Citations

Abstract Background: Frailty assessment has often been performed only at baseline in cohort studies. Little is known regarding factors associated with changes in frailty indices over follow up in patients with coronary artery disease (CAD). Methods: Between 11/2008 - 8/2012, 142 community-dwelling adults ≥65 years of age with prior history of CAD (angina or revascularization) participated in a study of frailty assessment at Mayo Clinic Health System in La Crosse, WI. A sample of participants (n=45) were included for frailty re-assessment using the Fried frailty criteria approximately 5 years after their baseline measures. Frailty classification was based on absence of deficits (non-frail), 1-2 deficits (intermediately frail), or 3 or more deficits (frail). Factors associated with a change in frailty indices were studied. Results: There were 45 patients that had a second assessment of frailty indices. At baseline, 24 patients (60%) were not frail while 16 patients (40%) had at least 1 frail feature. At follow up, 20 patients (50%) were not frail while 20 patients (50%) had a frail feature. Those improving were more often being married, had prior revascularization, and were without angina. Interval development of slower gait speed (r = 0.46; p=0.004) and decreased grip strength (r = -0.39; p = 0.01) were associated with worsening frailty. Conclusions: Older adults with CAD are not often frail by standard criteria; however, incident deficits develop during long term follow-up. Spousal support, absence of angina, and change in functional indices are less often associated with frailty features.

AbstractBackgroundHypertension is a major risk factor for cardiovascular and cerebrovascular disease including stroke, small vessel disease, and dementia. The Systolic blood PRessure INTervention (SPRINT) randomized trial prospectively evaluated the effects of intensive systolic blood pressure (SBP) control (target SBP<120mmHg) versus standard control (SBP<140mmHg) on cardiovascular outcomes in individuals without baseline diabetes or stroke, and included cerebral blood flow (CBF) measurements. Previous studies with much smaller sample sizes and shorter duration suggested stable CBF in response to intensive treatment (SBP<125mmHg) [1], but long term effects are unknown. We evaluated the long‐term effects of intensive blood pressure treatment on CBF.MethodWhole brain CBF was measured at 3T using pseudocontinuous arterial spin labeled (ASL) perfusion MRI at baseline and after 3.9±0.3 years. Total white matter lesion (WML) load was measured from Fluid Attenuated Inversion Recovery T2 MRI. Data from 324 subjects with adequate ASL scan quality acquired from 6 sites were included.ResultDemographics and scanner specific CBF values are provided in Table 1. The intensive treatment group was older (p=0.01), but was otherwise similar to the standard group at baseline. There was a significant effect on the longitudinal CBF change (p=0.006) of the intensive treatment (5.7% increase) compared to the standard treatment (4.0% decrease, Fig 1). Secondary analysis showed a significant increase in age‐adjusted fractional CBF for the intensive treatment group (p<0.001) with no change (p=0.24) in the standard treatment group. Change in CBF was not associated with change in WML.ConclusionSustained intensive antihypertensive treatment does not reduce whole brain CBF, in fact it showed an increase in whole brain CBF relative to standard therapy. While improved CBF might contribute to the reduced WML progression observed in the intensive‐therapy group versus standard therapy in SPRINT[2], we did not observe a direct correlation between CBF changes and WML changes. References: (1) Croall et al. JAMA‐Neurol,2018; (2) Nasrallah et al., JAMA‐Neurol, 2019.

Background: Treatment of a first-time anterior shoulder dislocation (FTASD) is sensitive to patient preferences. The operative or nonoperative management debate provides an excellent opportunity to learn how surgeons apply patient preferences in treatment decisions. Purpose: To determine how patient preferences (repeat dislocation risk, recovery difficulties, fear of surgery, treatment costs) and surgeon factors influence a surgeon’s treatment plan for FTASD. Study Design: Cross-sectional study. Methods: Eight clinical vignettes of hypothetical patients with FTASD (including age, sex, and activity level) were presented to members of the Magellan Society. A second set of matched vignettes with patient preferences and clinical variables were also presented. The vignettes represented scenarios in which evidence does not favor one treatment over another. Respondents were asked how they would manage each hypothetical case. Respondents also estimated the risk of redislocation for the nonoperative cases for comparison with the published rates. Finally, respondents completed a Likert-scale questionnaire to determine their perceptions on factors influencing their decisions. Results: A total of 103 orthopaedic surgeons completed the survey; 48% practiced in an academic hospital; 79% were in practice for 10 years or longer; and 75% had completed a sports medicine fellowship. Patient preferences were the single most important factor influencing treatment recommendation, with activity type and age also important. Just 62% of the surgeon estimates of the risk of redislocation were consistent with the published rates. The inclusion of patient preferences to clinical variables changed treatment recommendations in 62.5% of our hypothetical cases. Respondents rated patient treatment preference as the leading factor in their treatment decision making. Conclusion: Patient preferences were important when deciding the appropriate treatment for FTASD. Respondents were inconsistent when applying evidence in their decision making and estimates of recurrent instability. Decision support tools that deliver patient preferences and personalized evidence-based outcome estimates improve the quality of decision making at the point of care.

