Journal articles on the topic 'NIV therapy referral'

Abstract Introduction Prolonged wait times to ENT surgery, combined with the risk for post-operative respiratory events in children with severe OSA led to a clinical pathway of implementing CPAP therapy in children with severe OSA whilst on waiting lists for adenotonsillectomy. This study evaluated the impact of this pathway on the clinical care of these patients. Methods A retrospective review of medical records of patients under 18yrs of age diagnosed with OSA and initiated on CPAP whilst awaiting review by ENT / Adenotonsillectomy, between January 2019 and December 2020. Results 36 patients were identified, age 4.3 ± 3.2 years, 86% male, and 80.6% had comorbidities. 16 (44.4%) were overweight or obese, and for 8 (22.2%) obesity was the primary comorbidity. Mean delays: Sleep study to Referral = 4.5 ± 10.5 weeks, Referral to NIV initiation 5.6 ± 8.7 weeks, and NIV to ENT surgery 13.6 ± 13.6 weeks. Total delay from referral to the surgery was 19.6 ± 19.4 weeks. 31 (86%) children were initiated on therapy in hospital, and five (13.9%) patients were non-compliant with the therapy. Discussion Current delays to ENT surgery for children identified with OSA on sleep study average 5 months. Where OSA is sufficient to recommend ENT surgery, the majority (80%) of children tolerated CPAP therapy while they await surgery. We suggest that the benefits obtained are that therapy can be instituted more rapidly than surgery, and where children are able to use CPAP therapy it reduced the requirement for high-dependency or intensive care admission post-operatively.

Abstract Introduction Chronic Obstructive Pulmonary Disease - Obstructive Sleep Apnoea Overlap Syndrome (COPD-OSA) prevalence is 1–4% in general population but higher in those with severe airways obstruction. With higher rate of hospitalisation, exacerbation frequency and mortality than in either condition alone, yet there are no randomised control trials (RCT) to guide management. Our aim was to assess the prevalence of obesity and OSA within a COPD home ventilation cohort as we hypothesise that COPD-OSA is under recognised. Methods A retrospective analysis of active patients in a UK NHS hospital Home Ventilation Service. 113 patients were initiated on non-invasive ventilation (NIV) between 2014–2021 and whose documented cause of respiratory failure was COPD. Using electronic healthcare records the body mass index (BMI), diagnosis of OSA, PaCO2 at time of referral and route of referral collected. Results 108 patients had BMI recorded; in 48% it was ≥30 and 26% ≥40. 28% had diagnosed OSA but in those with a BMI of ≥30, 49% had OSA. 54% of those with OSA had a previous trial of continuous positive airway pressure (CPAP). 57% of referrals were as outpatients. None had a documented formal diagnosis of ‘COPD-OSA Overlap Syndrome’. Conclusion 50% of COPD patients requiring home ventilation were obese and 28% had diagnosed OSA. Although this study was a retrospective electronic record review, it suggests COPD-OSA Overlap Syndrome is common and underrecognized. Given the high prevalence it needs greater recognition as a discrete disease entity and urgent RCTs to establish optimum therapy, CPAP or NIV.

The aim of this study si to revise the use of non-invasive ventilation (NIV) in patients with acute respiratory failure in emergency departments. A systematized database review will be carried out by the search of articles attending the presented subject following a unique approach; restricting the results to findings in the last five years either in Spanish or English. A research performed in paediatric population concluded that the early management of acute respiratory failure and the use of high flow nasal cannulae reduced the hospitalization period and the referral to specialized hospitals, and gave more independence to regional hospitals in its management; reducing, therefore, the number of patients needing the implementation of invasive procedures. With respect to patients with exacerbations of the chronic obstructive pulmonary disease (COPD) and its early management in the prehospital care, an increase in the mortality in those patients who were exposed to high flow compared to the conventional oxygen therapy was observed. Following the results of a meta-analysis, no benefits were found in the use of high flow nasal cannulae opposed to the conventional therapy or NIV in the emergency departments, in terms of need for intubations, failures in the treatment, hospitalization and mortality.The data are inconclusive in all the studies analyzed and there is no agreement between the different authors. There is a scarce piece of bibliography regarding the use of NIV in the emergency departments due to the fact that the majority of the research are focused on the use of this techniques in intensive care units. In conclussion, there is a diversity in the results of the revised articles according to the use of NIV in the emergency departments.

ObjectivesTo compare the clinical severity and outcome of hospitalised patients during the two waves of the COVID-19 pandemic in India.SettingA tertiary care referral hospital in South India.ParticipantsSymptomatic SARS CoV-2 reverse transcriptase PCR positive patients presenting to the emergency department during the two waves were recruited. The first wave spanned between April and December 2020 and the second wave between April and May 2021.Primary and secondary outcome measuresThe primary outcome of interest was mortality. Secondary outcomes included illness severity at presentation, need for oxygen therapy, non-invasive ventilation (NIV) and hospital or intensive care unit admission.ResultsThe mean (SD) age of the 4971 hospitalised patients in the first wave was similar to the 2293 patients in the second wave (52.5±15.4 vs 52.1±15.1 years, p=0.37). When compared with the first wave, during the second wave, a higher proportion of patients presented with critical illness (11% vs 1.1%, p<0.001) and needed supplemental oxygen therapy (n=2092: 42.1% vs n=1459: 63.6%; p<0.001), NIV (n=643; 12.9% vs n=709; 30.9%; p<0.001) or inotropes/vasoactive drugs (n=108; 2.2% vs n=77: 3.4%; p=0.004). Mortality was higher during the second wave (19.2% vs 9.3%; p<0.001). On multivariable regression analysis, age >60 years (risk ratio, RR 2.80; 95% CI 2.12 to 3.70), D-dimer >1000 ng/mL (RR 1.34; 95% CI 1.15 to 1.55), treatment with supplemental oxygen (RR 14.6; 95% CI 8.98 to 23.6) and presentation during the second wave (RR 1.40; 95% CI 1.21 to 1.62) were independently associated with mortality.ConclusionThe second wave of the COVID-19 pandemic in India appeared to be associated with more severe presentation and higher mortality when compared with the first wave. Increasing age, elevated D-dimer levels and treatment with supplemental oxygen were independent predictors of mortality.

Treatment of chronic respiratory failure with noninvasive ventilation (NIV) is standard pediatric practice, and NIV systems are commonly used in the home setting. Although practice guidelines on the perioperative management of children supported with home NIV systems have yet to be published, increasingly these patients are referred for consultation regarding perioperative management. Just as knowledge of pharmacology underlies the safe prescription of medication, so too knowledge of biomedical design is necessary for the safe prescription of NIV therapy. The medical device design requirements developed by the Organization for International Standardization provide a framework to rationalize the safe prescription of NIV for hospitalized patients supported at home with NIV systems. This review article provides an overview of the indications for home NIV therapy, an overview of the medical devices currently available to deliver it, and a specific discussion of the management conundrums confronting anesthesiologists.

Background. Long-term home noninvasive mechanical ventilation (NIV) is beneficial in COPD but its impact on inflammation is unknown. We assessed the hypothesis that NIV modulates systemic and pulmonary inflammatory biomarkers in stable COPD.Methods. Among 610 patients referred for NIV, we shortlisted those undergoing NIV versus oxygen therapy alone, excluding subjects with comorbidities or non-COPD conditions. Sputum and blood samples were collected after 3 months of clinical stability and analyzed for levels of human neutrophil peptides (HNP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha). Patients underwent a two-year follow-up. Unadjusted, propensity-matched, and pH-stratified analyses were performed.Results. Ninety-three patients were included (48 NIV, 45 oxygen), with analogous baseline features. Sputum analysis showed similar HNP, IL-6, IL-10, and TNF-alpha levels (P>0.5). Conversely, NIV group exhibited higher HNP and IL-6 systemic levels (P<0.001) and lower IL-10 concentrations (P<0.001). Subjects undergoing NIV had a significant reduction of rehospitalizations during follow-up compared to oxygen group (P=0.005). These findings were confirmed after propensity matching and pH stratification.Conclusions. These findings challenge prior paradigms based on the assumption that pulmonary inflammation isper sedetrimental. NIV beneficial impact on lung mechanics may overcome the potential unfavorable effects of an increased inflammatory state.

BackgroundOutcomes for patients with chronic obstructive pulmonary disease (COPD) with persistent hypercapnic respiratory failure are improved by long-term home non-invasive ventilation (NIV). Provision of home-NIV presents clinical and service challenges. The aim of this study was to evaluate outcomes of home-NIV in hypercapnic patients with COPD who had been set-up at our centre using remote-monitoring and iVAPS-autoEPAP NIV mode (Lumis device, ResMed).MethodsRetrospective analysis of a data set of 46 patients with COPD who commenced remote-monitored home-NIV (AirView, ResMed) between February 2017 and January 2018. Events including time to readmission or death at 12 months were compared with a retrospectively identified cohort of 27 patients with hypercapnic COPD who had not been referred for consideration of home-NIV.ResultsThe median time to readmission or death was significantly prolonged in patients who commenced home-NIV (median 160 days, 95% CI 69.38 to 250.63) versus the comparison cohort (66 days, 95% CI 21.9 to 110.1; p<0.01). Average time to hospital readmission was 221 days (95% CI, 47.77 to 394.23) and 70 days (95% CI, 55.31 to 84.69; p<0.05), respectively. Median decrease in bicarbonate level of 4.9 mmol/L (p<0.0151) and daytime partial pressure of carbon dioxide 2.2 kPa (p<0.032) in home-NIV patients with no required increase in nurse home visits is compatible with effectiveness of this service model. Median reduction of 14 occupied bed days per annum was observed per patient who continued home-NIV throughout the study period (N=32).ConclusionThese findings demonstrate the feasibility and provide initial utility data for a technology-assisted service model for the provision of home-NIV therapy for patients with COPD.

Noninvasive ventilation (NIV) settings determined during wakefulness may produce patient–ventilator asynchrony (PVA) during sleep, causing sleep disruption and limiting tolerance. This study investigated whether NIV titrated with polysomnography (PSG) is associated with less PVA and sleep disruption than therapy titrated during daytime alone.Treatment-naive individuals referred for NIV were randomised to control (daytime titration followed by sham polysomnographic titration) or PSG (daytime titration followed by polysomnographic titration) groups. Primary outcomes were PVA and arousal indices on PSG at 10 weeks. Secondary outcomes included adherence, gas exchange, symptoms and health-related quality of life (HRQoL).In total, 60 participants were randomised. Most (88.3%) had a neuromuscular disorder and respiratory muscle weakness but minor derangements in daytime arterial blood gases. PVA events were less frequent in those undergoing polysomnographic titration (median (interquartile range (IQR)): PSG 25.7 (12–68) events·h−1versuscontrol 41.0 (28–182) events·h−1; p=0.046), but arousals were not significantly different (median (IQR): PSG 11.4 (9–19) arousals·h−1versuscontrol 14.6 (11–19) arousals·h−1; p=0.258). Overall adherence was not different except in those with poor early adherence (<4 h·day−1) who increased their use after polysomnographic titration (mean difference: PSG 95 (95% CI 29–161) min·day−1versuscontrol −23 (95% CI −86–39) min·day−1; p=0.01). Arterial carbon dioxide tension, somnolence and sleep quality improved in both groups. There were no differences in nocturnal gas exchange or overall measures of HRQoL.NIV titrated with PSG is associated with less PVA but not less sleep disruption when compared with therapy titrated during daytime alone.

ObjectiveTo better characterize adult myotubularin 1 (MTM1)–related myopathy carriers and recommend a phenotypic classification.MethodsThis cohort study was performed at the NIH Clinical Center. Participants were required to carry a confirmed MTM1 mutation and were recruited via the Congenital Muscle Disease International Registry (n = 8), a traveling local clinic of the Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH and Cure CMD (n = 1), and direct physician referral (n = 1). Neuromuscular examinations, muscle MRI, dynamic breathing MRI, cardiac MRI, pulmonary function tests (PFTs), physical therapy assessments including the Motor Function Measure 32 (MFM-32) scale, and X chromosome inactivation (XCI) studies were performed.ResultsPhenotypic categories were proposed based on ambulatory status and muscle weakness. Carriers were categorized as severe (nonambulatory; n = 1), moderate (minimal independent ambulation/assisted ambulation; n = 3), mild (independent ambulation but with evidence of muscle weakness; n = 4), and nonmanifesting (no evidence of muscle weakness; n = 2). Carriers with more severe muscle weakness exhibited greater degrees of respiratory insufficiency and abnormal signal on muscle imaging. Skeletal asymmetries were evident in both manifesting and nonmanifesting carriers. Skewed XCI did not explain phenotypic severity.ConclusionThis work illustrates the phenotypic range of MTM1-related myopathy carriers in adulthood and recommends a phenotypic classification. This classification, defined by ambulatory status and muscle weakness, is supported by muscle MRI, PFT, and MFM-32 scale composite score findings, which may serve as markers of disease progression and outcome measures in future gene therapy or other clinical trials.

BackgroundEndovascular reperfusion techniques are a promising intervention for acute ischemic stroke (AIS). Prior studies have identified markers of initial injury (arrival NIH stroke scale (NIHSS) or infarct volume) as predictive of outcome after these procedures. We sought to define the role of collateral flow at the time of presentation in determining the extent of initial ischemic injury and its influence on final outcome.MethodsDemographic, clinical, laboratory, and radiographic data were prospectively collected on a consecutive cohort of patients who received endovascular therapy for acute cerebral ischemia at a single tertiary referral center from September 2004 to August 2010.ResultsHigher collateral grade as assessed by the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading scheme on angiography at the time of presentation was associated with improved reperfusion rates after endovascular intervention, decreased post-procedural hemorrhage, smaller infarcts on presentation and discharge, as well as improved neurological function on arrival to the hospital, discharge, and 90 days later. Patients matched by vessel occlusion, age, and time of onset demonstrated smaller strokes on presentation and better functional and radiographic outcome if found to have superior collateral flow. In multivariate analysis, lower collateral grade independently predicted higher NIHSS on arrival.ConclusionsImproved collateral flow in patients with AIS undergoing endovascular therapy was associated with improved radiographic and clinical outcomes. Independent of age, vessel occlusion and time, in patients with comparable ischemic burdens, changes in collateral grade alone led to significant differences in initial stroke severity as well as ultimate clinical outcome.

Objective: Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is reported in the literature ranging from 1 to 14.2%. The aim of the present study was to assess the impact on patient’s quality of life and symptoms of Flower pollen extract in association with vitamins (Deprox 500®) in comparison with Serenoa repens 320 mg (Permixon 320 mg® by Pierre Fabre) in patients with CP/CPPS. Methodology: All consecutive patients, with a diagnosis of CP/CPPS, referred to our center from January to August 2016, were screened to be enrolled in this single-center, randomized, controlled trial. The main outcome measure was the evaluation of IPSS/NIHCPSI (International Prostatic Symptom Score/NIH-Chronic Prostatitis Symptom Index) score variation and the assessment of the quality of life and symptoms at the end of the therapy. The second outcome measure was the evaluation of the comorbidity role in the CP/CPPS therapy. 63 patients were analyzed; patients were randomized into two groups: 29 patients were treated with Deprox 500® 2 tablets/day for 6 weeks and 34 patients with Serenoa repens 320 mg, 1 tablet/day for 6 weeks. Results: The mean score variation for IPSS was -12.7 ± 4.3 in the Deprox 500® group and -7.8 ± 4.7 in the Serenoa repens group (p=0.0005) while for NIH-CPSI was -17.3±3.1 in the Deprox 500® group and -13.6±4.8 in the Serenoa repens group (p=0.0016). By accounting only the symptoms part of NIH-CPSI questionnaire, the mean score variation reported was -11.5±2.5 in the Deprox 500® group and -9.02±4.0 in the Serenoa repens group (p=0.009321). Furthermore, analyzing the comorbidity subgroups, in patients with hypertension, the mean IPSS score variation was -14.3±3.2 in the Deprox 500® group and - 9.02±4.0 in the Serenoa repens group. Conclusion: In conclusion, in patients with CP/CPPS, Deprox 500® improves IPSS and NIH-CPSI scores up to 74.5% and 84.5% respectively. Furthermore, in patients with hypertension, the antioxidant effect of Deprox 500® reduces the mean IPSS score of 82.7%.

