OBJECTIVES:Research has indicated that many medical and psychosocial factors contribute to cognitive deficits in sickle cell disease (SCD). Some studies of SCD in early childhood found cognitive functioning to be associated with socioeconomic status but not disease severity. The current study examined how the home environment is associated with cognitive functioning and school readiness in children with SCD. METHODS:Young children (n = 29; M age = 4.4 years SD = 0.3) with SCD underwent an evaluation of cognitive and academic skills. Subsequently, researchers and caregivers completed the Home Observation for Measurement of the Environment (HOME), an in-home measure of cognitive stimulation. Linear regression was used to examine the relationship between each of the HOME subscales and cognitive and academic measures while controlling for genotype. RESULTS:The total score from the HOME inventory was associated with overall IQ, working memory, and school readiness. Among the subscales of the HOME inventory, Learning Materials, Modeling, and Variety were associated with cognitive and academic outcomes. CONCLUSIONS:Stimulation in a child's home may affect cognitive and academic development in young children with SCD. Future research should examine the benefits of increasing learning materials and the variety of activities in the homes of young SCD patients.

Severe aplastic anemia (SAA) is characterized by pancytopenia and is either inherited or acquired (idiopathic). Accurate diagnosis is critical for proper treatment; however, the frequent overlap in clinical presentation between idiopathic SAA and inherited bone marrow failure syndromes (IBMFS) presents diagnostic and management challenges. For patients with idiopathic SAA, immunosuppressive therapy (IST) is considered the standard of care, when there is no available matched related donor. While 70-75% of pediatric patients with SAA respond to IST, patients with IBMFS do not. To our knowledge, there are no published data on a specific age cut-off that predicts a higher likelihood of an inherited disease, to guide treatment with IST or hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate response to IST in children with SAA who are less than 3 years of age and to gain insight into the age below which response to IST is unlikely, suggesting an IBMFS. In a retrospective cohort study, we extracted data of patients diagnosed with SAA between 2002 and 2021 from 3 ethics board-approved multicenter databases: (1) North American Pediatric Aplastic Anemia Consortium (NAPAAC; 2002-2014), (2) Canadian Aplastic Anemia and Myelodysplasia Study (CAMS) and (3) Canadian Inherited Marrow Failure Registry (CIMFR). Patient characteristics, treatment and outcomes were collected. Patients were included if diagnosed with acquired SAA before the age of 3 years and received IST as a first line treatment for at least 3 months. Patients were excluded if they had physical malformations suggestive of an IBMFS, a first-degree relative with a history of bone marrow failure, or insufficient available data. Response rate was compared with published literature on pediatric patients with SAA over the age of 3 years. Descriptive statistics were utilized (SPSS V25). Among 31 patients aged 1.3-2.9 years (median 2.25) treated with IST as a first line therapy for SAA, 13 (42%) were male, 10 (32%) had hepatitis associated SAA, 3 (10%) had mild physical abnormalities (vesicoureteral reflux, patent ductus arteriosus, mild hearing impairment), none had short stature, and 7 (23%) had a family history of cancer (n=4), polycythemia vera (n=1), hyper-eosinophilic syndrome (n=1) or consanguinity (n=1). Twenty-nine patients (93%) were treated with horse anti-thymocyte globulin (ATG) and cyclosporine A (CSA), while 2 (7%) were treated with cyclophosphamide (CTX). Of the 31 patients, 24 (77%) had a complete response (CR) to IST (including the 2 patients post CTX). Twelve (50%), 22 (92%) and 24 (100%) were transfusion independent by 3, 6 and 12 months from the start of IST, respectively. CSA was discontinued after a median time of 20.4 months (range 5.6-55). No relapse was reported during long-term follow up (median 79 months, range 29-233). Seven patients (23%, age 1.95-2.83 years, median 2.44), had no response to a first IST course, 5 of whom received a second IST course with rabbit ATG. Of these 5 patients, 3 (age 1.95, 2.44 and 2.45 years) did not respond to the second IST and underwent HSCT, 1 (age 2.8 years) had a partial response and became transfusion-independent, 1 (age 2.83 years, who had a second IST with tacrolimus) achieved partial response and then switched to danazol with a CR. Two of the 7 patients who did not respond to the first IST did not receive a second IST before transplant; 1 of them (age 2.25 years) had an unsuccessful response to danazol and 1 (age 2.04 years) had no interim treatment. Complications during the first 3 months post IST included infections (bacteremia/sepsis, n=5; cellulitis, n=2; viral gastroenteritis, n=1), gross hematuria (n=1), hypertension (n=4) and gum hyperplasia (n=1). In the 3-6 months post-IST interval, 2 patients had bleeding events (gross hematuria, oral bleed) and 1 had a bacteremia episode. In the 6-12 months post-IST interval, 1 patient had bacteremia, 2 had hypertension and 1 developed a chronic kidney injury secondary to CSA. In conclusion, our study indicates for the first time a high complete response rate of 77% in SAA patients under 3 years of age who were treated with IST, a response rate comparable to what is reported in the literature for IST response in older pediatric patients. Although our study is limited by its retrospective nature and a relatively small cohort, due to the lack of previously published data, this research provides critical insight to help in managing this age group.

