Texas Children's Hospital Research Articles

Race and socioeconomic determinants of opioid use and disposal following pediatric surgery.

Opioids are a mainstay in treating acute post-surgical pain although there are limited data on post-discharge use. To assess post-operative opioid usage in children undergoing outpatient pediatric surgical procedures and provider variability in the number of doses prescribed by procedure. This cohort study included parents of children who were prescribed opioids following outpatient pediatric surgical procedures at Texas Children's Hospital from July 2019 to July 2020. Subjects participated in an opioid takeback program with an accompanying telephone survey to determine opioid utilization. Reported opioid usage included the following: none (0 percent), some (>0 percent but <100 percent), and all (100 percent). Provider prescribing patterns were stratified by doses and surgical intervention. Parents of 423 patients received follow-up calls, of which 350 (82.7 percent) reported use of some to all opioids and 73 (17.3 percent) reported using none. In the group reporting use of all opioids (n = 140 [33.1 percent]), parents were more likely to be single, have Medicaid, and report lower education levels when compared with parents reporting some or no opioid use. The number of opioids prescribed was not associated with the amount used (p = 0.51). The number of doses varied widely within each surgical procedure: The median number of doses prescribed ranged from 6 to 15 with some patients prescribed more than twice the median given the same procedure. This study suggests that opioids are indicated for acute post-surgical pain in children although select patient and parental factors are associated with the extent of usage. This study also highlights significant variability in prescribed doses for similar procedures and may indicate both overprescribing and underprescribing by physicians.

Contrasting academic approaches to COVID-19 vaccine production and distribution: What can the Oxford and Texas experiences teach us about pandemic response?

This article contrasts the different approaches to COVID-19 vaccine development adopted by Oxford University, on one hand, and Texas Children's Hospital and Baylor College of Medicine (collectively, Texas), on the other hand. Texas was praised widely in the press and academic literature for adopting an "open source" approach to vaccine development. Oxford, however, chose to license its vaccine technology to pharmaceutical manufacturer AstraZeneca and received significant public criticism as a result. Yet the Oxford vaccine reached far more individuals in developing countries than the Texas vaccine. We compare the two vaccines' experiences, drawing attention to a constellation of interrelated elements that contribute to a successful vaccine production program, including not only IP licensing, but also timing, technology transfer, and resource mobilization, all in the context of the prevailing funding environments. This comparative analysis sheds light on how the innovation ecosystem functioned during the COVID-19 pandemic, providing useful insights for policy makers and advocates as they prepare for future pandemics and other global health challenges.

Acute Hematogenous Osteomyelitis of the Pelvis in Children.

Pelvic involvement has been reported in 3%-14% of acute hematogenous osteomyelitis (AHO) cases in children. One guideline suggests need for a longer antibiotic course in pelvic AHO, however, recent data are lacking. We describe the clinical course of children with pelvic AHO and compare it to nonpelvic AHO. A retrospective review of patients with a diagnosis of AHO admitted to Texas Children's Hospital from January 2012 to December 2020 was conducted. Patients 6 months-<19 years old and with ≤14 days of symptoms at admission were eligible. Patients with sickle cell disease or immunocompromised were excluded. Wilcoxon rank-sum test assessed for differences between continuous variables and Fisher exact for categorical variables using STATA 17. We compared 104 cases of pelvic AHO to 314 cases of nonpelvic AHO. Patients had similar microbiology, length of stay and length of antibiotic therapy. Patients with pelvic AHO had pyomyositis identified by magnetic resonance imaging more often (28.8 vs. 9.4%, P < 0.001) and bone abscess less often (22.1 vs. 46.5%, P < 0.001). Rates of chronic complications were comparable between patients with pelvic AHO and nonpelvic AHO (8.4% vs. 15.1%, P = 0.1). Nineteen patients (18.3%) with pelvic AHO received ≤30 antibiotic days without complications, but they had less need for intensive care or bone abscesses than patients treated longer. Pelvic AHO in children may be more frequent than previously reported but is not associated with more complications. Four weeks of therapy may be sufficient in selected patients. Prospective studies to compare outcomes with different lengths of therapy are needed.

Barriers to long-term follow-up in pediatric Hodgkin lymphoma survivors.

Pediatric Hodgkin lymphoma (HL) survivors have an increased risk of late effects following treatment. Barriers at the patient, provider, and payor level adversely affect adherence to long-term follow-up. We conducted a retrospective chart review of HL survivors diagnosed from 1999 to 2014 at Texas Children's Hospital. HL survivors were considered lost to follow-up if there were no documented visits to Texas Children's Cancer Center Long-Term Survivor (LTS) clinic for 2 or more years after their last LTS clinic visit. Univariate and multivariable logistic regression analyses were conducted to explore factors contributing to loss to follow-up. Reasons for not attending subsequent LTS visits were assessed by phone interviews in a subset of lost to follow-up patients. There were 120 HL survivors who had at least one LTS clinic visit in this timeframe; 64 (53%) were classified as lost to follow-up, and of these, 23 (36%) were interviewed. Eleven (47%) indicated that the reason for failure to follow-up was lack of or inadequate insurance, and seven (30%) stated they were unaware of the importance of continued follow-up. Loss to follow-up was associated with lack of insurance, earlier diagnosis, and lack of comorbidities in univariate analyses. Only earlier year of diagnosis (odds ratio [OR] 0.84, 95% confidence interval [CI]: 0.7-0.9, p=.01) and lack of insurance (OR 22.2, 95% CI: 4-123, p<.001) were associated with loss to follow-up in multivariable analyses. Insurance status and awareness of the need for long-term follow-up care are key factors associated with loss to follow-up in survivors of HL. Targeted education and low-cost options for survivorship care are potential strategies for improving adherence to long-term follow-up care in HL survivors.

Establishing Mental Wellness Screening As Standard of Care in Pediatric Sickle Cell Patients

