Perspectives of pediatric oncologists on referral for CAR-T therapy: a mixed methods pilot study.

BACKGROUND: Receipt of chimeric antigen receptor T-cell (CAR-T) therapy at an institution different from the primary oncologist's institution is a complex, multistep process. Referral by oncologists plays an important role in the process but may be susceptible to bias. METHODS: Oncologists who previously referred patients for CAR-T therapy at 5 pediatric hospitals were sent surveys by email exploring their CAR-T referral practices. Descriptive statistics were generated, and multivariate analyses examined associations among oncologist characteristics, familiarity with CAR-T therapy, and referral practices. We conducted semistructured interviews with a subset of participants and used thematic analysis to code transcripts. RESULTS: Sixty-eight oncologists completed the survey; 77% expressed being "very familiar" with CAR-T therapy. Hispanic oncologists and oncologists at institutions with 50 or fewer new diagnoses per year were more likely to identify as less familiar with CAR-T therapy (odds ratio [OR] = 64.3, 95% confidence interval [CI] = 2.45 to 10 452.50, P = .04 and OR = 24.5, 95% CI = 3.3 to 317.3, P = .005, respectively). In total, 38% of respondents considered nonclinical features (compliance, social support, resources, insurance, language, education, and race or ethnicity) influential in referral decisions. Oncologists who were Hispanic and oncologists who had been practicing for 20 or more years were more likely to consider these features significantly influential (OR = 14.52, 95% CI = 1.49 to 358.66, P = .04 and OR = 6.76, 95% CI = 1.18 to 50.5, P = .04). Nine oncologists completed in-depth interviews; common themes included barriers and concerns regarding CAR-T therapy referral, the value of an established relationship with a CAR-T therapy center, and poor communication after CAR-T therapy. CONCLUSIONS: Nearly 40% of oncologists consider nonclinical features significantly influential when deciding to refer patients for CAR-T therapy, raising concern for bias in the referral process. Establishing formal partnerships with CAR-T therapy centers may help address physician barriers in referral.

Daratumumab therapy in a pediatric case of C3 nephritic factor-positive proliferative glomerulonephritis with monoclonal IgG deposits.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is an exceedingly rare cause of glomerulonephritis among children for which prognosis is generally poor, with low incidence of remission and high rates of recurrence after transplant. While there are more cases reported in the adult literature, substantial differences in pediatric vs. adult PGNMID render it essential that we further characterize pediatric cases to optimize management. We report the case of a 12-year-old male presenting initially with edema and hypertension who was subsequently diagnosed with IgG3/Kappa-dominant PGNMID. In the absence of any proven therapy and though without a detectable clone, he was empirically treated with daratumumab with positive effect to date. This is the first reported case of daratumumab monotherapy in pediatric PGNMID, as well as the first PGNMID case to detect presence of C3 nephritic factor.

Financial assistance and other financial coping strategies after a pediatric cancer diagnosis.

BACKGROUND: Families experience financial burden and household material hardship (HMH) after a pediatric cancer diagnosis. This study investigates types of financial assistance and other financial coping strategies (FCS) adopted by families during the first year after diagnosis. METHODS: Retrospective survey of caregivers of pediatric patients diagnosed with cancer from 2015 to 2019. The survey collected data on demographics, diagnosis, income, HMH, and private, hospital, and government assistance received and other FCS adopted after diagnosis. Bivariate and multivariable logistic regressions were used to analyze FCS by income. Subgroup analysis of families experiencing HMH was used to identify predictors of receiving government assistance. RESULTS: Of 156 respondents, 52% were low-to-middle income, 29% had public insurance, and 22% had non-English language preference. Low-to-middle-income families were more likely to incur debt (odds ratio [OR] 6.24, p < .001) and reduce consumption (OR 2.16, p = .03) than high-income families, and this association persisted in multivariable analysis. Among families with housing, food, and energy insecurity, 40%, 70%, and 39%, respectively, received hospital or government assistance specific to the experienced hardship. In subgroup analysis of families with HMH, after adjusting for income and other confounders, non-English language preference was associated with lower odds of receiving government assistance. CONCLUSIONS: After a pediatric cancer diagnosis, low-to-middle-income families are more likely to incur debt than high-income families. Most families experiencing food insecurity received some food assistance, while housing and energy assistance were less common. Future studies should investigate methods to equitably improve access to financial assistance and minimize long-term financial consequences.

Disparities in household material hardship, financial toxicity, and income loss in pediatric cancer.