Introduction: Glomerular hyperfiltration, an early manifestation of kidney disease in individuals with sickle cell disease (SCD), refers to a supraphysiologic elevation in the glomerular filtration rate (GFR) and is evident in early childhood. The contribution of hyperfiltration in childhood to the development of chronic kidney disease in early adulthood is not well defined. Our goal was to define the prevalence of glomerular hyperfiltration in sickle cell disease (SCD), assess its association with development of persistent albuminuria (PA) and evaluate the change in estimated glomerular filtration rate (eGFR) over time. Methods: Individuals with SCD enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP), a longitudinal, lifetime cohort study of individuals with sickle cell disease that tracks organ function throughout the lifespan (Clinicaltrials.gov #NCT02098863) were examined. Those with data from birth through adulthood were evaluated. Hyperfiltration was defined by an eGFR >135 ml/min/1.73 m2 using the bedside Schwartz 2009 equation (<18 years) and CKD-EPI-2021 equation (≥18 years). Hyperfiltration was stratified based on disease genotype (HbSS/HbSβ0thalassemia and HbSC/HbSβ+ thalassemia) and age groups (1-5, 6-10, 11-17, 18-20, 21-30 and 31-40 years). The maximum eGFR values were used for each individual, if there were multiple values. Chi-square and Fisher exact test was used to compare hyperfiltration outcomes between the strata. We assessed the effect of sex, genotype, hemoglobin, treatment duration with hydroxyurea, hyperfiltration, and APOL1 G1/G2 risk-variants on the development of PA utilizing a Cox regression model. PA was assessed after age 10 and was defined as an albumin-creatinine ratio (ACR) ≥30mg/g in ≥2 out of 3 consecutive time points. Hyperfiltration for PA analysis was defined as ever having an eGFR >180 ml/min/1.73m2 before the event time. To assess the change in eGFR over time in individuals with HbSS/HbSβ0, a mixed model approach incorporating linear, quadratic and cubic polynomials for age (age terms), was employed. The models were adjusted for baseline age, treatment status, and sex. We augmented the model by adding hyperfiltration status at first eGFR and then explored this impact on the trajectory of eGFR change over time by incorporating interaction terms of hyperfiltration status with age terms. P<0.05 was considered significant. Results: We examined 350 patients (HbSS/HbSβ0 - 237; HbSC/HbSβ+ - 113). There were no differences in the mean ages (23.4 3.4 years vs. 23.73.5 years, p=0.52) or sex (female - 117 [49.4%] vs. 61 [53.9%], p=0.42) by genotype. Participants with HbSS/HbSβ0 had a higher prevalence of hyperfiltration in all age groups up to 31-40 years when compared to HbSC/HbSβ+ (57.3% vs. 10.2%, p<0.01): 1-5 years (68.7% vs. 13.5%), 6-10 years (66.9% vs. 17.9%), 11-17 years (62.9% vs. 14%), 18-20 years (62.4% vs. 10.8%), 21-30 years (54.0% vs. 5.1%). In univariate analysis, the hazard ratio (HR, with standard error [SE]) for PA was higher in individuals with HbSS/HbSβ0 (HR: 5.3 0.371, p<0.001), hyperfiltration (HR: 2.8 0.238, p<0.001), APOL1 status (HR: 3.1 0.4, p=0.0023), and lower hemoglobin at age of PA confirmation (HR 1.24 SE 0.053, p<0.001). In multivariable analysis, PA was associated with hyperfiltration (HR 2.55 p=0.001) following adjustment for sex, genotype, and hydroxyurea treatment duration, but not after adjusting for APOL1 status. Evaluating change over time, eGFR increased and peaked by age 10 years, with subsequent decline (p<0.0001 for all age terms). Adding hyperfiltration status at first eGFR, a significant increase in eGFR in hyperfiltration group was found (estimate=12.9 , p<0.0001). The hyperfiltration group showed a greater initial eGFR increase followed by a greater eGFR decline (p<0.01, except cubic age term). Conclusion: Hyperfiltration is highly prevalent in SCD and is associated with development of PA, although this does not appear to be independent of APOL1 status. In patients with HbSS/HbSβ0, there is a significant association between eGFR and age, with hyperfiltration status impacting the trajectory of eGFR. More studies are required to determine whether hyperfiltration is independently associated with PA.