Abstract Introduction Lifestyle modification is often prescribed as first line-therapy for hypertension in childhood. We aimed to determine if there was an association between sleep duration and hypertension in children referred for evaluation to Nephrology for elevated blood pressure (BP). We hypothesized that, longer sleep duration would be associated with a reduced likelihood of a hypertension diagnosis. Methods Medical record data were retrospectively extracted from patients referred to the Children’s Hospital of Philadelphia’s pediatric nephrology clinic for the evaluation of elevated BP, without a prior hypertension diagnosis. Ambulatory blood pressure monitoring (ABPM) data collected between December 2015 to December 2018 were extracted. Hypertension was defined by ABPM according to American Heart Association recommendations for pediatric ABPM and we evaluated BP indexed to sex and height. Sleep duration was calculated as the difference between self-reported time of sleep onset and offset. Regression models were adjusted for age, sex, race, body mass index, and weeknight status. Results Our sample included 249 patients, with a mean age of 14.5 (SD: 3.1) years. Of these, 29% were obese and 42% met criteria for hypertension. Mean sleep duration was 9.3 (SD: 1.6) hours per night and duration was shorter with increasing age in years (β=-0.11, 95% CI: -0.18, -0.05) and on week vs. weekend nights (β=-0.62, 95% CI: -1.05, -0.24). Each additional hour of sleep was associated with lower daytime systolic BP Index Z-score (β=-0.12, 95% CI: -0.20, -0.05), lower daytime diastolic BP Index Z-score (β=-0.11, 95% CI: -0.19, -0.03) and 19% reduced odds of daytime hypertension (OR=0.81, 95% CI: 0.67, 0.98). Each additional hour of earlier timing of sleep onset was associated with lower daytime systolic BP Index Z-score (β=-0.10, 95% CI: -0.19, -0.01), lower daytime diastolic BP Index Z-score (β=-0.16, 95% CI -0.25, -0.06) and 16% reduced odds of daytime hypertension (OR=0.84, 95% CI: 0.68, 1.05). Conclusion In children referred for the evaluation of elevated BP, longer sleep duration and earlier sleep onset were associated with a reduced likelihood of being diagnosed with hypertension. Targeting improvements in sleep should be further investigated as part of first line therapy to treat pediatric hypertension. Support (if any) NIH/NHLBI K01HL123612

Abstract Objectives This study investigated the impact of COVID-19 infection and its persistent lingering symptoms on known risk factors for malnutrition. Methods Patients with confirmed history of COVID infection and persistent symptoms were referred to the Post-COVID Recovery Clinic. Standardized telehealth screening included: Patient Generated Subjective Global Assessment (PG-SGA), Shortness of Breath (SOBQ), Patient Health Questionnaire (PHQ9), CDC 18 common symptom COVID, Generalized Anxiety Disorder (GAD7), and (Instrumental) Activities of Daily Living (I)ADL. Results Eighty-six patients were evaluated in the first 2.5 months. Average age was 52 years (23–90), 67% were female, and 58% Caucasian. COVID+ test to clinic visit was 49 days (14–140). Forty eight percent did not require hospitalization, 62% were obese, and 73% had ≥1 comorbidity. At infection onset, 80% complained of GI symptoms (75% loss of taste, 61% loss of smell, 59% diarrhea, 57% nausea). At the telehealth visit, 51% reported lingering GI symptoms (45% taste, 41% smell, 41% diarrhea, 36% nausea). Other common symptoms were: dyspnea on exertion, chronic fatigue, cough, and weakness. Survivors required referrals for the following specialty services: 84% pulmonary, 77% physical/occupational therapy, 73% behavioral health, and 51% registered dietitian consult. Average PG-SGA score was 5.7 ± 5.02 with sub-scores: weight 1.37 ± 1.65, food 0.58 ± 0.64, symptoms 2.19 ± 3.30, activities/function 1.59 ± 0.93. Preliminary analysis of 2-day 24h dietary recalls of a subset of clinic patients (n = 33) found &gt;50% of COVID survivors failed to meet basic dietary recommendations. Daily caloric intake was low, protein intake was below 0.8 g/kg, and the daily distribution of protein skewed towards a single meal. Conclusions We found that the clinical symptoms experienced by COVID survivors, particularly fatigue, dyspnea, and eating difficulties (nausea, vomiting, changes in smell and taste, trouble breathing) created difficulties in maintaining an adequate nutritional intake. This is concerning because malnutrition, specifically inadequate protein, leads to weaker immune function, slower recovery from illness, and loss of lean body mass. Funding Sources NIA Pepper OAIC, CTSA NCATS

Background: therapy for frequently ill children (FIC) with chronic herpesvirus infection includes antivirals and immunomodulators as these patients are considered immunocompromised. According to our data based on the prevalence of diseases and the viral replication activity, therapy may fail in 22% of cases. Aim: to identify a spectrum of rare genetic variants associated with primary immunodeficiency (PID) detected in FIC with stable, active persistence of herpesvirus infections that were resistant to repeat courses of antiviral and immunotropic therapy Patients and Methods: DNA samples of 33 frequently ill children with chronic herpesvirus infection who did not respond to therapy were analyzed using targeted high-throughput multigene sequencing to identify mutations in PID-associated genes. Results: pathogenic variants matching the potential diagnosis of PID were identified in two (6.1%) children. Rare genetic variants associated with the development of autoinflammatory diseases were found in 54.5% of cases. The p.Gln705Lys NLRP3 gene variant was the most common finding — it was detected in 5 (15.2%) children. Rare variants of the MEFV gene (MEFV p.Thr767Ile and MEFV p.Lys695Arg) were found in three (9.2%) children. In seven (21.2%) children rare variants of the NOD2 gene were identified, in four of them (12.2%) it was NOD2 p.Leu1007fs. Conclusions: the inefficiency of therapy in frequently ill children with chronic herpesvirus infection could be associated with characteristics of the innate immune system. Such children should be referred to immunology consultant and undergo molecular genetic testing. The detection of rare genetic variants associated with autoinflammatory diseases in more than half of the patients indicates that frequent (occurring every month) diseases with fever may mimic hidden or sometimes typical autoinflammatory diseases, despite the detection of the markers of viral and bacterial agents in a child KEYWORDS: frequently ill children, chronic herpesvirus infection, rare genetic variants, primary immunodeficiency. FOR CITATION: Levina A.S., Babachenko I.V., Skripchenko N.V. et al. Therapy of chronic herpesvirus infection in frequently ill children. Possible causes of inefficiency. Russian Journal of Woman and Child Health. 2022;5(4):332–339 (in Russ.). DOI: 10.32364/2618-8430- 2022-5-4-332-339.

Introduction: Chronic pain in sickle cell disease (SCD) is a multifactorial complication that can contribute to high healthcare utilization. Multidisciplinary treatments going beyond medication alone are needed for the most effective chronic pain management. Cognitive-behavioral therapy (CBT) is effective for youth with chronic pain and focuses on improving daily functioning and coping, but the clinical effectiveness for chronic SCD pain has not been evaluated. This study examined changes in healthcare use over time for youth with chronic SCD pain who participated in CBT compared to controls with chronic SCD pain who never initiated CBT. Methods: Youth receiving care at comprehensive SCD clinics at three tertiary care locations at Children's Healthcare of Atlanta were included if they were aged 6-18 years, any SCD genotype, and referred to a pediatric psychology outpatient clinic for chronic pain management from November 2014-March 2018. Youth were excluded if they received bone marrow transplantation during the study period, had ongoing CBT past the study period, or were not actively followed for ≥1 year of medical care pre- or post-CBT. Patients were grouped based on therapy attendance: Established Care (i.e., attended ≥3 CBT sessions within 3 consecutive months); Early Termination (i.e., attended &lt;3 CBT sessions within 3 consecutive months); or Control (i.e., did not attend any CBT visits). Patient-reported outcomes included typical pain intensity, functional disability, and coping efficacy at pre- and post-treatment. Healthcare utilization outcomes were abstracted from electronic medical records including: number of inpatient admissions for pain, total inpatient days for pain, and emergency department dependency ratio (EDR; ratio of ED visits to sum of ED and outpatient visits). For the treatment groups, utilization outcomes were calculated from 12-months prior to the first CBT visit, and from 12-months following the last CBT visit. For the control group, outcomes were calculated for 12-months prior to the referral date, and from 12-months following the average duration of CBT for treatment groups (i.e., 3.5 months) to account for passage of time. Changes over time in inpatient admissions, hospital days, and EDR were evaluated separately using linear mixed effect models with a random effect for person-specific intercepts and slopes, which were retained based on model contribution determined by Bayesian Information Criterion. Time, patient characteristics, SCD-modifying treatments, therapy attendance, number of CBT sessions, and interaction effects were initially included in the models; the most parsimonious models were chosen based on backward selection. Results: At time of referral, youth (n=101) were on average (M) 13.4 years old (SD=2.92), 56.4% female, 68.1% HbSS or HbSβ0, 63.9% prescribed hydroxyurea, and 12.6% received chronic transfusions. The Control (n=44) and Treatment Groups (n=57) did not significantly differ by age, sex, genotype, or treatment with hydroxyurea or chronic transfusion. Based on therapy attendance, 36.1% Established Care, 21.8% were Early Termination, and 42% Controls. Adjusting for age, genotype, and hydroxyurea, patients who terminated CBT early had increased admissions and total hospital days over time compared to controls; those who established care had a reduction in admissions and hospital days over time compared to controls (F's=3.27-3.61, p's&lt;.05). EDR decreased by 0.1 over time for Established Care; for every 1 completed CBT session, EDR was further reduced by 0.01 (p&lt;.05). Patients who completed CBT (n=18) reported decreases in typical pain intensity (Mpre= 5.47, SD=2.24; Mpost=3.76, SD=2.84; p&lt;.01), functional disability (Mpre=26.24, SD=8.45; Mpost=15.18, SD=10.85; p&lt;.001), and improved coping efficacy (Mpre=8.0, SD=2.21; Mpost=9.65, SD=2.94; p&lt;.05) from pre- to post-treatment. Conclusions: Establishing care in CBT may support reductions in admissions for pain, length of stay, and ED dependency for youth with chronic SCD pain beyond the potential effects of age, genotype, and SCD-modifying treatments. Reductions in utilization may be partially supported by patient-reported improvements in functioning, coping, and lower pain intensity following CBT. Reducing barriers to access and enhancing clinical implementation of multidisciplinary treatments may optimize the health of youth with chronic SCD pain. Disclosures Lane: NHLBI: Research Funding; CDC: Research Funding; GA Dept: Other: Contract for newborn screeninjg follow-up services services; Bio Products Laboratory: Other: Sickle Cell Advisory Board; FORMA Therapeutics: Other: Clinical Advisory Board. Dampier:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Micelle BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Katz Foundation: Research Funding; Modus Therapeutics: Consultancy; NIH: Research Funding; Merck: Research Funding.

Abstract Background Cryptococcal meningoencephalitis (CM) affects individuals with AIDS, transplants recipients and those previously healthy, with 30–50% mortality in most groups despite anti-fungal treatment. In the previously healthy, a post-infectious inflammatory response syndrome (PIIRS) analogous to cryptococcal IRIS in AIDS patients has recently been described. PIIRS is defined as a deterioration in mental status and/or audio-visual capacity despite optimal treatment for CM and negative CSF cultures. Pathophysiology is related to excessive T-cell responses to lysed fungal cells during therapy but data on effective treatment regimens are limited. Methods Between March 2015 and February 2019, 11 consecutive patients with PIIRS who evidenced clinical deterioration over a period of up to 10 weeks despite effective antifungals were referred to the NIH clinical center. Patients were prospectively treated with adjunctive pulse solumedrol 1 g daily for 1 week followed by prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA) scores at baseline and 1 month were the primary endpoints and CSF parameters including WBC, glucose, HLA DR4+ CD4 and CD8 cells and cytokines were also determined at baseline and after 1 week of solumedrol. Paired nonparametric t-tests were conducted using GraphPad Prism 7.0. Results All patients demonstrated clinical improvement despite 7 being initiated at the point of stupor and 6 having received ventriculoperitoneal shunts without clinical response. MOCA scores at 1 month showed significant improvement (P = 0.002), accompanied by significant improvements in CSF: serum glucose ratios, CSF WBC, protein and HLADR4 positive T cells 1 week after receiving corticosteroids (P < 0.02). Patients with hearing or visual deficits exhibited clinical improvement. CSF cultures remained negative. Conclusion Our findings in this small observational cohort of refractory non-HIV CM with PIIRS demonstrated significant clinical benefit of high dose adjunctive pulse-taper corticosteroids. The study also demonstrates the utility of physiology-based immunophenotyping to guide therapy in neuroinflammation associated with infectious diseases. Disclosures All Authors: No reported Disclosures.

Abstract Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin autoantibodies (IAA) in patients without prior exposure to exogenous insulin. Differential diagnosis with other causes of hypoglycemia may be complex. We report three IAS cases with severe fasting hypoglycemia, referred to our Unit for the diagnostic workup of insulinoma. All three patients (two women and a man, age 66, 44, and 50 years) had history of severe fasting hypoglycemia leading to loss of consciousness along with weight gain. Both insulin and C-peptide were high, but their levels varied greatly among patients, ranging from 24 to 1500 μU/ml (n.v. &lt;16.3) and from 11 to 27 ng/mL (n.v. &lt; 4,2), respectively. Imaging studies for insulinoma were negative. In all patients, evidence of elevated IAA (ranging from 310 to 660 UA, n.v. &lt; 5) allowed diagnosis of IAS. Two patients were taking alpha lipoic acid, a sulphydryl compound consistently associated to IAS, while in the other the HLA-DRB1*0403 haplotype, conferring susceptibility to IAS, was detected. Continuous monitoring glucose (CGM) (iPro2; Medtronic Diabetes, CA, USA) showed in all patients the presence of prolonged hypoglycemia (with time spent with blood glucose below 54 mg/dL ranging from 9 to 20% of total monitoring time), and in one case the coexistence of high glucose levels after meals. One patient responded well to diazoxide treatment, while the others required both chronic steroid therapy and the use of plasmaphereses. Conclusion: Clinical manifestations of IAS vary widely among patients, without a direct correlation between symptoms severity and levels of both insulin and IAA; prandial hyperglycemia may also be present, leading to increases in glycated hemoglobin. Our patients displayed severe fasting hypoglycemic attacks that initially posed the suspicion of insulinoma. The assessment of IAA is thus mandatory in cases of fasting hypoglycemia, before proceeding to more expensive and probably unnecessary diagnostic and therapeutic procedures. CGM is a useful tool in evaluation and management of IAS, allowing the assessment of hypoglycemia duration and the detection of the wide glycemic variability secondary to the complex mechanism of insulin binding to IAA.

10555 Background: GIST represent a rare form of malignancy and one of best paradigms of molecularly targeted therapy. While the natural history of GIST following treatment with tyrosine kinase inhibitors is relatively well known, most information on imatinib naïve GIST are drawn form either small series or larger studies with possible referral bias. Methods: 1,021 GIST diagnosed between 1980 and 2000 were retrieved from the archives of 35 Departments of Pathology throughout Italy. Pathologic and clinical data were collected. All cases were centrally reviewed and stratified according to NIH 2002 and NCCN 2008 risk classifications. The prognostic meaning of a large set of morphologic and clinical parameters were evaluated by uni- and multi-variate analysis. Informed consent was obtained from all living patients. Results: 92 cases were excluded as non-GIST. Mean and median age were 63 and 65 years. Females were 52%. Disease status at diagnosis was localized in 767 and metastatic in 111 cases. 516 cases were gastric, 229 ileal/jejunal, 26 duodenal, 22 colonic, 28 rectal, and 25 peritoneal/retroperitoneal. NIH 2002 risk classification was available in 917 cases: 121 (13%) very low, 247 (27%) low, 201 (22%) moderate and 348 (38%) high risk. NCCN 2008 risk classification was available in 892 patients. Metastatic sites included liver (5%), peritoneum (10%), lymph-node (1%), skin and soft tissue (0.5%), and lungs (0.2%). Median follow-up was 75 months (range 1–323). Median survival was 88 months. 62% patients died (ED in 46%). Mitotic activity, tumor size and anatomic site correlated with overall survival at multivariate analysis. Striking differences were observed for groups with < 5 mitoses/50HPF, 5 and 10, 10 and 30, and >30. Non gastric GIST exhibit a significant poorer outcome. R2 surgery represents a negative prognostic factor. Conclusions: Mitotic rate has a deep prognostic impact if split in more than two intervals. Setting only two categories may be a limitation of existing prognostic classifications, although the mitotic count is affected by reproducibility issues. Survival curves according to the two main prognostic classifications will be shown. [Table: see text]

Aim. A clinical description of end-stage hereditary haemochromatosis manifested with chronic alcohol abuse.Key points. A 50-yo patient referred with marked general weakness as a major complaint. The patient had a history of long-term alcohol consumption at toxic doses, putative cirrhosis, paroxysmal atrial fibrillation, type 2 diabetes mellitus. The patient's severity on admission was conditioned by marked hypotension. Further examination aimed at excluding occult gastrointestinal bleeding, adrenal insufficiency, decompensated heart failure. Bronze skin and icteric sclerae were positive. Blood tests revealed severe macrocytic hyperchromic anaemia, thrombocytopae-nia, hyperbilirubinaemia, hypoalbuminaemia, hypocoagulation, elevated transaminases, hyponatraemia, elevated creatinine (CKD DPI 63 mL/min), severe hyperferritinaemia. Faecal occult blood test and EGDS for bleeding were negative. Abdominal ultrasound exposed signs of liver cirrhosis and portal hypertension (ascites, splenomegaly). Echocardiographic evidence of dilated cardiomyopathy of all chambers, a reduced 24% ejection fraction at absent acute myocardial infarction. Primary haemochromatosis was suspected upon high ferritin, transferrin iron saturation and multiple organ dysfunction. Genotyping revealed the HFE 845G > A variant diagnostic of haemochromatosis type 1. Clinical diagnosis: Primary disease: haemochromatosis (homozygous variant HFE 845G > A (A/A)): liver cirrhosis, Child-Pugh class C. Portal hypertension: splenomegaly, ascites. Dilated cardiomyopathy. Diabetes mellitus. Complications: multiple organ dysfunction (SOFA 16). Liver failure: jaundice, hypoalbuminaemia, hypocoagulation. Cardiac rhythm and conduction disorder: paroxysmal atrial fibrillation. Acute cardiac failure with underlying CHF IIb, NYHA class 3. Acute renal failure (anuria) with underlying CKD stage 3 (CKD DPI 63 mL/min). Moderate macrocytic hyperchromic anaemia. Acute and chronic adrenal failure. Despite a cardiovascular and renal failure compensation therapy and albumin transfusion, the patient died. Autopsy revealed a marked organ infiltration with haemosiderin (heart, stomach, liver, pancreas, lungs, kidneys, adrenal glands).Conclusion. The case describes a classical clinical manifestation of haemochromatosis: bronze skin hyperpigmentation, liver cirrhosis, diabetes mellitus, cardiomyopathy, adrenal insufficiency. Terminal haemochromatosis, severe cardiac and renal failure decompensation precluded phlebotomy and chelation therapy. A lethal outcome was conditioned by multiple organ dysfunction with underlying massive haemosiderin deposition in most organs.

