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Background: Early data from anti-CD19 chimeric antigen receptor (CAR) T-cell trials suggest that concurrent infection can lead to poor outcomes. 1,2 The relationship between CAR T-cell mediated inflammatory responses and infections is not well-established. With CAR T-cell therapies more readily available, practitioners must identify which patient, disease and CAR T-cell specific parameters are associated with an increased risk of infection to optimize outcomes. We provide a comprehensive analysis of infection risk within the first 30 days after CAR T-cell infusion across multiple types of CAR T-cell trials targeting distinct antigens. Methods: This was a single-center, retrospective study conducted at the National Cancer Institute analyzing infectious complications in subjects who underwent CAR T-cell therapy on one of four phase I clinical trials, targeting CD19, CD22, B-cell maturation antigen (BCMA) or disialoganglioside (GD2) from 2012 though 2018. Baseline characteristics are in Table 1. The primary objective was to establish the incidence of infections between initiation of lymphodepleting (LD) chemotherapy through day 30 after CAR T-cell infusion. The secondary objective was to identify risk factors for infection. Patients were censored at relapse and/or initiation of alternative therapy, including treatment for relapse or consolidative hematopoietic stem cell transplantation (HSCT). Univariate screening methods were used to identify parameters associated with increased risk of infection Results: Amongst 144 subjects, 52 (36.1%) received anti-CD19 CAR T-cells (CAR-T); 53 (36.8%) received anti-CD22 CAR-T, 26 (18.1%) received anti-BCMA CAR-T; and 13 (9%) received anti-GD2 CAR-T. The median age was 18 years (range: 4 to 66). Sixty-one (42.4%) had undergone at least one prior allogeneic hematopoietic stem cell transplant (HSCT) and 24 (16.7%) had at least one prior autologous HSCT. Sixty-eight (47.2%) had a history of a recent infection within 100 days of initiation of LD chemotherapy, of which 17 were a major chronic infection and 9 were considered severe. Fifty-eight (40.3%) subjects experienced a total of 103 infections from initiation of LD chemotherapy through day 30 post CAR T-cell infusion, with the median time to first infection being 6 days post-CAR infusion. Twenty-eight (19.4%) subjects had more than 1 infection; 20 (13.9%) subjects had C. difficile infection. The 103 infections consisted of 47 (45.6%) distinct episodes of focal bacterial infections (e.g., sinusitis, pneumonia, urinary tract infection), 25 (24.2%) episodes of bacteremia, 22 (21.4%) viral infections, and 9 (8.7%) invasive fungal infections. Fourteen infections (13.6%) occurred between initiation of LD chemotherapy and day 0 (prior to CAR T-cell infusion). Fever and neutropenia, without a source, was documented as a distinct entity in 85 patients (59.0%). Using univariate statistical screening methods, we identified 4 parameters that were individually associated with an increased risk of infection: increasing number of prior therapies (p=0.0034), prior history of recent infection within the past 100 days (p=0.0064), age > 18 (p =0.028), or enrollment on the CD22 CAR trial (p=0.0028). Eliminating the trial, since that is not generalizable, and combining these into a multivariable logistic regression model identified age > 18, prior history of infection and prior lines of therapies jointly associated with an increased risk of infection. Using these parameters, a predictive model was developed, which, when applied to the data set used to develop the model, can correctly predict 69 of 86 patients without an infection (80.3%; CI: 70.3-88.0%) as well as 32 of 58 patients with an infection (55.2%; 95% CI: 41.5- 68.3%). Conclusion: In this retrospective analysis, we provide the largest experience to date analyzing infection in the setting of CAR T-cell therapy across multiple CAR constructs. Our study demonstrates that adult age, prior history of infection, increased number of prior therapies and enrollment on a particular CAR T-cell trial, in this case the CD22 CAR-T trial, may lead to a higher risk of infection than in those without these risk factors. Further investigations are underway to evaluate clinical outcomes with infection which occur in the peri CAR T-cell setting and potential strategies to minimize infection risk. Generalizability of this model will be tested in an independent data set. Disclosures Lee: Kite, a Gilead Company: Research Funding; Harpoon Therapeutics: Consultancy; Juno Therapeutics: Other: External Advisory Board; ACI Clinical on behalf of Celgene:: Other: Independent Central Quality Review Committee. Mackall:Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board; Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kochenderfer:Kite and Celgene: Research Funding; Bluebird and CRISPR Therapeutics: Other: received royalties on licensing of his inventions. OffLabel Disclosure: Conditioning chemotherapy for CAR T-cell therapy; this is a retrospective study that used different lymphodepletion regimens.

