSE OF REVIEW: Haematopoietic stem cell transplant (HSCT) remains the only curative treatment option for many children with relapsed leukaemia, primary immunodeficiencies and haemoglobinopathies. Unfortunately, infectious and noninfectious pulmonary complications following HSCT continue to cause significant morbidity and mortality. This review will focus on recent advances in the field that enhance clinically available diagnostic tools and the role of novel diagnostic techniques. RECENT FINDINGS: Research continues to highlight the role of standard diagnostic modalities, including imaging using computed topography chest and Fluorodeoxyglucose-positron emission tomography (FDG-PET) in the diagnosis of posttransplant pulmonary infections. Similarly, bronchoalveolar lavage using bronchoscopy to obtain samples for microbiological analysis remains an important tool in the clinical and diagnostic algorithm for these children. The application of more novel diagnostic techniques such as metagenomic next-generation sequencing and the use of specific biomarkers remain potential future tools in children in whom the aetiology of posttransplant lung disease is unknown. The impact of the pulmonary microbiome on infectious and noninfectious pulmonary disease post HSCT is a future research direction. SUMMARY: Pulmonary infectious complications post HSCT remain a devastating complication for children and their families. Despite improvements in standard and novel diagnostic modalities, the aetiology of pulmonary disease remains unknown for many patients. There is an urgent need for ongoing collaborative research to bridge this critical knowledge gap and lead to better patient outcomes.

Dysregulation of BCL-2 family proteins by leukemia fusion genes.

The genomic lesions that characterize acute lymphoblastic leukemia in childhood include recurrent translocations that result in the expression of fusion proteins that typically involve genes encoding tyrosine kinases, cytokine receptors, and transcription factors. These genetic rearrangements confer phenotypic hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this Minireview, we discuss the molecular mechanisms that link these fusions to the control of cell death. We examine how these fusion genes dysregulate the BCL-2 family of proteins, preventing activation of the apoptotic effectors, BAX and BAK, and promoting cell survival.

Developing drugs for treatment of atopic dermatitis in children (≥3 months to <18 years of age): Draft guidance for industry.

Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high-level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for "the Agency's current thinking on a particular subject." Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

When Patient Diversity Informs Formulation: Reimagining Treatment for Seborrheic Dermatitis.

Seborrheic dermatitis (SD) impacts a diverse demographic, with treatment effectiveness and suitability varying across hair types and cultural practices. Available shampoo treatments contain surfactants that compromise hair moisture and integrity as well as requiring frequent use, which may not align with the routines of various hair types and cultural hair care practices. Most available topical foams and gels contain high concentrations of drying alcohols that damage hair color and moisture. Newly US Food and Drug Administration (FDA)-approved roflumilast 0.3% foam presents a significant advancement in the treatment of SD owing to its pH-balanced, residue-free formulation that is suited for all hair types, including patients with curly or coiled hair. It presents a culturally inclusive treatment option that offers effective management of SD while maintaining hair health and respecting diverse hair care needs and practices.

Putting the Formulation Back in Foam: Optimizing Seborrheic Dermatitis Treatment Across Diverse Hair Types.

Seborrheic dermatitis (SD) is a chronic inflammatory skin condition that commonly involves the scalp, and thus, affects a diverse demographic with varying hair care needs. Current SD treatments are limited based on optimized formulation, efficacy, adverse events, and lack of placebo-controlled trials. A novel roflumilast foam formulation has emerged as a promising therapeutic option optimally designed for use on the scalp and other hair-bearing areas. We conducted a comprehensive assessment of beauty industry standards, confirming the foam formulation's alignment with industry guidelines and exclusion of potentially harmful ingredients. In addition, consultation with an expert dermatologist panel yielded a strong endorsement, underscoring a high level of confidence in prescribing the foam across diverse hair and skin types.

Biomarkers to predict and diagnose pulmonary complications in children post haematopoietic stem cell transplant.

OBJECTIVES: Haematopoietic cell transplant (HCT) is a cellular therapy for a group of high-risk children with cancer, immunodeficiency and metabolic disorders. Whilst curative for a child's underlying condition, HCT has significant risks associated, including lung injury. These complications are associated with increased post HCT mortality and require improved methods of risk stratification, diagnosis and treatment. METHODS: Biomarkers measured in bronchoalveolar fluid and peripheral blood have been identified for both acute and chronic lung injury post HCT.This review evaluates the current research available investigating the use of these biomarkers to improve clinical care, with a focus on the paediatric cohort. RESULTS: Elevated levels of cytokines such as IL-6, IL-8, G-CSF and TNF were identified as potential predictive biomarkers for the development of post HCT lung disease. The pulmonary microbiome was found to have strong potential as a biomarker pre and post HCT for the development of pulmonary complications. General limitations of the studies identified were study design, retrospective or single centre and not exclusively performed in the paediatric population. CONCLUSION: To translate biomarker discovery into clinical implementation further research is required, utilising larger cohorts of children in prospective trials to validate these biomarkers and determine how they can be translated into better outcomes for children post HCT.

Pulmonary complications post allogeneic haematopoietic stem cell transplant in children.

