Citations

Background COVID‐19 is an infectious illness, featured by an increased risk of thromboembolism. However, no standard antithrombotic therapy is currently recommended for patients hospitalized with COVID‐19. The aim of this study was to evaluate safety and efficacy of additional therapy with aspirin over prophylactic anticoagulation (PAC) in patients hospitalized with COVID‐19 and its impact on survival. Methods and Results A total of 8168 patients hospitalized for COVID‐19 were enrolled in a multicenter‐international prospective registry (HOPE COVID‐19). Clinical data and in‐hospital complications, including mortality, were recorded. Study population included patients treated with PAC or with PAC and aspirin. A comparison of clinical outcomes between patients treated with PAC versus PAC and aspirin was performed using an adjusted analysis with propensity score matching. Of 7824 patients with complete data, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC. Propensity‐score matching yielded 298 patients from each group. In the propensity score‐matched population, cumulative incidence of in‐hospital mortality was lower in patients treated with PAC and aspirin versus PAC (15% versus 21%, Log Rank P =0.01). At multivariable analysis in propensity matched population of patients with COVID‐19, including age, sex, hypertension, diabetes, kidney failure, and invasive ventilation, aspirin treatment was associated with lower risk of in‐hospital mortality (hazard ratio [HR], 0.62; [95% CI 0.42–0.92], P =0.018). Conclusions Combination PAC and aspirin was associated with lower mortality risk among patients hospitalized with COVID‐19 in a propensity score matched population compared to PAC alone.

Abstract Richter’s syndrome (RS) arising from chronic lymphocytic leukemia (CLL) is a striking example of an aggressive malignant histology that emerges from indolent cancer. RS is a major barrier to disease control in CLL and is associated with poor clinical outcomes and limited survival. The genetic basis of RS is poorly understood, and its relationship to the antecedent CLL remains incompletely characterized. To study RS, we performed whole-exome sequencing (WES) on samples collected from 52 patients with RS of diffuse large B cell lymphoma (DLBCL) histology. For this genomic characterization, samples from 42 patients were analyzed as ‘trios’ (matched germline, CLL and RS tissue DNA) and those from 10 as ‘duos’ (matched CLL and RS DNA). Beyond addressing contamination of CLL DNA in the germline sample, we developed methods for discriminating between the RS and CLL clones which often coexist in the same samples. The discovery cohort revealed that RS and CLL were clonally-related in 45/52 (87%) cases based on WES analysis, with a distinct RS clone emerging from a CLL subclone. The remaining 13% were determined to be clonally unrelated. RS clones presented ~3x higher rates of additional mutations than the ancestral CLL clones from which they developed. We identified novel RS somatic driver mutations (in IRF2BP2, SRSF1, B2M, DNMT3A and others), a high rate of copy number variations with recurrent deletions (e.g., del(17p) [TP53], del(13q14.3), del(7q36), and del(15q13.11) [MGA], del(9p21.3) [CDKN2A/B], del(16q12.2)), focal amplifications (amp(7q21.2) [CDK6], amp(8q24.2) [RECQL4, MYC], amp(13q31.2) [ERCC5], and frequent whole genome duplication. To further investigate RS and CLL clonal evolution, we performed single-cell RNA-sequencing on biopsies at the time of RS diagnosis in 5 individuals with clonally related transformation. Using our novel tool, CNVSingle, we inferred allele specific single-cell copy number alterations, yielding cluster-specific copy number profiles that matched the WES results of individual subclones of the RS and CLL populations. This enabled mapping genetic clones to specific expression patterns. Finally, we devised and tested a methodology that uses cfDNA for early detection of emerging Richter’s disease and have successfully identified Richter‘s tumor DNA in the blood several months prior to the clinical diagnosis. Our study thus defines drivers, distinct molecular subtypes and evolutionary path to RS and suggests strategies for its improved detection. Citation Format: Erin M. Parry, Ignaty Leshchiner, Romain Guièze, Connor Johnson, Eugen Tausch, Sameer Parikh, Camilla Lemvigh, Conor Messer, Daniel Rosebrock, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Matthew Davids, Raquel A. Jacobs, Kara Slowik, Julien Broseus, Shanye Yin, Shuqiang Li, Geoff Fell, Ziao Lin, Binyamin A. Knisbacher, Neil Ruthen, Dimitri Livitz, Christof Schneider, Jialin Ma, Julian Hess, Laura Z. Rassenti, Thomas J. Kipps, Nitin Jain, William Wierda, Florence Cymbalista, Neil E. Kay, Kenneth J. Livak, Brian P. Danysh, Chip Stewart, Donna Neuberg, Jennifer R. Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, Catherine J. Wu. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter’s syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4007.