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized with multi-organ involvement and frequent pain crises. Somatic complaints can give rise to neuropsychiatric disorders, among which anxiety and depression are the most common. Although mental health plays an important role in health outcomes, there is not a standardized approach to screen sickle cell patients for depression at most sickle cell centers across the country and at Texas Children's Hospital (TCH). The long-term goal of this project is to screen sickle cell patients over the age of 12 for depression across TCH hospitals: TCH-West Campus (TCH-WC), TCH-Woodlands (TCH-WL) and TCH-Medical Center (TCH-MC). Over the past two years, we successfully implemented depression screening at TCH-WC as standard of care through a series of PDSA cycles. The focus of this quality improvement project is to implement depression screening at TCH-WL. At TCH-WC, all sickle cell patients aged 12 years of greater are screened for depression using the Patient Health Questionnaire-9 modified for Adolescents (PHQ-A) . From October 2022 to July 2023, 71% of the patients that qualified for screening identified low risk, 16% identified mild risk and 12% identified moderate to severe risk of depression. Eleven percent endorsed suicidality. Psychology/Social Work (SW) saw 77.4% of patients with moderate to severe depression and 100% who screened positive for suicidality on the same day as screening. Now that our depression screening protocol is standard of care at TCH-WC, we extended this screening to TCH-WL in February 2023. Our goal is to increase the annual depression screening rate from 0 to 50% in English/Spanish speaking patients aged 12 years and older with sickle cell disease who present for follow-up care to the TCH-WL. During our first PDSA cycle at TCH-WL, one hematologist administered the PHQ-A to sickle cell patients &amp;gt; 12 years. No intervention was needed if patient scored 0-6 on the PHQ-A. Psychological resources were provided via handout if patient scored 7-9. SW referral was placed and patient was preferably seen same day if patient scored &amp;gt; 10 on the PHQ-A. If unable to be seen same day, SW followed-up via phone call. If patient screened positive for suicidality, an urgent SW referral was made and patient was seen in clinic the same day. Three sickle cell patients &amp;gt;12 years presented for follow up with the assigned provider. Two-thirds (67%) of patients were given the PHQ-A; half (50%) screened positive. During the second PDSA cycle at TCH-WL, all patients with SCD over the age of 12 who presented to TCH-WL Hematology Clinic were screened. The patients were given the PHQ-A by the Medical Assistant/nurse prior to the start of the appointment and then they followed the outlined and detailed algorithm listed above based on score.Forty-five patients were eligible for screening. Forty-two percent (19/45) were given the PHQ-A; 73% endorsed mild risk of depression; 26% endorsed moderate to severe risk; 22% endorsed suicidal ideation. 80% of patients with moderate to severe risk received same day SW assessment; 100% of patients with suicidal ideation received same day SW assessment. Over the course of our project, we have been able to maintain our goals at TCH-WC and came close to achieving our goal of screening 50% of eligible patients for depression at TCH-WL. We are working with staff and providers at TCH-WL to determine barriers and optimize clinic flow in order to achieve &amp;gt;50% screening. In the future, we plan to expand our project to our largest sickle cell clinic, TCH-Medical Center, and for depression screening to become standard of care for all sickle cell patients at Texas Children's Hospital.

Recurrent Hypoglycemia Following Asparaginase Therapy for Pediatric Lymphoid Malignancies

Background: Asparaginase (ASP) is critical in acute lymphoblastic leukemia (ALL) and lymphoma (LLy) therapy. Hyperglycemia following ASP is described, but hypoglycemia is rarely reported. We previously reported on the risk factors, prevalence, duration, severity, recurrence, and outcomes of children at Texas Children's Hospital (TCH) developing ASP-induced hypoglycemia (defined as blood glucose [BG] &amp;lt;70mg/dL). Out of 723 ALL or LLy patients, there was a 7.6% prevalence of ASP-induced hypoglycemia in pediatric patients with ALL (n=50) or LLy (n=5), and occurred with both pegylated and Erwinia formulations of ASP. Given the median hypoglycemia duration was 11 days in our cohort and 76% of our cohort experience recurrent hypoglycemia with subsequent ASP doses, we here report the management details of these patients to provide guidance for other providers. Design/Method: Descriptive analysis of cohort of children with ASP-induced hypoglycemia at TCH between 6/1/2017 and 6/30/2022. Following identification of diagnosis and frequency of hypoglycemia events, we reviewed EMR to collect information on treatments utilized including evaluation with a registered dietician (RD), dietary changes recommended during hypoglycemia, and utilization of cornstarch supplementation, continuous feedings or use of continuous glucose monitor (CGM). Hypoglycemia severity was determined based on lowest recorded BG (Stages 1-2) and need for hospitalization or seizures (Stage 3). Results: 26% of patients had Stage 1 hypoglycemia (n=14), 47%% had Stage 2 hypoglycemia (n=26), and 25% had Stage 3 hypoglycemia (n=15) (Figure 1). Treatment to prevent symptomatic/severe hypoglycemia included: 1) dietary change (53%, n=29), 2) cornstarch (29%, n=16), and 3) continuous enteral feedings (13%, n=7). Dietary change included education on complex carbohydrates and a consistent carbohydrate diet. Cornstarch dosing was determined in consultation with endocrinology, and typically doses were provided prior to periods of prolonged fasting (e.g., overnight, NPO). Enteral feedings were administered through daytime bolus feedings and continuous overnight feedings, with the goal of a consistent carbohydrate infusion and maintaining BG levels &amp;gt;70 mg/dL. Five patients (9%) required all 3 interventions. Dietary education and subsequent follow up was completed by an RD in 54% of patients (n=30), and among patients with multiple recurrences, 67% had RD involvement (n=37). Nine patients in our cohort (16%) used CGM to closely monitor adequacy of carbohydrate intake. The primary team evaluated home BG logs weekly. Despite frequent treatment or nutritional management, only 39 (69%) of individuals had formal endocrine consultation, most commonly those with Stage 3 hypoglycemia (13 of 14; 93%). Patients with Stage 3 hypoglycemia tended to be younger (median age 2.8 years), tended to require the most intensive therapy (47% Vs 38% Vs 15% requiring medical therapy for Stages 3 ,2, and 1), and were more often to require nutritional counseling (79% Vs 46% Vs 42%). Only one patient had ASP held due primarily to hypoglycemia (Stage 3 hypoglycemia), while another patient had it held primarily for ASP-induced pancreatitis but had Stage 1 hypoglycemia. The overall survival of our cohort was 80% (85% if excluding patients receiving ASP for relapsed disease), with 3.5 years' median follow up. Conclusion: ASP-induced hypoglycemia is a fairly common, recurrent, and possibly severe potential side effect in children receiving treatment for ALL or LLy. Reassuringly, patients completed treatment without worsened survival. However, some patients required intensive therapy throughout the duration of ASP treatments and required multi-modal therapy and intensive monitoring (Figure 2). Our systematic approach was effective at reducing severe events and hospitalizations, without compromising survival after therapy completion. We recommend other centers consider close monitoring and developing treatment algorithms to detect and manage ASP-induced hypoglycemia.

Neighborhood Disadvantage Increases Risk of Adverse Clinical Events in Children with Sickle Cell Disease