Objectives: Haematopoietic stem cell transplant (HCT) is a cellular therapy that, whilst curative for a child's underlying disease, carries significant risk of mortality, including because of pulmonary complications. The aims of this study were to describe the burden of pulmonary complications post-HCT in a cohort of Australian children and identify risk factors for the development of these complications. Methods: Patients were identified from the HCT databases at two paediatric transplant centres in Australia. Medical records were reviewed, and demographics, HCT characteristics and pulmonary complications documented. Relative risk ratio was used to identify risk factors for developing pulmonary complications prior to first transplant episode, and survival analysis performed to determine hazard ratio. Results: In total, 243 children underwent transplant during the study period, and pulmonary complications occurred in 48% (117/243) of children. Infectious complications were more common (55%) than non-infective complications (18%) and 26% of patients developed both. Risk factors for the development of pulmonary complications included the following: diagnoses of MPAL (RR 2.16, P = 0.02), matched unrelated donor (RR1.34, P = 0.03), peripheral blood (RR 1.36, P = 0.028) or cord blood (RR 1.73, P = 0.012) as the stem cell source and pre-existing lung disease (RR1.72, P < 0.0001). Children with a post-HCT lung complication had a significantly increased risk of mortality compared with those who did not (HR 3.9, P < 0.0001). Conclusion: This study demonstrates pulmonary complications continue to occur frequently in children post-HCT and contribute significantly to mortality. Highlighting the need for improved strategies to identify patients at risk pre-transplant and enhanced treatments for those who develop lung disease.

Roflumilast Cream, 0.15%, for Atopic Dermatitis in Adults and Children: INTEGUMENT-1 and INTEGUMENT-2 Randomized Clinical Trials.

Importance: Safe, effective, and well-tolerated topical treatment options available for long-term use in patients with atopic dermatitis (AD) are limited and associated with low adherence rates. Objective: To evaluate efficacy and safety of once-daily roflumilast cream, 0.15%, vs vehicle cream in patients with AD. Design, Setting, and Participants: Two phase 3, randomized, double-blind, vehicle-controlled trials (Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2]), included patients from sites in the US, Canada, and Poland. Participants were 6 years or older with mild to moderate AD based on Validated Global Assessment for Atopic Dermatitis (assessed on a 5-point scale ranging from 0 [clear] to 4 [severe]). Intervention: Patients were randomized 2:1 to receive roflumilast cream, 0.15%, or vehicle cream once daily for 4 weeks. Main Outcomes and Measures: The primary efficacy end point was Validated Investigator Global Assessment for Atopic Dermatitis success at week 4, defined as a score of 0 or 1 plus at least a 2-grade improvement from baseline. Secondary end points included Eczema Area and Severity Index and Worst Itch Numeric Rating Scale. Safety and local tolerability were also evaluated. Results: Among 1337 patients (654 patients in INTEGUMENT-1 and 683 patients in INTEGUMENT-2), the mean (SD) age was 27.7 (19.2) years, and 761 participants (56.9%) were female. The mean body surface area involved was 13.6% (SD = 11.6%; range, 3.0% to 88.0%). Significantly more patients treated with roflumilast than vehicle achieved the primary end point (INTEGUMENT-1: 32.0% vs 15.2%, respectively; P < .001; INTEGUMENT-2: 28.9% vs 12.0%, respectively; P < .001). At week 4, statistically significant differences favoring roflumilast also occurred for the achievement of at least 75% reduction in the Eczema Area and Severity Index (INTEGUMENT-1: 43.2% vs 22.0%, respectively; P < .001; INTEGUMENT-2: 42.0% vs 19.7%, respectively; P < .001). Roflumilast was well tolerated with low rates of treatment-emergent adverse events. At each time point, investigators noted no signs of irritation at the application site in 885 patients who were treated with roflumilast (≥95%), and 885 patients who were treated with roflumilast (90%) reported no or mild sensation at the application site. Conclusions and Relevance: In 2 phase 3 trials enrolling adults and children, once-daily roflumilast cream, 0.15%, improved AD relative to vehicle cream, based on multiple efficacy end points, with favorable safety and tolerability. Trial Registration: ClinicalTrials.gov Identifiers: NCT04773587, NCT04773600.

Adverse effects of antibiotics in children with cancer: are short-course antibiotics for febrile neutropenia part of the solution?

INTRODUCTION: Febrile neutropenia is a common complication experienced by children with cancer or those undergoing hematopoietic stem cell transplantation. Repeated episodes of febrile neutropenia result in cumulative exposure to broad-spectrum antibiotics with potential for a range of serious adverse effects. Short-course antibiotics, even in patients with high-risk febrile neutropenia, may offer a solution. AREAS COVERED: This review addresses the known broad effects of antibiotics, highlights developments in understanding the relationship between cancer, antibiotics, and the gut microbiome, and discusses emerging evidence regarding long-term adverse antibiotic effects. The authors consider available evidence to guide the duration of empiric antibiotics in pediatric febrile neutropenia and directions for future research. EXPERT OPINION: Broad-spectrum antibiotics are associated with antimicrobial resistance, Clostridioides difficile infection, invasive candidiasis, significant disturbance of the gut microbiome and may seriously impact outcomes in children with cancer or undergoing allogenic hematopoietic stem cell transplant. Short-course empiric antibiotics are likely safe in most children with febrile neutropenia and present a valuable opportunity to reduce the risks of antibiotic exposure.

Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi Consensus.

Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy. Several international guidelines have been developed for the acute monitoring of cardio-oncology side effects. However, none are specific to pediatrics. We have addressed this gap in the literature by undertaking a rigorous Delphi consensus approach across 11 domains of cardio-oncology care using an Australian and New Zealand expert group. The expert group consisted of pediatric and adult cardiologists and pediatric oncologists. This Delphi consensus provides an approach to perform risk and baseline assessment, screening, and follow-up, specific to the cancer therapeutic. This review is a useful tool for clinicians involved in the cardio-oncology care of pediatric oncology patients.

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.