Background:Immune checkpoint inhibitors (ICI), such as anti-CTLA-4and anti-PD1/PD-L1 monoclonal antibodies, have produced impressive clinical results in different types of cancer. However, immune-related adverse events (irAEs) may develop a wide spectrum of disabling syndromes. Knowledge of different rheumatic irAEs induced by ICI is increasing over the last years, however clinical patterns, time to onset of different irAEs according to treatment and follow-up are less well known.Objectives:To describe different clinical patterns of rheumatic irAEs induced by ICI and their rheumatic and oncologic outcomes.Methods:We included consecutive patients with rheumatic irAEs from 3 different referral centers in Barcelona with special emphasis in articular irAEs. Four main clinical syndromes were identified: inflammatory arthritis (IA), non-inflammatory arthralgias (NIA), psoriatic arthritis (PsA)-like and polymialgia (PMR)-like. We conducted a baseline visit and then follow-up in order to determine their clinical pattern, treatment response and outcome. Longitudinal visits were done from January 2017 to January 2020. Patients with other non–articular diagnosis were not included in the follow-up analysis.Results:We included 55 patients. A total of 34 patients were male (61.8%) with a mean age of 65.0 ± 11.4 years. Oncologic underlying diagnosis was lung carcinoma in 24 (43.6%) patients, followed by melanoma in 17 (29%), urothelial cancer in 4 (7.3%), breast in 2 (3.6%) and 2 (3.6%) acute myeloid leukemia among others. Seven (12.7%) patients received ICI as combined therapy. Different ICI were used including: Pembrolizumab in 21 (38.2%), Nivolumab 13 (23.6 %), Atezolizumab 6 (10.9%), Nivolumab + ipilimumab 5 (9.0%), Durvalumab 3 (5.5%), Pembrolizumab + epacadostat in 2 (3.6%), 2 anti TIM3, Atezolizumab+ Ibatasertib, Avelumab and Ipilimumab in one case each. 12 out of 55 patients had an underlying rheumatic disease before ICI treatment. Eleven patients developed other irAEs before or at the same time as rheumatic syndromes (mainly colitis and thyroiditis). Main rheumatic irAE included: IA in 23 (41.8%), NIA in 16 (29.1%), PsA-like in 6 (10.9%), PMR-like in 5 (9.1%) among others. Time from ICI to irAEs was 8.3 ± 8.4 months(mo). irAE presented earlier in patients with combined ICI therapy than in patients with monotherapy (6.5 ± 4.0 vs 8.6 ± 8.9 mo, p=NS, Figure 1A). Time (in mo) from ICI initiation to irAE onset was different according to treatments. For Nivolumab 10.0 ± 10.6, Anti TIM3 10.0 ± 1.4, Durvalumab 9.0 ± 2.0, Ipilimumab 7.98 ± 9.21, Pembrolizumab 7.28 ± 7.53, Avelumab 6.0 and Atezolizumab 4.4 ± 5.38 mo (Figure 1B). Time from ICI initiation and onset also differs among rheumatic irAEs (Figure 2). Mean time follow-up was 13.4 ± 10.9 mo. At the last visit, 45% were under GC, mean dose of 3.6 mg/d (range 0-40). DMARD were needed in 15% of patients (6 patients MTX, 1 with LEF and 1 SFZ). At the last visit, 11 (22.9%) patients remain with persistent arthritis, 25% intermittent flares and 52% had a self-limited pattern. Regarding oncologic outcome, 30.2% were on remission, 30.2% in partial response and 39.6% with tumor progression. Eleven (20%) of patients died.Conclusion:We described different clinical patterns according treatment and irAEs. Combined ICI therapy and patients treated with Atezolizumab had earlier onset of symptoms. Vasculitis and PMR-like syndromes appear in earlier phases. After a mean follow-up of around 1 year, one-quarter of the patients remain with persistent arthritis and 15% require DMARD therapy.Disclosure of Interests:Jose A. Gómez-Puerta Speakers bureau: Abbvie, BMS, GSK, Lilly, Pfizer, Roche, Carolina Perez-Garcia: None declared, David Lobo Prat: None declared, Roberto Gumucio: None declared, Fabiola Ojeda: None declared, Ana Milena Millán Arciniegas: None declared, Sebastian Rodriguez Garcia: None declared, Virginia Ruiz Speakers bureau: Lilly, Pfizer, Héctor Corominas Speakers bureau: Abbvie, Lilly, Pfizer, Roche

Abstract Cushing syndrome (CS) secondary to ectopic ACTH secretion (EAS) is rare and accounts for 10% of CS with majority being bronchial or gut neuroendocrine tumors (NETs) and squamous cell lung cancer. There are only a few case reports of EAS due to appendiceal carcinoid. A 24-year-old woman was referred to endocrinology for 60-pound weight gain, acne, hirsutism, generalized weakness, heat intolerance, and hot flashes. She had secondary amenorrhea for 6 months prior to presentation. Family history was significant for bronchial carcinoid in mother. On examination, she had moon facies, wide purple striae on abdomen, hirsutism, dorsocervical and supraclavicular fat pads. She had normal blood pressure. Her laboratory workup showed potassium 3.2 mmol/L (N, 3.5-5.3), urine free cortisol (UFC) 539 mcg/24 hours (N&lt;50), ACTH 54 pg/ml (N, 6-50) and post 1-mg dexamethasone suppression test cortisol 8.8 mcg/dL. CT abdomen revealed a 3-cm enhancing appendiceal mass, enlarged periappendiceal mesenteric lymph nodes and a 4-cm enhancing right hepatic lobe lesion. Ga-68 Dotatate PET/CT confirmed increased radiotracer uptake in appendiceal mass, lymph nodes and hepatic mass. On liver biopsy, pathology showed well differentiated NET Grade 1 and positive ACTH stain. Repeat UFC was 65 mcg/24 hrs and serum cortisol went down to &lt;1 mcg/dL indicating severe cyclical CS. She was referred to surgical oncology for opinion on debulking surgery. Her genetic testing was negative. She was started on Lanreotide. Given severe cyclical CS with extensive tumor burden, she underwent robotic bilateral adrenalectomy with a plan for cytoreductive surgery once she is on physiologic doses of steroids. Appendiceal NET causing Ectopic CS is exceedingly rare. In 20 years’ experience at NIH, there was only one case of appendiceal NET reported. First reported case was in 1971, when CS was cured by resection of an appendiceal carcinoid incidentally detected on laparotomy for adrenalectomy. There are 3 additional case reports in literature of appendiceal carcinoid with ectopic CS. Management can be challenging particularly in patients with metastatic disease. Medical therapy should be individualized, and adrenalectomy should be considered early in patients with uncontrolled CS due to EAS. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Abstract Background People living with HIV (PLWH) and opioid use disorder (OUD) commonly experience criminal justice involvement (CJI). We sought to estimate the impact of CJI on 1) HIV care engagement, 2) antiretroviral therapy (ART) prescription rates, and 3) receipt of medications for opioid use disorder (MOUD), among PLWH and OUD in Vietnam. Methods Participants were PLWH enrolled in a 12-month MOUD treatment trial of HIV clinic-based buprenorphine vs. methadone referral in Vietnam. We compared those with CJI (arrest, incarceration, or compulsory “06” drug rehabilitation) during the first 9 months of the study to those with no CJI. To ensure participants with CJI had the opportunity to re-engage in treatment, only those who were released before their 9-month study visit were included; participants still incarcerated at 9 months were excluded. Logistic regression models estimated the association between CJI and HIV care engagement (≥ 1 visit), ART prescription, and receipt of MOUD between 9 and 12 months, controlling for demographics, substance use, past CJI, and HIV history. Results At baseline, 234 of 281 participants (83.6%) had a history of arrest/incarceration, and 172 (61.2%) reported prior 06 detention. During their first 9 months of study participation, 14 participants (5.0%) were arrested and 14 participants (5.0%) were sent to compulsory 06 rehabilitation. Being arrested (OR=0.04, 95% CI= (0.007, 0.25)), sent to compulsory 06 rehabilitation (OR=0.08, 95% CI= (0.02, 0.38)), or either (OR=0.07, 95% CI= (0.02, 0.24)), were negatively associated with receipt of MOUD. CJI involvement was also negatively associated with HIV clinic engagement after release (OR=0.20, 95% CI= (0.05, 0.84)). A similar negative association was noted for ART prescription, though it did not reach statistical significance (OR=0.17, 95% CI= (0.03, 1.22)). Conclusion Arrest, incarceration, and compulsory 06 rehabilitation negatively impact HIV and OUD care among people with HIV and OUD in Vietnam. Policies that decrease incarceration, and the impacts of incarceration, for people with OUD and HIV may improve care outcomes in Vietnam and elsewhere. Disclosures P Todd Korthuis, MD, MPH, Alkermes & Indivior (Other Financial or Material Support, Dr. Korthuis serves at principal investigator for NIH-funded studies that accept donated study medicine from Indivior (buprenorphine) and Alkermes (extended-release naltrexone).)

Abstract BACKGROUND: Individuals with immune mediated thrombotic thrombocytopenic purpura (iTTP) frequently exhibit cognitive impairment and are at higher risk of stroke than matched controls. However, the etiology of cognitive impairment in these individuals has not been established. We conducted this prospective study to examine the patterns of cognitive impairment and to test the hypothesis that cognitive impairment in iTTP survivors is associated with silent cerebral infarction (SCI, ischemic lesions on brain MRI without corresponding overt neurodeficits), which are also a risk factor for future stroke. METHODS: We prospectively enrolled adult (age ≥ 18 years) patients with iTTP and age- and sex-matched controls without prior iTTP or stroke. iTTP was diagnosed based on ADAMTS13 activity &lt;10% during an acute episode. All study assessments were performed after achieving hematological remission (platelet count &gt;150x10 9/L for at least 30 days after stopping plasma exchange and/or caplacizumab). Participants undergo annual study visits including the following study measures: 1) NIH stroke scale to rule out acute stroke, 2) NIH ToolBox Cognition battery, a comprehensive iPad based neurobehavioral tool that has been validated across multiple populations and for which normative control data are available. The NIH ToolBox Cognition Battery tests multiple cognitive domains (Figure 1) including executive function (dimensional change card sort test, flanker inhibitory control and attention test), processing speed (pattern comparison test), episodic memory (picture sequence memory test), working memory (list sort working memory test), language (oral reading recognition, picture vocabulary test). We used T scores adjusted for age, sex, race and educational attainment where the normative mean T score is 50 with standard deviation (SD) of 10. Mild and major cognitive impairment are defined as a T scores that are 1-2 SD below mean and &gt; 2SD below mean for any domain, respectively; 2) Brain MRI: SCI is defined as a infarct-like lesion (punctate T2 and FLAIR hyperintensity) without corresponding neurodeficits. The Chi-squared test and Mann Whitney test were used to compare categorical and continuous variables across groups, respectively. RESULTS: Between September 2020 and June 2021, we enrolled 34 participants including 28 iTTP patients and 6 controls. Demographics and clinical characteristics of patients and controls are summarized in Table 1. NIH Stroke Scale score was 0 in all controls and all but one iTTP patient (score = 1). Among iTTP patients, 28.6% (8/28) had prior stroke (including during acute episodes). (i) iTTP survivors demonstrate cognitive deficits affecting executive function and processing speed: Among iTTP patients, 46.4% had cognitive impairment in at least one domain including 25% (7/28) with major cognitive impairment and 21.4% (6/28) with mild cognitive impairment (&gt; 1 SD below mean T score). Among controls, 0% had major cognitive impairment and 16.6% (1/6) had mild cognitive impairment. Figure 1 shows detailed cognitive testing results for iTTP patients and controls. iTTP patients most commonly had deficits (T score &lt; 40) in executive function (flanker inhibition test, dimensional change card sort test) and processing speed (pattern comparison test) (Table 1). (ii) Silent cerebral infarction is associated with major cognitive impairment: MRI was completed in 24 iTTP patients and all controls. SCI was present in 50% (12/24) of iTTP patients (representative image, figure 2A) and 16.6% (1/6) controls. Another 29.1% (7/24) had evidence of prior stroke. Rate of SCI was 35.7% in patients without cognitive deficits, 50% in those with minor cognitive deficits and 83.3% in those with major cognitive deficits. SCI was present in 83.3% (5/6) with major cognitive impairment versus 38.9% (7/18) without major cognitive impairment (P = 0.05) (Figure 2B). CONCLUSIONS: Cognitive deficits in iTTP survivors primarily affect executive function and processing speed and are associated with SCI suggesting ischemic etiology. Whether SCI occur during acute episodes or during remission (with remission ADAMTS13 as a risk factor) is being studied prospectively with serial MRI and cognitive assessment. iTTP patients may benefit from neurocognitive testing and referral to neuropsychological therapy, where appropriate, and aggressive measures to address risk factors for cerebrovascular disease. Figure 1 Figure 1. Disclosures Naik: Rigel: Research Funding. Lanzkron: GBT: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Novo Nordisk: Consultancy; Imara: Research Funding; CSL Behring: Research Funding; Shire: Research Funding; Bluebird Bio: Consultancy. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation; Dova: Other: Advisory board member; Alexion: Other: Advisory board member.

Abstract Adoptive transfer of antigen specific T cells can be effective in treating viral infections complicating allogeneic hematopoietic stem cell transplant (HSCT) recipients. However, in practice, generation of T cells is often limited by insufficient supply of autologous antigen presenting cells; therapeutic activity in HLA disparate patients may also be impaired if the immuno- dominant T cells generated are restricted by HLA alleles not shared by the host. AAPCs have theoretical advantages for T cell therapies in terms of sustained supply and capacity to selectively stimulate T cells restricted by HLA alleles shared by donor and host. However, to date, only AAPC systems expressing HLA A*0201 have been characterized. Accordingly, we established a panel of AAPC consisting of NIH 3T3 mouse fibroblast cells, each transduced to express β2- microglobulin and a prevalent HLA class-I allele, specifically HLA A*0201, A*0301, A*2402, B*0702, B*0801 or C*0401, as well as the human co-stimulatory molecules B7.1, LFA-3 and ICAM-1. Novel promotor sequences were introduced to secure stable high expression of the allele on the AAPCs. Sensitization of T cells from seropositive donors with AAPCs expressing each of these alleles (4-8 donors/allele), either loaded with overlapping 15-mer peptides spanning the CMVpp65 sequence or transduced to express the CMV pp65 protein, resulted in 12-35 fold expansions of CD8 + T cells exhibiting CMV pp65 epitope-specific, HLA restricted activity, as quantitated by peptide -HLA tetramer binding, epitope specific production of interferon gamma, and cytotoxic activity against peptide loaded or CMV infected targets. Although both peptide pool loaded and transduced AAPCs induce CMV pp65 epitope specific T cells, yields were higher when transduced AAPCs were employed. In studies of T-cells from 5 donors when sensitized with either peptide pool loaded autologous dendritic cells (DC) or HLA sharing AAPCs, sensitization with DC selectively induced T-cells specific for 1-2 immunodominant CMV pp65 epitopes. In contrast, while sensitization with a panel of peptide loaded or transduced AAPCs expressing shared HLA alleles elicited responses to the same dominant epitopes, we could also regularly generate comparable cytotoxic T cell responses to subdominant epitopes which were either not produced or only present at low frequencies in T cells sensitized with autologous DC. Thus, this panel of AAPCs stably expressing a series of HLA alleles which, in aggregate, are detected in 70% of the patients referred for HSCT, can be employed for rapid generation of CMV-pp65 specific T cells of desired HLA restriction for adoptive therapy.

It has been proposed that patients with hematologic malignancy and autoimmune diseases receiving anti-CD20 monoclonal antibody (mAb) therapy are particularly at risk of severe Coronavirus disease (COVID-19) because the profound and long-lasting B-cell depletion induced by anti-CD20 mAb may impair virus clearance and may also contribute to reactivation of latent viruses, especially hepatitis B and JC viruses. As of July 20, 2020, the total number of COVID-19 cases reported by the Italian authorities reached 245,000. The north of the country was mostly hit, and Milan and Brescia were among the Italian provinces that registered the highest number of COVID-19 cases. Consistent with this, a high number of COVID-19 patients affected with multiple types of hematological disorders (n. 137) and with multiple sclerosis (MS, n. 114) were referred to ASST Spedali Civili di Brescia. Antibodies to SARS-CoV-2 were analyzed in 70 patients with hematological disease, and in few patients with MS. Among these, 10 patients (7 with hematologic disease and 3 with MS) had received treatment with rituximab or ocrelizumab, two anti-CD20 mAbs, within 3 months prior to COVID-19 onset. Clinical indication to CD20-depleting treatment for patients with hematological disorders included Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Non Hodgkin Lymphoma (NHL). Anti-spike protein (anti-S) and anti-nucleocapsid (anti-N) antibodies to SARS-CoV-2 were analyzed during the acute phase of infection and up to 3 months since the onset of symptoms by quantitative measurements of plasma or serum antibodies with luciferase immune precipitation assay systems (LIPS). With this technique, production of anti-S and anti-N antibodies has been demonstrated between day 8 and day 14 after onset of symptoms in immunocompetent individuals, whereas specific antibody production was delayed by few days in immunocompromised patients (Burbelo PD et al, medRxiv. 2020 Apr 24:2020.04.20.20071423). All 10 patients remained seronegative to SARS-CoV-2 for the first 20 days since onset of symptoms. One patient with DLBCL secondary to Follicular NHL had detectable anti-S and anti-N antibodies at day +25, and one patient with MS developed anti-N antibodies by day +23. Two patients, one with DLBCL secondary to Follicular NHL and one with Follicular NHL were still seronegative for both anti-S and anti-N antibodies at 133 and 74 days since onset of symptoms. Two MS patients were seronegative at the last examination, and one other MS patient was anti-S seronegative at day +74. Three of the 10 patients have died; all three were SARS-CoV-2 RT-qPCR+ and seronegative at the time of death. While it has been reported that SARS-CoV-2 is cleared without significant problems by the majority of people with MS or other autoimmune diseases on immunotherapy, these data indicate that treatment with anti-CD20 mAb may significantly alter humoral responses to the virus. Until a vaccine to SARS-CoV-2 is available, the risk-benefit ratio of anti-CD20 mAb therapy in areas with high rates of SARS-CoV-2 infection should be carefully weighed. Moreover, for patients with B-cell malignancies or autoimmune diseases, transient discontinuation of this therapy, or use of alternative therapeutic approaches, should be considered once an efficacious vaccine becomes available. This study was performed according to protocol NP-4000 (Comitato Etico Provinciale), and supported by Regione Lombardia and by the Division of Intramural Research, NIAID. Figure 1 Disclosures Imberti: Biogen: Honoraria; Genzyme-Sanofi: Honoraria; Meck-Serono: Honoraria; Novartis: Honoraria; Biogen: Other: Advisory board; FISM (Fondazione Italiana Sclerosi Multipla): Research Funding; Regione Lombardia: Research Funding. Capra:Biogen: Other: travel grants, Speakers Bureau; Roche: Other: travel grants, Speakers Bureau; Celgene: Other: travel grants, Speakers Bureau; Merck: Other: travel grants, Speakers Bureau; Novartis: Other: travel grants, Speakers Bureau. Rossi:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Notarangelo:NIAID, NIH: Research Funding. Cohen:NIAID, NIH: Research Funding.

