SARS-CoV-2-SPECIFIC T CELLS ASSOCIATED with LUNG DYSFUNCTION in LONG COVID-19

Background: After infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a significant number of individuals develop post-acute sequelae of COVID-19 (PASC) marked by prolonged symptoms, including persistent pulmonary dysfunction. An estimated 5-20% of those infected with SARS-CoV-2 will go on to develop PASC. T cells and inflammation contribute significantly to severe COVID-19 and similar chronic conditions;however, little is known about the role of persistent inflammation and SARS-CoV-2-specific immunity in PASC. The objective of this study is to compare inflammatory markers, frequencies of SARS-CoV-2-specific T cells, and pulmonary function in subjects who recovered from acute COVID infection (AC) and PASC. Methods: We collected blood samples from 35 individuals after recovery from SARS-CoV-2 infection and divided the cohort by symptom duration into AC or PASC. We measured T cell responses to SARS-CoV-2 surface proteins, assessed levels of inflammatory markers in the plasma and measured pulmonary function. The Mann-Whitney U test were utilized to examine differences between groups. Correlations were calculated using the nonparametric Spearman test. P values of <0.05 were considered statistically significant. Results: Compared to AC, subjects with PASC had significantly elevated plasma CRP and IL-6 and up to a hundred-fold increase in the frequency of IFN-γ-and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in blood. Importantly, the frequency of SARS-CoV-2-specific, TNF-α-producing CD4+ and CD8+ T cells in PASC positively correlated with plasma IL-6 and negatively correlated with measures of lung function, including FEV1, while increased frequencies of IFN-γ-producing T cells were associated with the duration of respiratory symptoms during the post-acute period. Conclusion: Significant immunological differences exist between subjects with PASC and AC that are associated with increased inflammation and pulmonary dysfunction, suggesting that persistent immunologic differences may drive ongoing symptoms in PASC. The persistence of SARS-CoV-2-specific T cells in PASC suggests the presence of persistent viral reservoirs as a possible mechanism behind PASC etiology.

Isolated Durable LVAD Bridge to Transplant: Institutional Review Following 2018 Allocation Changes

Purpose: The purpose of this study was to compare our institutional experience using durable left ventricular assist devices (dLVADs) as a bridge to transplant before and after the 2018 heart allocation policy change. Methods: Since the allocation change, 29 patients have been bridged to heart transplantation with an isolated dLVAD at our institution. We matched these patients with the most recent 29 consecutive patients bridged to heart transplantation with isolated dLVAD. Baseline pretransplant characteristics and comorbidities were compared between cohorts. Incidence of posttransplant complications, intensive care unit and hospital lengths of stay were compared, as well as 90-day mortality. Results: Annual number of recipients bridged to transplant using a dLVAD declined after the first year following the allocation policy change (Figure A). Median age, body mass index, and distributions of primary heart failure etiology and dLVAD usage were similar between cohorts. The new policy cohort had a higher incidence of female recipients (21% vs 3%;P=0.044), but a lower incidence of patients maintained on intravenous inotropic therapy at time of transplant (3% vs 21%;P=0.044). Rates of prolonged mechanical ventilation, re-intubation, stroke and renal failure were comparable between cohorts. Intensive care unit length of stay and hospital length of stay were also similar. At 90 days, the new policy cohort experienced higher mortality (21% vs 3%;P=0.044) (Figure B). Conclusion: From our institutional experience, there appears to be continual decline in patients bridged with dLVAD following the allocation policy change. While rates of many postoperative complications appear comparable to the prior era, short-term mortality appears to be higher. Changes in the heart transplant allocation system have resulted in changes in donor availability and selection for recipients with durable LVADs. These changes, along with the impact of the COVID-19 pandemic, may be responsible for these observations.

Pediatric venous thromboembolism prevention: Baseline data for a PICU quality improvement initiative

INTRODUCTION: Venous-thromboembolism (VTE) occurs frequently in critically ill children. Up to 25% with a history of limb related VTE will develop post-thrombotic syndrome, while up to 20% can develop a pulmonary embolus with a mortality rate of between 2-9%. Provision of VTE prophylaxis for critically ill children is highly variable. In preparation for a quality improvement initiative to improve the rate of appropriate VTE prophylaxis in critically ill children, we sought to identify the baseline rate of VTE prophylaxis in our pediatric intensive care unit (PICU). METHODS: A VTE prevention guideline was created by a multidisciplinary working group, adapted from published VTE risk assessment tools. Patients are risk stratified for the development of VTE and bleeding risk. To determine baseline provision of appropriate VTE prophylaxis this guideline was retrospectively applied to randomly selected patients aged 1-18 years admitted to the PICU from December 2020-April 2021. Children with COVID/MIS-C, trauma, ECMO or those receiving therapeutic anticoagulation were excluded. Appropriate VTE prophylaxis was defined as pharmacologic prophylaxis (PP) ± mechanical prophylaxis (MP) for patients with high risk for VTE and with no or low bleeding risk factors;MP for patients with high risk for VTE and bleeding risk factors or for patients with moderate VTE risk. RESULTS: A total of 78 PICU admissions, with a mean age of 10.6 years were reviewed. Of these, 52% did not have VTE prophylaxis, 42% received MP alone, 5% received combined MP and PP, and 1% received PP alone. Based on our VTE prevention guideline only 64% of patients received appropriate prophylaxis based on their risk stratification. Children older than 12 years of age were more likely to receive any kind of prophylaxis compared to children younger than 12 years of age (94% vs 9%). CONCLUSIONS: VTE prophylaxis was provided less often than indicated to our critically ill pediatric patients. Barriers include low utilization of PP when clinically appropriate, difficulties in providing MP to younger children and no defined process to identify VTE risk stratification. PDSA cycles have begun with the aim to provide clinically appropriate VTE prophylaxis to 85% of PICU patients.

