Jude Children's Research Hospital Research Articles

Multilevel Social Determinants of Patient-Reported Outcomes in Young Survivors of Childhood Cancer.

In this study, the social determinants of patient-reported outcomes (PROs) in young survivors of childhood cancer aged <18 years are researched. This cross-sectional study investigated social determinants associated with poor PROs among young childhood cancer survivors. We included 293 dyads of survivors receiving treatment at St. Jude Children's Research Hospital who were <18 years of age during follow-up from 2017 to 2018 and their primary caregivers. Social determinants included family factors (caregiver-reported PROs, family dynamics) and county-level deprivation (socioeconomic status, physical environment via the County Health Rankings & Roadmaps). PROMIS measures assessed survivors' and caregivers' PROs. General linear regression tested associations of social determinants with survivors' PROs. We found that caregivers' higher anxiety was significantly associated with survivors' poorer depression, stress, fatigue, sleep issues, and reduced positive affect (p < 0.05); caregivers' sleep disturbances were significantly associated with lower mobility in survivors (p < 0.05). Family conflicts were associated with survivors' sleep problems (p < 0.05). Residing in socioeconomically deprived areas was significantly associated with survivors' poorer sleep quality (p < 0.05), while higher physical environment deprivation was associated with survivors' higher psychological stress and fatigue and lower positive affect and mobility (p < 0.05). Parental, family, and neighborhood factors are critical influences on young survivors' quality of life and well-being and represent new intervention targets.

Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease.

Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. We identified 166 children from the UAB cohort (mean age: 13.49±4.47years) and 325 children from the SCCRIP cohort (mean age: 13.41±3.99years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p=.017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p=.028) after adjusting for age, sex, treatment, and site. This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

Response of bilateral wilms tumor to chemotherapy suggests histologic subtype and guides treatment.

Patients with bilateral Wilms tumor (BWT) initially receive neoadjuvant chemotherapy to shrink the tumors and increase the likelihood of successful nephron-sparing surgery. Biopsy of poorly responding tumors is often done to better understand therapy resistance. The purpose of this retrospective, single-institution study was to determine whether initial chemotherapy response is associated with tumor histology, potentially obviating the need for biopsy or change in chemotherapy. Patients with synchronous BWT who underwent surgery at St Jude Children's Research Hospital from January 2000 to March 2022 were considered for this study. A mixed-effects logistic regression model was used to evaluate the likelihood of the tumor being stromal predominant, as predicted by tumor response to neoadjuvant chemotherapy. Sixty-eight patients were eligible for this study. Tumors that increased in size had an odds ratio of 19.5 (95% CI: 2.46-155.03) for being stromal-predominant vs any other histologic subtype. Age at diagnosis was youngest in patients with stromal-predominant tumors, with a mean age of 18.8 months (SD = 14.1 months), compared to all other histologic subtypes (χ2=7.05, p = .07). The predictive value of a tumor growing, combined with patient age less than 18 months, for confirming stromal-predominant histology was 85.7% (95% CI: 57.18%-93.5%). Tumors that increased in size during neoadjuvant chemotherapy were most frequently stromal-predominant BWT, especially in younger patients. Therefore, nephron-sparing surgery, rather than biopsy, or extension or intensification of neoadjuvant chemotherapy, should be considered for bilateral BWT that increase in volume during neoadjuvant chemotherapy, particularly in patients younger than 18 months of age.

Awareness, access, and communication: provider perspectives on early intervention services for children with sickle cell disease.

This study aimed to identify determinants influencing the utilization of early intervention services among young children with sickle cell disease (SCD) based on perspectives from medical and early intervention providers. Early intervention and medical providers from the catchment area surrounding St. Jude Children's Research Hospital and Washington University were recruited (20 total providers). Interviews were completed over the phone and audio recorded. All interviews were transcribed verbatim, coded, and analyzed using inductive thematic analysis. Three overarching themes were identified from both groups: Awareness (e.g., lack of awareness about the EI system and SCD), Access (e.g., difficulties accessing services), and Communication (e.g., limited communication between medical and early intervention providers, and between providers and families). Although these three themes were shared by medical and early intervention providers, the differing perspectives of each produced subthemes unique to the two professional fields. Early intervention services can limit the neurodevelopmental deficits experienced by young children with SCD; however, most children with SCD do not receive these services. The perspectives of early intervention and medical providers highlight several potential solutions to increase early intervention utilization among young children with SCD.

Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.

Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies. We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated. Thirty-three patients (18 male; median age, 5 y) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n=10, 30%). Most tumors were in the cerebral hemispheres (n=22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3±8.3%; the 5-year overall survival (OS) rate was 96.4±4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6±15.2% (p<0.01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways. pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.

Preventing and Treating Pain and Anxiety during Needle-Based Procedures in Children with Cancer in Low- and Middle-Income Countries.

