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Abstract Background: SARS-Cov-2 infections are associated with increased mortality and morbidity, largely due to inflammatory cascades and cytokine release syndrome (CRS). Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of somatic, leukemia-associated driver mutations in apparently healthy individuals with normal blood counts. CHIP has been associated with increased inflammation, with cytokines such as IL1-b, IL6 and TNF-a being elevated at baseline in affected individuals. We hypothesized that the presence of CHIP in patients with COVID-19 would result in excessive inflammation-related mortality and morbidity. Methods: We used the Mayo Clinic COVID-19 database to identify patients with COVID-19 on whom peripheral blood mononuclear cells (PBMC) were available for research use (IRB approved). We carried out target-capture next generation sequencing for 220 CH related genes, by previously described methods (1000 x coverage, variant allele fraction/VAF detection limit >0.5%; Kusne Y et al AJH 2021). CHIP was defined by the presence of a CH mutation with a VAF>1% in an individual with normal baseline blood counts. Demographics, blood counts, and inflammatory markers (CRP and cytokine levels- ELISA assay) at COVID-19 diagnosis and during follow-up (as clinically indicated) were collected. COVID-19 disease severity was classified based on the presence and severity of CRS, graded using the Penn Grading Scale (Porter et. al., 2018), and the WHO ordinal scale (WHO Blueprint, 2020). We used Fisher's exact test and the Wilcoxon rank sum test to compare categorical and continuous variables. Survival analysis was performed using the Kaplan-Meier method. We accounted for differences in age and sex using multivariable-adjusted proportional hazards regression models. Results: Seventy-two CHIP mutations were detected in 56 (25%) of the 227 patients with COVID-19 that had PBMC available; median age 69 years (range; 42-99 years), 61% male. Fifteen (26%) patients had 2 CHIP mutations, while 1 patient had 3 CHIP mutations. Common mutations encountered included DNMT3A (32%) , TET2 (19%) , SF3B1 (8%) , ASXL1 (6%) , MPL (5%) , and TP53 (5%; Figure 1A). COVID-19 patients with CHIP were older in age (median 69 vs 57 years; p<0.0001) and had higher baseline MCP-1 (p=0.04) levels. However, there were no differences in sex, comorbidities, blood counts, IL1-b, IL6 and TNF-a levels between the two groups. The median follow-up for the entire cohort was 9 months. The relative change from baseline in blood counts and inflammatory markers (CRP and cytokines) during follow-up was similar in CHIP and non-CHIP patients, with the exception that COVID-19-onset neutropenia was more common in CHIP patients (8% vs 1%; p=0.017) compared to those without CHIP. At last follow up neutropenia had resolved in all patients. Both groups had comparable number of patients with CRS (61% CHIP vs 53% non-CHIP patients, p=0.354, Figure 1B), however, CHIP patients had more severe CRS (median Penn Grade 3 versus 2 in non-CHIP, p=0.018, Figure 1C). Based on the WHO ordinal scale, CHIP patients were more likely to experience hospitalization with severe disease and death (61% versus 45% in non-CHIP, p = 0.049). Moreover, COVID-19 CHIP patients experienced worse overall survival in comparison to patients without CHIP (median 13.1 months vs not reached, p<0.001, Figure 1D). This association remained consistent after adjusting for age and sex at the time of COVID-19 diagnosis (HR 3.15, 95% 1.32 - 7.55, p = 0.010). At last follow-up, 22 deaths were documented: 13 (23%) in patients with CHIP and 9 (5%) in the non-CHIP group (p=0.02), with the primary cause for mortality being hypoxic respiratory failure (62% in CHIP vs 44% non-CHIP, p=0.04). Conclusions: In this study, we observe an age-independent impact of CHIP on COVID-19 associated inflammatory morbidity (CRS) and mortality (hypoxemic respiratory failure). We are currently carrying out detailed single cell (ssDNA, RNA and ATAC-seq) and proteomic studies (O-link PEA assays) to better elucidate this pathophysiology. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; StemLine: Research Funding.