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.

Purpose: Prior research has noted similar functional and subjective outcomes between individuals with delayed amputation vs. limb salvage; however, these reports are generally retrospective in nature. Here, we prospectively compare functional and subjective outcomes from an individual with limb salvage to a delayed transtibial amputation using a single-subject design with sequential participation in a fall-prevention program. Materials and Methods: The subject participated in a fall-prevention rehabilitation training program, once before undergoing a delayed transtibial amputation and again after. As part of the fall-prevention program, the participant completed pretraining and post-training assessments which quantified trunk control by 1) trunk flexion and flexion velocity after trip-inducing perturbations on a treadmill and 2) trunk sway parameters during unstable sitting. In addition, the four square step test was administered, and patient-reported outcomes, including pain, prosthetic/orthotic comfort, and walking/running endurance, were collected. Results: In general, the participant demonstrated improved trunk control after amputation, as evidenced by decreases in trunk flexion and flexion velocity after perturbation and sway parameters during unstable sitting. In addition, four square step test times were shorter with amputation vs. limb salvage; the participant also reported reduced pain and greater comfort with amputation (vs. limb salvage). Conclusions: Although just a single participant, within-subject comparisons provide quantitative evidence that, for some individuals, delayed/late (transtibial) amputation after prolonged limb salvage may be beneficial in reducing pain and restoring function.

9135 Background: Bronchial carcinoid (BC) is often categorized into multifocal (MBC) or solitary (SBC). MBC, excluding tumorlet and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, is considered a relatively uncommon subgroup of BC, with much of the MBC literature stemming from case reports/small series. Our study analyzes MBC among a large cohort of 569 patients with BC and argues for change to the current clinical understanding of MBC. We suggest using the term bronchial neuroendocrine tumor (bNET) to more accurately represent its cells of origin and move away from “carcinoid” (historically meaning “carcinoma-like”) and the outdated associated connotation that carcinoids all have a similar, benign clinical and biological behavior. Methods: Using the Mayo Clinic Epidemiology and Genetics of Lung Cancer Database with Institutional Review Board approval, we retrospectively reviewed 569 patients with bNET (204 males, 365 females) presenting to Mayo Clinic Rochester between 1/1997-12/2012. We used univariate and multivariate Cox regression analyses to evaluate factors affecting overall survival. Results: 80 patients (of 569, 14.1%) were diagnosed with multifocal (MbNET) and 489 with solitary (SbNET). Two-sided Fisher’s exact tests found that older age, female gender, never having smoked cigarettes, and tumorlets were associated with MbNET diagnosis. Family lung cancer history, histopathologic grading (pathology: typical vs. atypical), Ki67, and presence of syndromes (carcinoid, Cushing, and MEN1 syndromes) were similar between MbNET and SbNET groups. Most MbNET cases were stage III-IV at the time of diagnosis, while the majority of SbNET cases were stage I. 5-year OS (83%) and 5-year PFS (75%) of MbNET patients were higher than those of their SbNET counterparts (74% and 68%, respectively). Metastasis status was an independent prognostic factor of poor OS in SbNET (P<0.001) but not in MbNET (P=0.71)(Table). Conclusions: Clinical, radiologic, and histopathologic characteristics and prognostic factors differed between SbNET and MbNET. MbNET arose as a new entity often with advanced stage disease, but good prognosis, which does not follow the NSCLC TNM staging system as in the 2009 NCCN guidelines (used during this study) or the updated 2021 NCCN guidelines which continue to stage lung carcinoid similarly to NSCLC. It may be beneficial to consider multifocal lung carcinoid instead as multifocal bNET, a new clinical entity, warranting a novel staging approach that more accurately reflects prognosis.[Table: see text]