Background: Hydroxyurea is the most widely used pharmacologic agent to treat patients with sickle cell disease (SCD). Hydroxyurea treatment has well established effects of inducing expression of fetal hemoglobin (HbF) and a beneficial impact on clinical outcomes such as reduced number of vaso-occlusive (VOC) events, transfusions, and hospitalizations. In non-SCD populations, living in socio-economic disadvantage is a well-established factor for poor health outcomes. However, there is a paucity of data to describe how social stressors impact children with SCD. We hypothesized that socio-economic disadvantage impacts risk of adverse clinical outcomes in pediatric SCD patients even while on hydroxyurea therapy. Methods: We performed a retrospective chart review on 121 pediatric patients with severe SCD genotypes (homozygous HbS and sickle-beta 0 thalassemia) seen at Texas Children's Hospital (TCH) between 2010-2021. All patients were treated with hydroxyurea for a minimum of five years. Adherence to hydroxyurea was assessed through lab markers including absolute neutrophil count and reticulocyte counts. Patients not adherent were excluded from analysis. We examined the incidence of all clinical events for a total of 1026 patient years, including the number of office visits, ER visits, hospitalizations, transfusions, VOC, acute chest syndrome episodes (ACS), acute splenic sequestration (ASS), and febrile illness. We collected laboratory data including absolute neutrophil count, hemoglobin level, and HbF levels for each patient per year they were on hydroxyurea. We used the area deprivation index (ADI) to determine a score of neighborhood disadvantage amongst our cohort of patients. The ADI is a factor-based index which uses 17 US Census variables including poverty, education, and employment. We used individual residential addresses during our observation period to assign a geocode specific to each individual and obtain an ADI score. The ADI scores are ranked from 1-10, with higher ADI rankings reflecting a higher level of disadvantage. Results: All individuals with SCD had a robust response to hydroxyurea within their first year of initiating the drug (&amp;gt;20% HbF). We stratified our cohort based on their ADI scores into low ADI (1-3; n=42); medium ADI (4-6; n=42); and high ADI groups (7-10; n=37), where high ADI is the group with highest levels of disadvantage. All three groups had a similar average duration of hydroxyurea treatment. There were no significant differences in age, sex, or reason given for starting hydroxyurea between the ADI groups. When we examined hydroxyurea response, there was no significant difference in HbF levels at 1 year (23.8 vs. 24.06 %HbF in the low vs. high ADI groups) or after 5 years (19.6 vs. 18.6 % HbF in the low and high ADI groups). Individuals with high ADI did started hydroxyurea at a younger age (2.9 years vs. 4.9 years, p=0.02). We found that any individual living in an area with higher ADI had an increased incidence of adverse clinical events. We calculated the incidence of each clinical event per 100 patient years in our 3 ADI groups and used a conditional maximum likelihood estimate of rate ratio method to compare incidences (Table 1). We found that among individuals living in an area with a higher ADI (more deprived region), there was increased frequency of ER visits, hospitalizations, transfusions, VOC, and ASS. In particular, patients with the highest ADI had a 3 and 5 times higher rate of VOC and ASS, respectively (Table 1). Discussion: While we did not observe an association between ADI and HbF expression, our results show that higher neighborhood disadvantage is associated with poorer clinical outcomes among hydroxyurea-adherent pediatric patients with SCD who maintained a robust response to the drug (&amp;gt;20% HbF). All individuals in our study had a similar number of routine office visits at our clinic but any patient living in an area of high ADI had significantly more ER visits and hospitalizations for VOC and ASS events. While hydroxyurea is shown to reduce hospitalizations and VOC events in pediatric sickle cell patients, we show that neighborhood disadvantage can influence clinical outcomes even among patients who respond to hydroxyurea. More analysis remains in order to better characterize this association, and to understand additional strategies that can be used to reduce clinical events in pediatric patients of lower socioeconomic status.

Prospective Clinical and Biomarker Validation of the ASTCT Consensus Definition for Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Introduction: Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-hematopoietic cell transplantation (HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. The American Society for Transplantation and Cellular Therapy (ASTCT) has proposed new consensus diagnostic criteria for standard risk (ASTCT-SR) and high risk (ASTCT-HR) but their correlation with older criteria based on microangiopathic hemolytic anemia (MAHA) or diagnostic complement biomarkers used in previous TA-TMA studies, such as levels of the terminal complement activation product sC5b-9 and the alternative complement pathway activation product Factor Ba, is unknown. Using data and samples from an ongoing prospective pediatric cohort study, we compared the two definitions and their associations with biomarkers. Methods: Patients aged 0 to 18 years who underwent first allogeneic HCT 2021-2023 at Texas Children's Hospital were included in the clinical and biomarker study. Those who did not have at least 100-day post-HCT event-free follow-up were excluded. Two different definitions for TA-TMA were applied. Clinical TMA (cTMA) was diagnosed if a patient 1) met 4/4 concurrent criteria of MAHA (schistocytosis, thrombocytopenia, anemia, and elevated lactate dehydrogenase (LDH)) at least twice in 14 days and 2) clinically adjudicated to exclude known mimics or alternative causes of TMA. In contrast, ASTCT-HR TMA was diagnosed if a patient 1) met 4/7 non-concurrent criteria (schistocytosis, thrombocytopenia, anemia, elevated LDH, elevated blood pressure, elevated urinary protein excretion, and elevated sC5b9) at least twice in 14 days and 2) had evidence of LDH &amp;gt;2x normal, proteinuria ≥1 mg/mg, elevated sC5b9, acute graft-versus-host disease, active bacterial/viral infection, or end-organ damage. Cumulative incidence of TA-TMA was assessed by the competing risk method. Overall survival was compared by the Kaplan Meier estimator and log-rank test. Biomarker levels for samples collected at day 15 (+/- 14 days) were compared using the t-test. Results: A total of 32 patients met the inclusion criteria. The median age was 5.7 years (range 1.1-18.8) and most were White (68.8%) and Hispanic (56.2%). Malignant disease was the indication for HCT in 50% of patients. While the classic MAHA-based cTMA definition had an incidence of 12.7%, the newly proposed ASTCT-HR definition doubled it to 28.5% by day-100 (Figure 1). In contrast to patients with concordant TA-TMA diagnosis (+/+) who had significantly worse post-transplant survival (p=0.0047) compared with those with concordant non-TMA (-/-), those reclassified as TA-TMA by the new definition only (-/+) had an unexpectedly good prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Longitudinal biomarker analysis was conducted on 29 patients. The highest average plasma levels of sC5b-9 and Ba during the first 100 days were observed in patients meeting both cTMA and ASTCT-HR criteria (+/+). When focused on early biomarkers measured around day 15, sC5b-9 (P=0.041) and Ba (P=0.004) were significantly elevated in the doubly positive TMA group (+/+) vs. non-TMA group (-/-) (Figure 2). We did not observe significant differences for ASTCT-HR singly positive (-/+) vs. non-TMA group (-/-). Conclusions: In the current prospective clinical and biomarker study, the recently proposed ASTCT-HR definition was more sensitive but less prognostic than the traditional cTMA definition for TA-TMA. Patients who solely met the ASTCT-HR diagnostic criteria but not the cTMA criteria had benign complement biomarker profiles and excellent survival prognosis without TMA-directed therapy. While clinicians need to be vigilant for this infrequent yet potentially severe complications, it is crucial that diagnostic criteria accurately identify affected patients given the expense and potential complications of treatment. We recommend ongoing validations of the new consensus diagnostic criteria from other prospective cohort studies with larger sample sizes and extended follow-up.