Abstract Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19. Methods: A total of 846 patients were retrospectively evaluated to determine if they were treated with guideline-appropriate anticoagulation while hospitalized with COVID-19, as well as if they developed venous or arterial thrombotic events, or major or minor bleeds. 317 patients were excluded for taking therapeutic anticoagulation prior to admission, or for having a COVID-19 diagnosis >7 days after admission. Appropriate anticoagulation was determined by an institutionally designed COVID-19 thromboprophylaxis algorithm, based on platelet count, d-dimer, bleeding risk, and level of medical care required. Regimen options included: no anticoagulation, prophylactic enoxaparin (40 mg SQ daily) or heparin in the setting of kidney dysfunction, weight-based dosing of enoxaparin (40 mg SQ BID if BMI>40), intermediate intensity enoxaparin without thrombus (30 mg BID if BMI<40, or 40 mg BID if BMI>40), and therapeutic anticoagulation (for example enoxaparin 1 mg/kg BID) with thrombus. Demographics: Demographic data and clinical characteristics were collected for 529 patients. Average age was 59 years old, and the majority were men (58.4%). Most patients were White (58.3%), followed by Hispanic (17.8%), or Native American (15.7%). Fewer patients had a normal BMI (21.3%; BMI 18.5 - 24.9) compared to those who were overweight (31.2%; BMI 25-29.9) or obese (43.1% BMI > 30). Other comorbidities included Type 1 or Type 2 diabetes mellitus (N= 172, 32.5%), hypertension (N = 271, 51.2%), and hyperlipidemia (N = 176, 33.3%). Results: A total of 42 patients (8%), were diagnosed with a venous thrombosis during hospitalization. Patients admitted to the ICU were significantly more likely to have a thrombotic event of any type compared to non-ICU patients (21.6% to 5.7%; p < 0.001). Specifically, critically ill patients had higher incidences of deep vein thrombosis (9.5% to 0.7%), pulmonary emboli (8.1% to 4.8%), and superficial thrombi (2.7% to 0.2%). Only 1.1% of patients (6/529) experienced any bleeding, of which 3 were classified as a major bleed. Discussion: Among patients hospitalized at our institution with COVID-19, the majority were anticoagulated appropriately according to the COVID-19 thromboprophylaxis algorithm. Overall incidence of thrombosis in the study population was 8%. A significantly higher percent of critically ill patients had thrombi, supporting reports of correlation between severity of illness and thrombosis risk. The two regimens of anticoagulation least adhered to were weight-based and intermediate-based dosing, likely reflecting a departure from the hospital's thromboprophylaxis regimens prior to COVID-19 pandemic. Further studies are needed to characterize whether identifiable risk factors correlate with the incidence of thrombosis, and whether treatment with lower than recommended doses of anticoagulation, based on the COVID-19 thromboprophylaxis algorithm, were associated with thrombosis. Disclosures No relevant conflicts of interest to declare.

Abstract Purpose Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. Materials and Methods From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. Results All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. Conclusion Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. Implications for Practice Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.

