Age 10y Research Articles

Motor skills and intelligence in children with fetal alcohol spectrum disorder.

To determine the relationship between motor abilities and intelligence in children and young people with prenatal alcohol exposure (PAE) being assessed for fetal alcohol spectrum disorder (FASD). This was a cross-sectional correlational study of children and young people with PAE being assessed for FASD. The relationship between motor abilities (Movement Assessment Battery for Children, Second Edition) and intelligence (Wechsler Intelligence Scale for Children, Fourth or Fifth Edition) was calculated using correlation and regression analyses. Attention and executive function were considered as potential confounding variables. The relationship between motor abilities and intelligence in 73 children and young people (48 males, 25 females; aged 6-17y, mean age 10y 5mo [SD 2y 9mo]) assessed for FASD was small and statistically non-significant (r=0.05, p=0.67). The findings confirm that motor abilities and intelligence should be assessed separately when investigating an FASD diagnosis. Intelligence scores should not be used to estimate motor abilities, nor should they dictate when motor testing be completed. Assessing intelligence and motor domains separately will enhance diagnostic accuracy, identify the need for strategies or interventions to address functional motor skills, and further define the role of physiotherapy and occupational therapy in FASD assessment and intervention.

Tumor response of FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type metastatic colorectal cancer: The subgroup-analysis of DEEPER trial (JACCRO CC-13).

109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC). We performed a randomized phase II study, DEEPER trial (JACCRO CC-13)[NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) in previously untreated mCRC patients with RAS wild-type tumors (Tsuji A, et al. ASCO 2021). Methods: The primary endpoint was DpR during the entire course. Secondary endpoints included overall response rate (ORR), disease control rate, R0 resection rate, progression-free survival, and overall survival. A post-hoc subgroup analysis by PS, tumor sidedness, age, and location of metastases was performed to evaluate the efficacy of triplet plus cet vs. bev regimen. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. Median DpR was 57.4% vs. 46.0% ( p = 0.001), and the ORR was 69.1% vs. 71.7% ( p = 0.60), in cet vs. bev, respectively. The subgroup analysis was present in the table. There was no significant difference in terms of ORR and R0 resection rate between groups according to PS, tumor sidedness, age, and liver metastases (LM). In patients with only LM, the R0 resection rate of cet vs. bev was 25.0% vs. 14.8% ( p = 0.21). Conclusions: The m-FOLFOXIRI plus cet showed to be significantly superior to the m-FOLFOXIRI plus bev in terms of DpR in first-line treatment for RAS wild-type mCRC. The better DpR of m-FOLFOXIRI plus cet was evident for RAS wild-type mCRC patients with left-sided tumors, LM or under 70 years old. Clinical trial information: UMIN000018217.[Table: see text]

Program for the Education and Enrichment of Relational Skills for adolescents with an acquired brain injury: A randomized controlled trial

To test the efficacy of a group social skills intervention on social functioning in adolescents with a brain injury. Thirty-six adolescents (mean age 14y, SD 1y 8mo, age range 12y 1mo-16y 3mo; 17 females) with acquired brain injury (ABI; ≥12mo postintervention; n=19) or cerebral palsy (n=17) were randomly allocated to the Program for the Education in Enrichment of Relational Skills (PEERS) or usual care. The primary outcome was the Social Skills Improvement System-Rating Scales (SSIS-RS). Secondary outcomes were scores derived from the Test of Adolescent Social Skills Knowledge-Revised (TASSK-R), Social Responsiveness Scale, Second Edition, and Quality of Socialization Questionnaire. Between-group differences postintervention and at the 26-week retention time point were compared using linear mixed modelling for continuous outcomes and Poisson regression for count data. There were no between-group differences on the primary outcome (SSIS-RS). Regarding the secondary outcomes, the PEERS-exposed group achieved significantly greater improvements on the TASSK-R (mean difference [MD]=6.8, 95% confidence interval [CI]=4.8-8.8, p<0.001), which were maintained at the 26-week retention time point (MD=8.1, 95% CI=6.0-10.2, p<0.001). PEERS was also associated with a significant increase in parent-reported invited get-togethers at 26 weeks (incidence rate ratio=4.0, 95% CI=1.0-16.0, p=0.05). Adolescents with brain injury who completed the PEERS learned and retained social knowledge and increased social participation.

COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort.

IntroductionInfection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort.MethodsWe used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression.ResultsThere were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38–1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95–1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98–1.25) and MI (HR 0.93, 95% CI 0.85–1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19–1.56) and PE (HR 1.82, 95% CI 1.57–2.10) in patients with COVID-19.ConclusionIn a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