TPS8604 Background: Chemoimmunotherapy followed by durvalumab maintenance yields a median overall survival of 12.9 months in patients with extensive stage Small Cell Lung Cancer (ES SCLC), which is an improvement over chemotherapy alone. However, 90% of these patients will have progressive disease. While topotecan and lurbinectedin have established modest activity in the second line, it is unknown whether continuing immunotherapy in this setting confers additional benefit. In preclinical studies lurbinectedin, a DNA minor groove binder, used with immune checkpoint inhibitors has synergistic effects. Methods: This phase 2 trial is enrolling patients with ES SCLC who have progressed on platinum based chemoimmunotherapy, to three treatment groups. Group 1 includes patients with platinum sensitive SCLC who will receive durvalumab (1500 mg given as an intravenous [IV] infusion once every 3 weeks) and topotecan (1.25 mg/m2/day IV for 5 consecutive days every 3 weeks). In Groups 2A and 2B, patients with platinum sensitive and platinum resistant disease respectively, receive durvalumab and lurbinectedin (3.2 mg/m2 IV on Day 1 of every 21-day cycle). Patients with platinum sensitive disease are assigned to Groups 1 or 2A based on the preferences of the treating physician and the patient. Patients with treated/stable CNS metastases are eligible. The primary endpoint is the proportion of patients who are alive at 6 months (6OS) for Group 1 and the proportion of patients who are alive and progression-free at 6 months (6PFS) in Groups 2A and 2B. Secondary endpoints include safety, adverse event profile, response rate, PFS, and OS. The sample size is based on a 2-stage Simon Optimal Design. For Treatment Group 1, with 22 eligible patients there is 80% power to detect a true 6-month OS rate (6OS) of 75%, with 10% alpha under the null hypothesis that the true 6OS is at most 50%. For Treatment Group 2A, with 20 eligible patients this design has 80% power to detect a true 6-month PFS rate (6PFS) of 65%, with 10% alpha under the null hypothesis that the true 6PFS is at most 40%. For Treatment Group 2B, with 22 eligible patients this design has 80% power to detect a true 6-month PFS rate (6PFS) of 40%, with 10% alpha under the null hypothesis that the true 6PFS is at most 19%. To account for possible drop-outs, accrual targets will be 24, 22, and 24 patients to Groups 1, 2A, and 2B respectively. For the safety analyses, 6 patients will be enrolled at the starting dose level for each treatment group (1, 2) and then briefly closed to accrual to assess adverse events. If we observe 2+ DLTs in these 6 treated patients during Cycle 1 within a treatment group (1 vs. 2), we will declare the combination treatment too toxic and lower the starting dose of chemotherapy for the next 6 patients. The study was open for all 3 groups as of January 2022 and has accrued 2 patients. Clinical trial information: NCT04607954.

TPS2676 Background: Solid tumors comprise > 90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively) (ACS. 2021). Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies (Neelapu S. et al. N Engl J Med. 2017). Translating engineered T-cell therapies to solid tumors has proven to be challenging due to a lack of tumor-specific targets that can discriminate cancer cells from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and mesothelin (MSLN) CARs resulted in dose-limiting on-target, off-tumor toxicities (Parkhurst M, et al. Mol Ther. 2011; Tanyi J. Cellicon Valley '21). To create a therapeutic safety window, Tmod CAR T-cell therapy utilizes dual-signaling receptors to create a robust NOT logic gate capable of killing tumor cells, while leaving healthy cells intact (Hamburger A, et al. Mol Immunol. 2020). The 2 receptors in Tmod CAR T-cell therapy comprise an activator that recognizes an antigen on the surface of tumor cells that may also be present on normal cells, such as CEA and MSLN, and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. The frequency of HLA LOH among advanced GI solid tumor cancers in the Tempus real-world dataset is 16.3% with a range of 15.6%-20.8% between colorectal, pancreatic, and gastroesophageal tumors (Hecht R. et al. ASCO-GI 2022. Abstract #190). As such, HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy. Different activator/blocker combinations can be engineered with the Tmod platform technology and may be applied to T cells and natural killer cells in autologous and allogeneic settings. BASECAMP-1 is a currently enrolling observational study with key objectives of 1) To identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) To obtain leukapheresis and feasibility for the future EVEREST Tmod CAR T-cell trial. Methods: BASECAMP-1 (NCT04981119) patient eligibility has 2 parts: 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central NGS. If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed for somatic mutations by xT-Onco NGS testing. 2) If the tumor demonstrates HLA-A*02 LOH and the patient is eligible after screening, the patient will undergo leukapheresis. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study to reduce waiting time at relapse. Clinical trial information: NCT04981119.