Evaluation of Safety and Efficacy of Ruxolitinib in Patients with Pediatric Lymphoproliferative Disorders

Introduction. Pediatric lymphoproliferative disorders (PLPD) encompass a wide spectrum of immune dysregulation conditions with heterogeneous clinical presentation and lab abnormalities. The underlying mechanisms of PLPD are diverse, including dysregulated differentiation of immune cell populations, aberrant recruitment of lymphocyte populations, and/or retention and pathologic survival of lymphocytes. Many PLPD are associated with inborn or acquired genetic factors impacting immune function. Standardized measures to characterize clinical and biological factors in PLPD patients and responses to therapy are lacking. One common feature in PLPD patients is activating IFNg signaling. Ruxolitinib is a drug that blocks hyperactivated IFNg signaling through the JAK-STAT pathway. The goal of this study is to describe the clinical responses of PLPD patients to ruxolitinib. Methods. Medical charts were reviewed to identify patients with PLPD treated with ruxolitnib at Texas Children's Hospital over a 7-year period. Clinical manifestations (recurrent fever, fatigue, lymphadenopathy, recurrent infections, pulmonary disease, endocrinopathy, enteropathy, hepatosplenomegaly, arthritis, CNS symptoms, atopy, dysphagia, underweight), lab values of complete blood count and pathologic inflammation markers (CXCL9, ferritin, sIL2R, IL-18, CD163, neopterin) were categorized with a severity system indicating: 0 no clinical signs and normal lab values; 1 mild to moderate symptoms and abnormal lab values; 2 severe symptoms, highly abnormal lab values (table 1). Total score was computed before and during the addition of ruxolitinib. Complete response (CR) represented a reduction of the total score to 0. Partial response (PR) signified reduction of criteria score ≥ 30% from the baseline with no progression or manifestation of new symptoms. Progression of the disease or improvement &amp;lt; 30% was marked as no response (NR). Results. Chart review identified 19 children and young adults with PLPD who received treatment with ruxolitinib (median age 8.5 years; range 1.2 to 21.6 years). Underlying disease states driving PLPD included HLH, inborn errors of immunity, juvenile rheumatoid arthritis, macrophage activation syndrome, malignant atrophic papulosis of Degos, Aicardi-Goutierres Syndrome, and T-cell large granular lymphocytic leukemia.Genetic variants known or predicted to be damaging were identified in 15 cases (79%), including STAT1, STAT3, TREX1, OFD1, NLRP12, NLRP4, UNC13, PRF1, AP3D1 and mosaic genome-wide paternal uniparental disomy. While 79% of patients received ruxolitinib in combination with other immune suppressants, 21% received only ruxolitinib out of which half received it as front-line therapy. Based on the PLPD Scoring System, overall response rate to ruxolitinib was 73.7%, with 5.3% achieving CR, and 68.4% PR. Overall survival on this study was 84.2% with median 11 months follow-up (range: 0.5 month to 7.1 years). Three patients died due to uncontrolled disease progression. Six patients in whom hematopoietic cell transplant was deemed essential for cure survived to conditioning. Toxicities potentially related to ruxolitinib included grades 1 to 4 cytopenias and grade 1 elevated liver enzymes. Conclusion. PLPD represents a population with overall poor outcomes. We developed standardized staging and response metrics to characterize extent of immune dysregulation and response to therapy. Ruxolitinib represents a potential “precision” therapeutic intervention for patients with pathologic IFNg pathway activation. Ruxolitinib was well-tolerated in this high risk population, and was associated with positive responses in the majority of patients. This study supports expansion of prospective studies to validate the PLPD Scoring System and to optimize therapeutic strategies to manage immune dysregulation, including ruxolitinib.

High Titer ANA at Pediatric ITP Presentation Associated with Progression to Systemic Lupus Erythematosus

Introduction: Immune thrombocytopenia (ITP) is a feature of systemic lupus erythematosus (SLE) in 5-20% of cases. ITP may present at the time of SLE presentation or may precede SLE diagnosis by up to nearly a decade. Even in the absence of an SLE diagnosis, ITP patients may have a positive ANA in ~20% of cases. Some studies suggest that a positive ANA in ITP may herald chronic and more refractory disease, while other studies have not demonstrated a link between ANA+ ITP and progression to SLE. The natural history of ANA+ pediatric ITP patients remains unclear. With the concept that hydroxychloroquine may modulate progression to systemic autoimmunity, European hematologists report using hydroxychloroquine in ANA+ pediatric ITP patients with titers as low as 1:160. However, whether ANA+ ITP patients represent a distinct cohort clinically and should receive different therapies is not well established. The goals of this study were to evaluate the significance and degree of a positive ANA titer at presentation in a cohort of pediatric ITP patients. Methods: Data from a retrospective cohort of 711 ITP patients treated at Texas Children's Hospital from 2012-2022 were reviewed. Patients were defined as SLE if diagnosed as such by rheumatology. To focus on the prognostic value of an ANA upfront, the cohort was refined to include only ITP patients with ANA testing within the newly diagnosed period (0-3 months). Individuals who received IVIG prior to ANA testing were coded as having a missing ANA result given the possibility of false positive results. Being diagnosed concurrently with SLE and ITP was defined as diagnoses within 1 month of each other. Fisher's exact tests were used to compare nonparametric data with a P &amp;lt;0.05 defined as statistically significant. P values were corrected for multiple testing. Results: One hundred sixty-one ITP patients were included for analysis. The cohort was an average of 11.9 years-of-age with a slight female predominance (58.4%). Most of the population self-identified as White and non-Hispanic (84.7%, 45.5%). Nearly 80% had primary ITP and 66.7% were ultimately diagnosed with chronic ITP (cITP). The mean follow-up time for the cohort was 2.2 years (with a range from 0 to 12 years). Forty-seven of 161 (29.2%) individuals had a high titer ANA ³1:1280 at ITP presentation. (Figure 1) There was a statistically significant difference in ANA titer and presence of secondary ITP (P&amp;lt;0.001). Sixty-eight percent (n=23) of secondary ITP patients had a high titer (≥1:1280) ANA versus 20% (n=24) of the primary ITP patients. There was no difference between ANA titer and development of cITP vs. non-cITP. Of this cohort, 20 patients had an ANA tested at ITP presentation and were diagnosed with SLE by rheumatology. Most of these patients had an ANA titer ≥1:1280 (84.2%). The remaining 3 patients had titers of 1:320. Of this cohort, 9 patients had SLE and ITP diagnosed concurrently and 2 had SLE preceding ITP diagnosis by an average of 3.8 years. All 11 patients had an ANA ≥1:1280. Of the 9 who were not diagnosed with SLE at ITP presentation, 6 (66.6%) had an ANA ≥1:1280 and 3 had a titer of 1:320. The lead time to being diagnosed with SLE after presenting with ITP was 1.76 years. Discussion and Conclusions: In this cohort, high titer ANAs in newly diagnosed ITP patients were linked to development of secondary ITP and SLE. Lower titer ANAs were less common, even in those who went on to develop SLE. These findings suggest that specifically high titer ANA results may herald SLE development in pediatric ITP patients. To allow the onset of SLE to be identified earlier, individuals with a high titer ANA at ITP presentation may warrant closer follow-up to monitor for progression to systemic autoimmune disease. This subset of ITP patients could benefit from earlier institution of SLE-directed therapy, such as hydroxychloroquine. Further analysis is underway, including expansion of this analysis to multiple sites within the Pediatric ITP Consortium of North America, as well as surveying pediatric ITP treaters on their practice regarding ANA testing and management in ITP patients.

