Abstract: Abstract 2581 Poster Board II-558 Tricuspid regurgitant jet velocity (TRJV) measurements are used commonly for estimating pulmonary artery pressures among individuals with sickle cell disease (SCD) undergoing screening for pulmonary hypertension, defined by TRJV ≥ 2.5 m/sec. Measurements, however, may be prone to variability and have not been subjected to reliability testing in this population. The objective of our study was to examine reliability as well as potential sources of variability associated with TRJV measurements in a cohort of children and young adults with SCD. Methods We evaluated TRJV at steady state in a convenience sample of 30 subjects (53% male) with SCD (SS n=25, SC n=1, S-Beta0 thalassemia n=4) during 2 separate visits 1 week apart. In a blinded fashion, peak TRJV was independently measured by 2 experienced sonographers and officially interpreted by 2 readers who were attending cardiologists at standard time points in the protocol that permitted assessment of reliability and agreement. We calculated within subject variability as well as intra-/inter-sonographer and reader reliability in this analysis using Intraclass Correlation Coefficient (ICC) and Cohen's kappa to assess TRJV as a continuous and categorical variable, respectively. Agreement was also examined graphically using Bland-Altman plots. Results Sonographers were able to measure TRJV in all subjects (mean age, 15.8±3.3 years, range 10 to 22). Readers, however, designated tricuspid regurgitation unquantifiable in 13% of their final interpretations, most commonly due to an inadequate Doppler window. We found that intra-reader reliability was highest (ICC=0.93 [95% CI 0.86, 0.97], p 〈 0.001) and within subject reliability lowest (ICC=0.36 [95% CI 0.02, 0.64], p=0.021) for single TRJV measurements. Inter-reader, intra-/inter-sonographer and between sonographer/reader reliability was in the moderate range, with ICCs that ranged from 0.54 to 0.68. Sonographers and readers also categorized their TRJV measurements and interpretations, respectively, as normal ( 〈 2.5 m/s), mild elevation (2.5–2.9 m/s), modest elevation (≥3.0 m/s) or unquantifiable. Using this classification schema, we found that agreement on categories paralleled that on TRJV as a continuous variable. Intra-reader agreement was highest (kappa=0.74 [95% CI 0.53, 0.95], p 〈 0.001) and within subject lowest (kappa=0.14 [95% CI −0.17, 0.46], p=0.38) for TRJV classification, with kappa values ranging from 0.30 to 0.45 for all other combinations of sonographer and reader agreement testing. We plotted absolute differences in sonographer TRJV measurements or reader interpretations against the averages of each pair of values to construct our Bland-Altman graphs (Figure 1). Variability was graphically evident despite finding that only 3.6 to 8.7% of absolute differences fell beyond ±2 standard deviations of the mean difference. For intra- and inter-reader agreement, we observed that absolute differences in readings increased with higher mean TRJV readings. Conclusions In summary, quantification of tricuspid regurgitation as well as classification of TRJV values in children and young adults with SCD are affected by several potential sources of variability, including intra-/inter-sonographer and reader differences in measurement and interpretation. Despite using a single sonographer for its determination, within subject reliability in our analysis was especially poor, which may in part reflect sonographer ability to obtain Doppler windows adequate for accurate quantification of tricuspid regurgitation. Our findings underscore the need for methodological improvements that ensure the reliability of measurements used to diagnose TRJV elevation in this population. Multi-institutional reliability testing may also be required to establish the degree of variability that should be considered acceptable in clinical trials involving individuals with SCD and TRJV elevation. Disclosures: No relevant conflicts of interest to declare.

Abstract: Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.