Background Right atrial pressure ( RAP ), a composite metric of right ventricular diastolic function, volume status, and right heart compliance, is a predictor of mortality in patients with heart failure due to acquired heart disease. Because patients with tetralogy of Fallot ( TOF ) might have abnormal right atrial and ventricular mechanics caused by myocardial injury and remodeling, we hypothesized that RAP would be associated with disease severity and cardiovascular adverse events in this population. Methods and Results We performed a cohort study of adults with TOF who underwent right heart catheterization at the Mayo Clinic Rochester between 1990 and 2017. The objective was to determine the association between RAP and multiple domains of disease severity in TOF (percentage of predicted peak oxygen consumption, atrial or ventricular arrhythmia, and heart failure hospitalization), as well as cardiovascular adverse events, defined as sustained ventricular tachycardia, resuscitated or aborted sudden death, heart transplantation, or death. Among 225 patients (113 male; mean age: 39±14 years), mean RAP was 10.7±5.2 mm Hg and median was 10 mm Hg (interquartile range: 7–13 mm Hg). Increasing RAP was associated with atrial or ventricular arrhythmias (odds ratio: 5.01; 95% CI, 1.22–23.49; P <0.001), heart failure hospitalization (odds ratio: 1.47; 95% CI, 1.10–2.39; P =0.033) per 5 mm Hg, and worsening exercise capacity (peak oxygen consumption; R 2 =0.74, r =−0.86, P <0.001). RAP was a predictor of cardiovascular adverse events (hazard ratio: 1.28; 95% CI, 1.10–1.47; P =0.028) per 5 mm Hg. Conclusions In symptomatic patients with TOF , increasing RAP correlates with multiple domains of disease severity (risk stratification) and predicts future cardiovascular events (prognostication). These data have potential clinical implications in the target population of symptomatic TOF patients.

Despite its rank as the fourth healthiest state in the United States, Minnesota has clear cardiovascular disease disparities between African-Americans and whites. Culturally-tailored interventions implemented using community-based participatory research (CBPR) principles have been vital to improving health and wellness among African-Americans. This paper delineates the establishment, impact, and lessons learned from the formation of a community steering committee (CSC) to guide the Fostering African-American Improvement in Total Health (FAITH!) Program, a CBPR cardiovascular health promotion initiative among African-Americans in Minnesota. The theory-informed CSC implementation process included three phases: (1) Membership Formation and Recruitment, (2) Engagement, and (3) Covenant Development and Empowerment. The CSC is comprised of ten diverse community members guided by mutually agreed upon bylaws in their commitment to FAITH!. Overall, members considered the CSC implementation process effective and productive. A CBPR conceptual model provided an outline of proximal and distal goals for the CSC and FAITH!. The CSC implementation process yielded four lessons learned: (1) Have clarity of purpose and vision, (2) cultivate group cohesion, (3) employ consistent review of CBPR tenets, and (4) expect the unexpected. A robust CSC was established and was instrumental to the success and impact of FAITH! within African-American communities in Minnesota.

Abstract Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.

Abstract Background Diabetes is a prognostic factor for some malignancies, but its association with outcome in patients with advanced or metastatic colorectal cancer (CRC) is less clear. Methods This cohort study was nested within a randomized trial of first-line chemotherapy and bevacizumab and/or cetuximab for advanced or metastatic CRC. Patients were enrolled at 508 community and academic centers throughout the National Clinical Trials Network. The primary exposure was physician-documented diabetes at the time of enrollment. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and adverse events. Tests of statistical significance were two-sided. Results Among 2326 patients, 378 (16.3%) had diabetes. The median follow-up time was 6.0 years. We observed 1973 OS events and 2173 PFS events. The median time to an OS event was 22.7 months among those with diabetes and 27.1 months among those without diabetes (HR = 1.27, 95% CI = 1.13 to 1.44; P &lt; .001). The median time to a PFS event was 9.7 months among those with diabetes and 10.8 months among those without diabetes (HR = 1.16, 95% CI = 1.03 to 1.30; P = .02). Patients with diabetes were more likely to experience no less than grade 3 hypertension (8.1% vs 4.4%; P = .054) but were not more likely to experience other adverse events, including neuropathy. Conclusions Diabetes is associated with an increased risk of mortality and tumor progression in patients with advanced or metastatic CRC. Patients with diabetes tolerate first-line treatment with chemotherapy and monoclonal antibodies similarly to patients without diabetes.