Abstract The development and implementation of clinical decision support (CDS) that trains itself and adapts its algorithms based on new data—here referred to as Adaptive CDS—present unique challenges and considerations. Although Adaptive CDS represents an expected progression from earlier work, the activities needed to appropriately manage and support the establishment and evolution of Adaptive CDS require new, coordinated initiatives and oversight that do not currently exist. In this AMIA position paper, the authors describe current and emerging challenges to the safe use of Adaptive CDS and lay out recommendations for the effective management and monitoring of Adaptive CDS.

Subcellular compartmentalisation is necessary for eukaryotic cell function. Spatial and temporal regulation of kinesin activity is essential for building these local environments via control of intracellular cargo distribution. Kinesin-binding protein (KBP) interacts with a subset of kinesins via their motor domains, inhibits their microtubule (MT) attachment, and blocks their cellular function. However, its mechanisms of inhibition and selectivity have been unclear. Here we use cryo-electron microscopy to reveal the structure of KBP and of a KBP–kinesin motor domain complex. KBP is a tetratricopeptide repeat-containing, right-handed α-solenoid that sequesters the kinesin motor domain’s tubulin-binding surface, structurally distorting the motor domain and sterically blocking its MT attachment. KBP uses its α-solenoid concave face and edge loops to bind the kinesin motor domain, and selected structure-guided mutations disrupt KBP inhibition of kinesin transport in cells. The KBP-interacting motor domain surface contains motifs exclusively conserved in KBP-interacting kinesins, suggesting a basis for kinesin selectivity.

Abstract Background Exercise intolerance is the cardinal manifestation of heart failure (HF), yet its underlying mechanism(s) remain poorly understood. Measures of ventricular function such as ejection fraction often have no relationship with exercise capacity in HF. 2D-STE has proved to be more reliable method to evaluate myocardial mechanical function. Our hypothesis is Resistance exercise training (Resist-HFpEF) will improve exercise tolerance and exertional symptoms in patients with HFpEF. Purpose The study aims to evaluate myocardial mechanical function by strain imaging during resistance exercise training in Heart Failure patients with Preserved Ejection Fraction (HFpEF) Methods This is a single centre prospective pilot study. 24 HFpEF patients were enrolled and their baseline comorbidities were recorded. Baseline 2D-STE imaging was performed at rest and during exercise (Visit 1). Patients were then randomized to either a novel resistance exercise training program for 36 sessions (3 sessions per week for 12 weeks) or a standard of care control group. 2D STE imaging was then repeated at follow-up (Visit 2). Peak Global Longitudinal strain (GLS), systolic strain rate (SSR), early diastolic strain rate (SRe) were measured offline. Results Mean age of the Rehab cohort was 68.57±10.52 years and the control cohort was 68.1±6.47 years. 23 study subjects were male (96%). 17% of the study subjects were hypertensive, 63% were diabetic, 42% had NYHA I, 46% had NYHA II and 13% had NYHA III of heart failure. The mean LV ejection fraction in the control and Rehab group after the training program at rest was 61.88±2.26% & 54.74±2.07% (p-value 0.04) and during exercise was 59.90±2.05% and 53.13±2.05% (p-value 0.04). The peak GLS was −18.80±4.29% and −17.7±2.21% in controls during rest and exercise at Visit 1 (p-value 0.27) while the rehab cohort had −18.71±4.7% and −20.82±2.4% respectively (p-value 0.0268). The peak GLS was −17.40±3.05% and −17.96±2.65% in controls during rest and exercise at Visit 2 (p-value 0.3430) while rehab cohort had −17.97±6.21% and −16.57±3.82% respectively (p-value 0.67). (Figure 1a and 1b shows GLS, SRS, SRe at Baseline and after exercise program respectively) Conclusion This pilot study suggest systolic and diastolic reserve can be measured reliably during low grade exercise. These results could reflect improvement in clinical status and exercise tolerance. Figure 1. Comparison of peak GLS, SSR, SRe amongst HFpEF patients at rest and during exercise before and after the rehab training program. Funding Acknowledgement Type of funding source: None