Abstract: Individuals with sickle cell disease (SCD) face the burden of managing a lifelong chronic illness, increasing vulnerability to social determinants of health (SDoH). However, how SDoH contributes to health disparities is understudied. We hypothesized that preschool children with SCD living in poor neighborhoods with higher socio-economic distress would experience increased acute care utilization (ACU; described as emergency department visits plus hospitalizations) despite disease-modifying therapy. Participants' home addresses (aged 0-6 years) were mapped using census tract environmental data from the US Department of Agriculture Food Access Research Atlas. In multivariable analyses controlled for sickle genotype and disease-modifying therapies (hydroxyurea and chronic transfusion), SDoH indicators, that is, limited access to food, lack of vehicle, low income, and inadequate education, were associated with higher ACU. Living in households with children >1 mile from a supermarket was associated with more hospitalizations (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.13-1.85) and ACU (OR, 1.37; 95% CI, 1.06-1.80) among children with SCD (aged <6 years). In households with at least 1 bachelor's degree, children with SCD experienced less ACU (OR, 0.67; 95% CI, 0.50-0.93) and hospitalizations (OR, 0.67; 95% CI, 0.49-0.92). Preschool children with SCD with limited access to food and transportation are at a higher risk of acute complications despite receiving free evidence-based therapy and social support. The family education level may have a protective effect. Although SDoH in crowded households and health care maintenance visits were not a focus of this study, future research should consider these factors. Understanding the SCD and SDoH association is crucial for directing resources to improve affected children's health.

Purpose Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. Patients and Methods The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGS(COMT)) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). Results In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGS(COMT) was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGS(COMT) was negatively associated with IQ performance among males but not females across all cohorts. Conclusion Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.

Pediatric patients with sickle cell disease (SCD) have decreased oxygen-carrying capacity in the blood and reduced or restricted cerebral blood flow resulting in neurocognitive deficits and cerebral infarcts. The standard treatment for children with SCD is hydroxyurea; however, the treatment-related neurocognitive effects are unclear. A key area of impairment in SCD is working memory, which is implicated in other cognitive and academic skills. N-back tasks are commonly used to investigate neural correlates of working memory. We analyzed functional magnetic resonance imaging (fMRI) of patients with SCD while they performed n-back tasks by assessing the blood-oxygenation level-dependent (BOLD) signals during working memory processing. Twenty hydroxyurea-treated and 11 control pediatric patients with SCD (7-18 years old) performed 0-, 1-, and 2-back tasks at 2 time points, once before hydroxyurea treatment (baseline) and ~1 year after treatment (follow-up). Neurocognitive measures (e.g., verbal comprehension, processing speed, full-scale intelligence quotient, etc.) were assessed at both time points. Although no significant changes in behavior performance of n-back tasks and neurocognitive measures were observed in the treated group, we observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- > 0-back contrast. Through searchlight-pattern classifications in the treated and control groups to identify changes in brain activation between time points during the 2-back task, we found more brain areas, especially the posterior region, with changes in the pattern and magnitude of BOLD signals in the control group compared to the treated group. In the control group, increases in 2-back BOLD signals were observed in the right crus I cerebellum, right inferior parietal lobe, right inferior temporal lobe, right angular gyrus, left cuneus and left middle frontal gyrus at 1-year follow-up. Moreover, BOLD signals elevated as the working memory load increased from 0- to 1-back but did not increase further from 1- to 2-back in the right inferior temporal lobe, right angular gyrus, and right superior frontal gyrus. These observations may result from increased cognitive effort during working memory processing with no hydroxyurea treatment. In contrast, we found fewer changes in the pattern and magnitude of BOLD signals across time points in the treated group. Furthermore, BOLD signals in the left crus I cerebellum, right angular gyrus, left cuneus and right superior frontal gyrus of the treated group increased continuously with increasing working memory load from 0- to 2-back, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. Collectively, these findings suggest that hydroxyurea treatment helped maintain working memory function in SCD.

