Citations

INTRODUCTION: Anemia and micronutrient deficiencies are common in newly diagnosed patients with celiac disease (CeD). We aim to determine the prevalence and etiology of anemia in a cohort of patients with CeD in the United States and examine the effect of a gluten-free diet (GFD) on the laboratory parameters related to anemia in CeD. METHODS: We analyzed a prospectively collected cohort of adults with biopsy-proven CeD followed in a specialized CeD center between January 2000 and June 2016. We used the level of hemoglobin (Hb) and micronutrients suggested by the World Health Organization to establish the diagnosis of anemia or deficiencies. Demographic data and laboratory parameters related to anemia and micronutrients were recorded at the time of diagnosis and on a GFD. A celiac expert nutritionist or gastroenterologist evaluated all patients. RESULTS: In 572 patients with laboratory evaluation before starting a GFD, approximately 25% presented with anemia at the time of diagnosis of CeD. Iron deficiency was present in 50.8% of the cohort and in 78.8% of the patients with anemia. Within the anemic population, 84.4% of female patients as compared with 58.3% of male patients ( P = 0.02) showed iron deficiency. Folate deficiency (23.2%), vitamin B12 deficiency (11%), and anemia of chronic diseases (7.8%) were also part of both sexes' anemia etiology. Of the initially anemic patients, 81% and 89% normalized their Hb levels within 1 year and 2 years of beginning a GFD, respectively. All patients received appropriate supplementation when needed. DISCUSSION: Approximately 25% of individuals have anemia at CeD diagnosis. The anemia etiology included iron deficiency, vitamin deficiencies, and anemia of chronic diseases. Most of the patients will normalize their Hb levels and the anemia laboratory parameters 1 year after starting a strict GFD.

Introduction: Linaclotide is approved for adults with moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C). Linaclotide is not indicated for weight loss or for patients with inflammatory bowel disease (IBD); it is contraindicated in patients with mechanical bowel obstruction (MBO). Some patients with obesity or eating disorders (ED) may use linaclotide off-label for weight loss or as a laxative. Objectives: To describe the use of linaclotide in clinical practice, including patients with potential for off-label use or misuse. Methods: Post-authorization safety study conducted in three databases from the linaclotide launch date to 2017: the Clinical Practice Research Datalink in the United Kingdom (UK), the Information System for Research in Primary Care database in Spain and the linked Patient, Prescription and Causes of Death Registries in Sweden. Cohorts of patients were identified as having IBS using diagnostic and treatment codes; IBS subtypes were identified using symptoms and treatment codes; patients with obesity, ED, MBO, and IBD were identified using diagnostic codes or body mass index. Results: There were 1319, 1981, and 5081 linaclotide users from the United Kingdom, Spain, and Sweden with a median age of 45, 57, and 51 years, respectively; most were females. In the United Kingdom, Spain, and Sweden, respectively: 59.0%, 60.3%, and 31.3% of linaclotide users had an IBS diagnosis recorded, and among those, 68.8%, 61.3%, and 92.7% were classified as IBS-C. The proportions of linaclotide users considered at risk for potential off-label use for weight loss or as a laxative were 17.1%, 29.7%, and 1.7%, and the proportions of users considered at risk of misuse due to a history of MBO or IBD were 3.5%, 4.6%, and 5.7% in the United Kingdom, Spain, and Sweden, respectively. Conclusions: Potential linaclotide off-label use and misuse appears limited, as evidenced by the small sizes of the patient subgroups at risk for off-label use and misuse.

Abstract Background Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi‐ancestry meta‐analysis of genome‐wide association studies (meta‐GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods A meta‐GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants ( p ≤ 5 × 10 −5 ) were assessed for replication in 36,477 European and 1078 non‐European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results One hundred and twenty‐six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule‐1/exostosin like glycosyltransferase‐2 ( VCAM1 / EXTL2 ) (discovery: odds ratio (OR T allele ) = 0.82, p = 9.05 × 10 −6 and replication: OR T allele = 0.89, p = 5.35 × 10 −3 ) and rs943126 from pantothenate kinase 1 ( PANK1 ) (discovery: OR C allele = 0.85, p = 3.10 × 10 −5 and replication: OR C allele = 0.89, p = 1.30 × 10 −2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions This multi‐ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Abstract Rationale The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non–COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