Abstract: Introduction: Geriatric assessment (GA) is a multidimensional evaluation of patient health and function that may detect impairments not identified as part of routine care, predict treatment-related morbidity and mortality, and inform treatment plans. Given evidence of these benefits, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend GA for older candidates of hematopoietic stem cell transplantation (HCT). However, both older and younger HCT candidates will often receive multiple rounds of chemotherapy before HCT, leading to functional impairments in all age groups. Furthermore, HCT patients often experience a significant gap between when they are first evaluated and actually proceed to transplant (e.g., while a donor search is conducted), creating an opportunity to identify impairments and optimize function prior to transplant. Methods: To address this opportunity, we created a clinical pre-HCT optimization program (C-POP) to evaluate physical function, cognitive function, nutritional status, and mental health in all adults who were deemed potential candidates for allogeneic HCT by a HCT physician. We applied this standard of care program to all adult candidates for HCT, regardless of age, with the goal of identifying functional impairments and then referring patients to services to optimize those impairments prior to HCT. We defined impairments using validated measures and compared results to established norms or scoring, controlling for age and gender where appropriate (e.g., the cut-off for six-minute walk distance was adjusted for age, gender, height, and weight, while the cut-off for falls was any fall regardless of characteristics). Patients with impairments were referred to the appropriate supportive care (e.g., physical function impairment - 〉 referral to physical therapy). Results were prospectively analyzed at new patient evaluation (NPE), which was the first time the patient met a HCT physician and sign-off, which occurred within a week before starting transplant. While the program is ongoing, we present here the results of patients evaluated between October 16th, 2017 and July 1st, 2019. Patients are divided into three pre-specified age groups: 〈 40 years old, 40-59 years old, and 〉 =60 years old, with results compared using a chi-squared test. Results: We evaluated 115 patients: 21 (18%) 〈 40 years, 40 (35%) 40-59 years, and 54 (47%) 〉 =60 years). There were no differences between the age groups in other demographics (gender, race, and ethnicity). At NPE, 93 (81%) met criteria for at least 1 impairment in physical function, cognitive function, nutritional status, or mental health; 62 (54%) met criteria for impairments in 2 or more areas. Surprisingly, patients 〈 40 years were more likely to screen positive for physical function (20/21, 95%) than patients 40-59 years (26/40, 65%) and patients 〉 =60 years (36/54, 67%) (p=0.03). Of those 115 patients, 52 (45%) proceeded to HCT, including 12 (57%) 〈 40 years, 18 (45%) 40-59 years, and 22 (41%) 〉 =60 years (p=0.75); of those patients who have not proceeded to HCT, 40 (35%) will never proceed to HCT (e.g., deemed not a candidate after functional evaluation or died of disease prior to HCT) while 23 (20%) are still awaiting HCT (e.g., donor search ongoing). Patients who proceeded to HCT were less likely to have mental health impairments (2/52, 4% vs. 9/40, 23%, p=0.006). Of the 52 who were seen at new patient evaluation and proceeded to transplant, 40 (77%) were seen at sign off. Of those who had impairments at NPE, 12/23 (52%) improved their physical function to normal limits, 4/9 (44%) improved their cognitive function, and 9/13 (69%) improved their nutritional status by the time of sign-off (of those who were seen at sign-off, none had mental health impairments at NPE). Discussion: These results demonstrate that younger as well as older candidates for HCT exhibit a high degree of functional impairment. However, this impairment could be amenable to improvement prior to HCT. These findings support application of GA to all HCT candidates regardless of age. We will investigate the effect of referred interventions (e.g., physical therapy, seeing a dietician) in improving functional impairments in future studies, as well as look at the effect of these findings on HCT outcomes. Disclosures Wiggins: Incyte, Inc.: Speakers Bureau. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Rizzieri:Millennium: Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; TEVA: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Horwitz:Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding.

Abstract: Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic & Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

Abstract: Background: Outcomes for CLL pts with TP53 aberrancy including deletion of 17p (del17p) or TP53 mutations treated with chemo+/-immunotherapy (CIT) have been historically poor. Despite improvements, pts with TP53 aberrancy treated with novel agent-based regimens such as ibrutinib (ibr), acalabrutinib and venetoclax (ven), still have inferior outcomes as compared to pts with intact TP53. In 5 year follow-up data from relapsed/refractory (R/R) CLL pts treated with ibr, pts with del17p had a shorter median progression free survival (PFS) and overall survival (OS) (26 and 57 months) vs. the overall cohort (median PFS 51 months, OS not reached, O'Brien et al Blood 2018). Additionally, for R/R CLL pts treated with 24 months of ven and rituximab (VR), del17p and/or a TP53 mutation was associated with an increased risk of CLL progression after stopping ven (p=0.01, Kater