Prognostic value of soluble ST2 in chronic heart failure

To assess the risk of clinical worsening in heart failure (HF) is an important goal because HF is a progressive disease with a severe prognosis. The risk is usually estimated by using clinical, biological and clinical variables and by the dosage of natriuretic peptides. Other biomarkers have been tested in this setting and among candidates, the soluble ST2 seems a relevant one. The objective of our study was firstly, to analyze the predictive value of blood levels of sST2 in a cohort of patients with chronic heart failure and secondly, to study the variables associated with sST2 levels and to compare its predictive value to that of BNP levels. Measurement of both BNP and sST2 was performed in patients who were followed in our department. Baseline clinical and biological characteristics were also obtained. The primary endpoint was a composite of unplanned HF-related hospitalizations and all-cause death or cardiac transplantation. Predictive values of sST2 and BNP levels were estimated by using survival curves and Cox models. Our cohort included 298 patients: age 61y (IQR 52-69), 27% female, 46% ischemic heart disease, 22% diabetes, 25% atrial fibrillation, LVEF 0.38 (IQR 0.28-0.48), eGFR 75 (IQR 55-92)ml/min/1.73m 2 . Median sST2 levels were 31 ng/L (24-46) and BNP levels were 192 pg/mL (IQR 87-420). Increase in sST2 levels was significantly associated with age, BNP and renal function. During a median follow-up of 36 months, there were 76 events (25.5%) including 32 deaths. The increase in sST2 levels was strongly associated with clinical events. The Fig. 1 shows survival curves by using the usual sST2 cut-off of 35 ng/l; after adjustment on BNP levels, the Hazard Ratio was 2.85 [1.77-4.58]. In patients with chronic HF, sST2 levels are significantly predictive of outcome on top of BNP. The clinical usefulness of systematic measurement sST2 in addition to natriuretic peptides deserves dedicated studies.

POSB60 Evolution of Direct Medical Costs Associated with Respiratory Syncytial Virus Disease in Older Adults: A Retrospective Database Analysis from 2008 to 2017

Respiratory syncytial virus (RSV) can cause serious complications, such as pneumonia. This study describes the evolution of RSV-related direct medical costs (DMCs) in adults ≥60 years of age (60Y+) between 2008 and 2017 in the United States (US).

"It's a Vicious Cycle": A Mixed Methods Study of the Role of Family Planning in Housing Insecurity for Women.

We sought to explore family planning needs and experiences in housing-insecure women. We recruited 90 women (median age 29y) across Salt Lake County, Utah to complete a self-administered survey, and 15 of them also completed a qualitative interview. Of those at risk for unintended pregnancy, 27 (59%) reported not using their ideal contraceptive method. Reported barriers included cost and inability to find a provider. Participants described the conflicting role of pregnancy as a window to health care and other services, as well as the competing challenges of high-risk sex and physical safety. Addressing comprehensive reproductive needs is essential during times of housing insecurity. Doing this may avert homelessness.

External validity of the Both Hands Assessment for evaluating bimanual performance in children with bilateral cerebral palsy.

To investigate the external validity of the Both Hands Assessment (BoHA), a new test evaluating bimanual performance in children with bilateral cerebral palsy (CP), by analysing its relationship to established measurements of hand function and self-care skills. In this cross-sectional study, we recruited children with bilateral CP and manual ability corresponding to Manual Ability Classification System (MACS) levels I to III attending three habilitation units in Norway. All participants completed the BoHA. Unimanual capacity was assessed using the Bimanual Fine Motor Function (BFMF) classification, the Boxand Block Test (BBT), and the Melbourne Assessment 2 (MA2). Self-care skills were assessed with the Pediatric Evaluation of Disability Inventory (PEDI). Thirty-nine children (19 males, 20 females; mean age 8y 2mo, SD 2y 8mo; age range 2y 8mo-12y 6mo) were included. Spearman's correlation coefficient (ρ) suggested high correlation between the BoHA and MACS (p=0.89; 95% confidence interval [CI] 0.79-0.94), BFMF classification (p=0.84; 95% CI 0.71-0.91), and BBT for the non-dominant (p=0.85; 95% CI 0.68-0.95) and dominant hand (p=0.72; 95% CI 0.53-0.85). The Spearman's ρ between the BoHA and the MA2 subscales varied between 0.48 and 0.83, while the PEDI's ρ was 0.51 (95% CI 0.33-0.67). The BoHA provides valid measures of hand use as suggested by its high correlation with other activity-based measures of hand function.

Abstract 13912: ECG-DualNet: A MultiLabel Model for Automated Diagnosis on Both Electrocardiographic Signals and Printed 12-lead Electrocardiograms

Background: Electrocardiograms (ECGs) are frequently stored as printed images, but tools developed for artificial intelligence (AI)-based automated diagnosis and patient phenotyping exclusively rely on signal data, limiting their application. Methods: We developed a model that simultaneously incorporates both signal and image-based ECG data in clinical diagnosis and patient phenotyping. We used all 12-lead ECGs from a large deidentified database from Brazil, with signals transformed to a standard 12-lead ECG image. Both ECG signals and images were randomly subset into training, validation and test sets (90%-5%-5%). We used 6 physician-defined clinical labels spanning rhythm and conduction disorders as labels (atrial fibrillation [AF], sinus tachy/bradycardia [ST/SB], 1 st degree AV block [1dAVB], RBBB, LBBB). In addition, ECG-based identification of patient sex was assessed as a higher dimensional label. Convolutional Neural Networks were constructed with custom Inception net architecture for signals and EfficientNet-B3 for images. Model performance was evaluated in the holdout test set and US-based external validation dataset, PTB-XL. Results: The derivation dataset included 2,228,236 ECGs in 1,506,112 individuals (mean age 54y, 60% female). The ECG-DualNet model successfully labeled all 6 clinical diagnoses and patient gender with a high model performance (AUC of .81-.99 for signal and .92-.99 for images, F1 scores, .31-.78, and .49-82) in the 111,412 held-out test ECGs (Fig A-B). In external validation, with 21,785 ECGs, the model had excellent performance on both ECG signals and images (AUCs .75-.99 and .89-.99, F1 scores, .25-82, and .44-.86) (Fig C-D). Conclusion: A novel multilabel dual signal and image-based model achieved high performance in both clinical diagnosis and higher dimensional phenotypic labels across distinct ECG sources, with the ability to standardize automated diagnosis and patient phenotyping across ECG data formats.