BACKGROUND: Based on previous reports of disparities in financial burden following a cancer diagnosis, this study aims to characterize mechanisms of disparities experienced by caregivers of children with cancer, including the impact of work flexibility and social support. METHODS: Cross-sectional survey (in English or Spanish) of caregivers of children with cancer that assessed household material hardship (HMH), financial toxicity, and income change. RESULTS: Of 156 caregivers surveyed, 32% were Hispanic and 32% were low income. Hispanic caregivers were more likely to report HMH and financial toxicity compared to non-Hispanic White and Asian (HMH: 57% vs. 21% vs. 19%, p < .001; financial toxicity: 73% vs. 52% vs. 53%, p = .07). Low- and middle-income caregivers were more likely to experience HMH and financial toxicity compared to high-income caregivers (HMH: 68% low vs. 38% middle vs. 8.7% high, p < .001; financial toxicity: 81% vs. 68% vs. 44%, p < .001). All income categories demonstrated significant increases in HMH 1 year after diagnosis. Seventeen percent reported more than 40% income loss, more of whom were low income than high income (27% vs. 12%, p = .20). Work flexibility and social support were associated with income and financial toxicity. CONCLUSION: HMH, financial toxicity, and income loss are prevalent after a child's cancer diagnosis, suggesting that screening should be incorporated into routine care. This financial burden disproportionately affects low-income and Hispanic caregivers. Further research is needed to elucidate the roles of work flexibility and social support, how safety net services are utilized by families, and how best to support families with HMH.

Barriers to Pediatric Palliative Care: Trainee and Faculty Perspectives Across Two Academic Centers.

Objective: Barriers to palliative care for children with serious illness include system constraints and vastly different training and attitudes toward palliative care. This study aimed to explore trainee and faculty physician perceptions of barriers to palliative care across two pediatric centers to (1) examine differences between trainees and faculty and (2) compare these data with previous studies. Methods: A mixed-methods study was conducted in fall 2021 among pediatric trainees and faculty physicians at three pediatric hospitals in two pediatric centers in the western United States. Surveys were distributed through hospital listservs and analyzed descriptively and through inductive thematic analysis. Results: There were a total of 268 participants: 50 trainees and 218 faculty physicians. Of the trainees, 46% (23) were fellows and 54% (27) were pediatric residents. Trainees and faculty reported the same four most common barriers, which were consistent with previous studies: family not ready to acknowledge an incurable condition (64% trainees and 45% faculty); family preference for more life-sustaining therapies than staff (52% and 39%); uncertain prognosis (48% and 38%); and parent discomfort with possibility of hastening death (44% and 30%). Other barriers commonly reported included time constraints, staff shortages, and conflict among family about treatment goals. Language barriers and cultural differences were also cited. Conclusions: This study examining palliative care across two pediatric centers suggests that providers' perceptions of family preferences and understanding of illness persist as barriers to the delivery of pediatric palliative care services. Future research should examine family-centered and culturally mindful interventions to better elucidate family perspectives on their child's illness to align care.

Venetoclax in combination with chemotherapy as treatment for pediatric advanced hematologic malignancies.

BACKGROUND: Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. PROCEDURE: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Children's Hospitals from 2016 to 2022. RESULTS: We identified 13 patients (acute myeloid leukemia, n = 8; B-acute lymphoblastic leukemia, n = 3; myelodysplastic syndrome, n = 2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0-5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5-52 months) and 3 months (range 2 weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses. CONCLUSIONS: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population.

Access to Chimeric Antigen Receptor T Cell Clinical Trials in Underrepresented Populations: A Multicenter Cohort Study of Pediatric and Young Adult Acute Lymphobastic Leukemia Patients.

Chimeric antigen receptor T cell (CAR-T) therapy is a promising approach to improve survival for children and adults with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL), but these clinical trials might not be equally accessible to patients of low socioeconomic status (SES) or to patients from racial or ethnic minority groups. We sought to describe the sociodemographic characteristics of pediatric and adolescent and young adult (AYA) patients enrolled in CAR-T clinical trials and to compare these characteristics to those of other patients with r/r B-ALL. We conducted a multicenter retrospective cohort study at 5 pediatric consortium sites to compare the sociodemographic characteristics of patients treated and enrolled in CAR-T trials at their home institution, other patients with r/r B-ALL treated at these sites, and patients referred from an external hospital for CAR-T trials. The patients were age 0 to 27 years with r/r B-ALL treated at 1 of the consortium sites between 2012 and 2018. Clinical and demographic data were collected from the electronic health record. We calculated distance from home to treating institution and assigned SES scores based on census tract. Among the 337 patients treated for r/r B-ALL, 112 were referred from an external hospital to a consortium site and enrolled in a CAR-T trial and 225 were treated primarily at a consortium site, with 34% enrolled in a CAR-T trial. Patients treated primarily at a consortium site had similar characteristics regardless of trial enrollment. Lower proportions of Hispanic patients (37% versus 56%; P = .03), patients whose preferred language was Spanish (8% versus 22%; P = .006), and publicly insured patients (38% versus 65%; P = .001) were referred from an external hospital than were treated primarily at a consortium site and enrolled in a CAR-T trial. Patients who are Hispanic, Spanish-speaking, or publicly insured are underrepresented in referrals from external hospitals to CAR-T centers. External provider implicit bias also may influence referral of these patients. Establishing partnerships between CAR-T centers and external hospital sites may improve provider familiarity, patient referral, and patient access to CAR-T clinical trials.

