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Background. At 5 and 10 y after kidney transplantation, chronic histologic changes such as arteriolar hyalinosis and mesangial expansion are common; however, determining cause is difficult. We compared surveillance biopsies in living donor kidney transplants (LDKTx) from HLA-matched siblings (termed HLA-identical [HLA-ID]) with HLA non-ID to investigate which histologic changes were likely due to alloimmune injury and which were due to nonalloimmune injury. Methods. We performed a retrospective, cohort study comparing HLA-ID sibling LDKTx (n = 175) with HLA non-ID LDKTx (n = 175; matched for age, sex, and year of transplant ±2 y) performed at a single institution from March 1999 to November 2018. Results. Baseline characteristics and maintenance immunosuppression were similar. Mortality rates were similar, but in the HLA-ID group, 10-y death-censored graft survival was higher (93.8% versus 80.9% HLA non-ID LDKTx; P < 0.001), rejection rates were lower (after 1 y 9.6% versus 27.1%; P < 0.001), and Banff inflammation scores including glomerulitis and peritubular capillaritis were lower on surveillance biopsies at 1, 5, and 10 y. In contrast, chronic Banff scores (interstitial fibrosis, arteriolar hyalinosis, mesangial expansion, etc) were similar in prevalence and severity on surveillance biopsies at 1, 5, and 10 y. Conclusions. HLA-ID LDKTx have less inflammation and less transplant glomerulopathy, but most chronic histologic changes were similar to less well-matched LDKTx. We conclude that these types of chronic changes are not associated with HLA mismatches and may be due to nonimmunologic causes (hypertension, obesity, etc), suggesting that new management approaches to prevent these lesions may be needed.

Abstract Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept “preemptive” treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.

Abstract Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV− HIV− PCNSL and 2 EBV− HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV− PCNSL. As with prior studies, EBV− HIV− PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV− PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV− HIV− PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Introduction: Atrial fibrillation (AF) adversely affect the outcomes in the patients of heart failure (HF) with reduced ejection fraction, however there are limited data exploring such an association in HF with preserved ejection fraction (HFpEF). Hypothesis: AF is associated with worse outcomes in HFpEF. Methods: We included all the patients with the primary diagnosis of HFpEF from the national inpatient sample (NIS) database (2012-2014) using ICD-9 codes. Exposure of interest was AF. Primary outcome was in-hospital mortality and secondary outcomes were rates of sudden cardiac arrest (SCA), syncope, cardiogenic shock, embolic stroke, acute myocardial infarction (AMI), acute kidney injury (AKI), passive hepatic congestion, ventricular fibrillation (V fib) and flutter, ventricular assist device (VAD), AICD, cardiac resynchronization therapy (CRT), intra-aortic balloon placement (IABP) placement and heart transplantation. Hospitalization cost was also studied. Results: Our study cohorts included 26,51,970 patients of HFpEF with AF and 37,44,101 patients of HFpEF without AF. AF cohort had more numbers of older patients and less female representation. In-hospital mortality was more in AF cohort. Similarly, the odds of SCA, cardiogenic shock, embolic stroke, passive hepatic congestion, Vfib and flutter, AICD and CRT placement were higher in AF cohort. The odds of syncope, AMI and AKI were lower in AF cohort as compared to non-AF cohort. While the odds of heart transplantation and VAD and IABP use remained comparable between the study cohorts, AF cohort incurred greater of cost of hospitalization. Conclusion: AF in HFpEF patients is associated with increased in-hospital mortality and cardiogenic shock and should be aggressively treated for improved outcomes.

Introduction: Previous studies had provided evidence that vitamin D deficiency is a strong negative predictor for survival and recovery after severe vascular events but national estimate on disability related burden is not clear. Hypothesis: We evaluate the prevalence of vitamin D deficiency (VDD) amongst patients with cardiovascular disease (CVD) and cerebrovascular disorders (CeVD) and to find out whether or not CVD and CeVD in the presence of VDD increases the disability. Methods: We performed a retrospective analysis of the Nationwide Inpatient Sample data (years 2016-2017) in adults (≥18 years) hospitalizations. We identified patients with secondary diagnosis of VDD and primary diagnosis of CVD (AFib, CHF, IHD, acute MI, and angina) and CeVD (AIS, TIA, ICeH and SAH) using ICD-10-CM codes. We performed a chi-square test and multivariable survey logistic regression to analyze disability of patients with CVD and CeVD in presence of VDD. Disability/loss of function was investigated by APRDRGs severity using 3M Health Information Systems software. (Score 1-4 indicates minor to extreme loss of function) Results: Among 58,259,589 US hospitalizations, 3.44%, 2.15%, 0.06%, 1.28%, 11.49%, 1.71%, 0.38%, 0.23% and 0.08% had primary admission of IHD, acute MI, angina, AFib, CHF, AIS, TIA, ICeH and SAH, respectively and 1.82% had VDD. Prevalence of hospitalizations due to CHF (14.66% vs 11.43%), AIS (1.87% vs 1.71%) and TIA (0.4% vs 0.38%) was higher; and IHD (2.62% vs 3.45%), acute MI (1.58% vs 2.16), angina (0.05% vs 0.06%), AFib (1.14% vs 1.28%), ICeH (0.17% vs 0.23%) and SAH (0.05% vs 0.08%) was lower among VDD patients in compare to non-VDD. (p<0.0001) In regression analysis, VDD was associated with higher odds of severe or extreme disability amongst patients hospitalized with AIS (OR:1.1; 95%CI:1.06-1.14), ICeH (1.22; 1.08-1.39), TIA (1.36; 1.25-1.47), IHD (1.37; 1.33-1.41), acute MI (1.44; 1.38-1.49), Afib (1.10; 1.06-1.15), and CHF (1.03; 1.02-1.05) in comparison to without VDD. Conclusions: CVD and CeVD in presence of VDD increase the disability amongst US hospitalizations. Future studies should be planned to evaluate the discharge outcomes as well as the effect of identification and in-hospital management of VDD on improvement of the outcomes.