Introduction: Children with cancer experience significant pain and anxiety during needle-based procedures. Undertreated pain in children has long-lasting consequences and reduces the efficacy of subsequent analgesic efforts. A validated quality improvement (QI) intervention, known as the "Children's Comfort Promise", includes (1) topical anesthetics, (2) sucrose or breastfeeding for infants, (3) comfort positioning, and (4) distraction techniques, and has been shown to be highly effective in decreasing procedural pain and anxiety in children. However, there is limited data about the adoption, adaptation, and implementation of these interventions in low- and middle-income countries (LMICs). Methods: A QI pilot project utilizing the Model for Improvement of the "Global Comfort Promise" was implemented in four global pediatric cancer hospitals (Lima, Peru; Barretos, Brazil; Pietermaritzburg, South Africa; and Manila, Philippines). Between August 2021 and January 2023, the pilot sites identified a specific aim, co-designed the measurement strategy with St. Jude Children's Research Hospital, and adopted, adapted, and implemented the project at their individual sites. Results: A total of 2,185 different procedures were recorded in the first year of implementation. Most patients were less than 10 years old (60.5%) and solid tumors (37.9%) were the most common diagnosis. Overall, healthcare professionals (98.3%) were satisfied with the procedures. Parents and patients reported that only 33.7% of patients experienced pain during the procedure. All (100%) parents and patients felt the healthcare teams adequately addressed their child's pain. Median self-reported adherence to ≥2 interventions was 98.0%. Challenges to the implementation of the QI initiative included lack of training, turnover of the medical staff, maintaining staff enthusiasm, and access to topical anesthetics. Each site had unique change ideas to implement the initiative. Conclusions: This multi-site, multi-country QI initiative was feasible and was successfully adopted, adapted, and implemented in the LMIC context to improve procedural pain in children (Global Comfort Promise). Additionally, this intervention resulted in high satisfaction of both healthcare professionals and patients/families. Further work is needed to overcome the challenges of topical anesthetic access and education of the workforce. Additional plans include modifying the Global Comfort Promise to include high-quality communication and expanding to additional sites with further refinement of the implementation strategy.

Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital.

The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL). Twenty-four patients (aged 7 days - 22.2 years) with 26 OmR placements were identified for a total of 25,009 OmR days between 1990 and 2019. Methotrexate cerebrospinal fluid (CSF) concentrations (n = 124) were analyzed from 59 courses of OmR therapy in 15 patients. Twenty-one courses involved methotrexate dosing on day 0 only, whereas 38 courses involved booster dosing on days 1, 2, or both. We simulated the time CSF methotrexate concentrations remained > 1 µM for 3 days given various dosing regimens. CSF methotrexate exposure was higher in those who concurrently received systemic methotrexate than via OmR alone (p < 10- 7). Our simulations showed that current intraventricular methotrexate boosting strategy for patients ≥ 3 years of age maintained CSF methotrexate concentrations ≥ 1 µM for 72h 40% of the time. Alternatively, other boosting strategies were predicted to achieve CSF methotrexate concentrations ≥ 1 µM for 72h between 46 and 72% of the time. OmR were able to be safely placed and administer intraventricular methotrexate with and without boost doses in patients from 7 days to 22 years old. Boosting strategies are predicted to increase CSF methotrexate concentrations ≥ 1 µM for 72h.

COVID-19 in Pediatric Patients With Acute Lymphoblastic Leukemia or Lymphoma

COVID-19 in pediatric patients with acute lymphoblastic leukemia or lymphoma (ALL/LLy) has not been described in detail and may affect chemotherapy administration and long-term outcomes. To describe the clinical presentation of COVID-19 and chemotherapy modifications in pediatric patients with ALL/LLy. This is a retrospective case series of patients at St Jude Children's Research Hospital and its affiliate sites with newly diagnosed ALL/LLy who were treated on the Total XVII protocol (NCT03117751) between March 30, 2020, and June 20, 2022. Participants included patients aged 1 to 18 years who were receiving protocol chemotherapy. Acute symptoms and chemotherapy modifications were evaluated for 60 days after the COVID-19 diagnosis, and viral clearance, adverse events, and second SARS-CoV-2 infections were followed up during the 27-month study period. SARS-CoV-2; all patients were screened at least weekly and at symptom onset and/or after known exposure to SARS-CoV-2. Description of the spectrum of COVID-19 illness and chemotherapy modifications. Of 308 pediatric patients, 110 (36%) developed COVID-19 at a median age of 8.2 (IQR, 5.3-14.5) years. Sixty-eight patients (62%) were male. Most patients were in the continuation/maintenance phase of chemotherapy (101 [92%]). Severe disease was rare (7 [6%]) but was associated with older age, higher white blood cell counts at ALL/LLy diagnosis, lower absolute lymphocyte counts at COVID-19 diagnosis, abnormal chest imaging findings, and SARS-CoV-2 reinfection. Rare but serious thrombotic events included pulmonary embolism and cerebral venous sinus thrombosis (n = 1 for each). No multisystem inflammatory syndrome in children or death was seen. SARS-CoV-2 reinfection occurred in 11 patients (10%) and was associated with older age and with receiving standard or high-risk vs low-risk ALL/LLy therapy. Chemotherapy interruptions occurred in 96 patients (87%) and were longer for patients with severe disease, SARS-CoV-2 reinfection, and/or a COVID-19 diagnosis during the pre-Omicron variant period vs the post-Omicron period (after December 27, 2021). In this case series of COVID-19 in pediatric patients with ALL/LLy, severe COVID-19 was rare, but chemotherapy administration was affected in most patients. Long-term studies are needed to establish the outcomes of COVID-19 in this population.

Developing and sustaining high-quality care for children with cancer: the WHO Global Initiative for Childhood Cancer.