Associations between Adverse Childhood Experiences and the novel inflammatory marker glycoprotein acetyls in two generations of the Avon Longitudinal Study of Parents and Children birth cohort

BackgroundAdverse childhood experiences (ACEs) are associated with increased risk of non-communicable diseases in adulthood, potentially mediated by chronic low-grade inflammation. Glycoprotein acetyls (GlycA) is a marker of chronic and cumulative inflammation. We investigated associations between ACEs and GlycA at different ages, in two generations of the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. MethodsALSPAC offspring’s total ACE scores were generated for two age periods using prospectively collected data: 0-7y and 0-17y. GlycA was measured using high-resolution proton nuclear magnetic resonance at mean ages 8y, 18y, and 24y. Sample sizes ranged from: n = 5116 (8y) to n = 3085 (24y). ALSPAC mothers (n = 4634) retrospectively reported ACEs experienced before age 18y and GlycA was assessed at mean age 49y. We used multivariable linear regression to estimate associations between ACEs (total ACE score and individual ACEs) and subsequent GlycA in both samples, adjusting for key confounders. ResultsMean GlycA levels were similar in offspring and mothers and over time. In offspring, there was no evidence that ACEs (total score or individual ACE) were associated with GlycA at age 8y or 18y, or 24y after adjustment for maternal age at birth and parity, maternal marital status, household occupational social class, maternal education, maternal smoking, own ethnicity, sex, and age in months. In mothers, there was evidence of a positive association between the total ACE score and GlycA at age 49y (adjusted mean difference 0.007 mmol/L; 95%CI: 0.003, 0.01). Emotional neglect was the only individual ACE associated with higher GlycA after adjusting for confounders and other ACEs. ConclusionResults suggest the association between ACEs and GlycA may emerge in middle age. Future research should explore the extent to which inflammation in adulthood mediates well-documented associations between ACEs and adverse health outcomes in later life.

Longitudinal bidirectional relationship between children's appetite and diet quality: A prospective cohort study

This study explored the relationship between eating behaviours and diet quality, from 7 to 10y. The sample included 3879 children evaluated, from the Portuguese birth cohort Generation XXI, with complete information on Food Frequency Questionnaire (FFQ) and the Children Eating Behaviour Questionnaire (CEBQ). A healthy eating index (HEI) (range: 9–31) was developed to evaluate the child's diet quality. The eight CEBQ's eating behaviours were included in the analysis. Generalised linear models were used to estimate the associations. Adjusted structural equation modelling was performed to study the direction of the associations. Eating behaviours measured at age 7y tracked to age 10y. A bidirectional inverse association between the food fussiness trait and diet quality was found, with a similar magnitude (p < 0.001), thus a higher score on food fussiness predicted a lower quality of the diet. A higher HEI score at 7y was associated with lower satiety responsiveness at 10y (βstandardized = −0.039), and a higher HEI score at age 10y was associated with higher enjoyment of food at 7y (βstandardized = 0.046). Eating behaviours were linked to diet quality in children with high enjoyment of food and low food fussiness at age 7y linked to a high-quality diet at 10y. In addition, children with high-quality diets at 7y were more likely to have lower food fussiness and satiety responsiveness at 10y. Given the stability of eating behaviours and the bidirectional nature of effects between eating behaviours and dietary quality in the long term, tailored interventions may be needed to encourage the acquisition of healthy eating behaviours and habits in early life.