The Quest for Improving Sickle Cell Care: Creating High-Level Quality Improvement Goals with a Care Process Team

Background: A Care Process Team (CPT) is an interdisciplinary team focused on improvement effort across systems or a population cohort with high degree of variation in care, high volume, high cost, or institutional priority. The Texas Children's Hospital Quality &amp; Safety Department has implemented CPTs for several disease populations including, asthma, diabetes, and pain management. In 2021, the sickle cell CPT (SCCPT) was launched in partnership with the Texas Children's Cancer and Hematology Center. An early step in developing a CPT is delineating goals via a balanced scorecard, a comprehensive framework that translates the team's strategic objectives into a coherent set of performance measures. After establishing priority quality metrics, the SCCPT sought to establish an operational structure and to define and implement specific quality improvement (QI) initiatives to improve outcomes. Methods: The SCCPT assembled a multi-disciplinary expert panel which included providers, nurses, division leadership, data architects, analysts, and quality specialists. After a systematic review of the literature identified metrics with best practice evidence, a modified-Delphi process was used to rank quality metrics according to standards set forth by the National Quality Forum. High-priority metrics were organized into a balanced scorecard. Goals were developed based on Institute of Healthcare QI methodology. A QlikView® dashboard was created to abstract patient data from the electronic medical record. Results: The expert panel met 7 times between January to October 2021. The systematic review found 26 quality measures for SCD and subsequently panel review expanded the list to 34 measures. Expert consensus was reached and 5 metrics were selected for the final SCCPT balanced scorecard. The SCCPT initiated routine meetings in January 2022. Three goals and SMART aims were prioritized from balanced scorecard metrics relating to stroke screenings, disease-modifying drug education and prescriptions, and assignment of a primary Hematology team. Baseline data revealed that 60% of eligible children with SCD had obtained a transcranial Doppler ultrasound within the last 15 months. Hydroxyurea was prescribed to 70% of patients with Hb SS or S/beta-0-thalassemia disease. Primary Hematologist and nurse coordinator teams were assigned to 50% and 23%, respectively. To design and implement QI projects, two teams were created: one focused on prevention-related metrics and the other on treatment-related metrics. Discussion: The successful launch of the SCCPT involved the convening a team of multi-disciplinary members, creation of a balanced scorecard, prioritizing goals, and analyzing baseline data to set SMART aims related to improving SCD care. Two operational teams were created and have proceeded to design and implement QI projects related to SMART aims.

Establishing Real-World Data-Driven Response Criteria in Pediatric Acute Myeloid Leukemia

Introduction: Disease response criteria in pediatric acute myeloid leukemia (pAML) include complete remission (CR), complete remission without platelet count recovery (CRp), and complete remission with incomplete count recovery (CRi). Although clinicians use CR, CRp, and CRi as valid endpoints, the FDA only accepts CR as a valid response endpoint with the Cheson/European Leukemia Network (ELN) response criteria of absolute neutrophil count (ANC) &amp;gt;1,000 and platelets &amp;gt;100,000. Recent adult data show improved survival in patients achieving CR relative to CRp or CRi. Pediatric data from the Children's Oncology Group (COG) demonstrate similar survival regardless of achieving an ANC &amp;gt;500 or platelets &amp;gt;50,000. However, actual ANC and platelet data were not known, and COG data may not reflect outcomes of patients treated off study. Exclusion of CRp and CRi as valid efficacy endpoints limits clinical trials by potentially excluding patients who achieve remission but proceed to subsequent chemotherapy prior to meeting ELN recovery criteria. To address this data gap, we defined the ANC and platelet count trajectories in a 13-day window at end of course bone marrow (BM) after Induction I/II and Reinduction I/II of relapse therapy. We compared disease-free (DFS) and overall survival (OS) among CR categories and hypothesized that CR, CRp, and CRi after Induction I and Reinduction I would be associated with similar DFS and OS. Methods: Newly diagnosed pAML patients from 2011-2022 with at least one frontline chemotherapy course at one of six pediatric centers (Children's Hospital of Philadelphia, Children's Healthcare of Atlanta, Children's Hospital of Michigan, C.S. Mott Children's Hospital, Lurie Children's Hospital, and Texas Children's Hospital) underwent manual chart abstraction to capture demographic, therapy, toxicity, and BM response data: morphologic and minimal residual disease (MRD). The highest daily ANC and platelet counts were abstracted ±13 days around the last BM aspirate after Induction I/II and reinduction I/II post relapse. ELN and COG recovery criteria for ANC (&amp;gt;1,000 and &amp;gt;500, respectively) and platelet (&amp;gt;100,000 and &amp;gt;50,000, respectively) defined CR, CRp and CRi; CRi was further divided into CRnoANC and CRnoANCnoPlatelet. Standard descriptive statistics and Kaplan-Meier (KM) methods were used for analyses. Course-specific evaluations were restricted to subjects with an end of course BM documenting morphological response and ANC/platelet values on the day of course ending BM or 1 day prior. Results: The source population contained 486 patients with the analysis cohort restricted as described above to include 313 patients in Induction I, 290 patients in Induction II, 70 patients in Reinduction I, and 34 patients in Reinduction II. This represents 707 total courses and 8933 ANC/platelet observation days, restricted from 1166 courses (371 without morphologic response and 88 lacked ANC/platelet at course end BM). Demographic covariates included age, sex, race, ethnicity, risk group, MRD, extramedullary disease, weight category, and insurance. At Induction I, MRD differed significantly by CR category for ELN and COG criteria; risk group approached but did not reach significance; and Hispanic ethnicity differed by CR category only in COG criteria. No covariates differed significantly at Reinduction I in either ELN or COG criteria. At Induction I, CR proportion differed between ELN and COG criteria: 40.9% (95% CI 35.5-46.6%) vs 69.6% (95% CI 64.2%-74.7%). At Reinduction I, CR proportion differed between ELN and COG criteria: 18.6% (95% CI 10.3-29.7%) vs 47.1% (95% CI 35.1-59.4%). Panel 1a shows median ANC at Induction I BM is &amp;lt;1000 (ELN) but &amp;gt;500 (COG) in &amp;gt;75% of individuals. KM analyses showed no significant differences in CR strata in ELN or COG criteria in DFS or OS at Induction I. At Reinduction I, ELN CR strata did not differ, but COG CR strata were significantly different in DFS (p = 0.0007) and OS (p = 0.0019) with CRp and CRnoANC with higher DFS than CR or CRnoANCnoPlatelet (Panel 1b). Conclusion: These real-world data suggest that ELN/COG response criteria may lead to markedly different CR rates that may impact reported response rates in clinical trials. These analyses also support COG CR response criteria in de novo pAML and CR, CRp, and CRnoANC in relapsed pAML, recognizing that the modest relapsed pAML sample size requires additional data to determine optimal response criteria.