Cancer is a major public health concern, impacting nearly 20 million people each year, and it is responsible for 1 in 6 deaths worldwide. The burden of cancer is increasing rapidly, straining health systems that are unable to prevent and manage the disease. Childhood cancer constitutes a significant and relevant public health challenge; it was the ninth leading cause of childhood disease globally, according to findings by the Global Burden of Disease 2017 study. Almost 80% of all children diagnosed with cancer live in low- and middle-income countries where treatment is often unavailable or unaffordable. As a result, only about 15-45% of these children survive compared with more than 80% in high-income countries. This represents a great health inequity. Delivering on the mandate provided by World Health Assembly resolution 70.12, WHO together with St. Jude Children's Research Hospital and other global partners launched the Global Initiative for Childhood Cancer at the United Nations General Assembly during the third High-level Meeting on the prevention and control of noncommunicable diseases in September 2018. The Initiative aims to increase global survival for children with cancer to at least 60% by 2030, while reducing suffering for all children with cancer. Five years after launching the Initiative, more than 70 countries across the World Health Organization's 6 regions have advanced to different phases of action through implementation of the Initiative's CureAll framework for action. Many successful approaches to implementing the CureAll pillars and enablers have demonstrated that improving care for children with cancer in low- and middle-income countries is possible as long as there is strong political will, multisectoral commitments and strategic investment.

A bibliometric analysis of chemotherapy and pain in pediatric patients over the last decade.

Chemotherapy is an important treatment for children with cancer, and chemotherapy-induced pain is an important role in affecting patients' quality of life. In our study, bibliometric analysis was used to identify current research hotspots and future research trends of chemotherapy and pain in children over the last decade. Our findings can provide a reference for the research in the field of chemotherapy and pain in children. Publications of chemotherapy and pain in children were collected from the Web of Science Core Collection database. CiteSpace was used to analyze publication characteristics from 2013 to 2022. We identified 1,130 eligible publications in the field of chemotherapy and pain in children, with an increasing trend of publications over the last decade. In the field of chemotherapy and pain in children, the United States had the most publication with 346, followed by China with 135. The author with the most published papers was Pamela S Hinds (n = 8) from the United States. The journals that published the most papers were the Journal of pediatric hematology oncology (n = 44) and Medicine (n = 44). The Journal of Clinical Oncology was cited the most frequency (n = 422). St. Jude Children's Research Hospital had the most publication (n = 23). The specific keywords related to the field of chemotherapy and pain in children were "children", "chemotherapy", "management", "childhood cancer", "randomized controlled trial" and "efficacy". Emerging research focuses predominantly on symptomatic and supportive interventions for chemotherapy and pain in children. Attention to chemotherapy and pain in children with cancer was insufficient. This bibliometric analysis showed the upward trend of chemotherapy and pain in children over the last decade. More studies are needed to improve the quality of life in children with chemotherapy-induced pain. This study may provide useful information to guide future research on chemotherapy and pain in children.

A Genotype Validated Bimodal Method for the Large-Scale Identification and Phenotyping of Persons with Sickle Cell Disease Using Electronic Health Record Data

Introduction Clinical trials for using hematopoietic stem cell transplant (HSCT) with gene therapies to cure sickle cell disease (SCD) began in 2019. The Food and Drug Administration (FDA) requires that 1) all gene therapy participants receive at least 15 years of ongoing surveillance and 2) their outcomes be compared to a contemporaneous cohort that did not receive gene therapy. Previously we developed an automated contemporaneous cohort of children and adults with SCD from electronic health record (EHR) data (Cronin RM et al. 2023, Blood Adv). Our work was built upon previously explored algorithms utilizing ICD codes and laboratory data to identify persons with sickle cell anemia (SCA), a severe form of SCD (Singh et al. 2018, Blood Adv). Still, our algorithm additionally classifies other predicted genotypes. However, we could not test the SCD phenotypes against the SCD genotypes due to the absence of beta-globin gene sequence data. Here we tested the hypothesis that our Vanderbilt-EHR algorithm for identifying a contemporaneous cohort at Vanderbilt can classify their predicted genotype compared to beta-globin gene sequencing, the gold standard for SCD diagnosis, in the cohort. We subsequently tested the Vanderbilt-EHR algorithm in an established cohort of children from St. Jude Children's Research Hospital that have been deeply phenotyped. Methods We applied the Vanderbilt-EHR algorithm to a cohort of 275 samples from Vanderbilt's biorepository of DNA, BioVU, linked to de-identified medical records in a data warehouse called the Synthetic Derivative. These 275 samples were previously submitted for whole genome sequencing as part of the Genetic Variation of Heart, Lung, and Kidney Disease in Sickle Cell Disease: Pre- and Post-Curative Therapies TOPMed project (HLK-SCD phs002617). The returned genotypes were validated using the hemoglobin variant database HbVar (Giardine BM et al. 2021, Nucleic Acids Res) (Table 1). We applied the hemoglobinopathy genotype classification portion of the algorithm to the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort from St. Jude Children's Research Hospital, which includes putative genotype diagnoses derived from a comprehensive evaluation of clinical data for each member. We performed statistical analyses of the identification and classification results of the Vanderbilt cohort and the SCCRIP cohort's classification results. Results Of the 275 genotyped samples, the algorithm correctly predicted 255 SCD cases and 10 non-SCD cases. There were three cases predicted to be false positives; however, a comprehensive analysis showed that all have laboratory values indicative of SCA (high hemoglobin S levels &amp;gt;60%, absent or negligible hemoglobin A levels, elevated reticulocytes, and low mean corpuscular volume) suggesting that there may be a genotyping error. The remaining 7 cases were either indeterminate in the prediction or in the genotype (Table 1). Given the small number of indeterminate results, we performed a sensitivity analysis to identify the range of performance for SCD identification. The method performed very well with over 98% sensitivity and over 96% positive predictive value (PPV) (Table 2). The lower specificity and negative predictive value (NPV) could be largely attributed to the disproportionately high number of SCD cases in the dataset compared to non-SCD cases. The SCD classification algorithm performed similarly in both the VUMC and SCCRIP cohorts (Table 2). The algorithm performs best in identifying SC and SCA types of SCD with nearly 100% accuracy for SC and over 94% accuracy for SCA. Transfusions can confound the diagnosis of SCA vs. S beta thalassemia +, but the latter has a much lower prevalence consistent with our results (Table 2). Discussion and Conclusions Larger SCD cohorts will be identified using these approaches in singular EHR databases and in de-identified data warehouses that EHR companies have developed by aggregating data across multiple EHR systems (e.g., EPIC Cosmos and Cerner Real-World Data). The ongoing need for contemporaneous comparison cohorts of persons with SCD to understand outcomes related to treatment and phenotype can be greatly assisted by accurate automated approaches. The Vanderbilt-EHR algorithm is the first to comprehensively phenotype SCD and other hemoglobinopathies involving variant hemoglobin beta alleles.