Clofarabine with topotecan, vinorelbine, and thiotepa reinduction regimen for children and young adults with relapsed AML.

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline-based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate, defined as complete remission or complete remission with partial recovery of platelet count, was 71.4% (95% confidence interval [CI], 41.9-91.6) for those patients in first relapse (n = 14) and 47.4% (95% CI, 24.4-71.1) for patients in second or greater relapse or with refractory disease. Responses were seen across multiple high-risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year overall survival for patients in first relapse was 46.2% (95% CI, 19.1-73.3) and 50.0% (95% CI, 26.9-73.1) for patients who responded to TVTC. For pediatric and young adult patients with relapsed/refractory AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.

Low-dose Ketamine Infusion for Pediatric Hematology/Oncology Patients: Case Series and Literature Review.

Management of refractory pain in pediatric sickle cell disease (SCD) and oncology is reliant on opioids though high opioid dosing increases side effects and tachyphylaxis. We introduced low-dose ketamine infusion (LDKI) to our inpatient unit to determine if LDKI was tolerable. We subsequently hypothesized that LDKI would improve pain scores. We reviewed inpatients from LDKI initiation in March 2014 through October 2017, with the day before LDKI initiation compared with the day of LDKI initiation and 2 subsequent days. For patients with SCD, the LDKI admission was compared with up to 3 admissions in the prior year for a vaso-occlusive event. Nineteen patients (12 oncology, 7 SCD) with a median age of 14.6 years received LDKI for a median of 6 days at a median initial dose of 0.06 mg/kg/h (1.1 µg/kg/min). There was no change in pain scores or opioid utilization when comparing the day before LDKI initiation with subsequent days. No patient discontinued LDKI because of intolerability. For patients with SCD, there was a median 32% reduction in cumulative pain scores when comparing the LDKI admission with prior admissions. LDKI is well tolerated for refractory pediatric cancer-related and sickle cell-related pain.

Utilization of Thiopurine Metabolites and Allopurinol in Pediatric Acute Lymphoblastic Leukemia: Consideration for an Algorithmic Approach.

Persistently elevated absolute neutrophil counts during maintenance for acute lymphoblastic leukemia is a risk factor for relapse and may be related to wild-type thiopurine methyltransferase activity and overly efficient shunting of 6-mercaptopurine to hepatotoxic metabolites (6-methylmercaptopurine nucleotides), leading to low 6-thioguanine nucleotides. 6-mercaptopurine is also metabolized by xanthine oxidase, and therefore allopurinol, an inhibitor of xanthine oxidase, allows for increased 6-thioguanine nucleotides and decreased 6-methylmercaptopurine nucleotide. Here, we report our experience with allopurinol for persistently elevated absolute neutrophil count or hepatotoxicity and suggest an algorithmic approach for checking thiopurine metabolites and initiating allopurinol in acute lymphoblastic leukemia maintenance.

Therapy-related myeloid neoplasms resembling juvenile myelomonocytic leukemia: a case series and review of the literature.

Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.

Patient Outcomes With Febrile Neutropenia Based on Time to Antibiotics in the Emergency Department.