1692. Increasing incidence of Streptococcus anginosus group intracranial complications of sinusitis, otitis media and mastoiditis in a pediatric population

Abstract Background The Streptococcus anginosus group (SAG) pathogens (S. anginosus, S. intermedius, and S. constellatus) are oral flora with the potential to cause head and neck space infections including brain abscesses. Several centers noted an increase in intracranial abscesses in children in the SARS-CoV-2 era, prompting a CDC health alert in May 2022. Notably, a large proportion of such reported cases were associated with SAG and/or sinusitis. We examined the epidemiology of pediatric intracranial abscesses with a focus on SAG in the pre- and post-pandemic periods. Methods Cases of intracranial abscesses (parenchymal, subdural, epidural) of any microbiologic etiology from January 1, 2011 to December 31, 2022 were identified at Texas Children's Hospital by ICD10 codes. Subjects were cross referenced with culture results of the microbiology laboratory. Cases included were those associated with either otitis media, mastoiditis, or sinusitis. Temporal trend in these infections was investigated with linear regression. Results 157 cases were identified and 59.9% were due to SAG. The incidence of all sinogenic/otogenic intracranial infections (p=0.006), and SAG specific infections (p=0.01), increased from 2011 to 2022 (Figure 1). SAG infection was more often associated with multiple surgeries and these subjects were specifically more likely to require craniotomy or craniectomy (Figure 2). Among sinogenic abscesses, S. intermedius was the most common pathogen while among otogenic cases S. pyogenes predominated (Figure 3). There were 8 cases of craniectomies and one relapse (due to SAG) after replacement of autologous bone flap. After March 2020, 6/46 cases tested positive for SARS-CoV-2 (13%); the severity of infection was not significantly different with concomitant COVID and intracranial abscess. The proportion of SAG-associated infections was similar prior to and after the COVID pandemic. *- p= 0.01- &amp;lt;0.05 ** p&amp;lt; 0.01 Conclusion Over the last decade, intracranial complications of sinusitis/otitis have been increasing, and specifically those caused by SAG. This observed trend clearly predated the COVID pandemic. SAG cases were associated with greater need for surgical intervention and specifically neurosurgery. Further work is necessary to determine the explanation for these rising infections. Disclosures Sheldon L. Kaplan, MD, MeMed: Grant/Research Support|Pfizer: Grant/Research Support|Pfizer: Honoraria Jonathon C. McNeil, MD, Allergan: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support

DISP-17. BUILDING A MODEL PEDIATRIC NEURO-ONCOLOGY PROGRAM IN SUB-SAHARAN AFRICA AND ITS IMPACT

Abstract BACKGROUND Central nervous system tumors are the most common solid tumors in children and the second commonest childhood cancer globally. We describe the establishment of the first dedicated comprehensive pediatric neuro-oncology treatment center that may serve as a model for others in low-resource settings and the impact of this initiative. METHODS This is a descriptive interim report of a pediatric neuro-oncology capacity building program in the SSA setting established in March 2019 at Mulago National Referral Hospital in Uganda, including a retrospective study conducted at Mulago National referral Hospital, in patients below 18 years of age admitted with a radiological diagnosis of a brain tumor from March 2019 to March 2023, to demonstrate the impact of this program. The program is a collaboration between Makerere University, Mulago National Referral Hospital, Texas children's Hospital/Baylor College of Medicine, and other academic and philanthropy partners in North America and Europe. RESULTS A total of 14 pediatric oncologists have been trained over 6 years, with one further training in neuro-oncology. Multidisciplinary management involving local experts from Uganda and experts from Texas Children's Hospital has been strengthened. Between March 2019 and March 2023, 121 children were diagnosed radiologically with brain tumors. Majority (57%) of these patients were males. The commonest symptom at presentation was headache (42%). Most of the patients (52%) had infratentorial tumors. The commonest diagnosis was glioma (38%), craniopharyngioma (26%), medulloblastoma (11%). Fifty-two patients had surgical resection and a histological diagnosis. Ten percent of patients had no diagnosis. Radiotherapy was received by 24(20%) patients. Twenty patients received chemotherapy. Sixty-six are alive and attending clinic. The overall one-year survival was 63%(95%CI(50.3-73.4). CONCLUSION Capacity to improve the suspicion, referral, diagnosis and comprehensive care for children with central nervous system tumors in low-resource settings can be improved through innovative collaborations.

Responses to Combination Chemotherapy with MAPK Pathway Inhibition in Relapsed and Refractory LCH

MAPK pathway inhibition (MAPKi) is associated with high response rates in patients with Langerhans cell histiocytosis (LCH), but monotherapy may not be curative and efficacy in LCH-associated neurodegeneration (LCH-ND) is not known. Based on upregulation of Bcl-xL by MAPK activation, we hypothesize that MAPKi may render LCH cells more sensitive to chemotherapy-induced cytotoxicity. We assessed the safety and efficacy of combination therapy in 10 patients with refractory systemic disease and LCH-ND. Records of patients treated with combination therapy at Texas Children's Hospital from October 2018 to July 2023 were reviewed for clinical responses as well as peripheral blood/tissue BRAFV600E mutation status, ataxia rating scores, and toxicity. The median age at the start of combination therapy was 6.82 years (range, 0.48-20.45 years) with a median of 4 treatments prior to this therapy regimen (range, 1-14). Almost all Clofarabine was administered outpatient (typical starting dose 25 mg/m2/day x 5 days). MAPK inhibitors included BRAFV600E inhibitors (50%) and MEK inhibitors (50%). Overall response was 8/10 (80%), with 5/5 (100%) objective response rate (ORR) for systemic disease. Further, 5/6 (83%) demonstrated reduced or extinguished peripheral BRAFV600E+ fraction by the end of combination therapy. Ataxia rating scores were improved in 2/3 (67%) individuals with clinical neurodegeneration. Common toxicities during treatment included fever, skin rash, arthralgia, and cytopenia. Combining therapy was well-tolerated and associated with clinical and molecular improvement in most patients with highly refractory systemic LCH and LCH-ND. Further prospective multi-center trials are required to optimize this approach, determine potential for combination therapy to achieve cure, and compare risks and benefits to chemotherapy or MAPK inhibitor monotherapy.

Telomere Length Testing of Lymphocytes Alone By Flow-FISH Is a Highly Sensitive and Specific Test to Screen for a Telomere Biology Disorder in a Cohort of Children and Very Young Adults with Bone Marrow Failure