Impact of Cytarabine Pharmacogenomics on Survival of Adolescent and Young Adults with AML and Its Clinical Relevance in Black Patients

Cytarabine (also known as ara-C) has been the mainstay of AML chemotherapy for both pediatric and adult patients (pts) since 1970s, and when given in combination with anthracycline it induces remission in ~60% of adult and 80% of pediatric pts. However, almost ~40% of pts relapse. Cytarabine is a prodrug requiring activation to ara-CTP for its antileukemic effect. Our group has been investigating the relevance of cytarabine pharmacogenomics and recently reported a pharmacogenomics-based polygenic score (ACS10) that includes 10 SNPs spanning 9 genes within metabolic pathway of cytarabine. ACS10 is predictive of intracellular levels of ara-CTP as well as outcome in pediatric AML pts enrolled in multiple clinical trials led by St Jude Children's Research Hospital and Children's Oncology Group (Elsayed et al, JCO 2022;40:772-3). Overall, pediatric AML pts with ACS10 low (≤0), had inferior outcomes compared with ACS10 high pts. Thus far, the ACS10 score has not been tested for its performance in adult AML, especially adolescent and young adult (AYA) AML pts. We hypothesized that ACS10 might be predictive of chemotherapy resistance in this defined pt population that is commonly treated with intensive induction therapy. Moreover, as several SNPs included in ACS10 show ancestry-enrichments, we speculated whether this might help explain the high resistance to treatment recently observed in Black AYA AML pts. A total of 406 newly diagnosed AYA AML pts (age 17-39y, median: 30y), similarly treated in 8 Alliance for Clinical Trials in Oncology frontline protocols were included in the study. All pts had centrally reviewed cytogenetics, targeted gene mutation profiling and SNP data (Illumina 2.5 omni array, see Walker et al, Leukemia 2019;33:771-5). ACS10 score was calculated for each pt using the equation defined by Elsayed et al (&amp;gt;0, ACS10 high; ≤0, ACS10 low) and Kaplan-Meier method and the log-rank test was used for survival analysis and Fisher's exact test was used for frequency comparison. Two hundred eighty-three pts were ACS10 high and 123 pts were ACS10 low. Though not statistically significant, ACS10 low pts tended to have a shorter overall survival (OS) compared with ACS10 high pts (p=.11). Restricting the analysis to those who received chemotherapy only (excluding allogeneic transplant recipients), showed that ACS10 low group had significantly shorter OS compared with ACS10 high group (p=.03). Further, event-free survival (EFS) was shorter (3y rates, 32% vs. 42%, p=0.09) and number of early deaths (death within 30 days of treatment initiation) was higher (5% vs 1%, p=.07) in ACS10 low pts. Given that the majority of patients received etoposide as part of the induction regimen, analysis within this subset showed ACS10 high pts having higher complete remission (CR) rates (85% vs 72%, p=.05) and longer EFS and OS compared with ACS10 low pts (EFS, 3y rates, 41% vs 28%, p=.02; OS, 3y rates, 54% vs 32%, p=.007). We have previously shown significant difference in abundance of ACS10 low by race/ethnicity in pediatric AML, 70% of Black pts being ACS10 low as compared with only 30% of White pts. Similarly, the current cohort showed significant differences in ACS10 score groups by race/ethnicity: of 32 Black pts included in the analysis, 27 (84%) were ACS10 low and only 5 (16%) were ACS10 high. Given the enrichment of the racial-ethnic survival disparity in AYA pts (Larkin et al, Blood Adv 2022;6:5570-81), we further investigated the impact of ACS10 on survival of Black AYA pts. Though limited by numbers, we observed worse OS (p=0.05) of ACS10 low group, which comprised 80% of Black pts. We show the impact of cytarabine pharmacogenomics and its relevance in AYA AML pts. Consistent with the results in pediatric AML, pts with low ACS10 score, which is reflective of lower cytarabine activation and intracellular ara-CTP accumulation, had worse outcome than pts with high ACS10 score. Further, low ACS10 score was highly abundant in Black compared to White AYA AML pts. Given the low CR rates, high relapse rates and inferior survival of Black pts, our results imply cytarabine pharmacogenomics as a possible crucial contributor. In conclusion, given that cytarabine is the backbone of AML chemotherapy and is used as a frontline agent in essentially all induction regimens, our results highlight the need for in-depth evaluation of ACS10 score in AML that may open opportunities to improve treatment response in AYA AML.