Introduction: Serum folate (SF), vitamin B12 (B12), and iron deficiency (def) are common causes of nutritional anemias (NA). These deficiencies are usually multifactorial, with nutritional and non-nutritional causes playing a role. SF, B12, and iron levels are usually ordered in the setting of anemia, and malnutrition with or without neurologic symptoms. Clinical evidence suggests that these def have a strong dietary component and socioeconomic status (SES). The relationship of NA and area-based SES in the US has not been studied. We aimed to determine the relationship of SES with the prevalence of NA. Methods: We performed a cross-sectional analysis of adult patients with SF, B12 and iron levels at Mayo Clinic Arizona and Florida between 2010 and 2018. Race was classified using the NIH criteria. Normal laboratory values were determined according to our lab reference and the US NHANES III. SF levels (mcg/Lt) were defined as deficient <4, normal ≥4.0, and excess ≥20. B12 levels (ng/L) as deficient <150, borderline 150-400, normal >400-900, and excess ≥900. Iron def was determined by ferritin levels (mcg/L) as low <24, normal 24-336, elevated >336 for men, low <11, normal 11-307, elevated >307 for women. Area-Level SES indicators: Median Household income (MHI), unemployment rate (UR), median gross rent month (MGRM), % uninsured, median house value (MHV), % high school; were geocoded by zip code using the 2014 American Community Survey. Demographics and clinical variables were compared between groups by chi-square test for frequency data or Kruskal Wallis rank-sum test for continuous variables. Results: 202,046 samples from 128,084 patients were analyzed. In the sample-level analysis, there were statistically significant associations between SES and SF def; all SES indicators except UR for B12 def; and no differences for iron def, except % uninsured (Table 1). There was no statistically significant interaction between race and SES for SF def and iron def. Race was a statistically significant modifier between B12 def and MHI (p<0.001), % uninsured (p=0.002), and MHV (p=0.007). Asian and Other race had an increase in odds of B12 def with increasing MHI (Asian OR=1.11 , Other OR=1.18); white race had a decrease in odds of B12 def with increasing MHI (OR=0.95 for a $10,000 increase in MHI). Conclusions: We show significant relationships between SES and NA in the US. Differences were observed between SF def and all the SES indicators without race interactions. There were significant interactions between B12 def, race and SES for pts of White, Asian and Other race. There were no differences between SES and race for iron def. These relationships confirm that NA are related to area-level SES and other social determinants of health. Research regarding the causes of these disparities on a population level are needed. Disclosures No relevant conflicts of interest to declare.

Background. Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections. Conclusion. Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.

Abstract We report 8 cases of coccidioidomycosis associated with ruxolitinib treatment. Among 135 patients living in the coccidioidal-endemic region receiving ruxolitinib, 5 cases were diagnosed after starting and 4 had extrathoracic dissemination. Periodic serological screening while on ruxolitinib is warranted for patients residing in the coccidioidal-endemic region.

AbstractObjectiveTo determine the presence of racial/ethnic differences in patients with anemia and serum folate deficiency.MethodsWe performed a retrospective analysis of data from patient samples collected from January 2010 to October 2018. Reference laboratory ranges were determined by Mayo Clinic Reference Laboratories. Race and ethnicity were classified according to National Institutes of Health categories.ResultsThe analysis comprised 197 974 samples. Hemoglobin, hematocrit, and SF results were available for 173 337, 173 056, and 129 760 samples, respectively. Of the samples, 46 505 (26.8%) showed anemia, with a higher prevalence among American Indian/Alaskan Natives (AI/AN) 42.9% and African Americans (AA) 47.2% (P < .001). SF deficiency was present in 897 (0.7%), with a higher prevalence among AI/AN (9, [1.4%]) and AA (78, [1.2%]) and a lower prevalence in non‐Hispanic whites (NHW) (758, [0.7%]), Hispanics (40, [0.6%]), and Asians (8, [0.3%]). In multivariable analysis, the prevalence of anemia was higher in all non‐NHW racial/ethnic groups: AA (OR, 3.67, [95%CI: 3.47‐3.88, P < .001]), AI/AN (OR, 3.25, [95%CI: 2.71‐3.90, P < .001]), Asians (OR, 1.62, [95%CI: 1.47‐1.77, P < .001]), and Hispanics (OR, 1.41, [95%CI: 1.32‐1.50, P < .001]). SF deficiency was more common in AA (OR, 1.48, [95%CI: 1.17‐1.88, P.001]) and less common in Asians (OR, 0.35, [95%CI: 0.17‐0.70, P = .003]), compared with NHW.ConclusionsWe showed significant racial/ethnic differences in anemia and SF deficiency. Differences were observed especially among NHW, AA, and Asians. We believe that these differences may be explained by social determinants of health. More research is needed regarding the causes of these differences and their clinical implications at a population level.