2556 Background: Only a small part of the total cell population of a malignancy has the potential to grow and regenerate the total tumor mass. The rest are only differentiated forms of those stem cells. This biologic characteristic seems to be responsible for the failure to achieve long term remission for several peptide based vaccines. Method: To overcome this obstacle, we have established a technique that uses tumor stem cells (TSC) to develop a TSC-B cell vaccine. To test efficacy and best administration form of this vaccine, we have proceeded as follow: First: Pieces from total or partial resections of GBM or NSCLC were mechanically dissociated to a single cell suspension. Cells were cultured in an appropriate tissue culture medium and allowed to grow for two weeks or until they reach a semi confluent stage. Then, cells were harvested and re-seeded. This procedure was repeated 6 to 24 weeks according to vitality and growth characteristics of cells. Finally, Tumor cells were fused with autologous B cells. The hybrid was kept in culture and used for an intra lymph node immunization every 3 weeks. To potentiate its action, 3 days prior to its administration we co-incubated the hybrid with either autologous dendritic cells or autologous mononuclear cells. Adverse events were evaluated by the “Common terminology criteria for Adverse Events (AE), 2004” developed by NIH. Definitions are available on the web at http://ctep.cancer.gov/reporting/ctc.html . Clinical efficacy of this procedure was evaluated according RESIST criteria for NSCLC and a combination of MRI and spectroscopy for GBM. Results: At present 8 patients with GBM with post surgical second relapse and who had received complete radiotherapy doses were treated. We have also treated 6 patients with NSCLC:4 with minimal residual disease and 2 with measurable residual disease. Patients have presented minor adverse events, mainly referred to inflammation of the injection site. The median survival rates registered to the present are 22 months for GBM patients and 3 years for patients with stage IV NSCLC who had minimal residual disease at the beginning of the treatment. Conclusion: A tumor stem cell vaccine seems to be a feasible and effective therapy with very low toxicity for the treatment of advanced GBM and NSCLC patients. No significant financial relationships to disclose.

Abstract Introduction: Steady advances in the treatment of acute myeloid leukemia (AML) have improved outcomes in high-resource settings, with a 5-year overall survival rate of 29% and rising in the United States. In contrast, a diagnosis of AML in many resource-limited settings automatically confers a less than 10% one-year survival rate. To better understand this significant disparity, as well as how to narrow it, it is important to gather data illustrating the current landscape of AML management in resource limited-settings, including patient characteristics, disease-related and treatment-related factors. Here we examine the population of patients with AML at a single large academic medical center in Western Kenya that serves a catchment area of more than 20 million people. Objectives: To describe characteristics of patients presenting with AML at Moi Teaching and Referral Hospital (MTRH) hematology and oncology clinic between 2014 and 2020, to help identify areas of need to inform future interventions. Methodology: Retrospective, cross-sectional chart review study of all newly diagnosed patients (age 15 years and older) with AML presenting to the MTRH adult hematology and oncology clinic from January 2014 to December 2020. Results: We reviewed the charts of 113 patients with AML. The median age at diagnosis was 40 years (range 15-86 years), with an average age of 42 years. Forty-nine percent (n=55) were female. Thirty-five patients did not have French American British (FAB) subtypes documented (this method remains the main form of AML disease classification in this resource-limited setting). M2 subtype was the most common (n= 24). Seven patients had acute promyelocytic leukemia (APML), of which 4 died due to bleeding complications and lack of access to ATRA. Three APML patients who had access to ATRA were alive more than 1 year after diagnosis. White blood count (WBC) at diagnosis ranged between 600/cm3 and 336,000/cm3 with neutrophil predominance. Mean hemoglobin at presentation was 7g/dl (range 2.6g/dl-16g/dl). Most patients had been transfused with red blood cells prior to presentation and continue to require more transfusion. Platelet counts ranged between 4,000/cm3 to 782,000/cm3 with 36% of patients (n=41) having a count of less than 50,000/cm3. Fifty patients with AML received low dose subcutaneous cytarabine (20mg subcutaneous twice a day for 10 days every 4 to 6 weeks) and 3 patients had etoposide added to their treatment (50mg/m2 intravenous once a day for 7 days). No patient was treated with standard intensive induction chemotherapy, (7+3), due to lack of adequate supportive care. Only 5 of 63 (7.9%) non-APML patients whose outcomes were established survived for more than 12 months. The median overall survival at after diagnosis was 45 days. Thirteen percent of patients were lost to follow up (n= 15) and 1 patient was referred to another facility for possible induction with 7+3. Conclusion: AML remains a disparately lethal disease in resource-limited settings, where it impacts a relatively healthy, young patient population. In well-resourced settings, many of these patients would have a reasonable chance at long term survival and potential cure, but in Western Kenya most patients die within a few months of diagnosis. Due to the lack of adequate supportive care resources, even the younger patients mostly did not receive standard-of-care intensive induction therapy. The outdated FAB classification system is still in use. Lack of access to improved diagnostics, appropriate supportive care (antimicrobials and transfusion products) and limited availability of newer, effective, and less toxic treatment regimens are the main impedance to care. More efforts are needed to improve the management of acute leukemia in under-resourced countries. Disclosures LeBlanc: Pfizer: Consultancy, Other: Advisory Board; Otsuka: Consultancy, Honoraria, Other; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Flatiron: Consultancy, Other: Advisory board; Helsinn: Consultancy, Research Funding; Duke University: Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Amgen: Consultancy, Other: travel; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Other: Advisory board; American Cancer Society: Research Funding; Heron: Consultancy, Honoraria, Other: advisory board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; UpToDate: Patents & Royalties.

Abstract Background: Kaposiform lymphangiomatosis (KLA) is a rare, aggressive lymphatic malformation that can lead to significant morbidity and mortality (Croteau et al 2014). First described as a distinct entity from generalized lymphatic anomaly (GLA) in 2014, KLA is histologically defined by spindled "kaposiform" endothelial cells associated with abnormal proliferation of lymphatic vessels. High risk features include pleural/pericardial effusions and coagulopathy. Respiratory failure, infections, and hemorrhage are common causes of death. In the largest case series of patients with KLA (n=20), five-year survival was 51%. Mean interval between diagnosis and death was 2.75 years. In recent years, the oral agent sirolimus has been used to treat KLA as a single agent or in combination with steroids and vincristine. No update has been published about overall outcomes for patients since the more widespread use of sirolimus. Methods: We conducted a retrospective chart review of 44 patients with biopsy-proven KLA referred to the Vascular Anomalies Center at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center between 1995 and 2018. Twenty patients were previously analyzed in a retrospective review. Patient data were gathered through the electronic medical record and and the Lymphatic Anomalies Registry. Response to treatment was defined by clinical assessment via extraction from the medical record, improvement in patient or parent-reported quality-of-life, improved coagulopathy, and decreased size of lesions on imaging. Toxicities were graded according to the NIH CTCAE grading scale. Clinical outcomes were evaluated up until July 2018. Results: Among 44 patients with KLA, the median age at onset of symptoms was 7 years (range=0-40.6 years). The median time from development of first symptoms to diagnosis of KLA was 16.4 months (range=0-12 years). Seventy-eight percent of patients had pleural or pericardial effusions at presentation (Figure 1). Anatomic involvement varied, with 65% of patients having bony involvement and 68% of patients having visceral disease. Bleeding was also common, with 14% of patients requiring transfusions of blood products. Twenty-four (56%) of 44 patients were treated with sirolimus. Of those 24 patients, 20 (83%) patients reported ever having a sustained response to sirolimus (>6 months) based on our criteria. Despite improvement in disease symptoms, there was no significant difference in overall survival between patients who were treated with sirolimus and those who were not (log-rank p=0.62; Figure 1). Of the 44 patients evaluated in our study, fourteen died. Nine of the patients did not receive sirolimus (they died prior to its use in treating vascular anomalies). Of the 5 patients who received sirolimus and subsequently died, one reported marked improvement in his quality of life, but died from a pneumothorax during chest tube placement for a pleural effusion. The other patient who responded died from respiratory failure after a period of non-adherence with taking sirolimus. The remaining three patients did not respond to sirolimus and died of multi-organ failure. Among the 14 patients who died, the median time from diagnosis to death was 2.2 years (range 0.2- 7.1 years). Among 24 patients treated with sirolimus, 16 (67%) patients were treated concurrently with either vincristine (n=10) and/or steroids (n=15). Eight patients had sustained response with sirolimus alone. Minimal side effects were observed; there was only one grade 3 thrombocytopenia that did not require cessation of sirolimus. Sixteen patients remained on sirolimus at last follow-up. Conclusions: Most patients treated with sirolimus report stabilization of their disease symptoms and improvement in quality of life. Sirolimus is well-tolerated and most patients who respond remain on sirolimus as a form of chronic therapy. However, overall mortality for KLA remains high, even for those patients treated with sirolimus. More research is needed to investigate possible risk factors for poor outcomes. Investigation regarding phenotype-genotype correlation for KLA is ongoing, with the hope of identifying additional treatment options. In our study, there was a gap of > 1 year between time of symptom onset and diagnosis of KLA, highlighting a need for increased awareness of this unique disease entity and prompt referral of patients to a center with expertise in vascular anomalies. Disclosures No relevant conflicts of interest to declare.

Background:Little is known about mortality in patients with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms.Objectives:We aimed to evaluate all-cause and cause-specific mortality in patients with SLE and NP symptoms.Methods:All patients with the clinical diagnosis of SLE of 18 years and older that visited the tertiary referral NPSLE clinic of the Leiden University Medical Center between 2007-2018 and signed informed consent were included in this study. Patients were classified as NPSLE if NP symptoms were attributed to SLE and immunosuppressive or anticoagulant therapy was initiated, otherwise patients were classified as non-NPSLE. Municipal registries were checked for current status (alive/deceased). Electronical medical files were studied for clinical characteristics and cause of death. Standardized mortality ratios (SMRs) and 95% confidence intervals were calculated using data from the general Dutch population. In addition, a rate ratio (RR) was calculated using direct standardization to compare mortality in NPSLE with non-NPSLE patients.Results:351 patients with the clinical diagnosis of SLE were included, of which 149 patients were classified as NPSLE (42.5%). Compared with the general population, mortality was increased five times in NPSLE (SMR 5.0, 95% CI: 2.6-8.5) and nearly four times in non-NPSLE patients (SMR 3.7, 95% CI: 2.2-6.0), as shown in Table 1. Risk of death due to cardiovascular disease (CVD) was increased in non-NPSLE patients (SMR 6.2, 95% CI: 2.0-14.6) and an increased risk of death to infections was present in both NPSLE and non-NPSLE patients ((SMR 29.9, 95% CI: 3.5 – 105) and SMR 91.3 (95% CI: 18.8 – 266) respectively). However, mortality did not differ between NPSLE and non-NPSLE patients (RR 1.0, 95% CI: 0.5 – 2.0).Table 1.All-cause mortality in SLE patients presenting with neuropsychiatric symptoms attributed to SLE (NPSLE) or to other causes (non-NPSLE)NPSLE(N = 149)Non-NPSLE(N = 202)Deaths (N, %)13 (8.7)17 (8.4)Age at death (median, range)49 (32 – 79)59 (20 – 89)Follow-up time (years)9061047Crude mortality rate (per 1000 PY)14.316.2All-cause mortality*Female5.5 (2.8 – 9.6)3.4 (1.9 – 5.7)Male2.3 (0.1 - 12.8)6.2 (1.3 – 18.2)Combined5.0 (2.6 – 8.5)3.7 (2.2 – 6.0)*Standardized mortality ratio, ratio of the observed and expected number of deathsConclusion:Mortality was increased in both NPSLE and non-NPSLE patients in comparison with the general population, but there was no difference in mortality between NPSLE and non-NPSLE patients. Risk of death due to infections was increased in both groups.Disclosure of Interests:Rory Monahan: None declared, Rolf Fronczek: None declared, Jeroen Eikenboom: None declared, Huub Middelkoop: None declared, L.J.J. Beaart- van de Voorde: None declared, Gisela Terwindt: None declared, Nic van der Wee: None declared, Frits Rosendaal: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Margreet Kloppenburg: None declared, G.M. Steup-Beekman: None declared

Abstract Introduction Hydroxyurea (HU) is the only FDA-approved medication to treat adults with sickle cell anemia (hemoglobin SS disease, SCA). Two studies showed improved survival with long term HU therapy. Conversely, subsequent studies reported most patients continue to die by the fifth decade of life despite long term treatment. Further, no studies have shown that HU prevents organ dysfunction. In this work, we sought to assess the effect of HU dosing on survival and organ function in SCA in a cohort of patients at a single referral institution. Methods Adults with SCA enrolled on the Bethesda Sickle Cell Cohort Study between January 2001 and October 2012 were included in this retrospective analysis. The NIH Biomedical Translational Research Information System was used to electronically retrieve clinical notes, administration records, and medication orders. Computer-assisted review facilitated the extraction of HU dose histories. Survival, laboratory, and cardiopulmonary parameters were compared between enrollment and most recent follow-up based on HU status and fetal hemoglobin (HbF) response. Results Of 388 subjects with SCA, 254 (65%) were treated with HU at a median dose of 19.4 mg/kg/day. Mean follow-up was 3.58±3.53 years. Of subjects prescribed HU, 166 (65%) were on a therapeutic dose. Subjects taking HU had a significantly higher HbF (9.2 versus 6.8%, p=0.0003) and mean corpuscular volume (MCV, 96.2 versus 88.3fL, p<0.001) at their initial visit compared to those not taking HU. A similar pattern was seen at the last visit for HbF (12.0 versus 6.5%, p<0.0001) and MCV (99.2 versus 87.4fL, p<0.0001), suggesting that HU was administered for a prolonged period of time. Total hemoglobin was not different between groups at either visit (8.9 versus 9.0g/dL at initial visit, p=0.41 and 8.9 versus 8.8g/dL at most recent visit, p=0.66 in HU versus no HU patients, respectively). There was no difference in overall survival based solely on HU treatment (p=0.11). However, subjects prescribed therapeutic HU doses (15-35 mg/kg/day, N=166) were more likely to be alive than subjects who never took HU (N=131, p=0.04). Survival was similar when comparing sub-therapeutic HU (N=46) to no HU (p=0.52) groups, and survival was also similar between subjects prescribed sub-therapeutic HU versus therapeutic HU (p=0.46). Multivariate analysis confirmed HU dose is independently associated with prolonged survival (p=0.006). At enrollment, creatinine was lower (1.2 versus 0.8mg/dL, p=0.0016), total bilirubin was greater (3.3 versus 2.8mg/dL, p=0.02), and tricuspid regurgitant velocity was higher (2.6 versus 2.5m/s, p=0.03) in patients on HU. There were no significant differences in ejection fraction, brain natriuretic peptide, transaminases, alkaline phosphatase, or direct bilirubin. Further, there were no differences for any markers of organ function at the most recent follow-up. To determine if the best HU responses were associated with improved organ function, subjects were divided into groups based on whether their maximum HbF was within the lowest or the highest quartile. The HU dosages were 24.1 versus 4.8mg/kg/day in the high versus low HbF groups, respectively (p<0.0001). Maximum HbF was 26.1% as compared to 1.5% in the low HbF group. Ejection fraction was higher and transaminases and creatinine were lower at both visits in subjects with the highest HbF levels (see Table). After adjusting for age, only creatinine remained lower in the high HbF group at enrollment (p=0.007). Conclusions HU therapy correlates with prolonged survival and preservation of organ function, but only when given in therapeutic dosages. These HU associations are not observed for sub-therapeutic doses less than 15 mg/kg/day. Patients should be treated with a maximum tolerated HU dose to achieve the highest possible HbF response, ideally before organ damage occurs. Additional studies are indicated to further confirm these findings. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3564 Background: Autologous stem cell transplant (ASCT) with high-dose therapy (HDT) is an effective treatment modality for multiple myeloma (MM). MM is the leading indication for ASCT in North America. It was shown in a recent meta-analysis that a strategy of using ASCT early in the course of myeloma improves progression free survival (PFS) and quality of life. However, this study addressed only patients who had received conventional chemotherapy. Over the last decade, novel agents (thalidomide, bortezomib, and lenalidomide) have replaced conventional chemotherapy for induction in myeloma. These agents have demonstrated superior response rates when compared to conventional chemotherapy, and there is some indication that using novel therapies for induction before ASCT improves the duration of response and overall survival (OS). However, the question of whether early ASCT is the best strategy in the era of novel agents remains unanswered. We performed a retrospective analysis in order to compare the outcomes of patients with newly diagnosed MM treated with novel agents who received an early versus late ASCT. Methods: 179 newly diagnosed MM patients were treated or referred to The Ohio State University for ASCT between October 2006 and December 2009. All patients in the analysis received either thalidomide, bortezomib, or lenalidomide as part of their induction regimen and went on to receive HDT and ASCT. We compared the outcomes of patients who received ASCT within 12 months of diagnosis (early group, N=134) to those who received ASCT at a later date (late group, N=45). All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to compare PFS and OS. Result: In our sample of 179 subjects there were no statistically significant differences in age, sex, race, performance status, comorbidity index score, disease stage at diagnosis, genetic risk and preparative regimen dose between the two groups. The median time from diagnosis to transplant was 7.2 months in the early group (N=134) and 17.7 months in the late group (N=45). In the early group, 81% of patients had received one line of treatment before transplant vs. 49% in the late group (p < 0.001). The overall response rate (ORR) prior to transplant was 90% (9% complete (CR), 31% very good (VGPR), 45% partial (PR)) in the early group, and 83% (9% CR, 22% VGPR, 47% PR) in the late group (p = 0.277). The ORR post transplant was 92% in the early group and 82% in the late group (p = 0.082), with a statistically significant proportion of patients in the early group obtaining CR (52% vs. 27%, p = 0.003). One year non-relapse mortality was 2% for both groups. At a median follow up of 22 months, 36% vs. 47% of patients had progressed (p = 0.29) and 7.5% vs. 24% had died due to disease progression (p = 0.005) in the early vs. late group. Median PFS was 30 months vs. 27 months with 1 year and 3 years PFS of 83% vs. 75% and 64% vs. 55% in the early vs. late group respectively (p = 0.851, Fig. 1). Of patients who had only one therapy pre transplant, results trended toward equivalent PFS in the two groups (p = 0.090), however more than 1 line of therapy and late transplant resulted in a progression hazard ratio of 2.43 (p = 0.050). OS was significantly better in the early group vs. the late group (p = 0.005, Fig. 2). On Cox regression analysis, a late ASCT resulted in a mortality hazard ratio of 3.30. Conclusion: An early ASCT in newly diagnosed MM patients receiving novel agents for induction resulted in an improved OS but not PFS. Patients who are responding well to their first line treatment may have equivalent PFS regardless of time to ASCT. Patients who have had ≥ 2 lines of treatment and underwent ASCT within 12 months had significantly improved PFS compared to those who received ≥ 2 lines of treatment but were transplanted later. Therefore, patients who have not responded to their first line regimen and are within 12 months of diagnosis may have the greatest benefit from ASCT. An extended analysis will be presented at the meeting. A multicenter randomized study comparing early vs. late transplant is underway. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