Duffy-Null Patients with Sickle Cell Disease Are at Risk for Low Neutrophil Counts with HU Treatment

Introduction The Duffy blood group consists of two main antigens, Fya and Fyb, and is encoded by the atypical chemokine receptor 1 ( ACKR1) gene. About 60% of Black individuals have the Duffy null phenotype, Fy(a-b-) characterized by absence of expression of the Fya and Fyb antigens on red cells. The Duffy null phenotype in Black individuals is caused by homozygosity for a SNP (rs2814778; T&amp;gt;C; CC) in the ACKR1 gene promoter. This polymorphism results in the disruption of a binding site for the GATA1 erythroid transcription factor and silences expression of the Duffy antigens. There is a strong correlation between the Duffy null phenotype and the lower range of absolute neutrophil counts (ANC) observed in some Black individuals. The impact of Fy(a-b-) status on clinical outcomes in individuals with sickle cell disease (SCD) is not well studied. Neutropenia is a common toxicity with hydroxyurea (HU) in the treatment for SCD. We hypothesized that SCD patients with the Duffy null phenotype are at risk for lower ANCs with HU treatment, and potentially have different clinical outcomes compared to Duffy-positive patients. Methods Pediatric patients with SCD (HbSS and HbSB 0-thalassemia) treated with HU and enrolled in the St. Jude Children's Research Hospital observational cohort study, the Sickle Cell Clinical Research and Intervention Program (SCCRIP) were eligible. Patients who had available Duffy genotype and reached a maximal tolerated dose (MTD) of HU before 12/31/2021 were included. The MTD based on neutrophil counts was considered to be achieved at a dose when the ANC was between 1000 and 3000 /mm 3. Multivariate generalized linear regression model was used for association analysis after adjusting for age at HU initiation, sex, and 5 principal components. Mediation analysis was conducted to evaluate indirect effect of the Duffy null phenotype on time to MTD via baseline ANCs. Results A total of 250 patients met the inclusion criteria. One hundred eighty (72%) patients were Duffy null, and 70 (28%) patients were positive for at least one of Duffy antigen. The average patient age at starting HU was 5.9 ± 4 years old. Female patients accounted for 44.8% (n= 112) of the study population. The mean MTD of HU was 28.0 ± 5.5 mg/kg/day, the time to MTD was 2.3 ± 2.7 years, and there was no significant difference between Duffy-null and Duffy-positive patients. The Duffy null phenotype was associated with a significantly lower baseline ANCs (Duffy-null: 3800 ± 2684 /mm 3 vs. Duffy-positive: 4702 ± 3015 /mm 3; p = 0.005; Figure A), and more frequent episodes of ANC &amp;lt;1500 /mm 3 in the first two years after starting HU (Duffy-null: 1.2 ± 2.3 times/patent vs. Duffy-positive: 0.5 ± 1.2 times/patient; p = 0.006; Figure B). Although the Duffy null phenotype did not have a direct effect on the time to MTD, it affected the time to MTD indirectly via baseline ANC (mediation indirect effect test p = 0.01) since the higher the baseline ANCs were, the longer it took to reach MTD (p = 0.0002). We did not find the Duffy null phenotype associated with Hgb, MCV and HbF at base line, one or two years after starting HU. In addition, there was no association of Duffy status on frequencies of vaso-occlusive crisis and acute chest syndrome within 2 years after HU initiation. Notably, MCV increased significantly after HU initiation (Baseline: 83.5 ± 7.6 fl; two-year post HU: 99.0 ± 12.0 fl; p &amp;lt;0.00001), the increases were similar between Duffy-null and Duffy-positive patients (p = 0.36), suggesting similar HU adherence. Conclusion Patients with SCD and the Duffy null phenotype have more frequent episodes of lower ANC with HU treatment. However, Duffy status was not associated with risks for other adverse clinical outcomes.

The Impact of Socio-Economic Determinants of Health on PedsQL and Pain Outcomes Among Individuals with Sickle Cell Disease

Background: Pain in sickle cell disease (SCD) is the most visible symptom in patients. Many recent studies have shown that socio-economic status such as low income, educational achievement or even less affluent neighborhoods may contribute to the pain experience, with those of lower socioeconomic status (SES) reporting both acute and chronic pain more frequently. Furthermore, living in a less affluent area was associated with frequent use of analgesics after adjustment for pain intensity. The relationships between SES variables, pain-related anxiety, frequency of vaso-occlusive crises and/or acute care utilization have been explored; nevertheless, the relationship between SES and quality of life pain-related measures (pain hurt, pain interference, etc.) has yet to be reported. Methods: The St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) is an observation cohort study of clinical outcomes in patients with SCD. Patients enrolled in SCCRIP were retrospectively evaluated based on various SES measurements. Household SES was evaluated using the Barratt Simplified Measure of Social Status (BSMSS), a composite index of parent education and occupation. The Social Vulnerability Index (SVI) was used to classify individuals based on social vulnerabilities at the neighborhood level. The area deprivation index (ADI) ranks neighborhood in a region of interest based on social risk factors that may predispose individuals to worse clinical outcomes Quality of life measures, Pain Hurt, Pain Impact, and Pain Management/Control, were extracted from the PedsQL SCD Module. High scores on the SVI and ADI are associated with low SES and high scores on the PedsQL indicate better SCD related quality of life (QoL) with lower burden and impact of pain on function. Multivariate linear regression models were used to evaluate the associations of SES with QoL pain-related outcomes, based on a stepwise model selection strategy, with potential covariates including age, gender, disease-modifying therapy (e.g., Hydroxyurea and chronic transfusions), hemoglobin, hemoglobin F (HbF)%, and each SES variable. Results: 944 patients between the ages of 5-61 (Mean=13.75, Standard Deviation=7.57) years diagnosed with SCD completed PedsQL testing and were assessed for SVI and ADI. Multivariate models demonstrated that patients with lower SVI (i.e., higher neighborhood SES) at the neighborhood level displayed higher scores with regards to Pain Hurt (est=-7.44, standard error (SE)=2.84, p=0.01), Pain Impact (est=-9.56, SE=3.18, p=0.003) and Pain Management/Control (est=-9.35, SE=3.81, p=0.01). Similar relationships were observed for patients with lower ADI. Additionally, there was a significant association between pain impact and BSMSS (est=0.20, SE=0.10, p=0.04), suggesting that individuals with higher BSMSS (higher household SES) also had higher pain impact scores (better quality of life). Conclusions: This study demonstrated that neighborhood and household SES have an impact on pain experience in youth with SCD. Patients with increased social vulnerability and area deprivation experienced lower health-related quality of life-related to SCD pain. Increased household SES was associated with greater SCD pain impact independent of the effects of patient age, gender, SCD therapy, and HbF. Our study suggests that social determinants of health, such as SES, play a role in pain experience and QOL related to SCD pain and should be explored further.