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disorder which leads to progressive fibrosis and lung failure within 2-5 years1,2. Approximately 30% of IPF patients develop Chronic Kidney Disease (CKD) with renal dysfunction and fibrosis3. The treatment options for IPF are still limited and the disease is an unmet clinical need. The only animal model for IPF is represented by mice treated with bleomycin, a compound used for chemotherapy which has lung toxicity as its major adverse effect, that develop progressive fibrosis. Recent data indicate that bleomycin triggers lung fibrosis by increasing the release of the pro-inflammatory cytokine TGF-β by the resident megakaryocytes (MK)4. Using these observations as foundation, we investigated whetherGata1lowmice, a model for myelofibrosis induced by a TGF-β/P-selectin (P-sel) circuitry established by the abnormal MK5, includes fibrosis in lungs and kidney and whether these traits are rescued by genetic ablation (P-selnullmutation) and antibody neutralization (by RB40.34) of P-sel. MK were observed in lungs from wild-type (WT, n=9),Gata1low(n=22),P-selnull(n=4) andP-selnullGata1low(n=10) littermates. In frequency, MK were significantly lower inGata1low andP-selnullGata1lowthan in WT andP-selnulllittermates (median=1.3-1.5 vs 3-3.7/0.144mm2, p&lt;0.003) and mostly immature. In addition, lungs and kidney fromGata1low mice, but not those from the other experimental groups, contained great levels of TGF- β (Fig.1). Interstitial pneumonia was observed in lungs from WT (n=12, age=3-13 months, males=8, females=4),P-selnull(n=9, age=3-16 months, males=4, females=5),Gata1low(n=29, age=2-24 months, males=16, females=13) andGata1lowP-selnull(n=18, age=3-16 months, males=7, females=11) mice while nephritis was observed only in kidneys fromGata1low mice. Controlling for the effects of sex, there are statistically significant differences in severity of inflammation in kidney (p=0.001) but not in lungs (p=0.86) betweenGata1low and WT mice. These results indicate that lung inflammation is a baseline condition of the CD1 background used for the study while kidney inflammation is a trait exclusive toGata1low mutants independently from their gender. Great levels of fibrosis were observed in lungs and kidney fromGata1low mice but not in those from WT littermates. There are statistically significant differences in lung (p=0.01) and kidney (p&lt;0.001) fibrosis between the two groups; these differences remained after adjusting for age or sex. By contrast, there is insufficient evidence to conclude there exists a relationship between age and fibrosis grade in the other experimental groups. Age was found to be a statistically significant effect modifier on the relationship between genotype and fibrosis in lung (p=0.024) and kidney (0.004). In addition, although there is insufficient evidence for a relationship between sex and fibrosis grade in lung (p=0.62), there is a statistically significant effect of gender in kidney fibrosis inGata1low mice (p&lt;0.001). These results indicate that fibrosis in lung and nephritis and fibrosis in kidney are novel traits ofGata1low mice developed independently from the underlying state of inflammation and which are rescued by ablation ofP-sel. To further clarify the role of P-sel in lung and kidney fibrosis, 14Gata1lowmice (7 males, 7 females) were treated with either vehicle (8 mice) or RB40.34 (30 μg/mouse/day per 3 days/week by tail vein injection as described6). Mice were sacrificed on day 5 (males) and 12 (females) and histopathology, inflammation, fibrosis and TGF-β content in lungs and kidney analyzed. Treatment with RB40.34 restored the morphology and reduced inflammation, fibrosis and TGF-β content in the lungs and in kidney with respect to vehicle (Fig.1). In conclusion, Gata1low mice are a novel animal model for IPF with CKD. The phenotype is associated with highTGF-βcontent in lung and kidney and is rescued by targeting P-sel, suggesting that treatment with antibodies against P-sel may cure IPF in man. REF: 1Richeldi et al.Lancet389: 1941, 2017; 2Hutchinson et al.EurRespirJ46, 795, 2015; 3Ikezoeet al.Respiration94: 346, 2017; 4Zhouet al.CellDeathDis10:648, 2019: 5Spangrudeet al.StemCells34: 67, 2016; 6Emburyet al.Blood104: 3378, 2004. Disclosures Migliaccio: Novartis:Research Funding.