BACKGROUND Overall survival for adolescent and young adult (AYA) cancer population, ages 15 to 39 years, demonstrated minimal improvement during the last several decades. Potential factors influencing inferior outcomes within this group include the complex biology of AYA cancers, lower rates of clinical trial enrollment, the significant toxicities caused by therapies, and unmet psychosocial needs. AYA patients can often be treated in either pediatric or adult institutions. The type of institution where they receive treatment is influenced by age, type of cancer, and distance from a pediatric oncology center. There are concerns that differences in care between pediatric and adult treatment settings are influencing the slow progress in improving outcomes. Acute care utilization might reflect the burden of toxicities and access to care, which might vary based on treatment setting. There is limited research suggesting that AYAs treated at pediatric institutes are more likely to be enrolled in clinical trials. The AYA population also has challenging psychosocial needs and it is unknown if there is a difference in how those needs are addressed in different treatment settings. The objective of this study was to examine whether there are differences in clinical trial enrollment, acute care utilization, and psychosocial support between AYA oncology patients treated at a pediatric versus an adult facility. Our hypothesis was that AYAs treated at a pediatric facility will have increased enrollment in clinical trials, less acute care utilization, and more psychosocial referrals compared to AYAs treated at an adult facility. METHODS We conducted a retrospective cohort study of patients ages of 15 to 39 years who were diagnosed with a hematologic malignancy (acute lymphoblastic leukemia (ALL), acute myelocytic leukemia (AML), Hodgkin lymphoma (HL) and Non-Hodgkin Lymphoma (NHL)) and were cared for at a pediatric or adult facility during the years 2013-2017. The primary health outcomes examined were acute care utilization and psychosocial resources utilized, based on a patient's exposure time (defined as one year from diagnosis or 1 month after completion of therapy, whichever came first). Data were analyzed using SAS 9.4. To compare the health outcomes between patients treated at the two facilities, the Chi-square test or Fisher's exact test was used for categorical variables. For continuous variables, due to the skewness of the data, a log transformation was applied to the length of stay (LOS) variable, and then the Student's t-test was used. The Mann-Whitney test was used for the other continuous variables. This study was approved by the Children's Hospital of Wisconsin Institutional Review Board. RESULTS A total of 196 patients were treated as either newly diagnosed or relapse/progressive patients who received care at the pediatric or adult treatment facilities. Leukemia patients treated at a pediatric facility were more likely to be enrolled on a clinical trial than patients treated at an adult facility (84% vs 22%, p<0.0001). There was no statistically significant difference in enrollment in clinical trials for lymphoma patients at both treatment facilities (4% vs 8%, p=0.68) as shown in Table 1. There was no significant difference in acute care utilization for ED visits or inpatient hospitalizations for all diagnoses for the pediatric and adult facilities. Both ALL and HL patients had more ICU admissions per month at the pediatric facility compared to the adult facility (ALL: mean 0.25 vs 0.05, p=0.021; HL: mean 0.03 vs 0, p=0.0027). ALL and HL patients had longer hospitalization LOS at the adult facility (ALL p=0.020, HL p=0.014) There were more referrals for psychology, social work or case management and palliative care in the pediatric versus adult facility (p<0.0001, p=0.011, p<0.0001, respectively). CONCLUSION For AYA patients treated at a pediatric institute, leukemia patients have higher rates of clinical trial enrollment and all patients receive more psychosocial support compared to AYA patients treated at an adult institute. There was no difference in acute care utilization for ED visits or hospitalizations between patients treated at a pediatric or an adult facility. Patients with ALL and HL have more ICU admissions but overall shorter hospital LOS at the pediatric institution. Further work to determine the impact of these findings on the long-term outcomes and survival of AYA patients is needed. Disclosures Panepinto: NIH: Research Funding.

Background:Fatigue is commonly described in chronic illnesses, especially auto-immune disorders such as systemic lupus erythematosus (SLE).Objectives:We aim to study the prevalence of fatigue in SLE patients with NP symptoms and compare fatigue in SLE patients with NP symptoms attributed to major organ involvement due to SLE (NPSLE) with SLE patients with NP symptoms not caused by major nervous system involvement (non-NPSLE).Methods:All patients visiting the tertiary referral center for NPSLE in the LUMC between 2007-2019 with the clinical diagnosis of SLE and age >18 years that signed informed consent were included in this study. Patients underwent a standardized multidisciplinary assessment, including two questionnaires: SF-36 (2007-2019) and multidimensional fatigue index (MFI, 2011-2019). Patients were classified as NPSLE in this study if NP symptoms were attributed to SLE and immunosuppressive or anticoagulant therapy was initiated, otherwise patients were classified as non-NPSLE. The vitality (VT) domain of the SF-36 domain was used to assess fatigue, which generates a score from 0-100, 100 representing the complete absence of fatigue. Patients with a score more than 1 standard deviation (SD) removed from age-related controls of the Dutch general population were classified as fatigued; patients more than 2 SD removed were classified as extremely fatigued1. The MFI was also used, which consists of 5 subdomain scores between 0-20, leading to a total score between 0-100, 100 representing the most extreme fatigue. All scores are presented as mean and standard deviation.Results:373 patients fulfilled the inclusion criteria and SF-36 questionnaires of 328 patients were available (88%). The majority of these patients was female (87%) and 98 were classified as NPSLE (30%). In NPSLE patients, average age was 41 ± 13 years and in non-NPSLE the average age was 45 ± 14 years. The average score of the SF-36 vitality domain was 36.0 ± 20.7 in NPSLE vs 33.9 ± 18.8. in non-NPSLE. Overall, 73.5% of the patients were fatigued and 46.9% extremely fatigued in NPSLE vs 77.8% fatigued and 45.7% extremely fatigued in non-NPSLE.The MFI questionnaire and VAS score were available for 222 patients, of which 65 patients were classified as NPSLE (29.3%). Table 1 depicts the scores of NPSLE and non-NPSLE patients on the MFI subdomains and the VAS score.Table.Patient characteristics at registry entry.NPSLE(N = 65)Non-NPSLE (N = 157)MFI(mean, sd)General Fatigue10.8 (1.8)11.1 (1.5)Physical Fatigue11.4 (2.4)12.3 (1.9)Reduced Activity9.6 (2.9)10.7 (2.2)Reduced Motivation10.7 (2.6)11.1 (1.9)Mental Fatigue9.5 (3.0)9.8 (2.7)Total score51.8 (9.9)54.9 (6.9)SF-36 Vitality (mean, sd)35 (20.7)32.7 (18.2)Conclusion:Nearly half of patients with SLE and NP symptoms are as extremely fatigued as only 2.5% of the general Dutch population. Extreme fatigue is not influenced by major nervous system involvement.References:[1]Aaronsonet al.J Clin Epidemiol. Vol. 51, No. 11, pp. 1055–1068, 1998Disclosure of Interests:Rory Monahan: None declared, Rolf Fronczek: None declared, Jeroen Eikenboom: None declared, Huub Middelkoop: None declared, L.J.J. Beaart- van de Voorde: None declared, Gisela Terwindt: None declared, Nic van der Wee: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Margreet Kloppenburg: None declared, G.M. Steup-Beekman: None declared

Abstract Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p<0.001 compared to historical rate of 40%). Twenty-five (37%) had a matched related donor, 31 (45%) had a matched unrelated donor, 3 (4%) had a mismatched related donor, 8 (12%) had a mismatched unrelated donor, and 1 (1%) received an umbilical cord blood transplant. Sixty-six high-risk patients transplanted in CR/CRi have detailed data. Median time to HCT from CR1 was 76 days (range, 20-365). Fifty-seven patients (86%) received a myeloablative regimen and 9 (14%) reduced-intensity conditioning. Reasons for 39 high-risk CR1 patients not receiving a transplant in CR1 were: co-morbidities (n=1), death (n=6), no insurance (n=1), no donor (n=1), physician decision (n=3), patient decision (n=3), relapse (n=6), other (n=10), or unknown (n=8). The 2-year RFS estimate in the entire high-risk cohort is 32%, significantly higher than the 22% historical rate (p=0.05). Median RFS in the high-risk CR1 cohort (n=107) was 10 months [range, 1-32* (censored) months]. RFS and OS were similar among HCT patients using matched related [1 year estimates: 40% (95% CI 27%, 74%) and 56% (37%, 74%), respectively] and matched unrelated [1 year estimates: 52% (37%, 75%) and 56% (37%, 74%), respectively] donors in CR1. The HR (reference = unrelated) for RFS was 0.67 (0.32, 1.37) and for OS was 0.88 (0.41, 1.90). Median overall survival (OS) among all patients in the high-risk cohort (n=159) was 12 months [range, 1-33* (censored) months] and was 18 months [range 3-33* (censored) months] for those transplanted in CR1 (Fig. 1). Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Figure 1 Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Figure 1. Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients. We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger (&lt;65yo, n=25) patients. Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure). We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients (&lt;65yo, n=25) who received a CAR T. Baseline characteristics were similar among the two groups including: KPS, the prevalence of functional impairment, prior fall, and weight loss, and pre-treatment tumor burden measured by LDH (Table). The older group had more females (p&lt;0.001) and higher comorbidity burden measured by DCI/CCI (p=0.04) (Table). Numerically more younger patients (84%) received axicabtagene ciloleucel compared to tisagenlecleucel versus older patients (63%; p=0.11). Importantly, the two groups had similar incidences of cytokine release syndrome (CRS) and neurotoxicity (NT) of all grades (Table). We also examined the incidence of grade 3-4 hematologic and non-hematologic toxicities by CTCAE v5.0 and found that numerically, older patients appeared to have less infection and cytopenia, and more metabolic and other toxicities (Table). In addition, the rate of Intensive Care Unit admission was similar. At the time of last follow-up, we observed only 1 treatment-related death, a 69-year-old female with a history of prior allogeneic hematopoietic cell transplantation who died of influenza pneumonia 129 days after CAR T infusion. Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Kite: Consultancy. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Santomasso:Kite/Gilead: Consultancy; Novartis: Consultancy; Juno/Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyte/Gilead: Research Funding; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The ALPS Clinic at NIH has studied autoimmune lymphoproliferative disorders for over 30 years elucidating the genetic underpinnings and natural history of Autoimmune Lymphoproliferative Syndrome (ALPS) due to FAS gene defects (Blood 2014). Over the years, we continue to receive and work-up numerous referrals for diseases that masquerade like ALPS-FAS, presenting with multi-lineage cytopenias due to autoimmune peripheral destruction and splenic sequestration in the setting of non-malignant lymphoproliferation. In a review of 259 cases evaluated by our team, there were 150 ALPS-FAS, 54 Activated PI3K-delta Syndrome (APDS), 31 CTLA-4 Haploinsufficiency (CTLA4), 7 LRBA deficiency (LRBA), and 17 MAGT-1 deficiency (XMEN) patients. Non-malignant lymphadenopathy and splenomegaly occurred on average in 83% and 71% of all patients, respectively. Anemia, thrombocytopenia, and neutropenia were seen in 65%, 58%, and 46%, respectively. Thus, autoimmune cytopenias in the setting of non-malignant lymphoproliferation in themselves are not adequate to rule in or rule out a presumptive diagnosis of ALPS-FAS. Timely and accurate genetic diagnosis of ALPS-like conditions will improve the morbidity and mortality associated with these disease processes. Rapamycin, an m-TOR inhibitor provides salutary benefits for many of these conditions by restoring the TREG function and reversing immune-dysregulation. For example, in addition to lymphadenopathy and splenomegaly associated with an increased risk of malignant lymphoma like ALPS-FAS patients, APDS patients usually present with recurrent sinopulmonary and ear infections. Their serum IgM tends to be elevated with low IgG levels. Unlike for ALPS-FAS patients, a potential targeted treatment for APDS exists: Leniolisib, a targeted PI3Kinase p-110 delta inhibitor is currently undergoing clinical trials (Blood 2016). CTLA-4 is critical for T-cell activation and immune check-point regulation by tempering regulatory T cell function. Patients affected by CTLA4 and LRBA variants present with symptoms of lymphocytic infiltration of the bone marrow (often leading to hypoplastic anemia), gut (colitis, bowel obstruction), lungs (bronchiectasis, restrictive airway disease), and central nervous system (seizures and neurological deficits due to brain and spinal cord lesions). They also tend to have B cell lymphopenia, low IgG and IgM levels. CTLA4 and LRBA patients share pathophysiology as well as clinical phenotype because LRBA gene regulates intracellular lysosomal trafficking and recycling of CTLA-4 protein. Hence CTLA-4 haploinsufficiency or LRBA deficiency renders both patient types CTLA-4 deficient. This can be directly addressed with abatacept infusions, a CTLA-4 hybridized immunoglobulin given as a combination immunosuppressive therapy with rapamycin. Abatacept replaces the CTLA-4 molecule and reverses some of the immune dysregulation and thus morbidity associated with both CTLA4 and LRBA deficiency. Like APDS patients, XMEN patients are also prone to recurrent ear and sinopulmonary infection, but key differentiating features of this X-linked disorder are that only males are affected, these patients are unable to clear Epstein-Barr virus (EBV) once exposed, and they have a propensity to develop EBV-driven lymphomas. These patients also usually have a strong family history of multiple lymphomas in males. Even though a targeted treatment does not yet exist, steroid-sparing measures such as rituximab, rapamycin and mycophenolate mofetil are the first-line treatments often used in managing their refractory autoimmune cytopenias. Hence accurate early genetic diagnosis is key to accessing the appropriate treatment, thus decreasing the morbidity and mortality associated with these childhood onset ALPS-like rare inherited disorders (table). Table Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Rapamycin, Abatacept, Mycophenolate Mofetil.