Introduction: In the BABY HUG trial, fixed-dose hydroxyurea (20 mg/kg/day) was safe and effective in decreasing sickle cell anemia (SCA)-related complications in very young children (9-18 months). Nevertheless, children in the treatment arm of BABY HUG continued to experience vaso-occlusive symptoms and incur organ damage. In older children/adults with SCA, intensification of hydroxyurea to a maximum tolerated dosage, defined by mild to moderate myelosuppression, has been associated with improved laboratory parameters and clinical benefits compared to fixed lower dosing. However, relatively little has been published regarding hydroxyurea dose escalation in infants with SCA. We designed the Hydroxyurea Management in Kids: Intensive versus Stable Dosage Strategies (HUGKISS) to determine the feasibility of enrolling, randomizing, and treating very young children with SCA with either a fixed or intensified dose of hydroxyurea. Methods: We performed a single-blind, randomized, multicenter pilot trial of hydroxyurea in infants and toddlers (9-36 months old) with SCA to compare a "standard" treatment (20 mg/kg/day) with an "intensive" treatment defined by a goal absolute neutrophil count (ANC) of 1500-3000 cells/µL. Participants were randomized in a 1:1 ratio to receive "standard" or "intensive" therapy based on a block randomization and were stratified by clinical center and age (9 to <24 months or 24 to <36 months). In both the standard and intensive treatment arms, participants began hydroxyurea at 20 (±2.5) mg/kg/day. There was no dose escalation in the HUGKISS standard arm. Participants treated in the intensive arm were dose-escalated by 5 mg/kg/day increments (if tolerated) to a maximum of 35 mg/kg/day, adjusted every 8 weeks to maintain the goal ANC. Participants underwent clinical, laboratory, and medication adherence assessments every 4 (±2) weeks. The medical coordinating center staff and study center principal investigators were blinded to treatment allocation, while hydroxyurea volume was not blinded to participants or caregivers. Results: Twenty-six subjects were randomized to standard treatment and 25 to intensive treatment, with no statistical difference in the subjects' mean age at enrollment (12.8 months) or laboratory values at randomization. One year after randomization, 19 and 23 subjects were evaluable in the standard and intensive arms respectively. The mean hydroxyurea doses at exit were 27.2 mg/kg/day (intensive arm) and 18.8 mg/kg/day (standard arm). Significantly greater increases in fetal hemoglobin (HbF) were noted in the intensive versus standard arm (p=0.002, final levels, 38.8% vs 26.1%), and the median hemoglobin (Hb) (p=0.033, +1.2g/dl vs +0.4 g/dl). Significantly greater increases in mean corpuscular volume and greater decreases in reticulocyte count and ANC also occurred in the intensive arm. Significant differences were not seen in SCA-related adverse event rates. The intensive arm had more frequent neutropenic toxicity (ANC<1000 cells/µL) than the standard arm (52% versus 23%), but no serious infections occurred. Data from the BABY HUG treatment arm were pooled with our standard dose arm since both groups received the same dose of hydroxyurea and were of similar age. When the data were summarized and compared in longitudinal curves (Figure), similar differences from our intensive arm were found, often within 6 months of dose initiation. Conclusions: Intensive hydroxyurea treatment induced greater increases in HbF and Hb than standard dosing without significant toxicity in very young children with SCA, and may blunt or delay the fall in HbF seen after 6 months of therapy with lower doses. HUGKISS demonstrated the feasibility of treating very young children with SCA with intensive dose hydroxyurea. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Social determinants of health (SDoH) may impact outcomes in sickle cell disease (SCD). We conducted a comprehensive literature review of five electronic databases to elucidate the relationship between SDoH and SCD, and identify gaps in the literature. Our search yielded 59 articles, which we organized into five SDoH areas: Neighborhood and Built Environment, Health and Healthcare, Social and Community Context, Education, and Economic Stability. We found that social determinants, such as access to healthcare, were inconsistently evaluated. Improved recognition and understanding of SDoH should enhance the development of programs that directly address its detrimental effects on patients with SCD.