Background: Multiple myeloma (MM) negatively affects health-related quality of life (HRQoL), and with each relapse, patients with MM experience further declines in HRQoL. Patient-reported HRQoL is therefore an important treatment outcome, in addition to clinical response to therapy. CARTITUDE-1 (NCT03548207) is a phase 1b/2 study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed/refractory (R/R) MM. We evaluated symptoms, functioning, and overall HRQoL through patient-reported outcome measures, which is a secondary objective of CARTITUDE-1. Methods: Patients were ≥18 years of age with a diagnosis of MM per International Myeloma Working Group criteria, measurable disease, and Eastern Cooperative Oncology Group performance status ≤1. Patients had received ≥3 prior regimens for MM or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and had received an anti-CD38 antibody. Cilta-cel was given as a single infusion on Day 1 (target dose: 0.75×106 [range: 0.5-1.0×106] CAR+ viable T cells/kg) 5-7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). In the phase 2 portion of CARTITUDE-1, HRQoL was assessed at baseline, on Days 7, 28, 56, 78, and 100, and every 28 days thereafter using 3 patient-reported instruments: the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30), 4 items from the EORTC QLQ-Multiple Myeloma (MY20) module, and the 5-level EuroQol Five Dimension (EQ-5D-5L) measure. Raw EORTC QLQ-C30 and EORTC QLQ-MY20 scores were linearly transformed to a scale ranging from 0 to 100; the EQ-5D-5L visual analog scale (VAS) score ranges from 0 to 100. Clinically meaningful changes in EORTC QLQ-C30 symptoms, physical functioning, and overall HRQoL were based on anchor-based methods using a patient global impression of change item. Repeated-measures mixed-effects models were used to analyze mean changes in HRQoL from baseline to subsequent assessment time points in patients in the modified intent-to-treat population with ≥1 post-baseline assessment. Median time to event of HRQoL scores was calculated descriptively, using a change in score ≥0.5×standard deviation of values prior to cilta-cel infusion as improvement/worsening with death due to progression defined as worsening. Results: For the 68 patients in the phase 2 portion of CARTITUDE-1 (63.2% male; median age: 62.0 years [range: 43-78]), questionnaire completion rates at baseline and Day 100, respectively, were 92.6% and 69.2% for both the EORTC QLQ-C30 and EORTC QLQ-MY20 items and 92.6% and 70.8% for the EQ-5D-5L. For EORTC QLQ-C30 subscales, clinically meaningful improvements at Day 100 were seen for 71.1% of patients for pain, 62.2% for fatigue, 72.1% for physical functioning, and 51.1% for global health status. Mean changes in pain and fatigue showed a reduction in these symptoms over time (following an initial worsening of fatigue at Day 7; Figure). This trend of improvements over time was also observed for overall HRQoL and EORTC QLQ-MY20 single items. Clinically meaningful improvements at Day 100, defined by a literature-based minimal important difference of 10 points in mean score, were observed for the EORTC QLQ-MY20 single items: thinking about illness and worries about dying or future health. Approximately 50% of the population reported an event of improvement or worsening in EORTC QLQ-C30 and EQ-5D-5L scales, with the rest censored in this early data cut; among these patients, median time to improvement was approximately 1-2 months (with median time to worsening occurring less than 1 month after cilta-cel treatment). There was a trend for an improvement in mean EORTC QLQ-C30 global health status, physical functioning, pain, and fatigue, and EQ-5D-5L VAS at Day 100 with increased depth of response. Conclusions: Some patients with heavily pretreated MM showed rapid and clinically meaningful improvements in pain, fatigue, physical functioning, overall HRQoL, and future perspectives, consistent with their clinical outcomes. With additional follow-up, it is possible that these early improvements in symptoms will translate into greater improvement in overall HRQoL in the long term. Disclosures Martin: Janssen: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding; Seattle Genetics: Research Funding; GSK: Consultancy. Lin:Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Legend BioTech: Consultancy; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Patents/Intellectual property licensed, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Htut:City of Hope Medical Center: Current Employment. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:GSK: Consultancy; BMS: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Incyte Corporation: Consultancy; Janssen: Consultancy. Berdeja:Teva: Research Funding; Cellularity: Research Funding; Kesios: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Karyopharm: Consultancy; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Amgen: Consultancy, Research Funding; Acetylon: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Vivolux: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Constellation: Research Funding; Bluebird: Research Funding; Abbvie: Research Funding; Prothena: Consultancy; Bioclinica: Consultancy; Kite Pharma: Consultancy; Legend: Consultancy. Madduri:Foundation Medicine: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; AbbVie: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria. Usmani:Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Abbvie: Consultancy; Array Biopharma: Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau:Janssen: Current Employment, Current equity holder in publicly-traded company. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.