Abstract Abstract 2394 Background: Treatment of AL amyloidosis with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) results in hematologic complete response (CR) in 40% of patients and a median survival of about 5 years. Hematologic CR is associated with improved organ function and long survival. Whether patients who fail to achieve CR have any benefit from HDM/SCT has not been examined in a large series of patients. OBJECTIVE: The aim of this study was to investigate the outcome of patients with AL who do not achieve a CR after HDM/SCT and assess the transplant-related mortality (TRM) at a single specialized referral center. DESIGN and PATIENTS: Retrospective analysis of 421 patients with AL amyloidosis treated with HDM/SCT (100 to 200 mg/m2) in the Amyloid Treatment and Research Program at Boston Medical Center between July 1994 and December 2008. The subgroup of patients who did not achieve a CR at 1 year after transplant was analyzed in detail to assess their outcome in terms of organ response, event-free survival (EFS) and overall survival (OS). The median follow-up was 4 years (range, 0 to 15.6) for the entire cohort and 6.3 years (range, 1 to 15.6 years) for surviving patients. RESULTS: Three hundred and forty patients out of 421 included in the study (81%) were evaluable for response at 1 year post-HDM/SCT. The CR rate among the 1-year survivors was 43% while 195 patients (57%) did not achieve a CR, defined as disappearance of all signs of monoclonal gammopathy and bone marrow plasmacytosis. By consensus criteria, organ response rate in the non-CR group was 53.3%, compared to 78.6% for CR-patients (p<0.0001). Hematologic and/or clinical progression was observed in 68% (133/195) of non-CR patients, with a median time to progression of 1.5 years (range, 0.13 to 11.3). More than half of these patients (68/133) received second line therapy with melphalan (4), thalidomide (21), bortezomib (8), lenalidomide (24), dexamethasone (8), a second HDM/SCT (2), and a reduced-intensity allogeneic SCT (1). Fifty (26%) of the non-CR patients are alive and clinically stable, although 12 of them received further treatment due to persistence of clonal disease without evidence of clinical/organ progression. Median EFS in the non-CR population was 2 years (CI95% 1.6–2.7), as compared with 8.3 years for patients in CR (p<0.0001). Outcome of non-CR patients in terms of event rate and EFS was not influenced by the light chain isotype. The OS was significantly longer for evaluable patients who achieved a CR compared with those who did not (13.2 versus 5.9 years, p<0.0001). The estimated probability of survival for patients in CR was 86% (CI95% 79–91%) at 5 years and 67% (CI95% 57–76%) at 10 years, while it was 58% (CI95% 50–65%) and 24% (CI95% 16–32%) at 5 and 10 years, respectively, for those who did not achieve CR. At the time of this analysis, 234 (55.5%) of the 421 patients have died, 81 (19.2%) of them within the first year after HDM/SCT. Transplant-related mortality was 11.4%, decreasing to 5.6% for the 124 patients who received HDM/SCT in the last 5 years, despite the fact that the patients' clinical characteristics were similar in the two time periods. CONCLUSIONS: Treatment of selected AL patients with HDM/SCT resulted in durable hematological responses, high organ response rate and a median OS of almost 6 years even in those who do not achieve a CR after HDM/SCT. Supported by NIH HL-68705 and Instituto de Salud Carlos III (grant CM07/00108). Disclosures: Sanchorawala: Celgene corp: Research Funding.

Abstract Translocation of 8;21 (q22;q22), generating a fusion of RUNX1 and AML1 genes is considered leukemia-defining and typically presents as an unequivocal acute myeloid leukemia (AML) with peripheral blood blasts and a hypercellular marrow, although it has been reported in patients with Fanconi anemia and myelodysplastic syndrome (MDS) (Quentin S et al. Blood 2011 Apr 14;117(15)). Aplastic anemia is a rare disease characterized by severe pancytopenia and a hypocellular marrow. A few cytogenetic abnormalities, namely trisomy 8 and monosomy 7, are associated with particularly refractory aplastic anemia, and monosomy 7 is associated with clonal evolution to MDS and rapid progression to AML. We describe a case of newly-acquired severe aplastic anemia in a 23 year old woman. Laboratory studies at presentation showed white blood cells 1.38 k/uL, absolute neutrophil count 0 k/uL, hemoglobin 7.4 g/dL, absolute reticulocyte count 5 k/uL, and platelets 38 k/uL. Bone marrow biopsy was 5% cellular with trilineage hematopoiesis and absolutely no dysplasia, even on repeated review. Initial cytogenetic analysis performed outside the NIH at presentation was normal. The patient was transferred to our institution and promptly received standard immunosuppressive therapy given the severity of neutropenia. However, a repeat bone marrow analysis performed immediately prior to immunosuppression showed t(8:21) (q22;q22) by standard cytogenetics in 3 out of 20 metaphases, with confirmation by fluorescence in situ hybridization (FISH). Blasts were not identified despite multiple repeat bone marrow aspirations utilizing immunohistochemistry and flow cytometry. Testing for Fanconi anemia was negative and leukocyte telomere length was normal for age. She remained severely pancytopenic and transfusion dependent for many months. Chemotherapy for AML was withheld given the severe pancytopenia and absence of blasts, and a search for a bone marrow transplant donor was initiated. Progression to frank leukemia with circulating blasts occurred 8 months following initial presentation, just prior to unrelated donor allogeneic stem cell transplantation. To our knowledge, this is the first reported case of acquired severe aplastic anemia, profound marrow hypocellularity, hypocellular MDS or hypocellular AML occurring in association with the t(8;21)(q22;q22). This unusual case prompted us to perform comparative genomic hybridization (CGH) using the single nucleotide polymorphism (SNP) based CytoScan high density microarrays on DNA from the patient’s bone marrow mononuclear cells. We detected multiple, large regions of copy neutral loss of heterozygosity (also referred to as uniparental disomy) in the patient’s marrow, ranging in size from 3 to 29 Mbp on multiple chromosomes. We hypothesized that the copy-neutral loss of heterozygosity observed in this case would not be present in other patients with acquired aplastic anemia at diagnosis or in normal controls. CGH did not demonstrate any large regions of copy neutral loss of heterozygosity in 10 patients with acquired severe aplastic anemia and normal cytogenetics at diagnosis, nor in 35 healthy controls. Emerging data show that SNP arrays can detect abundant copy neutral loss of heterozygosity amongst select hematologic malignancies and are associated with the duplication of oncogenic mutations. In our patient, copy neutral loss of heterozygosity possibly provided a second lesion, in addition to the RUNX1/AML1 abnormality, that facilitated initiation or progression to leukemia. These results suggest SNP based CGH arrays may be useful in distinguishing hypocellular AML from aplastic anemia and further studies utilizing this technology are warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction In children with sickle cell disease (SCD), asthma is a common comorbidity and is associated with increased disease severity when compared to children with SCD without asthma. Other pulmonary conditions, such as obstructive sleep apnea (OSA), are also more common in SCD and adversely affect clinical outcomes. Despite the well-established burden of pulmonary disease in children with SCD, optimal treatment paradigms are not well defined. Methods An integrated pediatric SCD and pulmonary clinic guided by the chronic care model was implemented at the University of Florida in July 2017 with the goal of coordinating subspecialty care and improving the treatment of concomitant pulmonary conditions. Prior to the formation of this clinic (pre-intervention phase), patients were managed separately by pulmonologists and hematologists in a tertiary academic medical center. During the intervention phase, patients received care in an interdisciplinary clinic composed of a pediatric pulmonologist, a pediatric hematologist with expertise in SCD, a respiratory therapist with access to an onsite pulmonary function testing (PFT) laboratory, asthma educator, and a SCD nurse educator/clinic coordinator. The objective of this abstract is to evaluate preliminary clinical outcomes of the integrated SCD-pulmonary clinic during the intervention phase (July 2017-June 2018) compared to 24 months prior to implementation (July 2015-June 2017). We hypothesized an integrated clinic model would improve access to specialized pulmonary care for children with SCD and reduce hospitalizations for vaso-occlusive episodes (VOEs). The primary endpoints are adherence to pulmonary clinic appointments and unplanned acute healthcare utilization for SCD-related complications and/or asthma exacerbations. Secondary endpoints are the number of unplanned packed red blood cell (PRBC) transfusions, percentage of patients able to complete PFTs, and new diagnoses or prescribed treatments during the intervention phase. Results During the intervention phase, 24 unique patients accounted for 40 clinic visits. Reasons for referral to the integrated SCD-pulmonary clinic included asthma (16), a history of severe and/or recurrent acute chest syndrome (12), OSA (3), hypoxia (1), shortness of breath (1), and concern for pulmonary hypertension (1). The mean age of participants was 10 years (range 2-18 years); 79% were male, 22 had hemoglobin (Hb) SS disease, 16 (67%) were being treated with hydroxyurea, and 2 were on chronic transfusion therapy. Mean baseline Hb and reticulocyte count were 9.1 gm/dL (SD 1.2) and 8.5% (SD 4.5), respectively. PFTs were successfully completed in 21 (88%) patients and reported as pre-treatment percent predicted values after adjusting for age, gender, height, and race. Mean forced expiratory volume in 1 second (FEV1) was 90% (SD 12.5), forced vital capacity (FVC) 94% (SD 12), and diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for Hb was 103% (SD 26, measured in 12 patients). Mean duration of follow-up was 8 months (range 1-12 months). During the pre-intervention phase, this cohort accounted for 76 hospitalizations, 42 emergency department (ED) visits, 31 transfusions, and 26 missed pulmonary appointments. During the intervention phase, there were 9 hospitalizations, 7 ED visits, 3 transfusions, and 5 missed appointments. This represents an 86% reduction in unplanned acute healthcare utilization (mean difference (MD) 2.8, 95% CI 1.8-3.7; p<0.0001), a 90% reduction in PRBC transfusions (MD 1.9, 95% CI 0.96-2.78; p<0.001), and an 81% increase in adherence to pulmonary appointments (MD 1.3, 95% CI 0.71-1.92; p<0.001). Twenty-two patients had a confirmed asthma diagnosis, and 8 were diagnosed with OSA. Interventions included personalized asthma action plans (22 patients), inhaled corticosteroids (16), supplemental oxygen during sleep (5), tonsillectomy and adenoidectomy (2), and the initiation of hydroxyurea (1). Conclusions These results demonstrate that interdisciplinary clinics can improve access to subspecialty pulmonary care for children with SCD and support the continued development and implementation of integrated care models. With limited follow-up, the results also suggest integrated SCD and pulmonary care can reduce hospitalizations and ED visits for VOEs, though additional follow-up is required to determine the true treatment effect. Disclosures Black: Bioverativ: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Pfizer: Research Funding; Sancilio Pharmaceuticals: Research Funding; Prolong Pharmaceuticals: Consultancy.

Abstract Background. Even though remarkable progress has been made in the treatment of childhood acute lymphoblastic leukemia (ALL), salvage of relapse patients remains a challenge. The role of the bone marrow (BM) microenvironment is critical to protect leukemia cells from chemotherapy. The BM microenvironment promotes cell adhesion-mediated drug resistance (CAM-DR) in ALL.We and others have shown that the adhesion molecule integrin α4, referred to hereafter as α4, mediates drug resistance of B-ALL. In our previous studies, we showed that both α4 blockade by natalizumab and inhibition by the small molecule α4 antagonist TBC3486 can sensitize relapsed ALL cells to chemotherapy. However, no α4 targeting therapy is currently clinically available to treat leukemia. Here, we preclinically evaluate a novel non-peptidic small molecule antagonist, AVA4746, which has been safely used in clinical studies, as a potential new approach to combat drug resistant ALL. Method. Six refractory or relapsed primary pre-B ALL cases were used for in vitro studies. Viability was assessed by trypan blue counts or annexin V/7AAD flow cytometric analysis and metabolic activity was evaluated by Cytoscan WST-1 assay. For in vivo evaluation a NOD/SCID IL2Rγ-/- xenograft model of primary pre-B ALL (LAX7R) was used.AVA4746 (15mg/kg) was administered by oral gavage twice a day continuously for 14 days, and vincristine, dexamethasone, L-asparaginase (VDL) was given intraperitoneally (weekly) for 4 weeks. Overall survival was determined by Kaplan-Meier Survival analysis. Results. AVA4746 caused a significant decrease in mean fluorescence intensity (MFI) of α4 expression in six out of six ALL cases at doses of both 5μM and 25μM after 24 hours and 96 hours compared to DMSO control. Interestingly, decreased protein expression of α4 was also observed by Western Blot analysis all six ALL cases. We tested next in two cases (LAX53, ICN13), if AVA4746 de-adheres ALL cells from its counter receptor VCAM-1. The percentages of adherence after treatment with AVA4746 (25μM) were significantly lower than after DMSO treatment (10.3%±4.9% vs. 99.9%±7.6%, p= 0.00007 for LAX7R; 8.1%±1.0% vs. 100.1%±13.6%, p= 0.0003 for LAX53; 9.0%±1.6% vs. 100.0%±14.0%, p=0.0004 for ICN13). AVA4746 was not associated with apoptosis in vitro alone or in combination with chemotherapy (VDL). Metabolic activity as assessed by WST-1 assay was markedly decreased by AVA4746 in two of two ALL cases. AVA4746 also decreased ALL proliferation in two out of two ALL samples tested. In vivo, AVA4746 in combination with VDL chemotherapy treatment led to significant prolongation of overall survival (n=6) compared with the VDL only treated group (n=6) (MST= 78.5 days vs MST= 68 days; P<0.05). There was no significant difference in survival between the PBS control group (n=5) and the AVA4746 mono-treatment group (n=5) (MST=38days vs MST= 38days). Conclusion. We have identified α4 as a central adhesion molecule in CAM-DR of ALL and have shown that AVA-4746, an orally available and specific α4 antagonist, which has been safely used in clinical studies, downregulates α4 in primary ALL and functionally de-adheres them from VCAM-1. Critically, we demonstrated that inhibition of α4 in combination with standard chemotherapy can prolong the survival of NSG mice bearing pre-B ALL. These data support further study of inhibition of α4 using AVA4746 as a novel strategy to treat drug resistant B lineage ALL. Disclosures Bhojwani: Amgen: Other: Blinatumumab global pediatric advisory board 2015. Wayne:Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Kite Pharma: Honoraria, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties. Kim:Antisense Therapeutics Ltd: Patents & Royalties.

Abstract Abstract 5080 BACKGROUND Anemia in the elderly is common, and associated with substantial morbidity and even mortality. Approximately one third of patients with anemia will have no discernable etiology for their anemia, that is, so-called unexplained or idiopathic anemia of aging. Prior reports have suggested that 5-15% of elderly patients with anemia will have an underlying myelodysplastic syndrome (MDS). The purpose of this study was to prospectively evaluate a cohort of elderly outpatients for underlying causes of anemia. METHODS Men and women 65 years and older with anemia as defined by World Health Organization (WHO) criteria and seen either at Stanford Hospital and Clinics (SHC) or VA Palo Alto Health Care Systems (VAPAHCS) underwent a comprehensive hematologic evaluation to determine the etiology of the anemia. Assessment included a complete blood count, red cell indices, review of the peripheral smear, and evaluation of iron and cobalamin status and renal function. Patients were categorized as having MDS if diagnosed by WHO criteria. If a bone marrow evaluation was not performed or was nondiagnostic, patients were categorized as “suspicious for MDS” if the MCV was > 100 fl without an alternate explanation, the platelet count was < 130 K/αL, the WBC was < 4 K/αL, or there was dysplasia on the peripheral smear. If no etiology was found, patients were categorized as having “unexplained anemia” of aging. RESULTS A total of 196 patients have enrolled, and 156 have completed their diagnostic evaluation to date. Of these 156, 52 (33%) had unexplained anemia, 33 (21%) were found to have anemia related to a definite or suspected underlying hematologic malignancy, 24 (15%) had anemia related to a nonhematologic malignancy, 20 (13%) had previously unrecognized iron deficiency anemia, and 8 (5%) had anemia due to renal insufficiency. Additional etiologies included anemia of chronic inflammation (5 patients), thalassemia (2 patients), alcohol abuse (1 patient), B12 deficiency (1 patient), hypogonadism (1 patient), other (2 patients). In 7 patients (4%) the evaluation was not complete. Of those categorized with anemia related to an underlying hematologic malignancy, 12 of 33 (36%) were given a formal diagnosis, including acute myeloid leukemia, chronic myelomonocytic leukemia, Waldenstrom's, and, in 8 patients, MDS. An additional 21 of 33 (64%) were categorized as being “suspicious for MDS”. One patient initially categorized as being “suspicious for MDS” developed worsening cytopenias and underwent bone marrow evaluation which confirmed the diagnosis of MDS. Those suspected but not confirmed to have MDS had a median WBC of 4.9 K/αL, median hemoglobin (hgb) of 10.8 g/dL, median platelets of 170 K/αL, median mean corpuscular volume (MCV) of 96 fL, and median red cell distribution width (RDW) of 14%. In comparison, those confirmed to have MDS had a similar median WBC of 5.3 K/αL, lower median hgb of 10.3 g/dL, similar median platelet count of 199 K/αL, higher median MCV of 106.3 fL,and broader median RDW of 17%. Of the 20 patients with iron deficiency anemia, the diagnosis was made by standard laboratory iron indices in 14 (70%), by response to iron supplementation in 3 (15%), and by bone marrow aspirate and clinical diagnosis, respectively, in 1 patient (5%) each. Six of the 20 (30%) patients normalized their hgb following iron repletion, 5(25%) increased the hgb by at least one g/dL but did not reach a normal hgb level, and in 9 (45%) this information was not available. DISCUSSION In our study of elderly community-dwelling patients referred to an outpatient hematology clinic, 8% of patients were formally diagnosed with an underlying hematologic malignancy, and 13% were suspected to have MDS based on a high MCV, dysplasia on the peripheral smear, or additional cytopenias. Thus, overall, 21% were likely to have an underlying hematologic malignancy. Of the patients suspected to have MDS, none required specific therapy. Thirteen percent of patients were diagnosed with iron deficiency anemia, primarily by iron indices. A high proportion (25%) of these patients did not normalize their hemoglobin with iron repletion, suggesting additional underlying disease processes. The clinical advantage of recognizing that iron deficiency has been corrected is that further potentially expensive and invasive evaluation such as additional endoscopy can be avoided. Disclosures Price: NIH: Research Funding. Mehra:NIH: Research Funding. Schrier:NIH: Research Funding.