Conditioning Intensity and Probability of Live Birth after Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: The observed inter-individual variability in the probability of live birth after BMT is due to exposure to gonadotoxic agents (including total body irradiation [TBI]), age at exposure to gonadotoxic agents, sex of the BMT recipient, and post-BMT morbidity. The last decade has seen an increase in use of non-myeloablative (NMA) conditioning to reduce the risk of early post-treatment mortality. However, the impact of TBI in the context of conditioning intensity (NMA vs. myeloablative conditioning [MAC]) on the probability of post-BMT live birth remains unknown. We addressed this gap by utilizing the BMTSS - a multi-institutional collaborative designed to understand the burden of morbidity after BMT.Methods: This study included 1,607 BMT survivors who underwent BMT between 1974 and 2014 at age ≤45, had survived ≥2y, and were ≥18y of age at study. This study also included pair-matched nearest-age, same-sex biologic siblings (≥18y of age at study) to control for genetic or environmental factors that could affect fertility. Survivors and their siblings completed the BMTSS survey. Sociodemographic characteristics (race/ethnicity, annual household income, availability of health insurance, level of education), chronic health conditions, medical assistance for fertility assistance and details about all pregnancies and their outcomes were retrieved from the BMTSS survey. Clinical characteristics were obtained from the institutional BMT databases and/or participants' medical record. Within survivor analysis: Potential risk factors for not reporting a live birth after BMT were analyzed using multivariable logistic regression. Exposure to TBI and conditioning intensity were consolidated to create four distinct exposure groups: no_TBI/NMA (least intense), TBI/NMA, no_TBI/MAC, TBI/MAC (most intense). Matched-pair comparison with biologic siblings: We matched 172 survivors with their closest-age, same-sex, biological siblings and used conditional logistic regression to determine the failure to report live birth in BMT survivors when compared with their siblings.Results: In this cohort of 1,607 survivors, 599 (37.3%) were autologous BMT recipients, and 765 (47.6%) were female. Median age at BMT was 30y, and at study participation was 45y (IQR: 18-73); median length of follow-up from BMT to study was 14.4y (IQR: 2.4-41.4). The primary indications for BMT included HL/NHL (30.6%), AML/MDS (24.3%), CML (13.4%), ALL (12.2%), and other diagnoses (13.5%). Of the 1,607 survivors, 120 (7.5%) reported one or more live births after BMT. Within survivor comparison: Multivariable analysis (Figure) revealed that receipt of TBI/MAC (OR=2.9, 95%CI: 1.5-5.8; ref: no_TBI/ NMA) was associated with an increased risk of not reporting a post-BMT live birth. Of note, TBI/NMA (OR=1.5, 95%CI, 0.5-5.0), and no_TBI/ MAC (OR=0.9, 95%CI, 0.4-2.0) were at a similar risk of reporting a post-BMT live birth as no_TBI/NMA. Other factors associated with increased risk of not reporting a post-BMT live birth included older age at BMT (>35y: OR=3.5, 95%CI, 1.4-7.9; reference: <12y), lower income ($50k-100k: OR=2.0, 95%CI, 1.1-3.6; <$50k: OR=3.2, 95%CI, 1.6-6.4; reference: >$100k), no medical interventions to facilitate pregnancy (OR=2.7, 95%CI, 1.6-4.6), and history of pre-BMT live birth (OR=2.7, 95%CI, 1.6-4.6). Matched-pair comparison with biologic siblings: Multivariable conditional logistic regression revealed that BMT survivors were less likely to report live birth (OR=0.5, 95%CI: 0.3-0.8) compared to their siblings. However, once pregnant, they were also less likely to report a miscarriage (OR=0.4. 95%CI: 0.2-0.8).Conclusion: While full dose TBI in the setting of myeloablative conditioning is associated with a lower probability of live birth after BMT, lower doses of TBI in the setting of myeloablative or reduced intensity conditioning yield a similar probability of live birth as no TBI. These findings provide evidence for alternative conditioning regimens for patients who wish to have children after BMT. [Display omitted] DisclosuresWeisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

Flow-Cytometry Evaluation of Cellular Surface FVIII in Blood Cells and Its Correlation with FVIII Activity and Coagulation

FVIII deficiency or inactivity leads to coagulation malfunction known as Hemophilia A (HA). FVIII overactivity on the contrary is commonly linked to a hypercoagulability state. In steady state, FVIII remains quiescent by forming a non-covalent complex with vWF, and upon coagulation cascade activation, thrombin liberates active FVIII (FVIIIa) from vWF. FVIIIa binds to the plasma membrane of the platelets and other blood cells via its C2 domain phospholipids binding motif to exert its coagulative role.Recently, we developed a reliable Flow-Cytometry (FC) platform for FVIII protein detection (Elnaggar M. et al, 2020). The assay is suitable to measure both intracellular and extracellular FVIII. When applied to human blood it showed that by overexpressing FVIII through a lentiviral-vector-based transduction, a high proportion of circulating FVIII is bound on leukocytes membranes. Leukocyte abundance is reported to be highly associated with thrombotic events but with no clear mechanistic explanation. Therefore, we sought to evaluate the percentage of FVIIIa bound on different leukocyte subsets (T cells, B cells, monocytes and granulocytes) in different clinical scenarios, including HA and other abnormal coagulation states and to correlate it to the plasmatic levels of FVIII.The analysis was conducted on 31 pediatric/young-adult subjects (median age 9y), including patients diagnosed with HA (n=8), patients with coagulopathies (von Willebrand Disease, menorrhagia and unexplained bleedings (n=11) and 1 patient with known high levels of FVIII), and patients without coagulopathies/healthy controls (n=11) referred to Hematology/Oncology clinic at Sidra Medicine-Qatar.Fresh blood samples were analyzed with a Sysmex XN1000 Hematologic Counter for complete blood count and with a BD-Symphony FC for the following surface markers: CD3/CD4/CD8/CD14/CD16/CD19/CD33/Live/Dead and for FVIII protein A2 domain (Ab clone GMA8024), after light-chain Zenon-labeling, with proper IgG controls, as described in the publication above. In parallel, plasma FVIII measurements were performed for clinical diagnostic purposes, and results were correlated.Expectedly, HA patients showed the lowest FVIII percentage in plasma (p<0.0001), while leukocytes' surface FVIII was generally low (on average <1%), trended to a lower rate in patients with coagulopathies and HA compared to healthy-controls and was significantly higher in the patient with hypercoagulability (p=0.0007). Surprisingly, among leukocytes' subpopulations, screened on patients with bleeding diathesis and HA subjects vs healthy-controls, only CD8-surface bound FVIIIa was significantly lower compared to healthy-controls (p=0.015 healthy-controls vs HA, and p=0,0093 healthy-controls vs bleeding diathesis). These results raise the possibility of a CD8-cell mediated controlled binding mechanism regulating FVIII availability in case of biological need of the protein, as bleeding.We did not find any significant correlation between leukocyte-surface bound FVIII and plasma FVIII level, and this further indicates that the differences in FVIIIa leukocyte surface binding are not directly proportional to FVIII availability in the circulation, rather actively regulated by a biological still unknown mechanism.While the study is still ongoing and recruiting other subjects with hypercoagulation state, we showed in this preliminary analysis that our in-house FC platform for FVIII protein detection screens in depth FVIII protein adherence to blood cells, may shed light on coagulation novel mechanisms, and potentially serve as a diagnostic and prognostic tool. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Late Relapses Who Are Transplant-Eligible Have Excellent Outcomes and May Represent Unique Biology

Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Late Relapses Who Are Transplant-Eligible Have Excellent Outcomes and May Represent Unique Biology

Antibody Response to Sars-Cov-2 Vaccination in Patients Following Allogeneic Hematopoietic Cell Transplantation

Background: Vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved rapidly. However, pivotal studies have been conducted in healthy volunteers, while recipients of allogeneic hematopoietic cell transplantations (allo-HCT) may have different dynamics and patterns of response to the vaccine and data in this cohort is lacking.Methods: Here, we examined longitudinal antibody (AB) titers to SARS-CoV-2 vaccination with BNT162b (Comirnaty ®) or mRNA-1273 (Moderna Covid-19 Vaccine ®) in allo-HCT recipients who had undergone allo-HCT >3months (m) ago and in healthy controls (hospital employers). Serial AB titers (prior to (T0); 1m after 1 st dose (T1); 1m (T2), 3m (T3), 6m (T4) post 2 nd dose) were measured with an in-house developed multiplex Antibody CORonavirus Assay (ABCORA) that measures SARS-CoV-2 IgG, IgA, and IgM reactivities against RBD (receptor binding domain), S1 (subunit 1 of the spike protein), S2 (subunit 2 of the spike protein) and N (nucleoprotein), thereby allowing to differentiate immunity after vaccination versus immunity after infection. As neutralization activity correlates well with S1 AB binding, the potency of the AB response was defined as the sum of S1 IgG, IgA and IgM reactivities (cumulative S1 (cS1)). Based on computational methods high neutralization potency was predicted above a cS1 threshold of 17.Results: We enrolled 114 allo-HCT patients (median age 57y (range 18y-74y)) between March 9th 2021 and May 31st 2021 at the University Hospital Zurich, Switzerland. Currently, AB responses at T1, T2, and T3 are available for 99, 95 and 89 patients, respectively. Patients were grouped into those (A) 3-6m post-HCT (T1: n=25 at, T2: n=23, T3: n=20); (B) 6-12m post-HCT (T1: n=13, T2: n=13, T3: n=12); and (C) >12m post-HCT (T1: n=61, T2: n=59, T3: n=57). In addition, AB responses are available for healthy controls (median age 35y (range 23y-64y)) (T1: n=75, T2: n=69, T3: n=48). There were 10 patients and 5 healthy subjects with a reported or detected SARS-CoV-2 infection. There was a statistically significant difference of cS1 AB levels between the 4 groups at T1, T2, and T3 (ANOVA p-values (p) <0.001, respectively, Fig 1) with the lowest AB response in group A (cS1 median value 0.957 at T1, 5.22 at T2, 1.90 at T3) and B (cS1 median value 0.973 at T1, 4.76 at T2, 11.9 at T3) compared to group C (cS1 median value 6.21 at T1, 199 at T2, 76.4 at T3) and healthy controls (cS1 median value 54.9 at T1, 228 at T2, 91.1 at T3). Using a multivariate linear regression analysis adjusted on age and gender, we found that patients in groups A and B had significantly lower cS1 levels than groups C and healthy subjects (p<0.001, p<0.001, p=0.034 of healthy versus groups A, B, C respectively at T2, and p<0.001, p=0.004, p=0.12 at T3), and that preinfected patients had higher cS1 levels at T2 and T3 respectively (p=0.003 and 0.006). The dynamics of the AB response were more diverse in allo-HCT recipients. In a multivariate linear regression analysis (Fig 2) assessing factors associated with humoral immune responses in allo-HCT recipients, we found consistently lower cS1 responses in patients early post-HCT (group A+B (p=0.002)) and higher cS1 levels in those who had been preinfected with SARS-CoV-2 (p=0.012). Patients under immunosuppressive treatment (IST) and those who had relapsed disease post-HCT showed significantly lower cS1 immune responses (p=0.028 and 0.005, respectively). The presence of moderate or severe chronic GVHD was not a statistically significant factor influencing AB levels. This may be explained by (i) the heterogeneity of the condition of chronic GVHD and low patient numbers; (ii) the late time point >12m post-HCT with generally higher AB levels. Consistent with other reports age >65y was also associated with lower cS1 responses (p=0.03).Conclusion: Allo-HCT recipients early post-transplant, those of older age, and those given IST displayed insufficient AB titers to the vaccine. Such knowledge is of critical importance to transplant recipients and their physicians to guide treatment decisions regarding re-vaccination, and social behavior during this pandemic. Monitoring AB development in all allo-HCT recipients and vulnerable patients with other immunocompromising conditions may be crucial to determine those at increased risk for infection and for the timing of booster vaccines. [Display omitted] DisclosuresManz: CDR-Life Inc: Consultancy, Current holder of stock options in a privately-held company; University of Zurich: Patents & Royalties: CD117xCD3 TEA.