e19583 Background: Brexucabtagene autoleucel (BA) is an FDA approved therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL), based on results from ZUMA-2 study. We report the safety and efficacy of BA in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: 16 centers participated in this retrospective study. Patients (pts) who underwent leukapheresis by 12/31/2021 with an intent to manufacture BA were included. Baseline clinical characteristics, bridging therapy, adverse events after BA infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined. Survival outcomes were analyzed using the Kaplan-Meier method. Results: At the data cut-off date, 189 pts underwent leukapheresis, among whom 167 (88%) completed BA infusion, 22 (12%) did not receive infusion. The median age was 67 years. 16% had high risk simplified MIPI, 57% had Ki-67≥50%, 41% had aggressive histology, 49% had TP53 alteration, 51% with POD24 and 10% had CNS involvement. The median number of prior lines of therapy was 3 (range 1-10). 86% had prior BTKi treatment (89% refractory). 130 (78%) pts would not have met ZUMA-2 eligibility criteria. 113 (68%) pts received bridging therapy, which included BTKi, venetoclax, chemotherapy. Median time from leukapheresis to lymphodepletion chemotherapy: 28 days (range 17-140). Cytokine release syndrome (CRS) rate was 90% (8% grade ≥3; 1 grade 5), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 61% (32% grade ≥3). Grade 5 ICANS (n = 0). Medications used to manage CRS and ICANS were 125 (76%) for tocilizumab, 112 (68%) for corticosteroid, and 27 (16%) for anakinra. 32 (20%) pts required ICU admission, 18 pts required vasopressors, and 5 pts required mechanical ventilation. Day 30 response was evaluable in 155 pts (89% ORR, 70% CR). The best ORR was 89%, with 80% CR, 9% PR. The ORR/CR rates were 88%/79% for aggressive histology, 89%/77% for high Ki-67% (> 50%), 90%/72% for TP53 altered, 81%/75% for CNS involved, 89%/79% for BTKi-exposed, 91%/83% for BTKi-naïve, and 89%/78% for those not meeting ZUMA-2 eligibility criteria. The median duration of response was not reached and at 6-month was 67% (95% CI 57-75). With a median follow-up of 5.6 months (range 0.2-15.3), median PFS was not reached, the 6-month PFS rate was 63% (95% CI 54-71), and median OS was 15.3 months and the 6-month OS rate was 85% (95% CI 77-90). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of BA in R/R MCL in the real-world practice. Despite 78% of the pts being ineligible for ZUMA-2, the responses, CRS, ICANS and outcomes were comparable to ZUMA-2 data. Long term safety and efficacy will be reported.

7571 Background: In clinical trials of CAR T-cell therapies and real-world studies published to date, there is a paucity of data on outcomes by race and ethnicity. Here, we examined outcomes by race and ethnicity among LBCL pts who received axi-cel in the real-world setting. Methods: A total of 1389 pts with LBCL were identified from a non-interventional post-authorization safety study with pts receiving commercial axi-cel between 10/2017 and 08/2020. Race (African American or Asian vs White) and ethnicity (Hispanic vs non-Hispanic) were self-reported by pts. Pts with rescinded consent, enrolled in trials, having prior non-HCT cellular therapy, primary CNS lymphoma, unknown comorbidity or data in query were excluded. Median follow-up was 12.7 mo. Outcomes included ORR, CR rate, DOR, PFS and OS, grade ≥ 3 CRS (Lee 2014 criteria) and ICANS (ASTCT consensus grade). ORR and CR were evaluated in pts with ≥ 180 days of follow-up. Kaplan-Meier estimates were calculated for PFS and OS. Multivariable analyses comparing race and ethnicity were conducted via logistic and Cox regression. Results: Among all, 1127 (81%) were White, 70 (5%) African American and 81 (6%) Asian; 152 (11%) were Hispanic including 104 White, 2 Black, and 1 Asian Hispanic. African Americans, compared to White, were younger (median age 55.5 vs 62.8 years), more likely to have pulmonary impairment (41% vs 28%) and tended to have longer time from diagnosis (≥ 12 mo 71% vs 59%). Hispanic pts were younger (median age 58.5 vs 62.6 years) than non-Hispanic pts. ORR was 74% (CR 57%, 12-mo PFS and OS 48% and 63%) for White, 57% (CR 45%, 12-mo PFS and OS 36% and 62%) for African American, 67% (CR 53%, 12-mo PFS and OS 55% and 65%) for Asian and 73% (CR 55%, 12-mo PFS and OS 50% and 65%) for Hispanic pts. Grade ≥ 3 CRS and ICANS occurred in 7% and 18% of African American, 10% and 19% of Asian, and 8% and 27% of White pts, respectively. Hispanic pts had lower rates of grade ≥ 3 CRS and ICANS (4% and 15%) vs non-Hispanic (9% and 27%). African American race was associated with inferior ORR (OR 0.40; 95% CI, 0.24-0.69) and CR rate (OR 0.55; 95% CI 0.32-0.93) vs White. Asian pts had favorable DOR compared to both White (HR 0.46; 95% CI 0.24-0.87) and African American (HR 0.39; 95% CI 0.17-0.88). No statistical differences were found in OS and PFS across races, nor in any efficacy outcome between Hispanic and non-Hispanic pts. Asian (OR 0.52; 95% CI 0.29-0.96 vs White) and Hispanic pts (OR 0.51; 95% CI 0.31-0.85 vs non-Hispanic) had lower risk of grade ≥ 3 ICANS. Conclusions: Overall, axi-cel showed favorable OS, PFS and safety profile regardless of race and ethnicity in the real-world setting. No notable differences in outcomes were observed for Hispanic or Asian pts. Lower response rates in African American pts noted here warrant further investigation including any underrepresentation not explained by a lower incidence rate for DLBCL (SEER), access to care, and disease burden.