Background Uncovering an underlying telomere biology disorder (TBD) in patients with bone marrow failure (BMF) has crucial implications for treatment and outcomes, including hematopoietic cell transplantation and malignancy risk. Telomere length (TL) testing of peripheral blood leukocytes by clinical Flow-FISH has become an important test in diagnosing TBDs. In seminal studies, Alter et al. compared age-adjusted TL lengths (&amp;lt; or ≥1 st percentile) in lymphocytes (lymphs), granulocytes (grans), and four lymph subsets in individuals with a known TBD and their unaffected relatives. They found that very low (VL) TL (&amp;lt;1 st percentile) in lymphs had a sensitivity (Sens) of 97%, specificity (Spec) of 91%, and positive predictive value (PPV) of 85% for a TBD diagnosis. VL TL in 3 or 4 lymph subsets had slightly better test performance with a Sens of 98%, Spec of 94%, and PPV of 89%. We hypothesized that test performance characteristics of flow FISH would be different if applied to a ‘real-world’ cohort, which could inform the use of TL in lymphs alone versus in the four lymph subsets for different clinical indications. Methods We performed a search of the electronic medical record to identify all individuals who had Flow-FISH performed at Texas Children's Hospital from 2007 - 2022 (Figure 1). We excluded those who had the 2-panel test (lymphs and grans) or family TL cascade testing. We collected the indication for and results of Flow-FISH, demographic and clinical characteristics, and genetic testing information via chart review. A composite score (Comp Score) was created to define TBD (Comp Score of 1 or 2) vs. Not TBD (Comp Score &amp;lt;1). Performance of lymph TL alone and TL in 3 or 4 lymph subsets in predicting TBD was evaluated using Sens, Spec, PPV, NPV, area under ROC curve (AUC), and Cohen's Kappa statistic (k). Results Our final cohort included 433 individuals who received the 6-panel test (lymphs, grans, and four lymph subsets) with a median age of 9.7 years, range 0.06-22.6. Top indications for Flow-FISH were severe aplastic anemia (SAA) (n=106), mild aplastic anemia (AA) (i.e., not fulfilling criteria for MAA or SAA) (103), cytopenias without known or documented bone marrow hypoplasia or dysplasia (70), moderate aplastic anemia (MAA) (37), non-therapy-related myelodysplastic syndrome (26), and an incidental TBD gene variant identified through comprehensive sequencing (17). Twenty-two subjects (5.1%) had a TBD, 17 (3.9%) of which had a pathogenic/likely pathogenic variant (P/LPV) in a known TBD gene (Figure 1). Seven of those with SAA (6.6%) had VL TL in lymphs, 5 (4.7%) of which also had VL TL in 3 or 4 of the lymph subsets, and only 1 (0.9%) had a TBD based on Comp Score. Importantly, none had VL TL in 3 or 4 of the lymph subsets without VL TL in lymphs. Five of those with MAA (13.5%) had VL TL in lymphs, all of which had VL TL in 3 or 4 lymph subsets. Three had a TBD based on Comp Score, and each had a PV in a TBD gene; a TBD variant was not identified in two despite exome sequencing and chromosomal microarray testing. Eighteen of those with mild AA (17.5%) had VL TL in lymphs, 15 (14.6%) also had VL TL in 3 or 4 lymph subsets, 9 (8.7%) had a TBD based on Comp Score, and 7 (6.8%) had a P/LPV in a TBD gene. The Sens of TL in lymphs &amp;lt; vs. ≥ 1 st percentile and TL &amp;lt; 1 st percentile in 3 or 4 vs. &amp;lt; 3 lymph subsets against TBD based on Comp Score in those with AA regardless of severity was 100%, and the Spec ranged from 90.4% (lymph TL testing alone in mild AA) to 96.2% (lymph subsets testing in SAA) (Table 1). The PPV for both test approaches was low (≤20%) in SAA due to the low prevalence of TBD in this population. PPV was between 50-60% in the other AA groups. The AUC for detecting a TBD in the various AA groups was comparably high for both test approaches (0.95-0.98). The two tests had a substantial to almost perfect agreement (k=0.82, p&amp;lt;0.001). Conclusions This single institutional cohort demonstrates that the prevalence of TBD in young patients presenting with SAA is remarkably low, and the Sens and Spec of TL testing in lymphs alone are sufficiently high to detect the rare TBD patient and prompt additional testing (e.g., genetics) in few patients due to false positive testing. The prevalence of TBD is higher in those with MAA or mild AA, yet both test approaches detect all TBD patients. Spec level in mild AA is marginally higher with lymph subset TL testing but, at ~94%, underscores the need for other clinical parameters (e.g., genetics) to establish a TBD diagnosis in a small percentage of patients.

Retrospective Analysis of Clofarabine Salvage Therapy in Refractory Multifocal Langerhans Cell Histiocytosis (LCH)

Purpose: LCH is a neoplastic inflammatory disorder driven by recurrent somatic mutations in the MAPK pathway in myeloid precursors. Over 50% of patients with systemic LCH are not cured with front-line therapies and data to guide salvage options are limited. In this study, we describe 58 patients with relapsed/refractory LCH who were treated with clofarabine. Methods: Data were extracted from clinical records of patients treated with clofarabine for LCH by Texas Children's Hospital physicians or collaborators between May 2011 and 2023. Results: Patients were treated with a median of two chemotherapeutic regimens prior to receiving clofarabine; median age was 3.49 (4 months to 61 years). The typical treatment course was 25mg/m2 daily for 5 consecutive days per month; 19%(11/58) received treatment for less than 6 months; 26%(15/58) for 6-9 months; and 55%(32/58) for 9-24 months. OS in this cohort was 100%(58/58) and PFS was 75% with median 2-year follow-up (range: 5 months to 11 years); The objective response rate (ORR) for all patients was 84% with 9%(5/58) maintaining stable disease and 7%(4/58) developing progressive disease during the study period. Patients treated for LCH-associated neurodegeneration had relatively worse outcomes (ORR: 63%) compared to patients with systemic disease without LCH-ND (ORR: 88%). Patients treated with clofarabine showed significant decreases in the amount of detectable BRAFV600E alleles in their circulating peripheral blood mononuclear cells. Toxicities included cytopenia, vomiting, and bacterial infections, but the majority tolerated chemotherapy in the outpatient setting. Conclusion: Clofarabine monotherapy has activity against LCH in heavily pretreated patients, the majority of whom achieved durable remission. Prospective multi-center trials are warranted to determine optimal dosing as well as long-term efficacy, late toxicities, relative cost and patient reported outcomes of clofarabine compared to alternative salvage therapy strategies (e.g. MAPK inhibitors) in patients with relapsed/refractory LCH.