et al JCO 2019). In addition, pts with mantle cell lymphoma (MCL) with TP53 mutations have a poor response to CIT and autologous stem cell transplantation. In a series of MCL pts who discontinued ibr, 75% who discontinued for progression harbored TP53 alterations (Jain et al Br J Haematol 2018). These studies highlight an unmet need for improved treatments for CLL and MCL pts with TP53 mutations. APR-246 is a novel small molecule that is converted to methylene quinuclidinone (MQ), a reactive electrophile that forms a covalent bond with the p53 core domain to reactivate mutant p53 and restore wild type p53 function and apoptotic activity (Zhang et al Cell Death Disease 2018). Additionally, APR-246 has been shown to deplete glutathione and induce reactive oxygen species (Liu et al Nat Commun 2017). Clinical activity has been demonstrated in phase II studies of APR-246 + azacitadine in TP53 mutant MDS (ORR 88%, CR 61%, Sallman et al ASH 2019; ORR 75%, CR 57%, Cluzeau T et al EHA 2020). A phase I trial of APR-246 in combination with venetoclax is ongoing in AML (NCT04214860). APR-246 induces apoptosis in TP53 mutated CLL cells (Jaskova et al, Leuk Res 2020) and single agent activity in CLL has been described in the APR-246 first-in-human clinical trial (Lehmann S et al JCO 2012; Deneberg S et al Blood Canc J 2016). Study Design and Methods: This is a phase 1, open-label, 3+3 dose de-escalation and dose expansion study investigating APR-246 in combination with (cohort 1) ibrutinib or (cohort 2) VR in pts with R/R TP53 mutant CLL or MCL (Figure 1). The safety lead-in portion of the study includes two safety cohorts of CLL pts with TP53 mutations: APR-246 in combination with (1) ibrutinib (ibr), n~28 pts or (2) APR-246 in combination with VR, n=~28 pts. Treatment will be administered according to Figure 2. Eligible pts must have a TP53 mutation. Based on the results of an integrated assessment of the safety, tolerability and preliminary clinical activity in the safety lead-in cohorts, ibr and/or VR will be selected for further study in combination with APR-246 in a dose expansion portion of the study which will include pts with TP53-mutant (1) R/R CLL (n≤20) and (2) R/R MCL (≤40). The primary study endpoints will be (1) the occurrence of DLTs according to the NCI CTCAE, version 5.0, (2) the frequency of treated-emergent adverse events (AE) and SAE, and (3) the recommended phase 2 dose (RP2D) of APR-246 in combination with ibr or VR. Secondary study endpoints include pharmacokinetic parameters, the complete response rate, objective response rate, duration of response and PFS for APR-246 in combination with ibr or VR. Correlative studies are planned to examine the effect of APR-246 combinations on the p53 pathway and examine genome and transcriptome correlates of response and resistance. Patient samples will be collected at multiple timepoints to measure p53 protein expression by immunoblot of protein lysates from mononuclear cells. Specifically, p53, BCL2, BAX, NOXA and PUMA levels will be examined to assess the effect of APR-246 + ibr or VR on the p53 pathway. These studies will be complemented by BH3 profiling, a functional technique to assess the propensity of the tumor cells to undergo apoptosis and their dependence on specific anti-apoptotic proteins. Additionally, intracellular flow cytometry will evaluate the effect of the combinations on key markers within the p53 pathway. DNA and RNA sequencing will be performed to identify potential biomarkers of response. This study is planned to be open for enrollment by September 2020 at the first study site and is planned to open at up to 10 study sites. Disclosures Davids: Bristol Myers Squibb: Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Zentalis: Consultancy; Genentech: Consultancy, Research Funding; Eli Lilly: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy; Sunesis: Consultancy. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Fate Therapeutics: Research Funding; BMS: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Soumerai:AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; Beigene: Consultancy, Research Funding; BostonGene: Research Funding; Genentech/Roche: Research Funding; GlaxoSmithKine: Research Funding; Verastem: Consultancy. Gubits:Aprea Therapeutics: Current Employment. Hickman:Aprea Therapeutics: Current Employment. Wennborg:Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Attar:Aprea Therapeutics: Current Employment. Abdel-Wahab:Merck: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding; Janssen: Consultancy. Mato:TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Adaptive: Consultancy, Research Funding; BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

Abstract: Introduction: Dysbiosis of the gut microbiome during hematopoietic stem cell transplantation (HCT) is associated with adverse post-transplant outcomes such as graft-versus-host disease, bloodstream infections, and mortality. In order to learn more about the role of the microbiome in HCT in adverse clinical outcomes, researchers collect stool samples from patients at various time points throughout HCT. However, unlike blood samples or skin swabs, stool collection requires active subject participation, particularly in the outpatient setting, and may be limited by patient aversion to handling stool. By providing study participants with compensation for their stool samples, we hypothesize that we can significantly increase stool collection rates. Methods: We performed a prospective cohort study on the impact of financial incentives on stool collection rates for microbiome