TPS613 Background: Approximately 50% of newly diagnosed breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), & (RS <11, RS 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence. Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). The study is powered to detect a non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 (835 per arm) pts are required to be randomized. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, pts will be required to register (1,714 pts) to ensure that our final randomized cohort is 1,670 pts. Current accrual (2-2-2022) is 52 screened and 45 randomized. Support: U10CA180868, -180822, NCT04852887. Clinical trial information: NCT04852887.

Abstract H3K27-altered diffuse midline glioma (DMG) is a uniformly lethal CNS cancer that predominately occurs in children. In the last decade, while studies revealing the molecular underpinnings of the disease have paved the way for novel therapeutic strategies, this tumor remains a death sentence. Our lab and others have identified numerous drugs of high interest for treating this devasting disease, however, every trial has failed to show benefit. Is our failure to translate these laboratory findings due to the fact we have not found the right drugs or treatment regimens yet? Or is this a failure to get the drugs to the tumor? Or is this simply a very bad disease to treat? The answer is likely multifactorial. Our lab, in collaboration with others, have strong data to show that simply getting drugs to the tumor will not result in a positive benefit. Most drugs are rapidly cleared from their target space. Utilizing techniques that increase the drug-tumor resonance time is necessary to translate our basic science findings to our patients. Picking the right drug and the delivery mechanism is not enough for a positive effect. Here, we assessed the efficacy of a previously identified inhibitor, alisertib, delivered by short-term convection-enhanced delivery or a continuous osmotic pump and found that continuous, direct delivery results in a significant increase in survival (p = 0.0002). Furthermore, long-term survivors showed a decreased tumor burden and on-target drug effects. These data support that translation into patients must consider three factors: 1) selection of a potent therapy, 2) selection of the proper delivery method for that therapy, 3) modulation to ensure that the therapy remains in the targeted tissue long enough for desired effect. Keeping these basic tenets at the forefront of development may finally lead to a more effective treatment strategy for this devastating disease

Abstract High-grade gliomas (HGG) encompass a large proportion of malignant tumors within the central nervous system. Despite advances in our understanding of underlying disease mechanisms, the prognosis remains dismal and efficacious therapies are lacking. As such, there is a dire, unmet, gap in clinical practice for treating this devastating disease. Here, we performed convection-enhanced delivery (CED) of GB-13 (also known as IL13.E13K-PE4E), a tumor-specific immunotoxin, into the mouse brain in an effort to assess safety and efficacy. Fifty-five nude mice were inoculated with cells from 3 distinct patient-derived HGG cell lines (low, medium and high IL-13Rα2 expression). After tumor size reached a pre-determined threshold, mice underwent stereotactic cannula placement into the tumor followed by a single 40-min ramped infusion (rate 0.2-0.8 ul/min) of GB-13 (volume of infusion 20 ul) at concentrations ranging from 5 to 50 ug/ml. Tumor progression was monitored semiweekly and animals were euthanized at the indication of progressive neurologic deficit. All animals tolerated the infusions without exhibiting any neurological changes. GB-13 decreased tumor burden and prolonged survival in a manner strongly associated with IL-13Rα2 expression. While no survival benefit was observed in animals harboring IL-13Rα2-low expressing HGG, IL-13Rα2-medium and -high animals lived significantly longer after GB-13 infusion than vehicle-treated animals (median survival prolongation &gt;25 days). Postmortem examination of the brains revealed no morphological changes beyond the site of the cannula tract. While GB-13 decreased cell proliferation and increased the number of apoptotic cells, neuronal cell density in ipsilateral brain regions was retained and no monocyte infiltrate was evidenced following GB-13 exposure. These findings indicate that a single therapeutic infusion of GB-13 administered by CED is well tolerated and underscore the potential of IL-13Rα2-targeted therapies in a subset of HGG with increased IL-13Rα2 expression.