Myelodysplastic Syndromes: Have You Seen Your Patient Beyond His Hemoglobin?

Background: Palliative care (PC) is a patient-centered care model that aims to relief suffering by establishing a plan of care that integrates physical, psychosocial, cultural, familial and spiritual issues during the course of disease's evolution. Thus, PC applies not only to patients who face a diagnosis beyond the possibility of cure, but to all those who experience significant symptoms throughout the course of the disease. Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by cytopenias and an elevated risk of developing acute leukemia. As MDS display a wide genetic heterogeneity, patients have a variable clinical presentation, ranging from asymptomatic patients to individuals with severe cytopenias and high-risk disease. MDS are more prevalent in the elderly population, which usually experience several morbidities; thus, MDS frequently lead to notable symptoms and deterioration of quality-of-life, making most of them eligible to PC in addition to standard hematologic care. In spite of that, previous studies demonstrated that patients with hematologic malignancies appear to have restricted access to PC services and receive more aggressive therapies at the end of life.Aims: To evaluate eligibility criteria for PC in a cohort of MDS patients and correlate with clinical and laboratory data.Methods: Clinical and demographic data of MDS patients were collected through interviews using a standardized questionnaire: time from diagnosis, number of morbidities, need for seeking the emergency during the last 12mo, delirium events, wounds, dysphagia, recurrent falls, adverse events to medication, quality of communication with the medical team, fears regarding the disease and its complications, religious support, age, gender, monthly household income and level of schooling. Specific PC scores were also applied: Edmonton Symptom Assessment Scale (ESAS) and Palliative Performance Scale (PPS). Clinical and laboratory data were collected: hemoglobin (Hb), platelet and neutrophil counts, Revised International Prognostic Scoring System (IPSS-R) and transfusion burden. Statistical univariate and multivariate analysis were performed. P value <.05 was considered statistically significant. This research was approved by the Institutional and National Review Board; written informed consent was obtained from all subjects.Results:Thirty-six patients were evaluated: median age 68y (21-90), sex 16F/20M. According to ESAS, tiredness and anxiety were the most relevant symptoms in MDS patients [median (min-max)]: pain 0 (0-10), tiredness 4.5 (0-10), drowsiness 1.5 (0-10), nausea 0 (0-7), lack of appetite 0 (0-10), shortness of breath 0 (0-10), depression 0 (0-10), anxiety 3.5 (0-10), best wellbeing 2.5 (0-8). Younger patients (<60y, n=10) had a worse ESAS for best wellbeing (5 (2-8)) when compared to older individuals (≥60y, n=26): (2 (0-7)), p=.007, and tended to have worse ESAS scores for tiredness: 8.5 (0-10) vs 3.5 (0-10), p=.56. Importantly, ESAS for tiredness was not correlated to Hb levels, the number of red blood cell transfusions nor with IPSS-R (all p>.05). ESAS for drowsiness was significantly higher in patients with two (5 (0-10)) and ≥three morbidities (3 (0-8) vs those with only one morbidity (0 (0-10)): p=.01 and p=.03, respectively. ESAS for best wellbeing was better in individuals with higher household income 0 (0-0) vs patients with lower financial resources 3 (0-7), p=.04). PPS median was 90% (60-100%) and negatively correlated with transfusion burden (r=0.407, p=.01) and with the need for seeking the emergency in the past 12mo (r=-0.332, p=.04). Finally, despite facing a potential life-threatening disease, 94.4% of the patients reported that their doctors had never talked to them about aspects related to end-of-life care. Conversely, 75% of them reported fears and doubts regarding this phase.Conclusions: In our casuistic of MDS patients, tiredness was the most important symptom observed. Surprisingly, it was not correlated with Hb levels and transfusion burden, suggesting that Hb levels alone should not be used to justify symptoms. The number of morbidities and lower household income also impacted ESAS scores. Finally, a great part of the patients revealed miscommunication with their hematologists regarding end-of-life planning. Our data indicate that MDS patients might benefit from a PC multidisciplinary team approach. DisclosuresCosta: Novartis: Consultancy.