studies. The intervention group consisted of allogeneic (allo)-HCT patients from 05/2017-05/2018 who were compensated with a $10 gas gift card for each stool sample. The intervention group was compared to a historical control group consisting of allo-HCT patients from 11/2016-05/2017 who provided stool samples before the incentive was implemented. To control for potential changes in collections over time, we also compared a contemporaneous control group of autologous (auto)-HCT patients from 05/2017-05/2018 with a historical control group of auto-HCT patients from 11/2016-05/2017; neither auto-HCT groups were compensated. Allo-HCT patients were required to give samples at pre-HCT, day 0 (the day of HCT), and days 7, 14, 21, 30, 60, and 90 post-HCT. Auto-HCT patients were required to give samples at pre-HCT and days 7, 14, and 90 post-HCT. Collection rates were defined as the number of samples provided divided by the number of time points for which we attempted to obtain samples. Patient characteristics were summarized by proportions for categorical variables and median with interquartile ranges for continuous variables. Chi-square tests or Fisher's exact tests were used to compare categorical variables, as appropriate, and Wilcoxon Rank Sum tests or t-tests were used to compare continuous variables, as appropriate. This study was approved by the Duke Institutional Review Board, and informed consent was obtained from all patients. Results: There were 35 allo-HCT patients in the intervention group, 19 allo-HCT patients in the historical control group, 142 auto-HCT patients in the contemporaneous control group, and 75 auto-HCT patients in the historical control group. Groups were similar with regard to baseline demographics such as age, race, and gender. While allo-HCT patients were more likely to have leukemia and auto-HCT patients were more likely to have lymphoma and multiple myeloma, there were no differences in disease rates across the study periods. Allo-HCT patients in the intervention group had significantly higher average overall collection rates when compared to the historical control group allo-HCT patients (80% vs 37%, p 〈 0.001), as well has significantly higher average outpatient collection rates (84% vs 23%, p 〈 0.001) and average inpatient collection rates (71% vs 46%, p=0.04). In contrast, there were no significant differences in overall average collection rates between the auto-HCT patients in the contemporaneous control and historical control group (36% vs 32%, p=0.28), as well as the average outpatient collection rates (30% vs 28%, p=0.54) and the average inpatient collection rates (46% vs 59%, p=0.25). Discussion: Our results demonstrate that even a modest incentive can significantly increase collection rates. Use of a contemporaneous control group to account for potential differences in stool collection rates over time strengthens our finding that financial incentives increase stool collection rates. Furthermore, the significant increase in collection rates in the outpatient setting highlights the role of the incentive when patient participation is needed, as opposed to the inpatient setting in which the nurse assists with collection. While this study uses a specialized HCT patient population, these results may be generalizable to future studies and aid other researchers in obtaining stool samples needed for future microbiome studies. Disclosures Peled: Seres Therapeutics: Other: IP licensing fees, Research Funding. van den Brink:Acute Leukemia Forum (ALF): Consultancy, Honoraria; Juno Therapeutics: Other: Licensing; Merck & Co, Inc.: Consultancy, Honoraria; Seres Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Therakos: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Flagship Ventures: Consultancy, Honoraria; Evelo: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Magenta and DKMS Medical Council: Membership on an entity's Board of Directors or advisory committees. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding.

Abstract: Myelodysplastic neoplasms (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Accurate pathologic diagnoses present challenges due to interobserver variability in interpreting morphology and quantifying dysplasia. We compared local clinical site diagnoses with central, adjudicated review from 918 participants enrolled in the ongoing National Heart, Lung, and Blood Institute National MDS Natural History Study (NCT02775383), a prospective observational cohort study of participants with suspected MDS or MDS/myeloproliferative neoplasms (MPNs). Locally, 264 (29%) were diagnosed as having MDS, 15 (2%) MDS/MPN overlap, 62 (7%) idiopathic cytopenia of undetermined significance (ICUS), 0 (0%) acute myeloid leukemia (AML) with & lt;30% blasts, and 577 (63%) other. Approximately one-third of cases were reclassified following central review with 266 (29%) diagnosed as MDS, 45 (5%) MDS/MPN overlap, 49 (5%) ICUS, 15 (2%) AML & lt;30%, and 543 (59%) other. Site miscoding errors accounted for over half (53%) of the local misdiagnoses, leaving a true misdiagnosis rate of 15% overall, 21% for MDS. Therapies were reported in 37% of patients, including 43% of patients with MDS, 49% of MDS/MPN, and 86% of AML & lt;30% blasts. Treatment rates were lower (25%) in cases with true discordance in diagnosis compared to those where local and central diagnoses agreed (40%), and receipt of inappropriate therapy occurred in 7% of misdiagnosed cases. Discordant diagnoses were frequent, which has implications for the accuracy of study-related and national registries and can lead to inappropriate therapy.