OBJECTIVE: Although bacteremia in pediatric oncology patients with febrile neutropenia (FN) is not uncommon, sepsis and mortality are rare. Because of the lack of clinically meaningful decision tools to identify high-risk patients with bacteremia, time to antibiotic administration (TTA) is increasingly considered an important quality and safety measure in the emergency department. Because little evidence exists suggesting that this benchmark is beneficial, we sought to determine whether TTA of 60 minutes or less is associated with improved outcomes. METHODS: We retrospectively reviewed patients presenting to a pediatric emergency department with FN from November 2013 to June 2016. Clinical outcomes including mortality, pediatric intensive care unit admission, imaging, fluid resuscitation of 40 mL/kg or greater in the first 24 hours, and length of stay were compared between TTA of 60 minutes or less and more than 60 minutes. RESULTS: One hundred seventy-nine episodes of FN were analyzed. The median TTA was 76 minutes (interquartile range, 58-105). The incidence of bacteremia was higher in patients with TTA of more than 60 minutes (12% vs 2%, P = 0.04), but without impact on mortality, pediatric intensive care unit admission, fluid resuscitation, or median length of stay. The median TTA was not different for those who were and were not bacteremic (91 vs 73 minutes, P = 0.11). CONCLUSIONS: Time to antibiotic administration of more than 60 minutes did not increase mortality in pediatric oncology patients with FN. Our study adds to the existing literature that TTA of 60 minutes or less does not seem to improve outcomes in pediatric FN. Further larger studies are required to confirm these findings and determine which features predispose pediatric FN patients to morbidity and mortality.

Diagnosis and management of pediatric primary bone tumors in the emergency department.

Musculoskeletal pain is a common chief complaint of children in the emergency department. Although nonspecific and typically benign, musculoskeletal pain should be investigated thoroughly with consideration for an underlying bone tumor, especially when it is a recurrent visit for pain. This issue reviews the specific signs, symptoms, and unique presentations the emergency clinician should know when evaluating a pediatric patient with musculoskeletal pain. Additionally, assessment of relevant radiographic findings to assist in differentiating bone tumors and guide further management are discussed.

Virtual reality as complementary pain therapy in hospitalized patients with sickle cell disease.

OBJECTIVE: Due to incomplete management of vaso-occlusive pain episodes (VOE) in patients with sickle cell disease (SCD), we sought to determine if immersive VR would be feasible for inpatients. Secondarily, we hypothesized that a single VR session would improve the VOE pain experience. PROCEDURES: Consecutive patients with SCD eight years and older admitted for VOE were offered one 15-minute VR session, utilizing a relaxing underwater world specifically created for pediatric patients and to minimize potential simulator side effects. Safety and acceptability were evaluated with a brief survey before and after the session. Pain was evaluated utilizing the validated adolescent pediatric pain tool (APPT). Survey data and pain scores were analyzed using Wilcoxon signed-rank test as the data were nonnormally distributed. RESULTS: Thirty patients, 21 female, with a median age of 16 years were enrolled, the majority having hemoglobin SS disease. The VR session had no reported side effects; all patients requested VR again in the future. Median pain intensity (pre-VR 7.3 [interquartile range, IQR, 6.1, 8.8], post-VR 5.8 [4.7, 7.9]), number of affected body areas (pre-VR 3.0 [2.0, 7.8], post-VR 2.0 [0, 4.8]), and qualitative measures including sensory, affective, evaluative, and temporal pain domains were all statistically reduced (i.e., P ≤0.01). CONCLUSIONS: VR therapy was feasible in a cohort of patients with SCD admitted for VOE. In addition to standard therapies, VR may help reduce the pain experience with SCD VOE. Further study is required to determine the impact of VR therapy on opioid usage and length of stay in hospital.

Establishing a Pediatric Hematology-Oncology Program in Botswana.

PURPOSE: Annually, 300,000 children are diagnosed with cancer, and the majority of these children live in low- and middle-income countries (LMICs). Currently, there is incomplete information on pediatric cancer incidence, diagnosis distribution, and treatment outcomes in Africa. Since 2007, a pediatric hematology-oncology program has been operating in Botswana through a partnership between the Botswana government, Baylor College of Medicine, and Texas Children's Hospital. METHODS: To better understand patient characteristics and outcomes at Botswana's only pediatric cancer program, a hospital-based data base-the Botswana Pediatric Oncology Database-was established in 2014. Children younger than 18 years of age at the time of diagnosis who presented between 2008 and 2015 were included. Data for this study were extracted in February 2016. RESULTS: Of the 240 potential enrollees, 185 (77%) children met eligibility for this study. The median age was 6.4 years, and 50.8% were male. Leukemia was the most common malignancy representing 18.9% of the cohort and 88.1% of the total cohort had a histopathologic diagnosis. HIV seropositivity was confirmed in 13.5%. The 2-year overall survival of all pediatric cancer diagnoses was 52.4%. Abandonment of treatment occurred in 3.8% of patients. CONCLUSION: In the first 9 years of the program, capacity has been developed through a longstanding partnership between Botswana and Baylor College of Medicine/Texas Children's Hospital that has led to children receiving care for cancer and blood disorders. Although continued improvements are necessary, outcomes to date indicate that children with cancer in Botswana can be successfully diagnosed and treated.