Clonal Hematopoiesis Driven By MDM4 Amplification Defines a Canonical Route Towards Secondary MDS/AML in Fanconi Anemia Patients

IntroductionFanconi anemia (FA) is the most frequent inherited DNA-repair disease in human, driving hematopoietic stem cell (HSC) failure in children and a major predisposition to poor-prognosis myelodysplastic syndrome (MDS) and acute leukemia (AML) in children or young adults. MDS/AML secondary to FA have a dismal prognosis in this frail population with a high chemotherapy-related toxicity. How bone marrow (BM) cells progress to myeloid malignancies in a background of cell intrinsic genomic instability and stem cell exhaustion is still poorly understood. Here we aimed to identify the molecular and functional determinants of BM progression to MDS/AML in FA patients.MethodsWe studied a cohort of 335 FA patients, representing virtually all FA patients seen in France from 2002 to 2020. We performed longitudinal clinical studies (cytopenia, BM morphology and staging, HSCT, survival), somatic genomics (karyotype, myeloid cancer gene panel, aCGH, WES, WGS), expression analysis by RNAseq on clonal cells, and functional studies (gene modulation in HSPCs, transgenic MDM4 mice, CFU and competitive engraftment experiments). Paired clonal BM and skin fibroblasts samples were available for 62 MDS/AML FA patients; WES and WGS files from age-matched non FA MDS/AML were used as controls.Results98 out of 335 patients (29%) experienced clonal evolution, first seen at a median age of 13y, including 51 (15%) with blastic evolution (>5% BM blasts, median age 16y). Unbalanced chromosomal translocations rather than point mutations underlaid clonal evolution in comparison to age-matched, sporadic (non-FA) AML cases. The most prominent driver lesion was chromosome 1q duplication (1q+), found in 52% of the clonal FA patients, while other recurrent lesions were gain of 3q (3q+/EVI1; 40%), translocations/del/mut involving the RUNX1 gene (35%), monosomy 7/7q- (31%), and signaling gene mutations (18%). Based on longitudinal studies and ranking models, we evidenced that 1q+ occurred early, yielding preleukemic clonal hematopoiesis, whereas 3q+, -7/del7q, RUNX1 and signaling mutations occurred later along with BM transformation.Regarding genomic instability, WGS analysis of FA AML cells revealed a unique mutational signature that shares features with BRCA-related solid cancers [homologous recombination deficient (HRD)-type substitution signature, accumulation of small/intermediate-size deletions and large structural variants (SV)]. SV breakpoint analysis identified microhomology-mediated end joining (MM-EJ, also known as Alt-EJ) as the preferential DNA repair mechanism in the FA context. Specifically, a fragile site in the 1q pericentromeric repeated region underlaid 1q+ translocations.Next, we found that the MDM4 oncogene, a negative modulator of p53 response located in the minimal 1q duplicated region, was overexpressed in 1q+ but not in clonal non-1q FA cells. We hypothesized that 1q+ may attenuate the FA-associated p53 pathway hyperactivation through increased gene dosage of MDM4. Consistently, RNA-seq of patient cells before and after clonal progression showed p53 pathway activation before clonal evolution and subsequent p53 downregulation along with 1q+. When evaluated in vitro by CFU assay, lentiviral overexpression of MDM4 rescued clonogenicity defect of HSCPs from both FA patients and Fanc-/- mice, at the same level as TP53 knockdown. We produced a transgenic mouse bearing a duplicated Mdm4 locus and showed that MdM4 overexpression conferred an advantage to FA-like HSPCs in competitive transplant experiments, modeling clonal hematopoiesis. Exposure of 1q+ FA cells to Mdm4 inhibitors raised therapeutic potential.ConclusionsThe somatic genomic landscape of FA MDS/AML reveals a unique FA mutational signature, characterized by structural rearrangements and copy number abnormalities rather than point mutations. Our results define a canonical oncogenic route towards secondary MDS/AML in FA patients, in which the early modulation of the p53 pathway through 1q+/MDM4 oncogene overexpression plays a pivotal role, raising novel monitoring and therapeutic prospects for the FA patients. DisclosuresSebert: BMS: Consultancy; Abbvie: Consultancy. Dalle: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)

Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 302 Patients with Relapsed or Refractory (r/r) Acute Myeloid Leukemia after Intensive Chemotherapy (ASTRAL-2 Study)

Vaccine Efficacy after Rituximab Exposure: First Interim Analysis of Virtue Project on Behalf of West Midlands Research Consortium, UK