Abstract: Background: The FDA approved hydroxyurea (HU) for the treatment of sickle cell disease (SCD) in children because it was deemed a safe and efficacious treatment. HU modifies the course of the disease, reduces complications, improves survival, and has few long-term side effects. Despite these benefits, HU uptake remains low for young children. Over 75% of patients who could benefit from HU do not receive the treatment. NHLBI clinical practice guidelines recommend use of shared decision making for HU initiation but currently, there is no "gold standard" for hematology providers to follow when beginning their discussion about HU. Thus, there is likely a gap between care guidelines and clinical practice. A first step in closing this gap is to better understand the current practice utilized by hematology providers when discussing HU as a therapeutic option. Objectives: The goal of the present study is to describe current practice used by hematology providers when discussing HU with parents of young children with SCD (0 - 5 years of age), Our primary aims are: 1) Map the process of offering HU to identify common themes, overlaps, and variations, 2) Examine the impact of a brief video presentation about the NHLBI HU guidelines on provider knowledge and comfort levels. Methods: The dissemination of methods to increase adherence to NHLBI HU guidelines are being evaluated as part of a clinical trial (NCT03442114). Hematology providers at 6 children's hospitals serving young patients with SCD completed process maps that described their current practice for discussing HU initiation with parents. Twenty five hematology providers at 10 institutions across the United States viewed a video didactic presentation on the NHLBI HU guidelines for SCD. Knowledge and comfort regarding discussing HU was assessed using a 10-point scale before and after the video. We also collected data on provider demographics, years practicing, and percentage of patients seen with SCD each week in their practice. Results: Preliminary analyses identified common themes (see Table 1 for provider characteristics). All 6 sites reported that labs and vitals were taken prior to the visit so they could be reviewed with the family. A medical doctor, nurse practitioner, or licensed practical nurse (LPN) led the HU initiation discussion. The majority of sites give their families HU-related materials to take home after the discussion and followed-up regarding the family's decision at the next clinic visit (i.e. planned for a two-visit HU initiation process). Variations identified included providing HU-related materials to the family prior to the visit, when the discussion would occur, and whether NHLBI HU guidelines framed the discussion (Figure 1). Paired samples t-tests assessed for change in medical provider reported HU knowledge and comfort before and after the SCD didactic presentation. Data revealed that there were no differences in provider comfort,t(21) = .77, p = .45, d = .03. In contrast, there was a trend towards a significant increase in medical provider knowledge from before (M = 8.4, SD = 2.3) to after (M = 8.7, SD = 2.1) the presentation, t(21) = 1.8, p = .08, d = .11, small effect. Correlation analyses determined that higher baseline provider knowledge and comfort with HU were significantly correlated with seeing more SCD patients on a weekly basis (Figure 2). Discussion: This study identified common elements of clinical practice for HU initiation in young children with SCD, but variations were also revealed. All institutions in the study obtained lab work prior to the discussion with the family; however the provider initiating the discussion varied by site (e.g., 1 site used an LPN). Most institutions plan for a two-visit discussion as families may not be ready to make a decision during the first visit but feel more supported over time. It is critical that patients and families make their decision based on SCD-specific HU information. Study data indicated that a brief didactic presentation elicited a small improvement provider HU knowledge. Moreover, exposure to the SCD population was strongly related to knowledge and comfort with HU, suggesting that hematology providers with more experience working with patients with SCD may be in the best position to initiate discussions about HU. The incorporation of decision support tools might help to support hematology providers and reduce the variation across institutions observed in our study. Disclosures King: Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; WUGEN: Equity Ownership; Celgene: Consultancy; Cell Works: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Incyte: Consultancy. Piccone:Hemex Health, Inc.: Patents & Royalties. Neumayr:Terumo: Research Funding; Apopharma: Consultancy; PCORI: Research Funding; NHLBI: Research Funding; Bluebird Bio: Research Funding; Sancillo: Research Funding; Seattle Children's Research Grants: Research Funding; Doris Duke Foundation: Research Funding; Novartis: Research Funding; Bayer: Consultancy; Celgene: Research Funding; Imara: Research Funding; Sangamo: Research Funding; Silarus: Research Funding; Pfizer: Consultancy, Research Funding; Emmaus: Consultancy; CTD Holdings: Consultancy; GBT: Research Funding; La Jolla Pharmaceuticals: Research Funding; HRSA: Research Funding; CDC: Research Funding. Meier:CVS Caremark: Consultancy.