Introduction Essential thrombocythemia (ET) and polycythemia vera (PV) patients suffer from various symptoms that worsen quality of life (QOL), yet serial data on symptom changes resulting from therapy are sparse in the literature. Patient questionnaires from 2 large multicenter trials (MPN-RC 111, 112) were used to assess change in symptom burden and QOL over 12 months and impact of baseline symptom burden on subsequent change in ET / PV patients on hydroxyurea (HU) or pegylated interferon alfa-2a (PEG). Methods Trials MPN-RC 111 was a single-arm, open-label, phase II trial evaluating response to PEG in high-risk ET / PV patients with HU resistance/intolerance or splanchnic vein thrombosis (SVT; NCT01259817). MPN-RC 112 was a randomized, open-label, phase III trial comparing response to PEG versus HU in cytoreductive therapy naïve high-risk ET / PV patients diagnosed &lt; 5 years ago (NCT01258856). Measures Patients reported disease-related symptoms via the validated Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF), QOL via the European Organisation for the Research and Treatment of Cancer Core QOL Questionnaire (EORTC QLQ-C30), and (if applicable) PEG-related symptoms (flu-like symptoms, injection site irritation, blurry vision, vision change, flushing) at baseline, 3, 6, 9, and 12 months. Analysis Mixed models assessed mean changes from baseline in the MPN-SAF Total Symptom Score (TSS), MPN-SAF items, QOL, and PEG-related symptoms in MPN-RC 111, 112 PEG, and 112 HU patients. Mixed models also assessed the impact of baseline symptom burden (high [TSS ≥ 20] versus low) on subsequent change in PEG (MPN-RC 111 and 112) and HU patients. Results Patients Of the 135 enrolled MPN-RC 111 patients, 20 with SVT and 1 with no questionnaires were excluded. Of the remaining 114, 64 (56%) / 50 (44%) had ET / PV. Patients were 51% / 48% female. Median age was 65 / 64 years, and median time since diagnosis was 38 / 55 months. 31% / 22% had prior thrombosis, and 19% / 56% had splenomegaly. Of the 168 enrolled MPN-RC 112 patients (82 PEG, 86 HU), 2 with no questionnaires were excluded. Of the remaining 166, 79 (48%) / 87 (52%) had ET / PV. Patients were 50% / 33% female. Median age was 60 / 62 years, and median time since diagnosis was 3 / 3 months. 25% / 29% had prior thrombosis, and 11% / 37% had splenomegaly. Symptoms Questionnaire completion rates ranged from 90 - 99%, 87 - 100%, and 75 - 96% for on-treatment MPN-RC 111, 112 PEG, and 112 HU patients. At baseline, TSS (0 [absent] - 100 [worst imaginable]) and QOL (0 [very poor] - 100 [excellent]) means (SDs) were 19.5 (18.4) and 71.6 (20.1) for MPN-RC 111, 17.0 (13.6) and 67.9 (24.3) for MPN-RC 112 PEG, and 14.6 (11.4) and 73.8 (18.8) for MPN-RC 112 HU patients. On average, MPN-RC 111 patients had significant improvement of TSS, fatigue, abdominal pain, abdominal discomfort, dizziness, numbness, night sweats, and fever; MPN-RC 112 PEG patients had significant worsening of fever; and MPN-RC 112 HU patients had significant worsening of inactivity (no mean changes indicating improvement were observed). PEG patients had significant worsening of PEG-related symptoms. The greatest improvements occurred in the 46 (40%), 27 (33%), and 23 (28%) MPN-RC 111, 112 PEG, and 112 HU patients with high baseline symptom burden. On average, PEG patients with high baseline symptom burden had significant improvement of TSS, fatigue, early satiety, abdominal pain, abdominal discomfort, inactivity, headache, concentration, dizziness, numbness, insomnia, cough, night sweats, itching, bone pain, fever, weight loss, and QOL, while those with low baseline symptom burden had significant worsening of TSS, early satiety, headache, itching, and bone pain. On average, HU patients with high baseline symptom burden had significant improvement of TSS, early satiety, abdominal discomfort, headache, dizziness, numbness, insomnia, itching, and weight loss, while those with low baseline symptom burden had significant worsening of TSS, early satiety, abdominal discomfort, inactivity, concentration, and sexual desire/function (Figures 1 and 2). Conclusions Although no statistical comparisons were made across trials, overall improvements were seen in MPN-RC 111 but not 112. Patients with high baseline symptom burden experienced the greatest improvements in symptom burden and QOL during treatment with PEG or HU, which may explain the improvements seen in the more advanced patients in MPN-RC 111 compared to 112. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Yacoub:Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Silver:PharmaEssentia: Speakers Bureau. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.