7556 Background: The majority of R/R NHL progressions after CART involve pre-existing sites, suggesting a promising role for bridging radiotherapy (bRT). We assessed the local control rate of disease sites bridged with radiotherapy prior to CART and identified predictors of in-field recurrence. Methods: We retrospectively reviewed 35 patients with aggressive B-cell NHL who received bRT between leukapheresis and CART infusion between 2018 and 2021 at a multi-site single institution. bRT local control rate (LC), calculated based on the total number of irradiated sites, was defined from bRT end date. Progression-free survival (PFS) and overall-survival (OS) were defined from the date of CART infusion. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. Kaplan-Meier plots and cox regression modeling were used to estimate the desired output. Results: Median age of the cohort at time of CART infusion was 59 (range 19-73). The median equivalent 2 Gy dose (EQD2) administered was 23.3 Gy (range 4-41 Gy). The median time from end of bRT to CART infusion was 14 days (range 6-42). Five (14%) patients also received bridging chemotherapy with bRT. Among the 34 evaluable patients, 30 (88%) achieved an objective response (59% complete response and 29% partial response). At a median follow-up of 12 months, 1-year PFS was 48% and 1-year OS was 72%. No progression occurred beyond 240 days. On review of treatment plans and pre-treatment PET/CT scans, 59 sites were identified that received bRT prior to CART infusion. The median size and SUVmax of the irradiated sites were 8.7cm (range 1.5-22) and 13 (range 4-46), respectively. Of the 59 irradiated sites, 8 sites (13.6%) in 7 patients had in-field local recurrence, translating to 1-year LC of 84%. No in-field recurrence occurred beyond 180 days. Moreover, no local recurrence occurred in patients who received radiation to all known sites of active disease to EQD2> 30 Gy (n = 4 patients); these patients remained in remission except for 1 who experienced progression outside the bRT field. On univariate analysis, triple hit lymphoma (THL) (OR 22.8, 95% CI: 3.8-138.3; p < 0.001), tumor size (OR 1.25, 95% CI: 1.1-1.4; p < 0.001), specifically ≥ 9cm (OR 9.4, CI: 1.2-77.3; p = 0.036) and SUVmax (OR 1.1, CI: 1.02-1.15; p = 0.008), specifically ≥ 20 (OR 5.6, CI: 1.3-23.7; p = 0.018), were significantly associated with increased risk of in-field recurrence. On multivariate analysis, THL (OR 32.9, CI: 3.2-336.0; p = 0.03) and tumor size (OR 1.3, CI: 1.1-1.6; p = 0.01) retained significant association with in-field recurrence. Conclusions: Bridging radiotherapy prior to CART provides excellent and durable in-field local control for R/R B-cell NHL. Patients with triple hit histology and bulky disease are likely at higher risk of in-field recurrence and may benefit from higher doses of bRT.