OBJECTIVE Nocturnal enuresis is more prevalent in youth with sickle cell disease (SCD) compared to the general population. The purpose of this study is to estimate prevalence of nocturnal enuresis using diagnostic criteria and identify associated sociodemographic, medical, and health-related quality of life (HRQOL) factors. METHODS Youth with SCD (N = 248; ages 6.00-17.99 years) and their caregivers completed semi-structured interviews and questionnaires. HRQOL was measured using the Pediatric Quality of Life (PedsQL) Inventory. Medical information was abstracted from medical record. We generated multivariable logistic regression models to examine associations between factors and current nocturnal enuresis and nocturnal enuresis occurring any time in the past (lifetime). RESULTS Among participants (mean age, 11.3 ± 3.6 years; 50.8% male), 21.4% reported current nocturnal enuresis and 46% reported lifetime nocturnal enuresis. Male sex [odds ratio (OR), 2.57; p = .001], difficulty arousing from sleep (OR, 3.57; p < .001), higher school functioning HRQOL (OR, 1.02; p = .014), and higher fetal hemoglobin levels (OR, 1.03; p = .048) were associated with lifetime nocturnal enuresis. Younger age (OR, 1.16; p = .005), higher youth-reported fatigue (OR, 1.01; p = .045), difficulty arousing from sleep (OR, 4.92; p < .001), and higher lactate dehydrogenase levels (OR, 1.00; p = .042) were associated with current nocturnal enuresis. CONCLUSIONS Nocturnal enuresis is prevalent in youth with SCD and is associated with HRQOL, diminished sleep, greater fatigue, and disease severity markers. Routine assessment of sleep behaviors and fatigue are necessary when treating patients with SCD to understand the impact of nocturnal enuresis on HRQOL.

PURPOSE OF THE STUDY:Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA. PATIENTS AND METHODS:The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR). RESULTS:HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05. CONCLUSION:As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention.

Introduction: The acute and chronic complications of sickle cell anemia (SCA) are well-known, with many of them arising in the first few years of life. The BABY HUG trial showed that 20 mg/kg/day of hydroxyurea therapy is safe, blunts the decline of fetal hemoglobin (HbF), and is clinically beneficial for very young infants and children with SCA. Nevertheless, children treated with hydroxyurea continued to develop acute complications and acquire end organ damage. Although the BABY HUG trial established the safety and efficacy of fixed dose hydroxyurea in very young children with SCA, further study was needed to define the optimal dosing regimen to maximize benefit in this group. We describe our approach to designing and implementing the Hydroxyurea Management in Kids: Intensive versus Stable Dosage Strategies (HUGKISS) study, which assessed the feasibility of enrolling and randomizing very young children with SCA to intensified versus fixed doses of hydroxyurea. The hematologic and clinical effects of both doses were also monitored. Methods: The HUGKISS trial was designed as a single-blind, multicenter, randomized controlled pilot study. It was felt that the objectives of HUGKISS could be safely and more efficiently obtained with a single-blind design (with investigators blinded), because a double-blind design would be logistically challenging and would place significant burden on families and pharmacies. For example, in one double-blind design, caregivers would have to administer two aliquots of study drug (hydroxyurea + hydroxyurea or hydroxyurea + placebo), thereby providing a potential source for medication error. However, because the HUGKISS study required dosage adjustment of hydroxyurea based on complete blood count results, a HUGKISS Enabled Local Provider for Evaluating Response (HELPER) was utilized. Each HELPER was an unblinded local medical provider, unaffiliated with the steering committee or data analysis, who was knowledgeable about SCA. This individual monitored hydroxyurea concordance and toxicities in real time. All patients received hydroxyurea at 20 mg/kg/day for 8 weeks. If they were stable and adherent, they were randomized to either continued fixed dosing or intensified dosing, which involved escalation of hydroxyurea dosing every 8 weeks to a maximum of 35 mg/kg/day. While the primary endpoint was assessing feasibility of enrollment and randomization, the main secondary endpoint assessed was changes in HbF levels. This choice reflected the age of the patient population, which would be undergoing a physiologic decline in HbF during the study period. We monitored adherence via the Medication Adherence Measure (MAM) and measurement of remaining hydroxyurea suspension in the prescribed bottle. Both were performed every four weeks. A medication possession ratio was calculated using the results from both methods, and used to quantitate adherence. Enrollment screening logs were also maintained at all sites. The most common reason for declining participation in HUGKISS was that families desired more time to "think about" hydroxyurea and participation in a trial, followed by disinterest in using hydroxyurea, and a fear of participating in clinical trials. Conclusion: Important considerations when designing trials involving young children with SCA include choice of endpoints, obtaining adequate enrollment, maintaining blinding of a liquid formulation with dose adjustments, and assessment of medication adherence. The HUGKISS study employed a novel single-blind design to facilitate safe and efficient administration of hydroxyurea for families, while also ensuring close monitoring of toxicities through a HELPER.