Introduction: COVID-19 has multiorgan involvement and it is believed that outcomes are poor amongst patients with hypertension (HTN) and pre-existing cardiovascular disorders (CVD). Hypothesis: The objective of this meta-analysis is to evaluate outcomes [mortality and invasive mechanical ventilation (IMV) utilization] of COVID-19 in patients with pre-existing HTN and CVD. Methods: English full-text-observational studies having data on epidemiological characteristics of patients with COVID-19 were identified searching PubMed using MeSH-terms from December 1, 2019, to April 30, 2020. Studies having CVD or HTN as one of the pre-existing comorbidities and described outcomes including IMV and mortality were selected with a consensus of three reviewers. 29 studies met these criteria. Following MOOSE protocol, data on patients’ characteristics especially age and history of CVD, HTN, IMV, and mortality were pooled using a random-effects model. The pooled prevalence of CVD and HTN were calculated. Meta-regression was performed and correlation coefficient (r) and odds ratio (OR) were estimated to evaluate the effects of pre-existing CVD and HTN on outcomes of COVID-19 patients. Results: Out of 29 studies with COVID-19 epidemiology data, 21, 17, 18 and 19 studies have details on mortality, IMV, HTN, and pre-existing CVD, respectively. Pooled prevalence of HTN was 28.2% [95%CI:22.1%-35.1%; p<0.001; 4858/11626 patients; Heterogeneity (I 2 ):97.8%] and pre-existing CVD was 12.2% [8.9%-16.6%; p<0.001; 2044/11664 patients; I 2 :96.8%]. In age-adjusted meta-regression analysis, IMV was significantly higher among COVID-19 patients with pre-existing CVD [r:0.28; OR:1.3 (1.1-1.6); I 2 :89.7%; p=0.0028] without significant association with HTN [r:0.01; OR:1.0 (0.9-1.1); I 2 :95.9%; p=0.8161]. HTN [r:0.001; OR:1.0 (0.9-1.1); I 2 :96%; p=0.9685] and pre-existing CVD [r:-0.01; OR:0.9 (0.9-1.1); I 2 :96.3%; p=0.8772] had no significant association with mortality amongst COVID-19 patients. Conclusion: In the age-adjusted analysis, though we identified pre-existing CVD as a risk factor for higher utilization of IMV, pre-existing CVD and HTN had no independent role in increasing mortality.