Abstract: A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-β pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.

Abstract: Background: Children with ITP who are prescribedsecond line treatments vary in terms of their clinical phenotype, prior treatments, and health related quality of life (HRQoL). Objective: To describe the clinical characteristics and HRQoL of North American pediatric patients with ITP initiating second line treatments. Methods: A longitudinal observational cohort of 118 children with ITP starting second line treatments was enrolled from 2013-2015 at 21 ICON centers. Enrollment requirements included age 1-17y and starting a second line treatment (not IVIG, steroids or anti-D) as monotherapy. Baseline demographic and clinical characteristics were recorded, including response to prior treatments, worst bleeding scores, and baseline platelet counts. Fisher's exact test was used to compare treatment with phase of ITP, age cohort, and gender. HRQoL was measured by patient/caregiver report using the Kids ITP Tool (KIT) where 0 is worst and 100 is best, while physicians assessed the perceived effect of ITP on patient HRQoL using a 5-point scale. Spearman correlations were used to test for association between bleeding, HRQoL, and duration of ITP. ANOVA was used to compare the mean KIT scores of the treatment groups. Results: The clinical characteristics of the cohort are shown in the Table. Median age at enrollment was 11.4 y and 15% had newly diagnosed ITP, 31% had persistent ITP, and 54% had chronic ITP. The median number of prior treatments was 3 (range: 1-9). The prior response rate (platelet 〉 30 x 109/µL and no bleeding) to prednisone was 59% and IVIG 66%. Fifty-five (47%) patients had received at least one prior second line treatment. At enrollment, physicians reported that ITP had impacted the patients' HRQoL severely in 15%, significantly in 44%, moderately in 38%, and almost not at all in 3%. The mean score of the child KIT report was 71.4 (SD 17.2), the parent proxy KIT was 64.7 (SD 16.4), and the parent impact KIT was 36.1 (SD 19.2). The physician's assessment of the patient's HRQoL significantly correlated with the child report (p 〈 .001) and parent proxy report (p 〈 .001). The number of prior treatments and the worst bleeding score did not significantly correlate with the child or parent proxy KIT scores with the exception of gynecologic bleeding on the parent proxy report (p=.002). The duration of ITP significantly correlated with child (p=0.001) and parent proxy KIT scores (p=0.005) where a longer duration was associated with better HRQoL. The number of prior treatments, worst bleeding, and phase of ITP did not correlate with the parent impact KIT score. Treatments selected for second line treatment included: rituximab (n=42), romiplostim (n=31), eltrombopag (n=20), oral immunosuppressants (n=16), splenectomy (n=4), and dapsone (n=3). The selected treatment was not significantly different by age, gender, baseline child KIT score, or duration of ITP. Baseline parent proxy KIT scores varied significantly between selected treatments (p=0.03) and were significantly lower in children starting on eltrombopag in comparison to romiplostim (56.4 (SD 15.1) vs. 70.3 (SD 15.1), respectively; p=0.03). Conclusions: Children with ITP starting on new second line treatments often have received multiple prior treatments and nearly half start these treatments prior to being diagnosed with chronic ITP, including 15% who were in the newly diagnosed phase. Physician assessment of patient HRQoL correlates well with child and parent proxy report of HRQoL. The number of prior treatments and worst bleeding score did not correlate with HRQoL. Longer duration of ITP was associated with a better HRQoL, suggesting that the level of concern related to ITP may lessen over time. Baseline KIT scores were significantly different in children starting on specific treatments. Future analysis will compare the change from baseline in HRQoL in children treated with second line therapies. Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Neufeld:Novartis: Consultancy. Bussel:Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Cangene: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Genzyme: Research Funding; BiologicTx: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haley:Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria. Thompson:Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Mast: Research Funding; Mast: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Eli Lily: Research Funding; Eli Lily: Research Funding.