BACKGROUND:Transcranial doppler (TCD) ultrasonography can be used to identify stroke risk in children with sickle cell anemia. Previous studies have reported mixed findings on neurocognitive outcomes in children with elevated TCD. This study examined associations between TCD velocity and neurocognitive outcomes in children and adolescents without prior history of stroke. PROCEDURE:Participants were selected from the Sickle Cell Clinical Research Intervention Program cohort. The highest recorded mean maximum TCD velocity was selected for analysis, along with participant's most recent data from serial neurocognitive surveillance. RESULTS:A total of 200 children with sickle cell anemia completed neurocognitive testing (109 males, 91 females; mean age 12.7 years [SD = 3.56]). Most participants were prescribed hydroxyurea (72%) at the time of neurocognitive testing and nearly 16% had a history of chronic transfusions prior to neurocognitive evaluation. Mean age at time of highest TCD value was 6.6 years (SD = 2.5) and 13.5% of screenings were abnormal (≥200 cm/s). Mean interval between TCD and most recent neurocognitive evaluation was 6.1 years (±3.5). There were no significant differences in the interval between TCD and neurocognitive testing across normal, conditional, and abnormal groups. Maximum TCD velocity was not significantly associated with neurocognitive outcomes in multivariate models. CONCLUSIONS:History of elevated TCD in the absence of overt stroke should not be considered a risk factor for poor neurocognitive outcomes in children and adolescents with sickle cell anemia on modern disease-modifying therapy.

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.

ABSTRACT Background Transition-age patients with sickle cell disease (SCD) are at risk for poor outcomes associated with incomplete transition readiness and neurocognitive deficits. Study objectives were to: 1) test if a SCD-specific measure of self-management skills was associated with transition outcomes and 2) evaluate if caregiver-reported executive functioning was associated with self-management skills and transition outcomes among youth with SCD. Research design and methods Youth/caregivers were selected from a longitudinal cohort study. Caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF); caregivers and youth completed the Self-Management Skills Checklist (SMSC) at a median age of 16.8 ± 0.6 years. Non-parametric tests compared SMSC and transition outcomes. Regression assessed the incremental validity of SMSC in predicting transition outcomes. Results In total, 95 participants (54% male, 55% severe genotype) completed the SMSC assessment. Most participants (87%) transferred to adult care within six months and 87% were retained for at least 12 months. BRIEF and caregiver-reported SMSC assessments were weakly, negatively correlated (ρ = −0.25, p = 0.0392) but were not significant in predicting transition outcomes (p > 0.05). Conclusions The SMSC and executive function did not predict adult care engagement. Development of readiness assessments that predict care engagement and reflect self-efficacy is important for monitoring transition-aged patients with SCD.