Background: Real world multi-institutional data of anti-CD19 CAR-T therapy from across the US shows similar response rates and toxicities as that of the registration trials. For axicabtagene ciloleucel (axi-cel), bridging therapy (BT) during CAR-T manufacturing was not allowed. Real world data shows that patients who received BT had lower complete remission (CR) rates, duraiton of response (DOR) and overall survival (OS). Whether the poorer outcome is due to the effect of the BT or the aggressive biology of the disease is unknown. Patients with lower disease burden had higher response rate in the registration study ZUMA-1 for axi-cel. We examined the impact of response to BT on CAR-T outcome. Specifically, we also describe our experience using polatuzumab vedotin, bendamustine and rituximab (Pola-BR), also a recently approved therapy for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), prior to CAR-T as salvage (ST) and BT. Methods: A retrospective review of 63 patients who received axi-cel for NHL from June 2016 - March 2020 at Mayo Clinic, Rochester was performed. ST was defined as the last therapy prior to leukapheresis and grouped into categories - autologous stem cell transplant (ASCT), and non-ASCT (chemotherapy and immunotherapy) . BT was defined as lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Response to all lymphoma-directed therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death. Results: Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing that would reduce the likelihood of eligibility to receive CAR-T. The decision and choice of BT was at the discretion of the treating physician. Sixty-eight percent (n=43) of the patients received BT (19 chemo, 24 immunotherapy). Demographics of the patients based on their response to BT are shown in table 1. More patients in the BT responder group had received chemotherapy as type of bridge (58% vs. 33%). With a median follow up of 12-months for those still alive, significant improvement in EFS was seen in patients who had partial response (PR) or stable disease (SD) to BT than patients who continued to progress (median 12 months vs. 3 months, p = 0.01) [Figure 1A]. OS however, was not significant between the two groups (median OS 18 months - responders vs. 12 months non-responders, p = 0.19) [Figure 1B]. We also describe in the case series below 11 patients who received Pola-BR in salvage setting (ST) and/or BT (Table 2). Due to the lymphopenic effects of bendamustine, it was avoided before T-cell collection if possible. Two patients, however, received bendamustine as part of Pola-BR for salvage therapy as its need was determined per the managing physician. Axi-cel was successfully manufactured for all 10 patients. One patient did not have measurable disease after Pola-BR BT and remains on observation. A second patient died before CAR-T infusion from progressive disease. Four of the nine patients treated with CAR-T remained in response. Updated outcome will be presented. Conclusion: While patients who received BT have worse EFS than those who didn't, having some control of lymphoma after BT was associated with better EFS compared to patients who continued to have progressive disease after BT. Preliminary data from Pola-BR case series shows 60% (6/10) patients achieved PR/SD before CAR-T infusion, but requires longer follow up for its impact on survival. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Ansell:AI Therapeutics: Research Funding; Takeda: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy.

AbstractBackgroundThe leadless Micra transcatheter‐pacing system (Micra‐TPS) is implanted via a femoral approach using a 27‐French introducer sheath. The Micra Transcutaneous Pacing Study excluded patients with inferior vena cava (IVC) filters.ObjectiveTo examine the feasibility and safety of Micra‐TPS implantation through an IVC filter.MethodsThis multicenter retrospective study included patients with an IVC filter who underwent a Micra‐TPS implantation. Data for clinical and IVC filter characteristics, preprocedure imaging, and procedural interventions were collected. The primary outcome was a successful leadless pacemaker (LP) implantation via a femoral approach in the presence of an IVC filter. Periprocedural and delayed clinical complications were also evaluated.ResultsOf the 1528 Micra‐TPS implants attempted, 23 patients (1.5%) had IVC filters. The majority (69.6%) of IVC filters were permanent. Six (26.1%) patients underwent preprocedural imaging to assess for filter patency. One patient's filter was retrieved before LP implantation. The primary outcome was achieved in 21 of 22 patients (95.5%) with an existing IVC filter. An occluded IVC precluded LP implantation in one patient. Difficulty advancing the stiff guidewire or the 27‐Fr sheath was encountered in five patients. These cases required repositioning of the wire (n = 2), gradual sheath upsizing (n = 2), or balloon dilation of the filter (n = 1). Postprocedure fluoroscopy revealed intact filters in all cases. During a median 6‐month follow‐up, there were no clinical complications related to the filter or the Micra‐TPS.ConclusionThis multicenter experience demonstrates the feasibility and safety of Micra‐TPS implantation via an IVC filter without acute procedural or delayed clinical complications.

BackgroundProzone is a known phenomenon affecting immunoassays causing falsely low or negative results when excess target is present in the test system. For assays used to evaluate immune‐mediated platelet (PLT) transfusion refractoriness, prozone‐like phenomenon has been described in solid‐phase human leukocyte antigen (HLA) antibody testing and can be mitigated by diluting samples or pretreating samples with ethylenediaminetetraacetic acid (EDTA) or dithiothreitol. Prozone phenomenon has not yet been described in solid‐phase red blood cell (RBC) adherence PLT crossmatch assays.Case ReportA 40‐year‐old female with myeloid sarcoma and PLT transfusion refractoriness underwent repeated solid‐phase PLT crossmatches; however, crossmatch‐compatible PLTs units did not yield adequate PLT count responses. Class I HLA antibody testing with neat, diluted, and EDTA‐pretreated serum demonstrated significant prozone‐like effect and the presence of numerous high strength HLA antibodies. Based on this HLA antibody profile, HLA antigen–negative PLTs gave an adequate PLT count response. It was noted that the HLA types of her crossmatch‐compatible PLTs were incompatible with her HLA antibody profile (eg, HLA‐A2). With ABO‐identical, HLA‐A2–positive PLT units, a solid‐phase PLT crossmatch was repeated using undiluted and diluted EDTA plasma. Undiluted EDTA plasma demonstrated negative or weakly positive PLT crossmatches while the diluted EDTA plasma demonstrated strongly positive PLT crossmatches.ConclusionThe prozone phenomenon can cause false‐negative results in solid‐phase RBC adherence PLT crossmatch assays, which can be mitigated with sample dilution. In immune‐mediated PLT transfusion–refractory patients with high‐strength HLA antibodies, sample dilution should be considered to correctly identify compatible PLT inventory.

AbstractCancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.