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma

Background: DLBCL is highly heterogeneous in underlying biology and clinical behavior. Several high-risk disease features and poor prognostic factors are associated with a higher propensity for refractory disease or relapse after standard R-CHOP therapy;these subset patients require novel strategies to improve upon outcomes. Single-agent TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pre-treated DLBCL (Gordon et al., Clin Cancer Res, 2020). We report results of a phase I single institution, single arm dose escalation study that assessed safety of 1 st line treatment with R-CHOP and adjunctive TAK-659 for treatment naïve high-risk DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage I-IV DLBCL with high-risk features defined as, ABC/non-GCB subtype, high-intermediate or high-risk NCCN-IPI (score ≥4), MYC gene rearranged by FISH including double hit lymphoma (DHL), double expressing DLBCL (DEL;overexpression of MYC ≥40% AND BCL2 ≥50% by IHC respectively), or previously treated transformed low-grade lymphoma without prior exposure to anthracycline, were eligible. Patients were treated with R-CHOP for 1 cycle on or off study followed by combined treatment with R-CHOP and TAK-659 for an additional 5 cycles on study. TAK-659 was dosed daily with dosing escalated from 60mg (dose level 1), to 80mg (dose level 2) to 100mg (dose level 3) based on a 3+3 design. The primary objective was to determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL. Secondary objectives were to assess preliminary efficacy of this combination as determined by overall response rate (ORR) by PET-CT (Lugano 2014 criteria), progression free survival (PFS), overall survival (OS) and establish the pharmacokinetics of TAK-659 according to dose. Results: 12 pts were enrolled from Dec 2019 to Nov 2021. The median age was 64 yrs (range 25-75);8 (67%) had stage III/IV disease, 4 (33%) with high risk NCCN-IPI ≥ 4. Histology included 7 (58%) with de novo DLBCL (4 GCB, 3 non-GCB subtype DLBCL) including 7 (58%) with DEL, 3 (25%) with transformed FL, 1 (8%) with Richter's and 1 (8%) with DHL. Dose level 3 (100 mg) was established as the MTD. PKs were measured pre- and post-dose D1 and D15 of cycle 2;Cuzick's test signaled an increase in AUC by dose level on D1 (p = 0.01) but not on D15 (Fig 1). ORR was 100% (CR 92%;Fig 2). With a median follow-up of 14.2 months, 1 pt had primary refractory disease (ABC and DEL), 2 pts with CR subsequently progressed (1 non-GC DLBCL, 1 Richter's) and 1 died of cardiogenic shock unrelated to study drug. The 12-month PFS and OS rates were 82% and 90% respectively with estimated 18-month PFS and OS rates of 68% and 90% respectively. The most common treatment related adverse events (TRAEs) attributed to TAK-659 were lymphopenia (n=12, 100%), infection (6=, 50%), AST elevation (n = 12, 100%) and ALT elevation (n = 10, 83%) (Table). Incidence and severity of transaminitis was consistent with prior reports for this agent. Most common grade 3/4 toxicities were hematologic. Median number of cycles of TAK-659 delivered was 5 (range 3-5). TRAEs led to TAK-659 dose modifications in 8 (67%) pts, though none at dose level 1: 2 (17%) required permanent dose reductions (both for lung infections), while 5 (42%) required discontinuation (4 for infection, and 1 for febrile neutropenia). R-CHOP administration was delayed in 2 pts because of TAK-659 related TRAEs. Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. Infections encountered included bacterial and opportunistic infections (1 each for PJP, CMV and aspergillosis) and 1 case of COVID. Growth factor prophylaxis and anti-fungal therapy were not mandated;PJP prophylaxis was advised for CD4 counts < 200 at initial diagnosis. Conclusion: TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follic lar lymphoma and DEL produces high CR rates;survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination. [Formula presented] Disclosures: Karmali: BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;Takeda: Research Funding;Karyopharm: Consultancy;EUSA: Consultancy;Janssen/Pharmacyclics: Consultancy;AstraZeneca: Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;Genentech: Consultancy;Epizyme: Consultancy;Roche: Consultancy. Ma: Beigene: Research Funding, Speakers Bureau;Juno: Research Funding;AstraZeneca: Honoraria, Research Funding, Speakers Bureau;Loxo: Research Funding;Janssen: Research Funding, Speakers Bureau;Abbvie: Honoraria, Research Funding;TG Therapeutics: Research Funding;Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board;Agios: Other: Husband: Consultancy;Actinium Pharma: Consultancy;Janssen: Other: Husband: Consultancy;Epizyme: Other: Husband: Data and Safety Monitoring Board;Gilead: Other: Husband: Consultancy;Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board;Karyopharm (Curio Science): Honoraria;Merck: Consultancy, Honoraria, Research Funding;Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties;Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: TAK-659 will be discussed for the treatment of DLBCL (not FDA approved for this indication)