Development of a Novel Methotrexate-Related Neurotoxicity Risk Score in Pediatric Acute Leukemia: A Report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Introduction: Methotrexate (MTX) chemotherapy is a critical component of contemporary pediatric acute lymphoblastic leukemia (ALL) treatment regimens. However, intrathecal (IT) and intravenous (IV) MTX can result in dose-limiting acute neurotoxicity, which has been associated with an increased risk of ALL relapse. Emerging data suggest the likelihood of MTX neurotoxicity is elevated in Latino patients and those diagnosed at older age or treated with high-dose MTX (&amp;gt; 1g/m2); however, there are no established methods for identifying those at greatest risk. Therefore, we used machine learning algorithms to develop a neurotoxicity risk prediction model in a diverse, multi-ethnic cohort of pediatric patients with ALL. Methods: The Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium enrolls patients diagnosed with ALL from six participating treatment centers in the Southwestern U.S. This interim analysis included pediatric patients (age &amp;lt;20 years) diagnosed and treated for ALL at Texas Children's Hospital (2005-2019). Individuals diagnosed with infant leukemia (&amp;lt;1 year of age) and/or with preexisting neurologic disease were excluded. We retrospectively reviewed medical records to identify clinical, sociodemographic, and Common Terminology Criteria for Adverse Events (CTCAE) grading of toxicities such as transaminitis and hyperbilirubinemia. Address information at the time of diagnosis was geocoded and aligned to the American Community Survey at the census-tract level to define residential social determinants of health (SDOH). Cases of MTX neurotoxicity were identified by manual review of records for any patient who underwent brain MRI imaging during ALL therapy. Cases of acute MTX neurotoxicity were defined following Ponte di Legno Delphi Consensus definitions as neurologic episodes (e.g., seizure, stroke-like symptoms, altered mental status) occurring within 21 days of IV or IT MTX with no other identifiable underlying cause. Demographic and clinical factors were compared between cases of acute MTX-related neurotoxicity and controls using logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI). The dataset was randomly split with 80% of observations used in the training stage and 20% reserved for testing. Random forest algorithms with boosting and down sampling were grown using 5-repeat, 10-fold cross validation to optimize tuning parameters. Model performance was evaluated using test and train error rate, area under the curve of the receiver operating characteristic (AUC-ROC), sensitivity, and specificity. Results: A total of 770 patients were eligible and met inclusion criteria. Patients were a mean age of 7.0 years at diagnosis, 54% male, 55% Latino and 45% treated with high-risk protocols. Acute MTX neurotoxicity developed in 134 (17.4%) of patients. In logistic regression models, neurotoxicity odds increased with older age at diagnosis (OR = 1.20, 95% CI: 1.15-1.26), Latino ethnicity (OR = 2.14, 95% CI: 1.38-3.38), treatment on high-risk protocols (OR=4.32, 95% CI: 2.75-6.99), obesity at diagnosis (vs normal weight, OR = 2.54, 95% CI: 1.51-4.22), and CTCAE grade 3 or higher transaminitis (OR = 2.02, 95% CI: 1.03-4.47) or hyperbilirubinemia (OR = 4.71, 95% CI: 1.21-18.41) during induction therapy. Overall, the random forest machine learning algorithm resulted in an AUC-ROC of 0.79 with an error rate of 0.26 in both the training and test sets. The overall sensitivity was 0.71, with a specificity of 0.67. Recognizing ethnic disparities in MTX neurotoxicity may exist, random forest models were generated stratifying on ethnicity (Figure 1), which yielded slightly better performance in non-Latino patients (AUC-ROC = 0.77) than Latino patients (AUC-ROC = 0.73). Conclusions: This interim analysis of data from the REDIAL Consortium demonstrates the potential utility of machine learning algorithms to develop a novel risk prediction model for acute MTX-related neurotoxicity. Efforts to expand this work within the larger REDIAL cohort (n&amp;gt;2,000) and incorporate inherited genetic data are ongoing. Ultimately, this work may inform efforts to preemptively risk-stratify patients and deliver targeted interventions to vulnerable individuals.

Global regulatory reforms to promote equitable vaccine access in the next pandemic.

There is broad consensus that the global response to the Covid-19 pandemic was inadequate, leading to unacceptable levels of avoidable morbidity and mortality. Three strategic missteps led to the lack of equitable vaccine access: The heavy reliance on commercial vaccine manufacturers in high-income countries (HICs) versus low- and middle-income countries (LMICs); the emergence of vaccine nationalism restricting and delaying the supply of vaccines to LMICs; and an inadequate support or recognition for LMIC national regulatory authorities. To avoid these inequities in a future pandemic, we focus on three successful vaccine development and technology transfer case studies-the Hepatitis B vaccine produced in South Korea in the 1980s; the Meningitis A vaccine for Africa led by Program for Appropriate Technologies in Health (PATH) and the World Health Organization (WHO) in the 2000s; and a recombinant SARS CoV-2 protein-based vaccine technology from the Texas Children's Hospital transferred to India and to Indonesia. In addition to expanding support for academic or non-profit product development partnerships, our analysis finds that an essential step is the strengthening of selected LMIC regulatory systems to become Stringent Regulatory Authorities (SRAs), together with a re-prioritization of the WHO Prequalification (PQ) system to ensure early vaccine availability in LMICs especially during pandemics. Advancing LMIC National Regulatory Authorities (NRAs) to Stringent Regulatory Authorities (SRAs) status will require substantial resources, but the benefits for future pandemic control and for health in LMIC would be immense. We call on the WHO, United Nation (UN) agencies and SRAs, to collaborate and implement a comprehensive roadmap to support LMIC regulators to achieve stringent status by 2030.

SAT146 Recurrent Hypoglycemia Following Asparaginase Therapy For Childhood Cancer: Institutional Experience

Abstract Disclosure: M. Tantoush: None. Background: Asparaginase (ASP) is a cornerstone pediatric leukemia and lymphoma therapy. Hyperglycemia following ASP is described, but hypoglycemia is infrequently identified as a complication. Following hypoglycemic events in children receiving ASP therapy, evaluation of associations and outcomes was undertaken. Aim: Evaluate and describe the risk factors, prevalence, duration, severity, recurrence and outcomes of children developing ASP-induced hypoglycemia. Method: Retrospective cohort study using electronic medical records to identify all patients who received ASP (PEGylated or non-PEGylated), and had diagnosis of hypoglycemia between 6/1/2017 and 6/30/22 at Texas Children's Hospital. We defined ASP-induced hypoglycemia as blood glucose (BG) &amp;lt;70 mg/dl 2-8 weeks from ASP administration, without alternative causes. If hypoglycemia evaluation was completed, hyperinsulinism was defined by: BG &amp;lt; 50 mg/dL; insulin &amp;gt; 2 mIU/mL; β-hydroxybutyrate &amp;lt; 1.8 mmol/L; free fatty acids &amp;lt; 1.7 mmol/L; or a post-glucagon BG &amp;gt; 30 mg/dL. Demographic and clinically relevant data were collected. Descriptive analysis was completed. Univariate regression models using Stata16 were analyzed. A p-value &amp;lt;0.05 was statistically significant. Results: Patients receiving ASP totaled 722, with 56 (7.6%) having ASP-induced hypoglycemia. Cancer diagnosis included acute lymphoblastic leukemia (n=50), lymphoblastic lymphoma (n=5) or acute myeloid leukemia (n=1). Median age was 4.4 years (IQR: 2.6 - 8.1), with 46% Hispanic and 59% male. Median BMI z-score was +0.4 (IQR: -0.3 - 1.2). Initial hypoglycemia event was during Induction therapy in 86% (n=48), with median time from ASP to hypoglycemia diagnosis 11 days (IQR: 6-15). Median lowest BG was 51 mg/dL (IQR: 43-57) with median duration 11 days (IQR: 7-19). Treatment included dietary change (52%, n=29), cornstarch (29%, n=16), and continuous feedings (13%, n=7). Continuous BG monitoring was utilized in 9 (16%). A critical sample was obtained in 18 (32%) with all evaluations consistent with hyperinsulinism. Recurrent hypoglycemia with subsequent ASP doses occurred in 42 (74%), with a median duration 14 days (IQR: 8-21; max: 56 days). Overall cancer survival following ASP-induced hypoglycemia was 80% (85% if excluding relapse disease), with 3 years’ median follow up. Severity of hypoglycemia (lowest BG, number of events, or length of events) was not associated with age, sex, ethnicity, or BMI z-score in univariate analysis. Conclusion: ASP-induced hypoglycemia is relatively common, often recurs with subsequent dosing, and may become severe requiring intensive therapy. Prospective screening of patients receiving ASP may be appropriate to prevent and manage events. Patients completed chemotherapy without change in survival at 3 years’ follow-up. Further studies to elucidate prognostic factors of ASP-induced hypoglycemia are needed. Presentation: Saturday, June 17, 2023