The Methylome Atlas of Acute Leukemia Enables Novel Clinical Diagnostic Tool for AML

In 2022, both the World Health Organization (WHO) and the European LeukemiaNet (ELN) highlighted the formidable challenges of categorizing certain Acute Leukemia subtypes, such as AML with rare recurring translocations, complex karyotypes, not otherwise specified, and myelodysplastic-like entities. As characterizations of new variants and fusion partners become more prevalent, it is difficult to assess which ones, alone or in combination, generate which leukemia phenotypes. To that end, WHO posed methylation profiling as “the technology at present best suited for addressing lineage and thereby the cell population of origin of tumors” (PMID: 34921008), which invites an opportunity to evaluate the DNA methylome as a clinical diagnostic avenue in hematopoietic malignancies like AML. Thus, we hypothesize that the DNA methylome holds promise in further refining AML classification. In this study we describe the assembly of the largest publicly available methylation dataset of acute leukemias so far, which combines 11 high-quality clinical trials/studies: NOPHO ALL92-2000 (n=796), AAML0531 (n=628), AAML1031 (n=581), BeatAML (n=316), TCGA AML (n=194), French GRAALL 2003-2005 (n=153), TARGET ALL (n=131), CETLAM SMD-09 (n=83), AAML03P1 (n=72), Japanese AML05 (n=64), and CCG2961 (n=41), resulting in a total of 3,059 subjects after preprocessing. Samples were obtained either from bone marrow or peripheral blood, with DNA methylation (meDNA) data procured using the Illumina methylation array 450k or EPIC array, which share 452,453 probes with same chemistry and design. To independently validate the findings derived from the discovery cohort, we processed in parallel meDNA array data from bone marrow specimens at diagnosis of AML patients treated on the multi-center clinical trials AML02 (n=159) and AML08 (n=42) led by St. Jude Children's Research Hospital. Processing the raw data followed best practices from the literature using SeSAMe (PMID: 30085201, 27924034). To generate the atlas, we used a novel dimensionality reduction unsupervised learning algorithm called Pairwise Controlled Manifold Approximation (PaCMAP), which allowed compression of 319,738 processed CpG values into two components for visualization (Figure 1) and five components for downstream classification analysis. To empirically assess classification accuracy of PaCMAP results, we implemented a machine learning pipeline with hyperparameter tuning, 10-fold cross validation, and assessed accuracy per class in discovery and validation cohorts. Not all samples, however, had clinical diagnostic annotation available in the dataset, so only those with the annotations were used in the supervised machine learning model (n=1399 in discovery and n=110 in validation). Our resulting atlas unveils several clusters of samples that defined 6 hematopoietic lineages: AML, ALL, MDS-related or secondary myeloid neoplasms (MDS-like), Acute promyelocytic leukemia (APL), mixed phenotype leukemia, and otherwise-normal control. These are further subdivided into 30 subclasses overlapping with WHO 2022 and ELN 2022 clinical diagnostic annotations. Subsequent analyses comparing methylation-based subtype prediction to clinically annotated subtypes revealed an overall concordance score of 0.936, with per class 10-fold CV concordance ranging from 0.82 for MDS-like to 1.00 in APL and NUP214 fusions. Importantly, the validation (test) cohort showed accuracies per class of 0.91 for AML with KMT2A-r (n=47) and 1.00 for AML rare recurring translocations (n=10). These are subtypes with large genomic heterogeneity that may be better represented at the epigenomic level. Additionally, these are largely considered standard to high-risk groups with poor prognosis, which invites further studies aiming at uncovering the biological mechanisms behind the methylation patterns governing this classification. Finally, the resulting classifier allowed prediction of WHO/ELN clinical diagnosis for 91 samples in the validation cohort that were previously categorized as “Normal Karyotype”, “Other” or blank. In conclusion, our study effectively showcases the use of a methylome atlas in enhancing the diagnosis of AML subtypes.

Prediction of attributable mortality in pediatric patients with cancer admitted to the intensive care unit for suspected infection: A comprehensive evaluation of risk scores.