Abstract Abstract 743 Background: Acute Graft versus host disease (aGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Conventional treatment with high dose steroids fails to achieve a complete and sustained response in more than 50% of patients. Several second line treatments have been described but none of these can be considered superior or a standard of care (Paul J. Martin et al, BBMT 2012). Among these treatments, the use of third party mesenchymal stromal cells (MSC) has been proposed (LeBlanc et al, Lancet 2008). In this study, we assessed the safety and efficacy of third party human MSC, in a prospective, multicenter, phase I study (EudraCT 2008–007869-23). Methods: Forty-seven patients with steroid-resistant, acute or chronic grade II-IV GvHD were enrolled into this study. Human MSC were obtained from bone marrow harvests of healthy donors and expanded in vitro using serum free medium supplemented with human platelet lysate (Capelli C et al, BMT, 2007; Capelli C. et al, Cytotherapy 2009). In vitro expanded MSC were produced in two officially authorized Cell Factories and tested in four Italian Hematology Units. The primary endpoint of this study was the safety. Secondary endpoints were the response of GvHD (evaluated 28 days after the last MSC infusion), as well as the overall survival and transplant-related deaths. Blood samples were periodically collected before and after MSC infusion to measure plasma levels of IL2Ralpha by ELISA, as previously described by our group (Dander E et al, Leukemia 2012). Results: Between August 2009, and June 2012, 47 patients (16 children, 31 adults, median age 25.5 years, range 1 to 67) were treated. The median dose of infused MSC was 1.5×106 cells per kg bodyweight. Enrolled patients presented with aGvHD in 37 cases, chronic overlap syndrome in 7 cases, and chronic classic GvHD in 3 cases. Fifteen pts had grade II GvHD, 23 grade III and 9 grade IV, according to NIH criteria. In 17 cases GvHD involved a single organ, in 24 cases 2, and in 6 cases 3 organs. Prior to MSC infusion 22 patients had received only high dose steroids, 12 patients received one cycle of pentostatin (1 mg/kg bodyweight for 3 days, Schmitt T. et al BMT, 2011: 46 580–585), while 13 received other conventional immunosuppressants. Patients received a median of 3 MSC infusions (range 1 to 8). No side effects were registered immediately after MSC infusion and no complications were lately referred as MSC-related. Overall, in 30 patients (63.8%) a clinical response of GvHD was registered. Thirteen of these patients (27.6%) had a complete response and 17 (36.1%) a partial response to treatment. Twenty-two of the 30 responding patients did not require further lines of immunosuppression after MSC infusion. Response was significantly more likely in patients exhibiting grade II GvHD versus those exhibiting more severe gradings (87.5% vs. 51.6%, p = 0.02) and in patients receiving MSC in a time interval of 30 days from the onset of GvHD (75.9% vs. 43.7%, p= 0.05). Current median follow up for this cohort is 200 days (range 30–1066). Responders show a significant lower transplant-related mortality (10.0% vs. 88.2%, p <0.05) and a better overall survival probability than non responders (23.3% vs. 88.2%, p <0.05, Fig. 1). Within the limit of a small subgroup analysis, adult patients receiving pentostatin before MSC had an apparent better response and survival (65% vs 27%, at 1 year), without an increased risk of infections. Measurements of plasmatic levels of IL2Ralpha, when comparing responders vs non-responders patients, showed a statistically significant difference in terms of fold decrease of the marker (p=0.027), corroborating clinical results. Similarly, a significant trend of fold decrease change (p=0.058) was observed when comparing responding patients receiving MSC within or after 30 days from the onset of the disease, in line with clinical results. Conclusions: This study confirms that human MSC prepared in academic cell therapy facilities may represent a safe and effective treatment of patients with steroid-refractory GvHD. Plasmatic inflammatory markers may help in evaluating and monitoring of clinical response. The sequential or combined administration of MSC and other immunosuppressants, such as pentostatin, is equally safe and feasible and deserves further investigation. We suggest to consider the use of MSC promptly, as early as possible, after steroid failure. Disclosures: No relevant conflicts of interest to declare.

The SARS-CoV-2 coronavirus (COVID-19) pandemic has precipitated an enormous collaborative global effort within the scientific and medical community in search of therapeutic and preventative solutions. The aim of this review is to collate the key developments regarding pharmacological treatments tested and vaccine candidates that have been approved to treat and arrest the spread of COVID-19. Introduction COVID-19 Transmission The COVID-19 outbreak has caused one of the most widespread and significant public health crises in decades. It has become one of the leading causes of death internationally. The primary route of transmission from person-to-person is from airborne aerosol spread through close physical contact, particularly in enclosed, poorly ventilated areas.(1) Transmission through contaminated objects was originally considered a major transmission contributor; however, it is no longer considered a significant driver of the spread. Wearing masks has shown to be effective at preventing or curtailing viral transmission, especially when combined with other measures like social distancing and depopulation of indoor communal spaces.(2) Mechanism of action: The mechanism of action and entry into human physiology at a cellular level has been described previously.(3) Briefly, the virus binds and enters the host cell through a spike protein expressed on its surface. The infection begins when the long protruding spike proteins that latches on to the angiotensin-converting enzyme 2 (ACE-2), a receptor involved in regulating blood pressure ACE-2 protein. From this point, the spike transforms, unfolding and refolding itself, using coiled spring-like parts that start out buried at the core of the spike. The reconfigured spike hooks and docks the virus particle to the host cell. This forms a channel allowing the viral genetic material into the unsuspecting cell, in the case of COVID-19, type II lung cells. From this point onwards, most of the damage caused by COVID-19 results from the immune system going into overdrive to stop the virus from spreading.(4) The influx of immune cells to the infected tissue causes severe damage in the process of cleaning out the virus, infected cells, and bacterial infections with potentially lethal consequences. Treatments Medical therapies to treat COVI-19 evolved rapidly. Treatments include drugs that were approved by the US Food and Drug Administration (FDA) and drugs made available under FDA emergency use authorizations (EUA). The Centers for Disease Control and Prevention (CDC) has strongly encouraged clinicians, patients, and their advocates to consult the treatment guidelines published by the National Institute of Health (NIH). These guidelines are based on scientific evidence and expert opinion.(5) Several therapeutic modalities have been tested and deployed to treat the disease, some of which are summarized here. Anti-virals: Antivirals are drugs that arrest the replication of the virus. They are generally considered most effective when administered in the early phase of infection. Remdesivir: To date, remdesivir is currently the only antiviral approved under EUA by the FDA to treat COVID-19. The approval was based on findings that hospitalized patients who receivedremdesivir recovered faster.(6)Remdesivir can be administered either alone or in combination with other medications. Molnupiravir: An antiviral drug, previously known as EIDD-2801, appears safe and effective. Viral levels reduce to undetectable levels in COVID-19 patients after five days of administration, according to data from a US-based Phase II clinical trial. While molnupiravir is proven to inhibit coronavirus replication in infected patients, more data is required to determine whether it can prevent severe illness.(7) Lopinavir/ritonavir: Lopinavir/ritonavir are anti-human immunodeficiency virus (HIV) drugs. Both have been investigated and neither drug showed any efficacy in large randomized controlled trials in hospitalized COVID-19 patients.(8) Anti-inflammatories: One reason for mortality in COVID-19 infected patients is an overactive response by the patient’s immune system. This response leads to several inflammatory disorders, not least of which is the much publicized “cytokine storm”. The following outlines agents have been tested to dampen the inflammatory response to COVID-19. Dexamethasone: Dexamethasone is an anti-inflammatory corticosteroid used for many years to treat autoimmune conditions and allergic reactions. It is cheap and widely available and has been shown to reduce mortality in the sickest hospitalized patients by dampening the immune response.(9) A meta-analysis study evaluating the results of seven trials shows the death rates were lower in hospitalized patients who took one of three different corticosteroids — dexamethasone, hydrocortisone, or methylprednisolone.(6) Baricitinib: Baricitinib is an anti-inflammatory drug used for the treatment of rheumatoid arthritis. In November 2020, the FDA issued an EUA to use baricitinib in combination with remdesivir in hospitalized adults and children two years and older requiring respiratory support. However, there is not enough evidence to support the use of this therapy with or without remdesivir.(10) Antibody Based Treatments: Antibodies are proteins generated by the immune system to help fight infections, such as viruses, by binding to and destroying them. Antibody-based treatments are likely most helpful soon after infection, rather than after the disease has progressed. Monoclonal antibodies: Monoclonal antibodies are synthesized in the laboratory. The FDA has approved two monoclonal antibody treatments, one single antibody from Eli Lilly, and a combination of two antibodies from Regeneron. The Eli Lilly antibody, Bamlanivimab (LY-CoV555), works by blocking COVID-19 from entering and infecting human cells. Preliminary results indicated that patients with mild-to-moderate COVID-19 who received bamlanivimab were less likely to be hospitalized. Studies are still underway, both as a monotherapy and combination therapy. Regeneron’s treatment utilizes a combination of two monoclonal antibodies, casirivimab and imdevimab (REGN-COV2), referred to as an antibody cocktail. Preliminary trial data reported that REGN-COV2 reduced viral load and relieved symptoms sooner in non-hospitalized patients. These treatments are available for patients under EUAs, but more data is required before becoming part of routine care.(6) Convalescent plasma: One of the first groups of antibody-based treatments used convalescent plasma (plasma from recovered COVID-19 patients). This treatment involves administering plasma from a recovered individual into someone infected with the virus. Theoretically, the antibodies fromthe recovered individual neutralize the virus in the infected individual. Although the FDA issued an EUA for convalescent plasma for hospitalized patients with COVID-19, the data to date has been conflicting and inconclusive.(6) Anti-coagulants: Because of the systemic nature of COVID-19 where the circulatory system supplies all parts of the body, some COVID-19 deaths are believed to be caused by blood clots forming in major arteries and veins. A recent study has reported that full-dose blood thinners decreased the need for life support and improved outcome in hospitalized COVID-19 patients. (11) This worldwide large clinical trial, where full dose treatments were administered to moderately ill patients hospitalized for COVID-19, reduced the requirement of vital organ support—such as the need for ventilators. In addition to some of the FDA approved drugs cited in the previous section, multiple treatments were investigated during the early phase of the COVID crisis, with varying results.(12) In contrast to the overall trials for COVID-19 treatments, the programs initiated for vaccine development have been incredibly successful, surpassing all expectations. Vaccines From the outset of the COVID-19 pandemic, vaccines ultimately offer the most appealing and robust therapeutic modality as they prevent the disease from taking hold. This has led to a global vaccine R&D effort that is unprecedented in terms of scale and delivery. The urgency to create a vaccine for COVID‑19 led to expedited schedules that compressed the standard vaccine development timeline from years to months. At the time of writing, three vaccines have been authorized for emergency use by the FDA in the US, with more likely to come onstream as they progress through the development pipeline. A fourth vaccine, from Oxford-AstraZeneca, has also been approved for distribution within the European Union (EU). The three vaccines approved in the US are highly effective at preventing hospitalization, death, and severe disease. Vaccines work by triggering an immune response that generate highly specific antibodies against an antigen, in the case of COVID-19, the virus spike protein expressed on the surface of the virus. Moreover, the immune system is taught to recognize the spike protein specific to the virus. If this spike protein is encountered in the future, an immune response is swiftly mounted, thus preventing escalation of the virus. Two of the authorized vaccines, developed by both Pfizer/BioNTech and Moderna, have revolutionized a technology referred to as messenger RNA (mRNA) technology. This technology acts as a delivery system to cells within our bodies with specific instructions to carry out a specific task.(13) Of importance: mRNA vaccines do not use live virus, but rather a portion of the message encoding for the spike protein. mRNA is produced by DNA, but does not enter the nucleus of the cell containing the DNA. Once the mRNA vaccine finishes producing the protein that is expressed on the cell surface, it is broken down and removed by normal cellular processes. The Johnson and Johnson (J&J) and Oxford-Astra Zeneca vaccines utilize a more conventional approach, referred to as a viral vector. This vaccine utilizes a harmless modified version of a common cold virus to deliver the gene encoding for the spike protein into the cell.(13) Vaccine comparison: Both the Pfizer/BioNTech and Moderna vaccines have been reported to confer over 94% protection rates against symptomatic COVID-19 infection.(14,15) The single shot J&J vaccine has shown to be 85% effective at protecting against severe disease, 66% against preventing moderate to severe disease, and also appears to be effective against the South African variant of the virus (B.1.351).(16) Although superficially the single shot J&J appears less effective, it is difficult to compare all three vaccines directly because of differences in trial design and outcomes. From a logistical point of view, the J&J vaccine is advantageous as it is a single-dose regimen that can be stored for up to three months in a refrigerator. The most recent data from the AstraZeneca phase three trial reports that the vaccine is 76% effective against symptomatic cases of the virus.(17) Several other trials are ongoing Several other trials are ongoing. The most important point from the information collected from 7 large efficacy trials is that all vaccines confer 100% protection against severe disease, hospitalizations, and death. Moreover, it is not just the vaccinated individual who benefits from vaccination. Most vaccines also reduce transmission of infection among people, and in so doing, help protect those who fail to mount an effective immune response to vaccines or who cannot receive the vaccinate because of their age or compromised immune system.(18) Vaccines and viral variants: Several variants of the virus have been reported, with the two properties causing the most concern being enhanced contagion and immune response evasion. The current vaccines were developed based on the spike protein before it contained the mutations identified in the variants. A recently published study investigated the effectiveness of the FDA approved Pfizer/BioNTech vaccine against the newly-emerged variants from the United Kingdom (UK) and South Africa (SA).(19) While both variants are deemed more transmissible, the levels of antibody generated in response to the vaccine are so high that it seems unlikely that it will impact the overall efficacy of the vaccine for these strains. This preliminary study also highlights the ongoing evolution of COVID-19, necessitating continuous monitoring of the significances of viral mutations for vaccine efficacy. While research suggests that COVID-19 vaccines have lower efficacy against the variants, and further research is needed, the vaccines appear to provide protection against severe COVID-19.(20) Vaccine manufacturing and distribution: The development of the vaccines, from basic R&D through human clinical trials, has been carried out within a very rapid time frame. Ramping up production, however, has been slow and cumbersome. After a slow start, Pfizer/BioNTech andModerna have raised output by gaining experience, scaling up production lines, and taking other steps like making certain raw materials on their own.(21) Of the three candidates, AstraZeneca has already struck a deal with COVAX, the global initiative to distribute COVID-19 vaccines equitably. Moderna has partnered with Lonza and Catalent Inc. to manufacture and distribute millions of doses.(22) Moreover, a recent agreement between J&J and Catalent has secured a US FDA emergency clearance that allows Catalent’s facility to manufacture and distribute, thus aiding the vaccination supply. Vaccination and reinfection: The first large scale study investigating whether reinfection can occur recently reported that the vast majority of people who had COVID-19 are protected from catching it again, for at least six months.(23) This Danish study found that protection against repeat COVID-19 infection is both robust and detectable in the majority of individuals, 80% or more of the naturally infected population younger than 65 years. However, individuals aged 65 years and older had less than 50% protection against repeat infection, since the older age group is more susceptible serious illness. Their finding highlights the need for continued vigilance to keep themselves and others safe. This also indicates that vaccination of previously infected individuals should be done because natural protection cannot be relied upon, consistent with the general consensus that vaccines confer a level of immune response that is higher than previous COVID-19 infection. Follow-up studies will give a better idea of the duration of vaccine protection. Conclusion As the COVID-19 pandemic has demonstrated, it is extremely difficult to eliminate a virus from the human population once it has entered. The pandemic spread has been compounded because the virus spreads asymptomatically. That said, the virus is manageable, similar to the manner in which vaccines have worked against other preventable communicable diseases. Monitoring the protective effects of the different vaccines will likely last for several years. For now, the outlook is positive as global cases decline, the vaccines roll out, and the momentum to investigate and repurpose drugs continues. Acknowledgments The author is grateful to Tara Finn for the careful reading of this manuscript. Conflict of interest There is no conflict of interest. References Coronavirus disease (COVID-19): How is it transmitted? Bai, N. Still Confused About Masks? Here’s the Science Behind How Face Masks PreventCoronavirus. Murphy, J.F. COVID-19: An Immunological Perspective. MOJ Immunol. 2020, 7(1), 10. Kupferschmidt K, Cohen J. Science. Race to find COVID-19 treatments accelerates. 2020. Information for Clinicians on Investigational Therapeutics for Patients with COVID-19Centers for Disease Control and Prevention. Tran, J. The Latest Research on COVID-19 Treatments and Medications in the Pipeline. Drug launched at Emory reduces virus that causes COVID-19 to undetectable levels. Group RC. Lopinavir-ritonavir in patients admitted to hospital with COVID-19(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. Baragona, S. Treating COVID-19 One Year In: Better, but No Breakthrough. Harvard Health Publishing. Treatments for COVID-19. NIH: National Institutes of Health. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. Lehrer, S., Rheinstein, P.H. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2. 2020. Murphy JF. COVID-19 mRNA vaccines. Baden, L.R. et al Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. 2021 Information about the Moderna COVID-19 Vaccine. 2021 Ledford, H. J&J’s single-dose COVID vaccine raises hopes for faster rollout. 2021 Cohen, J. AstraZeneca lowers efficacy claim for COVID-19 vaccine, a bit, after board's rebuke. 2021 Emanuel, E. Take whatever COVID vaccine you can get. All of them stop death and hospitalization. 2021 Xuping, X et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. 2021 COVID-19 vaccines: Get the facts 2021. Loftus P. Covid-19 Vaccine Manufacturing in U.S. Races Ahead. 2021. COVAX Announces additional deals to access promising COVID-19 vaccine candidates; plans global rollout starting Q1 2021. Hansen HH et al Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study.2021.