Background: Severe aplastic anemia (SAA) is a rare, life-threatening disease characterized by pancytopenia and hypocellular bone marrow (BM). Immunosuppressive therapy (IST) is the standard of care for pediatric patients (pts) who lack a matched sibling donor. Approximately one-third of pts do not respond to IST or relapse following treatment. Therefore, effective and well-tolerated therapies are needed to improve outcomes of IST in pediatric pts with untreated or refractory/relapsed SAA. Aims: ESCALATE (CETB115E2201; NCT03025698) is a multi-institutional Phase II dose-escalation study to evaluate the pharmacokinetics (PK), safety, efficacy, and acceptability of the thrombopoietin receptor agonist eltrombopag (ETB) in pediatric pts who have refractory/relapsed SAA after IST for SAA (Cohort A) or who have previously untreated SAA (Cohort B). Methods: Patients (1 to <18 years [y] of age) received ETB as tablets or powder for oral suspension. Cohort A pts received ETB with IST (horse antithymocyte globulin [hATG] + cyclosporin A [CsA]) or ETB + CsA, based on investigator choice. Cohort B pts received ETB + hATG + CsA. The ETB starting dose was 50 mg/day (25 mg/day in pts aged <6 y) and was adjusted to achieve a target platelet count of 50-200×109/L. The maximum allowed daily dose was 150 mg. ETB was administered for 26 weeks and initiated together with CsA (duration of ≥104 weeks) +/- hATG (Days 1-4). Study follow-up included an additional 52 weeks during which ETB could be continued (data to Week 52 included here). ETB PK were the primary endpoint; secondary endpoints included safety/tolerability, overall response rate (ORR), BM cellularity, morphology, cytogenetics, paroxysmal nocturnal hemoglobinuria (PNH) clonal evolution, and acceptability/palatability (full data to be presented). ORR was defined as the proportion of pts with a complete (CR) or partial (PR) response (see Table 1 footnote). Results: Fifty-one pts (14 in Cohort A, 37 in Cohort B) were enrolled. The ORRs at Week 26 were 71% (95% CI 42-92) and 46% (30-63), respectively, for Cohorts A and B, and 57% (95% CI 29-82) and 51% (34-68) at Week 52 (Table 1). The most common ETB/hATG/CsA-related adverse events (AEs) (>20%) over the study period were increased bilirubin (43%), increased ALT (41%), increased creatinine (39%), increased AST (33%), hypertension (31%), hypomagnesemia (26%), and increased blood urea (24%). The most common serious AE was pyrexia (29%). Twenty-six pts discontinued ETB treatment, including 11 pts due to physician decision, 7 pts due to AEs (increased ALT/AST/blood bilirubin), 4 pts due to pt/guardian decision, 3 pts no longer requiring treatment, and 1 pt due to progressive disease. Two pts had BM chromosomal abnormalities post baseline (1 with 47XY+Y[2]/46XY[18] at Week 26 [normal at baseline and at Weeks 12 and 52]; 1 with 46,XY,t(2,3)(p23,q12)[2]/46,XY[18] at Week 182 [normal at baseline]). One pt evolved to PNH and 1 pt progressed to acute myeloid leukemia. Most pts reached the maximum daily dose of 150 mg regardless of age. The median dose intensity was 116.6 mg/day in pts aged <6 y and 94.8 mg/day in those aged 6 to <18 y. In pts who maintained the highest dose achieved for ≥14 days, the geometric mean (CV%) AUCtau was μg⋅h/mL (43%, n=8) and 733 μg⋅h/mL (63%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. Corresponding Cmax values were 71.6 μg/mL (33%, n=9) and 36.2 μg/mL (62%, n=22). Dose-adjusted (to 50 mg) geometric mean AUCtau was 447 μg⋅h/mL (54%, n=8) and 321 μg⋅h/mL (58%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. Corresponding Cmax values were 25.8 μg/mL (46%, n=9) and 16.6 μg/mL (52%, n=22). The higher ETB exposure in younger pts was a consequence of slower clearance: geometric mean CLss/F was 0.112 L/h (54%, n=8) and 0.156 L/h (58%, n=19) for pts aged 1 to <6 y and 6 to <18 y, respectively. This age effect on ETB PK is supported by data in adult SAA pts (dose-adjusted AUCtau and Cmax of 257 μg⋅h/mL and 13.4 μg/mL, respectively). Conclusion: The overall response rate to ETB in pediatric refractory/relapsed SAA pts was encouraging. ETB exposure was higher in pts aged 1 to <6 y than in those aged 6 to <18 y because of the age-related increase in ETB clearance. Despite the higher exposure in the younger pts, the daily dose achieved was generally 150 mg in both the 1 to <6 y and 6 to <18 y groups. The observed AEs reflected the disease itself and the safety profiles of hATG, CsA, and ETB. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Children with sickle cell disease (SCD) frequently have diminished academic attainment and are particularly vulnerable to reading dysfunction. We explored the effectiveness of a multisensory reading intervention offered during the summer to children with SCD at our institution. Subjects with reading deficits were identified through parent report, clinical findings, or school meetings. Summer reading programs utilizing Phonemic Awareness and Symbol Imagery were provided. The Lindamood-Bell Auditory Conceptualization/Phonemic Awareness Test, Third Edition (LAC-3), and the Symbol Imagery Test were used as pre- and postintervention examinations to measure progress. Fifteen students (median age 9.4 years, range 6-14 years, eight females, all African American) received the Phonemic Awareness intervention, two times a week for 6 weeks. The subjects showed statistically significant gains in standard scores derived from the LAC-3 (mean change 7.9 points, p < .001), with associated improvements in age equivalency (AE) and grade equivalency (GE). Twenty-nine students (median age 9 years, range 6-17 years, 13 females, all African American) participated in the Symbol Imagery reading program, also two times a week for 6 weeks. These students showed significant gains in overall standard scores (mean change 9.8 points, p < .001). Although results should be interpreted with caution due to small sample sizes, we found that summer reading clinics for children with SCD improved phonological processing and symbol imagery skills, potentially leading to substantial gains in reading capability.