To evaluate the performance of existing sepsis scores for prediction of adverse outcomes in children with cancer admitted to the ICU with suspected sepsis. Retrospective chart review using data available at 1, 6, 12, and 24 h after ICU admission to calculate the Pediatric Risk of Mortality 3 (PRISM-3), Pediatric Sequential Organ Failure Assessment (pSOFA), Paediatric Logistic Organ Dysfunction 2 (PELOD-2), and Quick Pediatric Sequential Organ Failure Assessment (qSOFA) scores. Area under the receiver operator characteristic curve (AUROC) was used to evaluate performance for prediction of attributable mortality. Sensitivity analyses included recalculation of scores using worst preceding values for each variable, excluding hematologic parameters, and prediction of alternative outcomes. St. Jude Children's Research Hospital, a pediatric comprehensive cancer center in the USA. Pediatric patients (<25 years of age) receiving conventional therapy for cancer admitted to the ICU with suspected sepsis between 2013 and 2019. Of 207 included episodes of suspected sepsis, attributable mortality was 16 (7.7%) and all evaluated sepsis scores performed poorly (maximal AUROC of 0.73 for qSOFA at 1 and 24 h). Sensitivity analyses did not identify an alternative approach that significantly improved prediction. Currently available sepsis scores perform poorly for prediction of attributable mortality in children with cancer who present to ICU with suspected sepsis. More research is needed to identify reliable predictors of adverse outcomes in this population.

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

Survivors of childhood cancer experience premature aging compared with community controls. The deficit accumulation index (DAI) uses readily available clinical data to measure physiological age in survivors; however, little data exist on how well deficit accumulation represents underlying biological aging among survivors of cancer. To examine the associations between the DAI and epigenetic age acceleration (EAA) and mean leukocyte telomere length (LTL). This cross-sectional study analyzed data from the St Jude Lifetime Cohort, an assessment of survivors of childhood cancer who were treated at St Jude Children's Research Hospital in Memphis, Tennessee. Data were collected between 2007 and 2016, assayed between 2014 and 2019, and analyzed between 2022 and 2023. Participants were adult survivors who were diagnosed between 1962 and 2012 and who survived 5 years or more from time of diagnosis. The analyses were restricted to survivors with European ancestry, as there were too few survivors with non-European ancestry. The DAI included 44 aging-related items, such as chronic health conditions and functional, psychosocial, and mental well-being. Item responses were summed and divided by the total number of items, resulting in a ratio ranging from 0 to 1. These DAI results were categorized based on reported associations with hospitalization and mortality: low, defined as a DAI less than 0.2; medium, defined as a DAI of 0.2 to less than 0.35; and high, defined as a DAI of 0.35 or higher. Genome-wide DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. The EAA was calculated as the residuals from regressing the Levine epigenetic age on chronological age. The mean LTL was estimated using whole-genome sequencing data. This study included 2101 survivors of childhood cancer (1122 males [53.4%]; mean [SD] age, 33.9 [9.1] years; median [IQR] time since diagnosis, 25.1 [18.7-31.9] years) with European ancestry. Compared with survivors in the low DAI group, those in the high DAI group experienced 3.7 more years of EAA (β = 3.66; 95% CI, 2.47-4.85; P < .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (β = 1.77; 95% CI, 0.84-2.69; P < .001), independent of treatment exposures. The EAA and DAI association was consistent across 3 common diagnoses (acute lymphoblastic leukemia, Hodgkin lymphoma, and central nervous system tumors) and across chronological age groups. For example, among acute lymphoblastic leukemia survivors, those in the medium DAI group (β = 2.27; 95% CI, 0.78-3.76; P = .001) experienced greater EAA vs those in the low DAI group. Similarly, among survivors younger than 30 years, the high DAI group experienced 4.9 more years of EAA vs the low DAI group (β = 4.95; 95% CI, 2.14-7.75; P < .001). There were no associations between mean LTL residual and the DAI. This cross-sectional study of survivors of childhood cancer showed that the DAI was associated with EAA, suggesting an underlying biological process to the accumulation of deficits. Both the DAI and EAA were effective at identifying aging phenotypes, and either may be used to measure aging and response to interventions targeting aging pathways.

Characteristics of COVID-19 Infections and Severe Outcomes in a Multinational Study in Latin America During the Circulation Period of the Delta Variant in the Pediatric Population