▪Background: Anti-CD20 B cell depleting agents are amongst the most commonly used immunotherapeutics employed in the treatment of haematological malignancy and autoimmune diseases. By inducing peripheral B cell aplasia, anti-CD20 depleting agents are hypothesised to significantly impair serological responses to neoantigens, including the SARS-CoV-2 spike glycoprotein within SARS-CoV-2 vaccines. Seropositivity following SARS-CoV-2 is the strongest, measurable correlate of protection from severe COVID-19. Understanding the kinetics of B cell reconstitution and vaccine responsiveness following exposure to B cell depleting agents is essential to maximise vaccine efficacy in patients vulnerable to severe COVID-19.Methods: 80 patients with underlying haematological malignancy and 38 patients with underlying rheumatological disease previously treated with anti-CD20 B cell depleting agents were studied following their second dose of a SARS-CoV-2 vaccine (median time to sampling: 46.5d, IQR: 33.8-63.3). Lymphocyte subset (CD4, CD8, CD19, CD56/16) enumeration was performed using 6 colour flow cytometry (BD Trucount). Total anti-SARS-CoV-2 spike glycoprotein antibodies were measured by enzyme-linked immunosorbent assay (The Binding Site, Human Anti-IgG/A/M SARS-CoV-2-ELISA). The relationship between immune reconstitution following B cell depletion and vaccine responsiveness was explored.Results: In the haematology cohort (median age 70y, IQR 60.3-76.0, 62.5% male), overall seropositivity following vaccination was 60.0%. Individuals on active chemotherapy had significantly lower seroprevalence than those vaccinated following the completion of chemotherapy (22.7% vs 74.1%, p<0.0001). In the rheumatology cohort (median age 65y, IQR 58.3-70.8, 39.9% male), overall seropositivity was 69.4%. In both cohorts, vaccine non-responders had significantly smaller populations of peripheral CD19+ B cells (haematology: 0.20 vs 0.02 x10 9/L, p=0.004, rheumatology: 0.07 vs 0.01 x10 9/L, p=0.03). The magnitude of the antibody response following vaccination did not differ between recipients of Tozinameran and Vaxzeveria in either cohort. Vaccine responsiveness was lower in the first 6 months following B cell depletion therapy; 42.9% in the haematology cohort and 33.3% in the rheumatology cohort, increasing to 100% and 75% respectively in individuals receiving their second dose 6-12 months following B cell depletion (Figure 1).B cell reconstitution in the 7-12 month window following B cell depletion was faster in haematology compared to rheumatology patients (77.8% v 22.2% achieving normal B cell count, p=0.005) and associated with improved vaccine responsiveness. However, persistent immunodeficiency occurred in some haematology patients following completion of treatment: 25% of patients who had completed therapy at least 36 months previously failed to respond to vaccination. In this cohort of vaccine non-responders, 83.3% of individuals had B cell numbers within the normal range. These patients had all previously been treated for follicular lymphoma suggesting a specific mechanism for long-range secondary immunodeficiency in these patients.Conclusions: Serological responsiveness to SARS-CoV-2 vaccines is poor during active chemotherapy for haematological malignancy and in the first 6 months following B cell depletion, regardless of underlying disease. Vaccine responsiveness significantly improves in the 7-12 month window following B cell depletion. Compared to haematology patients, B cell reconstitution is slower in rheumatology patients and associated with reduced vaccine responsiveness, possibly due to the use of additional concurrent disease-modifying anti-rheumatic therapies. Furthermore, long-term secondary immunodeficiency occurs in a minority of haematology patients. To maximise the efficacy from SARS-CoV-2 booster vaccination and optimal utilisation of available vaccine doses, immunisations should be delivered at least 6 months following the administration of anti-CD20 depleting drugs.Figure 1: Kinetics of return of vaccine responsiveness following B cell depletion in haematology and rheumatology patients. [Display omitted] DisclosuresPaneesha: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company.

Neurological and cognitive outcomes after antibody‐negative autoimmune encephalitis in children

AIMTo characterize the neurological and cognitive outcomes in children with antibody‐negative autoimmune encephalitis (Ab‐negative AE).METHODA cohort of children presenting to our institution over a 10‐year period with autoimmune encephalitis was identified by structured retrospective review of medical records. Clinical features at presentation and final follow‐up were recorded. Neuropsychological testing was performed in a subset of patients. Outcomes after Ab‐negative AE were compared with outcomes after N‐methyl‐D‐aspartate receptor antibody encephalitis (NMDARE).RESULTSForty‐four patients (26 females, 18 males, median age 9y 2mo [interquartile range 4y 5mo–11y 8mo], 23 with NMDARE) with a diagnosis of autoimmune encephalitis were included. Postencephalitic epilepsy was more frequent after Ab‐negative AE compared to NMDARE (61% vs 14%, p=0.002). Cognitive testing was performed in a subset of patients (n=21; Ab‐negative AE=11, NMDARE=10). Full‐scale IQ was lower after Ab‐negative AE than NMDARE (mean IQ 75 vs 92, p=0.02), primarily because of reduced verbal comprehension index (80 vs 98, p=0.01) and working memory index (77 vs 95, p=0.09). The cognitive function most commonly impaired was executive function (80% [8/10] vs 22% [2/9]).INTERPRETATIONAb‐negative AE was associated with poorer cognitive outcomes than NMDARE at 1‐year follow‐up. Further studies are required to evaluate if immunotherapy can be optimized to improve outcome.