Background Transcranial Doppler (TCD) screening of the large intracranial arteries can detect elevated blood velocity and is a strong predictor of stroke risk in children with sickle cell anemia (SCA, HbSS and HbSβ0-thalassemia). Initiation of chronic blood transfusion for patients with confirmed abnormal TCD velocities (time-averaged mean velocity, TAMV≥200 cm/sec) is shown to effectively reduce primary stroke. Current guidelines recommend annual TCD screening for children with SCA ages 2-16 years. Screening intervals were developed following evidence from the STOP studies1 (Figure 1). The estimated prevalence of normal TCD velocities is 83%2 and these children will have received 15 TCD exams from ages 2 to 16 if all results remain within normal range. The cumulative incidence of conversion from normal to conditional TCD velocities is dependent on age, whereby the risk is four times lower in children >10 years, compared to those <10 years of age3. Although TCD screening is non-invasive and safe, it consumes time and requires specialized equipment and trained examiners. Identifying sub-populations for whom TCD screening frequency could be safely reduced could lessen time burden on patients and caregivers and could be cost saving. Main objective To estimate the risk of TAMV conversion from normal to conditional or abnormal categories among children with SCA relative to age. Design/Method We included all participants with SCA from the Sickle Cell Clinical Research and Intervention Program, a longitudinal lifetime cohort of patients with SCD with at least one TCD measurement available both before and after age 10 years. We classified participants into two groups based on TCD screening results before 10 years of age; one group with all normal TCDs, and the other group with at least one non-normal TCD. We then compared the time to first non-normal study after ten years of age between the two groups using the log rank test. Time to first conversion was defined as time from age 10, to time of conversion if conversion occurred, or time to last follow up if no conversion occurred. We correlated the number of TCD exams before age 10 with time to first conversion using the Cox proportional regression model. Exposure to chronic transfusion or hydroxyurea before age 10 and age at first TCD measurement were covariates and were correlated with the time to first conversion. Results Of the 614 patients with TCD screening, 297 had SCA and at least 1 screening before and after age 10 (Table 1). Of these, 174 patients had only normal TCD screening before age 10 and the remaining 123 patients had at least 1 non-normal TCD screening before age 10. During the time they were followed,no patients with only normal TCD screenings before age 10, regardless of exposure to hydroxyurea or transfusions, had a conditional or abnormal TCD exam. Conversely, 41.5% of patients with at least one non-normal TCD before age 10 had a conditional or abnormal TCD screening after age 10. Conclusion In a large retrospective cohort study analysis of children with SCA, patients with TCD exams consistently within the normal range under age 10 years were not at risk of conversion to conditional or abnormal TAMV. These results suggest that children with SCA with all normal TCD velocities before age 10 years may not require additional TCD screening exams after age 10. These results translate to 6 fewer TCD exams per each child with SCA over age 10 with all prior normal TCD exams, potentially conserving resources and reducing burden on patients, families, and the health system. De-implementation studies to reduce the use of TCD screening exams in low-risk cases are needed References 1. Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006;108(3):847-852. 2. Adams RJ, McKie VC, Carl EM, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial doppler. Ann Neurol. 1997;42(5):699-704. 3. Hankins JS, Fortner GL, McCarville MB, et al. The natural history of conditional transcranial Doppler flow velocities in children with sickle cell anaemia. Br J Haematol. 2008;142(1):94-99. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSβ0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.