Abstract Background SARS-CoV-2 infection had specific characteristics in the pediatric population described in previous studies. These clinical features included specific COVID-19 presentation, antibiotic usage, and predictors of disease severity. In addition to patient related factors, external influences could affect COVID-19 outcomes. The features of children with COVID-19 of five Latin American countries were described. Study participants were members of the Prevencionistas e Infectólogos para Cáncer Pediátrico en América Latina (PRINCIPAL) Network of the Global Infectious Diseases Program at St Jude Children's Research Hospital. This study aims to analyze the differences between patients with non-severe and severe disease when the circulation of the Delta variant was predominant, and few children had received SARS-CoV-2 vaccines. Methods This is a retrospective, observational, multinational study that included children with a confirmed diagnosis of COVID-19 between January 2021 and January 2022. Epidemiological, clinical, and treatment characteristics are described and compared between patients with severe and non-severe disease. Frequencies and percentages are presented as well as median and interquartile ranges (IQR). Comparisons were made using the chi-squared test for proportions and the Wilcoxon test for nonparametric quantitative variables. Results 745 patients were included. Patients had a median age of 51 (13-139) months, 194 (26%) had comorbidities, and 701 (94%) presented with symptomatic disease. Fever was present in 524 (74.8%) patients, respiratory symptoms in 550 (78.5%), followed by gastrointestinal manifestations in 218 (31.1%). X-ray findings were abnormal in 175/362 patients, with interstitial infiltrates being the most common finding, 123 (70.7%). Almost a third of patients (29%) received an antibiotic; ceftriaxone was most frequently prescribed in 123/216 cases. Of 745 patients, 526 (70.8%) were hospitalized, of which 165 (31.4%) required PICU admission. Patients presenting with severe disease and requiring PICU admission we more likely to have a comorbidity, 128 (22%) vs. 66 (40%), p&amp;lt;0.001. Mucocutaneous findings or adenitis were more frequently described in severe cases, 19 (11.5) vs. 18 (5.0%), p=0.007. Regarding laboratory results, low lymphocytes 2445 vs. 1676 (p&amp;lt;0.001) and low platelets 294,000 vs. 250,000 (p=0.0002) were most common in patients with severe disease. The proportion of patients with lymphocytopenia was also higher in those with severe disease, 39% vs. 52% p= 0.010. Not surprisingly, antibiotic usage (broad and narrow spectrum) was higher in patients admitted to the PICU (32 vs. 16.5%) p=0.001, despite no significant difference in the frequency of bacterial coinfection (5.56% vs. 9.7% p=0.081) when compared to patients with non-severe disease. Specific treatment strategies were more frequent in PICU patients (39.1% vs. 72.1%) p&amp;lt;0.001, and steroids were the most frequently used drug, 35.2% vs. 70.7% (p&amp;lt;0.001). Table 1. Conclusions Regardless of the variant, COVID-19 is an important cause of hospitalization in children. Fever, respiratory and gastrointestinal symptoms are the most frequent manifestations in children. Despite the low frequency of bacterial coinfection, a high proportion of antibiotic usage is described. Compared to recent publications, mucocutaneous involvement, lower lymphocyte and platelet counts, and higher inflammatory markers were more frequently found in admissions to the PICU. Currently, with higher vaccine coverage and more comprehensive knowledge of the disease, optimization of pediatric COVID-19 management is expected, especially concerning antibiotic use. It is essential to continue multicenter surveillance of the behavior of COVID-19 in the pediatric population.

Retrospective analysis of outcomes for pediatric acute lymphoblastic leukemia in South American centers.

Acute lymphoblastic Leukemia (ALL) is the most common pediatric malignancy. While the survival rate for childhood ALL exceeds 90% in high-income countries, the estimated survival in low-and middle-income countries ranges from 22-79%, depending on the region and local resources. This study retrospectively reviewed demographic, biological, and clinical parameters of children under 18 years of age with newly diagnosed ALL presenting between 2013-2017 across five pediatric centers in 4 countries in South America. Survival analyses were estimated using the Kaplan-Meier method. Across the five centers, 752 patients were analyzed (Bolivia [N=9], Ecuador [N=221], Paraguay [N=197], Peru [N=325]) and 92.1% (n=690) patients were diagnosed with B-cell and 7.5% (n= 56) with T-cell ALL. The median age was 5.5 years old (IQR 7.29). At diagnosis, 47.8% of patients were categorized as standard and 51.9% as high risk per their institutional regimen. Advanced diagnostics availability varied between modalities. MRD was evaluated in 69.1% of patients; molecular testing was available for ETV6-RUNX, BCR-ABL1, TCF3-PBX1, and KMT2A-rearranged ALL in 75-81% of patients; however, karyotyping and evaluation for iAMP21 were only performed in 42-61% of patients. Central nervous system (CNS) involvement was evaluated at diagnosis in 57.3% (n=429) patients; of these, 93.7% (n=402) were CNS 1, 1.6% (n=7) were CNS 2, 0.7% (n=11) were CNS3, 1.9% (n=8) had cranial nerve palsy, and 2.1% (n=9) results unavailable. Chemotherapy delays >2 weeks were reported in 56.0% (n=421) patients during treatment. Delays were attributed to infection in 63.2% (n=265), drug-related toxicities in 47.3% (n=198), and resource constraints, including lack of bed availability in 23.2% (n=97) of patients. The 3-year Abandonment-sensitive EFS and OS were 61.0±1.9% and 67.2±1.8%, respectively. The 3-year EFS and OS were 71.0±1.8% and 79.6±1.7%, respectively. This work reveals opportunities to improve survival, including addressing severe infections, treatment interruptions, and modifications due to drug shortages. In 2018, healthcare professionals across South America established the Pediatric Oncology Latin America (POLA) group in collaboration with St. Jude Children's Research Hospital. POLA collaborators developed an evidence-based, consensus-derived, adapted treatment guideline, informed by preliminary results of this evaluation, to serve as the new standard of care for pediatric ALL in participating institutions.

Health literacy on quality of life for children with cancer: modules on pediatric palliative care.

To describe the development of educational materials for parents and other caregivers of children with cancer, which utilized a culturally sensitive approach to reduce acceptance barriers to palliative care (PC). The Pan American Health Organization (PAHO), St. Jude Children's Research Hospital, and partners in Latin America and the Caribbean collaborated in a three-phase project, beginning with a needs assessment survey of caregivers of children with cancer in Peru. Based on this finding, an interdisciplinary team of pediatric PC experts developed educational content that was designed and validated by an international committee of PC and communication experts. The collaboration resulted in the development of an eight-module series that introduces caregivers to key concepts of pediatric PC, including management of pain, quality of life, and end of life care. The series was designed to reduce caregiver stigma associated with PC through culturally sensitive education that addresses the low levels of health literacy among caregivers in Latin America and the Caribbean. In the 15 months since the launch, these modules have been distributed throughout Latin America and were downloaded 2 825 times. Educational materials and anticipatory guidance of PC were considered to be a priority for parents and other caregivers of children with cancer throughout Latin America. The materials developed through this project have been widely utilized and are available through the PAHO website and the Together by St. Jude™ online resource.