Bronchial-associated lymphoid tissue lymphoma (BALT) is a rare subtype of extranodal marginal zone lymphoma that is often diagnosed incidentally, without symptoms or compromise of pulmonary function. It usually progresses slowly . However, in contrast to other subtypes, oncologists may feel compelled to initiate treatment at the time of diagnosis, because of concern for progression resulting in irreversible lung damage. It is unclear, in many cases, whether the morbidity of treatment would be greater than that of the lymphoma itself. To address this issue, we compared patients with BALT initially managed expectantly to those receiving front-line treatment. A retrospective single institutional review of newly diagnosed primary BALT treated at Memorial Sloan Kettering Cancer Center between 1995 and 2017 was performed. Patients with evidence of extra-thoracic disease (except for isolated bone marrow involvement) and those with concurrent malignancy were excluded. Expectant management (active surveillance) was defined as a management plan of observation rather than treatment at diagnosis and at least 3 months of follow-up from completion of all diagnostic workup until initiation of subsequent therapy if necessary. Surgical Resection referred to complete resection of all disease lesions for diagnosis. Overall (OS) and event-free survival (EFS) were determined from diagnosis as time to treatment or death of any cause, among patients with surgical resection, active surveillance, and time-to-next treatment among those treated at diagnosis with systemic immuno/chemo-immunotherapy (systemic treatment). Medical records of 200 consecutive patients with MZL involving the lung were reviewed, and 127 met the criteria for primary BALT. Of the remaining 73 patients, 25 had concurrent malignancy and 48 had extra-thoracic disease. Nearly half (48%; n=61) had initial active surveillance, 40% (n=51) surgical resection, and 12% (n=15) systemic treatment at diagnosis. Median age was 65 years (IQR 54-74). Females predominated (64%, n=81). Rates of current or prior smoking (61%; n=78) and of autoimmune/connective tissue disease (20%; n=26) were high. Nearly half of the cases with concurrent cancers were primary carcinomas of the lung (n=11). Most patients presented with a single lesion (76%; n=96) with median size 2.5 cm (IQR 1.6-3.6) and without lobar predominance. A minority (5.5%; n=7) presented with thoracic nodal involvement, while 25% (n=32) presented with pleural involvement or effusion. Overall, few patients had bone marrow involvement, B symptoms, cytopenia or elevated LDH. With a median follow-up of over 60 months (IQR 25 - 107), estimated 6-year OS for the entire cohort was 92% (0.86, 0.98). Notably, high survival rates were found in all 3 groups (Figure 1). Estimated 6-year survivals were 88% (0.77,1.00) for patients with disease remaining after biopsy managed by active surveillance, 100% with initial complete diagnostic excision (surgical resection) and 78% (0.59, 1.00) for those with initial systemic treatment who likely had extensive initial disease and/or symptoms. Active surveillance patients had a shorter EFS than surgical resection patients but not than systemic treatment patients (6yEFS 63% vs. 74% vs. 57%, respectively; p=0.006). Estimated 6-year EFS (survival without treatment) of patients initially managed by active surveillance was 63% (95% CI 0.5-0.8), and 12% required only a single line of therapy (6yEFS2 85%; 95% CI 0.7-1.0). In conclusion, BALT is an indolent disease in most patients that can be managed expectantly and may not require therapy for many years. Slightly better survival in patients with fully resected disease could represent a selection bias of earlier detection or biologically less active disease. Initial observation of the pace of the disease in asymptomatic patients may clarify the minority who require treatment and avoid or delay its potential risks in the majority. Figure 1 Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Zelenetz:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palomba:STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Equity Ownership; Noble Insights: Consultancy; Merck & Co Inc.: Consultancy; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Portola: Consultancy; Trillium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Kura: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Astex: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding. Moskowitz:Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Matasar:GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Kumar:Seattle Genetics: Research Funding. von Keudell:Bayer: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Genentech: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Younes:Syndax: Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; Abbvie: Honoraria; HCM: Consultancy; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Genentech: Research Funding. Straus:Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees.

Background: The acute and lymphoma subtypes Human T-lymphotropic virus 1-associated adult T-cell leukemia/lymphoma (HTLV-1 ATLL) are frequently characterized by chemo-refractoriness, a generally aggressive clinical course, and poor outcomes. Despite progress in characterizing the disease biology and the development and implementation of newer agents such as mogamulizumab, survival remains poor, especially for patients with relapsed or refractory disease. Furthermore, besides these many challenges, there is a paucity of comprehensive published data in Western (i.e. non-Japanese) patients. Methods: In a retrospective analysis, we identified 109 patients with pathologically-confirmed ATLL evaluated at our institution since 2001. 11 were excluded due to lack of clinical follow-up. Patient, disease, and treatment information was extracted for analysis. The International Prognostic Index (IPI) and Prognostic Index for PTCL-U (PIT) were calculated at time of diagnosis. Response rate was calculated based on the best response (CR/PR) during induction, with response retrospectively assessed based on available data using Lugano criteria. Median survival was calculated using Kaplan-Meier analysis and follow-up using a reverse Kaplan-Meier method, with survival and follow-up as of July 2019 Results: Ninety eight patients were included in our cohort (Table 1); 46 patients (47%) received initial treatment at another institution. The most common ATLL subtypes were lymphoma (n=43, 44%) acute (n=39, 40%), and smoldering/chronic (n=16, 16%). The median age at diagnosis was 53 years (range 30-92) and the median duration of follow-up from diagnosis was 65 months (95% CI: 41 to 178). With a median follow-up in survivors of 41.2 months, 21 patients are alive. The most common cause of death was disease (69/77 patients, 90%). The median overall survival (OS) among all patients was 13.2 months (Figure 1; range 1.3-240). For acute/lymphoma subtype disease, most patients initially received EPOCH/CHOEP (54 patients), CHOP (18 patients), or BV-CHP (3 patients); practice patterns evolved since the late 2000's to include more etoposide and BV-CHP rather than CHOP. Among 76 patients with lymphoma/acute with reviewable restaging information, 30 (40%) achieved CR. For patients with active disease following induction, a variety of subsequent therapies were used, most commonly romidepsin and pralatrexate, each utilized in 15 patients. Of 68 patients considered for transplant (55 saw a transplant physician, 13 had HLA typing sent), 23 patients ultimately underwent transplant, including 5 autologous and 18 alloSCT. Among patients referred who did not undergo transplant (N = 30), the most common reason was disease-related (24 patients, 80%) followed by patient preference (4 patients, 13%). Since 2010, only two patients underwent autoSCT at our center: one experienced primary graft failure necessitating autologous reconstitution and another lacked suitable allograft donor. Most patients, 13/18 (72%), were in CR at time of alloSCT; 11 patients underwent transplant in first remission, 7 at subsequent timepoints. Donor and graft sources included matched related (n=6), one identical twin, matched unrelated (n=2), mismatched related (n=1), mismatched unrelated (n=2), cord blood (n=4) and haploidentical (n=2). Four patients relapsed after autoSCT, 6 patients following alloSCT, and 2 treatment-related deaths occurred post alloSCT. Progression-free and OS at median follow-up of 39.2 months among alloSCT recipients was 60.6% and 64.1%, respectively (Figure 2). Conclusions: We describe the treatment patterns and outcomes for a large series of non-Japanese patients at our center with ATLL. We confirm the poor outcomes with conventional therapy seen in other studies, with only 40% of lymphoma/leukemia subtype patients achieving CR with first-line therapy, and a median OS of 13.2 months among all patients. AlloSCT offers promise as an effective option that achieved durable long-term responses in many patients, yet its applicability is limited by chemorefractory disease. Larger studies are needed to confirm our findings and to identify effective salvage therapies to attain remission and bridge patients to alloSCT. For patients ineligible for alloSCT due to age/comorbidity, lack of suitable donor, or disease refractoriness, novel therapeutic approaches are urgently needed to improve outcomes. Disclosures Moskowitz: Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Perales:Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Astex: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Trillium: Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Innate Pharma: Consultancy; Mundipharma: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy.

Introduction: Scorpion envenomation is a life-threatening paediatric emergency. Prazosin-an alpha-1 blocker is the gold standard therapy for scorpion envenomation. Many children with scorpion envenomation were under-treated at Primary Healthcare (PHC) and Secondary Healthcare (SHC) level because of lack of awareness about prazosin therapy. If prazosin is started earlier at PHC and SHC level, complications and mortality can be reduced. Aim: To conduct sensitisation programme for PHC and SHC doctors regarding the management of paediatric emergencies including scorpion envenomation, and to evaluate the effectiveness of sensitisation programme on prazosin therapy for scorpion envenomation at PHC and SHC level. Materials and Methods: This non concurrent clinical trial consisted of training PHC and SHC doctors at the Department of Paediatrics, Government Dharmapuri Medical College Hospital, Tamil Nadu, India for a period of two years (January 2018-December 2019). After the training, children aged 1 month-12 years with features of scorpion envenomation referred from PHC and SHC to this tertiary care centre, during January 2021-September 2021 were evaluated. The data regarding initiation of prazosin therapy at PHC and SHC level and the clinical profile, complications and outcome at tertiary care level were noted. The present study parameters were compared with previous study on scorpion envenomation, done before the sensitisation programme in the same centre, and the data were compared. Results: Training was given to 120 medical officers of PHC and SHC. Sixty-two children, with scorpion envenomation referred from PHC and SHC, were included in the study. A total of 7 (10%) children brought to the tertiary care centre directly were excluded. Prazosin therapy was initiated in 43 (69.3%) children at PHC and SHC level before referral. Initiation of prazosin within four hours of scorpion sting was done in 45 (72.6%). Common symptoms were pain {42 (68%)}, diaphoresis {26 (42%)} and salivation {25 (40%)}. Cold peripheries, myocarditis and pulmonary oedema were noted in 24 (39%), 4 (6%) and 6 (10%) children, respectively. Dobutamine and Non Invasive Ventilation (NIV) were needed in 13 (21%) and 11 (18%) cases, respectively. When compared to the observations pretraining, peripheral circulatory failure (76% to 39%) (p=0.019), pulmonary oedema (27% to 10%) (p=0.010), myocarditis (17% to 6%) (p=0.039), ionotrope support (41% to 21%) (p=0.024), and NIV (39% to 18%) (p<0.003) were significantly reduced. There was no mortality. Conclusion: Following the sensitisation programme, initiation of prazosin for scorpion envenomation at PHC and SHC level significantly improved. Complications like myocarditis, pulmonary oedema, need for inotropes and ventilator support decreased significantly.

Abstract The Persian Gulf War of 1990 to 1991 involved the deployment of nearly 700,000 American troops to the Middle East. Deployment-related exposures to toxic substances such as pesticides, nerve agents, pyridostigmine bromide (PB), smoke from burning oil wells, and petrochemicals may have contributed to medical illness in as many as 250,000 of those American troops. The cluster of chronic symptoms, now referred to as Gulf War Illness (GWI), has been studied by many researchers over the past two decades. Although over $500 million has been spent on GWI research, to date, no cures or condition-specific treatments have been discovered, and the exact pathophysiology remains elusive. Using the 2007 National Institute of Health (NIH) Roadmap for Medical Research model as a reference framework, we reviewed studies of interventions involving GWI patients to assess the progress of treatment-related GWI research. All GWI clinical trial studies reviewed involved investigations of existing interventions that have shown efficacy in other diseases with analogous symptoms. After reviewing the published and ongoing registered clinical trials for cognitive-behavioral therapy, exercise therapy, acupuncture, coenzyme Q10, mifepristone, and carnosine in GWI patients, we identified only four treatments (cognitive-behavioral therapy, exercise therapy, CoQ10, and mifepristone) that have progressed beyond a phase II trial. We conclude that progress in the scientific study of therapies for GWI has not followed the NIH Roadmap for Medical Research model. Establishment of a standard case definition, prioritized GWI research funding for the characterization of the pathophysiology of the condition, and rapid replication and adaptation of early phase, single site clinical trials could substantially advance research progress and treatment discovery for this condition.

Abstract Background Non-invasive ventilation (NIV) is a recommended treatment for COPD patients suffering from chronic hypercapnic respiratory failure. Prolonged dyspnea after mask removal in the morning, often referred to as deventilation syndrome, is a common side effect but has been poorly characterized yet. This study aimed to explore the pathomechanism, identify risk factors and possible treatment strategies for the deventilation syndrome. Methods A prospective, controlled, non-blinded study was conducted. After a night with established NIV therapy, the patients underwent spirometry, blood gas analyses and 6-min walking tests (6MWT) directly, at 2 and 4 h after mask removal. Dyspnea was measured by the modified Borg scale. Bodyplethysmography and health-related quality of life (HRQoL) questionnaires were used. Patients suffering from deventilation syndrome (defined as dyspnea of at least three points on the Borg scale after mask removal) were treated with non-invasive pursed lip breathing ventilation (PLBV) during the second night of the study. Results Eleven of 31 patients included (35%) met the given criteria for a deventilation syndrome. They reported significantly more dyspnea on the Borg scale directly after mask removal (mean: 7.2 ± 1.0) compared to measurement after 2 h (4.8 ± 2.6; p = 0.003). Initially, mean inspiratory vital capacity was significantly reduced (VCmax: 46 ± 16%) compared to 2 h later (54 ± 15%; p = 0.002), while no changes in pulse oximetry or blood gas analysis were observed. Patients who suffered from a deventilation syndrome had a significantly higher mean airway resistance (Reff: 320 ± 88.5%) than the patients in the control group (253 ± 147%; p = 0.021). They also scored significantly lower on the Severe Respiratory Insufficiency Questionnaire (SRI; mean: 37.6 ± 10.1 vs 50.6 ± 16.7, p = 0.027). After one night of ventilation in PLBV mode, mean morning dyspnea decreased significantly to 5.6 ± 2.0 compared to 7.2 ± 1.0 after established treatment (p = 0.019) and mean inspiratory vital capacity increased from 44 ± 16.0% to 48 ± 16.3 (p = 0.040). Conclusions The deventilation syndrome is a serious side effect of NIV in COPD patients, characterized by increase of dyspnea. It is associated with decrease in vital capacity, exercise tolerance after mask removal and lower HRQoL. Patients with high airway resistance are at greater risk of suffering from morning dyspnea. Ventilation in PLBV mode may prevent or improve the deventilation syndrome. Trial registration: The study was registered in the German Clinical Trials Register (DRKS00016941) on 09 April 2019.

Diabetic peripheral neuropathy is one of the most common causes of disability in diabetic patients. Applying a method to achieve the highest therapeutic effect in patients is desirable. Therefore, this study aimed to evaluate the impact of leech therapy on diabetic neuropathy of lower limbs in comparison to gabapentin as a standard method. This randomized controlled parallel-group clinical trial was conducted among 40 patients with type II diabetes who were diagnosed with lower limb diabetic neuropathy and referred to specialized outpatient clinics in Babol, Mazandaran province, Iran from 23 September 2020 to 17 March 2021. The patients were randomly divided into two groups. One group was treated with leech therapy and the other group was treated with gabapentin as the standard method. The severity of neuropathy was assessed every 15 days until the 45th day. The Visual Analog Scale (VAS), Neuropathy Symptom Score (NSS), Neuropathy Disability Score (NDS), and Nerve Conduction Velocity (NCV), and Electromyography (EMG) were used for assessing the study outcomes. The repeated measure and Friedman tests were used by SPSS.V.23. The results of our study indicated that pain (P value:0.03), numbness (P value˂0.0001), and paranesthesia (P value:0.01) significantly reduced in patients undergoing leech therapy versus patients taking gabapentin on the 45th day. The total NSS (P value˂0.0001) and total NDS (P value˂0.0001) improved significantly for patients with leech therapy over 45 days compared to the patients with gabapentin. The results of our study showed that using leech therapy for patients with diabetic neuropathy was more effective in improving clinical symptoms and the functions of lower limb muscles and nerves in comparison to gabapentin. The severity and symptoms of neuropathy greatly improved for the patients treated with leech therapy versus patients taking gabapentin.

For phase III RCTs, sample heterogeneity is useful for both generalizability of findings and providing insight into treatment effects for specific subgroups. Prior studies in stroke rehabilitation have rarely explored differences in intervention effects between racial and ethnic subgroups across participating sites. We examined participant characteristics across centers, with the hypothesis that strategic use of a multi-center structure across 3 distinct urban geographical areas (Atlanta, GA, Los Angeles, CA and Washington, DC) would generate a sample diverse enough to explore differences in treatment effects by racial and ethnic subgroups Methods: The ICARE Stroke Initiative is a randomized multi-center clinical trial designed to compare the effectiveness of the Accelerated Skill Acquisition Program (ASAP) to an equivalent dose of usual and customary outpatient occupational therapy (DEUCC) and a monitoring only usual therapy group (UCC). Demographics, stroke characteristics and cognitive outcomes collected at baseline for randomized participants (N = 361) were compared across the 3 centers using ANOVA or χ2 tests for continuous and categorical outcomes, respectively. Results: We found significant differences in race and ethnicity (p<0.001); the highest proportion of African-Americans came from the Atlanta and DC centers, and the highest proportion of Hispanic/Latinos came from the Los Angeles center. Additional unanticipated differences between centers in baseline characteristics include: age, referral source, stroke location, stroke severity as measured by the NIH Stroke Scale, Short Blessed Memory Test, DKEF’s verbal fluency sub-score of category switching, and pre-randomization hours of outpatient occupational therapy (p<0.05). Conclusions: ICARE’s strategic center selection resulted in a diverse and robust dataset, allowing for post hoc exploration of treatment effect differences by subgroup and for the intention-to-treat analysis, determination of generalizability of treatment effects across a racially and ethnically diverse population.