e19049 Background: Prognosis of COVID-19 is poor in the setting of immunosuppression. Casirivimab/imdevimab (REGEN-COV), bamlanivimab, and sotrovimab are investigational monoclonal antibodies (MoAbs) authorized for treatment of mild/moderate COVID-19 for patients (pts) 12 years or older and who are at high-risk for progression to severe COVID-19. These neutralizing antibodies, against SARS-CoV-2 spike proteins, have been shown to decrease risk of progression to severe disease. Recipients of allogeneic stem cell transplants (allo-SCT) or chimeric antigen T cell therapy (CAR T cell) represent a high risk population. However, treatment outcomes with these MoAbs in these pts are not well described. Methods: This retrospective study included 33 consecutive adult pts who developed mild/moderate COVID-19 and received anti-spike SARS-CoV-2 MoAbs between December 2020 and November 2021. Allo-SCT (N=27) or CAR T cell (N=6) recipients were included, and outcomes were analyzed separately. Pts received REGEN-COV (N=19), bamlanivimab (N=11), or sotrovimab (N=1), missing (N=2). Results: In the allo-SCT cohort (N=27), median age at time of COVID-19 was 55 (23-76) years. Median time from allo-SCT to COVID-19 was 31 (22-64) months. Two pts received CAR T-cell therapy prior to allo-SCT. Diagnoses included leukemia or myeloid diseases (82%), lymphoma (11%), or myeloma (7%). Transplant characteristics are summarized (Table). Thirteen pts were vaccinated against SARS-CoV-2 prior to breakthrough COVID-19. Events considered included hospitalization due to COVID-19, disease progression, or death from any cause. The 6-month event-free and overall survivals were 81% and 91%, respectively. In the CAR T cell recipients cohort (N=6), 4 pts received axicabtagene ciloleucel for diffuse large B-cell or follicular lymphoma and 2 received brexucabtagene autoleucel for mantle cell lymphoma. The median follow-up was 8 (1-11) months. Two pts received autologous SCT prior to COVID-19. Median time from CAR T cell therapy to COVID-19 was 10 (3-24) months. Three pts were vaccinated prior to COVID-19. Only 1 pt was hospitalized due to severe COVID-19 requiring mechanical ventilation leading to death. Conclusions: These results show a potential benefit of MoAbs in high-risk pts, namely allo-SCT or CAR T cell recipients. Future studies should evaluate the role of prophylactic use MoAbs in these populations. A comparative analysis with a matched control cohort (who did not receive MoAbs) will be provided at the meeting. [Table: see text]

Abstract Background In patients with newly diagnosed glioblastoma, rapid early progression (REP) refers to tumor regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis appraised previously published data on REP to better characterize and understand it. Methods Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to October 21, 2021. Studies describing the incidence of REP—tumor growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly diagnosed glioblastoma were included. The primary outcome was REP incidence. Results From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0–58.8 y). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1–1.5). The median number of days between MRI scans was 34 days (IQR 18–45 days). The mean incidence rate of REP was 45.9% (range 19.3%–72.0%) and significantly lower in studies employing functional imaging to define REP (P &lt; .001). REP/non-REP groups were comparable with respect to age (P = .99), gender (P = .33) and time between scans (P = .81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30–2.43, P &lt; .001), shortened progression-free survival (HR 1.78, 95% CI 1.30–2.43, P &lt; .001), subtotal resection (OR 6.96, 95% CI 4.51–10.73, P &lt; .001) and IDH wild-type versus mutant tumors (OR 0.20, 95% CI 0.02–0.38, P = .03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72–2.28, P = .39). Conclusions REP occurs in almost half of patients with newly diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.

INTRODUCTION: Peptic ulcer disease (PUD) is a common cause of hospitalization worldwide. We assessed temporal trends in hospitalization for PUD in 36 Organisation for Economic Co-operation and Development (OECD) countries since the turn of the 21st century. METHODS: The OECD database contains data on PUD-related hospital discharges and mortality for 36 countries between 2000 and 2019. Hospitalization rates for PUD were expressed as annual rates per 100,000 persons. Joinpoint regression models were used to calculate the average annual percent change (AAPC) with 95% confidence intervals (CIs) for each country, which were pooled using meta-analyses. The incidence of PUD was forecasted to 2021 using autoregressive integrated moving average and Poisson regression models. RESULTS: The overall median hospitalization rate was 42.4 with an interquartile range of 29.7–60.6 per 100,000 person-years. On average, hospitalization rates (AAPC = −3.9%; 95% CI: −4.4, −3.3) and morality rates (AAPC = −4.7%; 95% CI: −5.6, −3.8) for PUD have decreased from 2000 to 2019 globally. The forecasted incidence of PUD hospitalizations in 2021 ranged from 3.5 per 100,000 in Mexico to 92.1 per 100,000 in Lithuania. Across 36 countries in the OECD, 329,000 people are estimated to be hospitalized for PUD in 2021. DISCUSSION: PUD remains an important cause of hospitalization worldwide. Reassuringly, hospitalizations and mortality for PUD have consistently been falling in OECD countries in North America, Latin America, Europe, Asia, and Oceania. Identifying underlying factors driving these trends is essential to sustaining this downward momentum.