Abstract Introduction Patients with myeloproliferative neoplasms (MPN) typically experience debilitating symptom profiles and profound quality of life (QoL) decrements. Characterizing symptom burden in MPN clinical trials is vital to inform efficacy analyses. Previous studies have shown clinicians and researchers depend on patient-reported outcomes (PROs) to glean disease-related symptoms and signs of QoL decline. The current literature also shows that integrating PROs into the routine care of patients with cancer is associated with increased survival compared with usual care. However, the extent to which PROs are employed in MPN clinical trials is undescribed. ClincalTrials.gov is a registry of clinical trials mandated by the US Congress and implemented in 2000 by the National Institutes of Health. This study used data from ClinicalTrials.gov to evaluate the characteristics of MPN clinical trials over time and their use of PROs as primary and secondary outcomes. Methods The statistical software R and the rclinicaltrials package were used to download data from ClinicalTrials.gov. Trial data were included in this study if the following criteria were met: (1) the words essential thrombocythemia, polycythemia vera, myelofibrosis, or myeloproliferativeneoplasm (MPN) were used in the registered primary disease condition or official trial title; (2) the trial start date was between January 1, 2000 - July 1, 2018; (3) primary/secondary outcome data were available. Trial outcome data were then parsed for PRO text phrases including MPN-Symptom Assessment Form, quality of life, questionnaire, patient-reportedoutcome, and more specific PRO items (e.g., bone pain, concentration problems, and depression). Descriptive statistics and regression analysis were used to assess rates of primary/secondary outcomes over time. Results Clinical trial characteristics There were 535 trials satisfying the inclusion criteria. Since 2000, the number of registered MPN-related clinical trials ranged from 11 to 36 trials per year with 28 trials registered annually on average (Figure 1). Of the 535 trials, 470 (88%) were interventional and 65 (12%) observational. Trials often employed multiple intervention types including: drug (77%); procedure (28%); biological (19%); radiation (13%); genetic (3%); behavioral (2%); device (2%); dietary supplement (1%); other (24%) [percentages do not sum to 100% as categories are not mutually exclusive]. Eligibility criteria varied widely, though most used 18 years old as the minimum age requirement (71%; 379/535) and nearly all included both genders (>99%; 533/535). PRO outcomes over time Of the 535 MPN trials, the number of primary outcomes within MPN trials did not change over time (p=.50) with an average of 1.6 per trial. Around 8% of MPN clinical trials had PRO-related primary outcomes; this rate also did not change over time (Figure 1: solid red line; p=.97). However, the total number of secondary outcomes per trial has increased since 2000 (p<.001). From 2000-2005, 2006-2011, and 2012-2018 there was an average of 2.8, 3.3, and 5.2 secondary outcomes per trial, respectively. Also, the proportion of MPN clinical trials with PRO-related secondary outcomes has increased steadily over time (Figure 1: dashed blue line; p<.001). On average, from 2000-2005, 2006-2011, and 2012-2018 the proportion of MPN clinical trials with PRO-related secondary outcomes increased from 8% to 23%, to 33%. Conclusion Analysis of ClinicalTrials.gov data suggest that patient-reported outcomes are being implemented into MPN clinical trials at increasing rates. While this suggests that MPN trials are becoming more patient-centered, PROs are included more often as secondary endpoints than primary endpoints. This analysis also suggests an increase in the number of secondary endpoints in recent years in MPN clinical trials, consistent with observed trends of growing complexity and increasing amount of data captured in clinical trials in general. Disclosures Mesa: Ariad: Consultancy; Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; Novartis: Consultancy; CTI: Research Funding; Celgene: Research Funding. Scherber:Orphan Pharmaceuticals: Honoraria; Incyte: Consultancy. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

INTRODUCTION: Histologic response rates to steroids for eosinophilic esophagitis (EoE) vary from < 50% to >90% in controlled trials. We have used varied steroid preparations and higher doses than typically used and aimed to study if steroid dose and delivery vehicle might explain the wide variation in response. METHODS: A database of patients with EoE created in our esophageal clinic was reviewed and patients treated with at least an 8 week course of topical steroid therapy and undergoing pre and post-steroid histologic evaluation were included. Histologic remission was defined as eosinophil count < 15/hpf. Symptomatic remission was defined as complete resolution of symptoms and eating an unlimited diet. Endoscopy reports were reviewed. RESULTS: 94 patients were included, 45 on 3 mg budesonide-Rincinol gel twice daily (HBRG), 29 on 3 mg budesonide capsules BID (BC), and 20 on lower doses of BRG (1.5 mg daily to 2 mg BID) (LBRG). 88.5% had dysphagia at time of steroid initiation. Mean eosinophil count before steroids was 58.6/hpf. 38.3% had esophageal dilation just prior to steroids. Average EFERS prior to steroid treatment was 1.8. There were not significant differences between the groups in terms of demographics, initial eosinophil counts, symptoms, visual EoE assessment (EREFS) or dilation rates. Histologic remission rate for HBRG was 82.2% vs 55.1% for all others combined ( P < 0.001), 51.7% for BC ( P = 0.005 vs 3 mg BRG BID), and 60.0% for LBRG ( P = 0.06 vs 3 mg BRG BID). Symptomatic remission was similar between groups, as was change in EREFS and change in eosinophil counts. Non-responders to HBRG had mean decrease in eosinophil count of only 0.3/hpf (vs 53.2/hpf for responders, P < 0.003) and mean change in EREFS of +1.6 (vs −1.1 for responders, P < 0.001). 62.5% of non-responders to HBRG actually had increase in eosinophil count after steroids. Response rate to HBRG at < 5 eos/hpf was 77.8% overall and 94.6% in those achieving remission. CONCLUSION: A higher remission rate achieved with a more viscous steroid preparation compared to other formulations suggests the importance of both dose and esophageal delivery in treatment of EoE. Further, with adequate mucosal delivery and dosing of topical steroids, steroid refractory EoE appears to be uncommon. On the other hand, these results suggest the existence of a small truly steroid refractory group of EoE patients with negligible histologic, symptomatic and endoscopic response to high dose steroids that warrant further investigation.