Abstract: Cancer screening deficits during the first year of the COVID-19 pandemic were found to persist into 2021. Cancer-related deaths over the next decade are projected to increase if these deficits are not addressed. Objective To assess whether participation in a nationwide quality improvement (QI) collaborative, Return-to-Screening, was associated with restoration of cancer screening. Design, Setting, and Participants Accredited cancer programs electively enrolled in this QI study. Project-specific targets were established on the basis of differences in mean monthly screening test volumes (MTVs) between representative prepandemic (September 2019 and January 2020) and pandemic (September 2020 and January 2021) periods to restore prepandemic volumes and achieve a minimum of 10% increase in MTV. Local QI teams implemented evidence-based screening interventions from June to November 2021 (intervention period), iteratively adjusting interventions according to their MTVs and target. Interrupted time series analyses was used to identify the intervention effect. Data analysis was performed from January to April 2022. Exposures Collaborative QI support included provision of a Return-to-Screening plan-do-study-act protocol, evidence-based screening interventions, QI education, programmatic coordination, and calculation of screening deficits and targets. Main Outcomes and Measures The primary outcome was the proportion of QI projects reaching target MTV and counterfactual differences in the aggregate number of screening tests across time periods. Results Of 859 cancer screening QI projects (452 for breast cancer, 134 for colorectal cancer, 244 for lung cancer, and 29 for cervical cancer) conducted by 786 accredited cancer programs, 676 projects (79%) reached their target MTV. There were no hospital characteristics associated with increased likelihood of reaching target MTV except for disease site (lung vs breast, odds ratio, 2.8; 95% CI, 1.7 to 4.7). During the preintervention period (April to May 2021), there was a decrease in the mean MTV (slope, −13.1 tests per month; 95% CI, −23.1 to −3.2 tests per month). Interventions were associated with a significant immediate (slope, 101.0 tests per month; 95% CI, 49.1 to 153.0 tests per month) and sustained (slope, 36.3 tests per month; 95% CI, 5.3 to 67.3 tests per month) increase in MTVs relative to the preintervention trends. Additional screening tests were performed during the intervention period compared with the prepandemic period (170 748 tests), the pandemic period (210 450 tests), and the preintervention period (722 427 tests). Conclusions and Relevance In this QI study, participation in a national Return-to-Screening collaborative with a multifaceted QI intervention was associated with improvements in cancer screening. Future collaborative QI endeavors leveraging accreditation infrastructure may help address other gaps in cancer care.

Abstract: The purpose of the COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device) registry was to evaluate the generalizability of the safety and efficacy of the Penumbra System (Penumbra, Inc, Alameda) in a real-world setting. Methods: COMPLETE was a global, prospective, postmarket, multicenter registry. Patients with large vessel occlusion–acute ischemic stroke who underwent mechanical thrombectomy using the Penumbra System with or without the 3D Revascularization Device as frontline approach were enrolled at 42 centers (29 United States, 13 Europe) from July 2018 to October 2019. Primary efficacy end points were successful postprocedure angiographic revascularization (modified Thrombolysis in Cerebral Infarction ≥2b) and 90-day functional outcome (modified Rankin Scale score 0–2). The primary safety end point was 90-day all-cause mortality. An imaging core lab determined modified Thrombolysis in Cerebral Infarction scores, Alberta Stroke Program Early CT Scores, clot location, and occurrence of intracranial hemorrhage at 24 hours. Independent medical reviewers adjudicated safety end points. Results: Six hundred fifty patients were enrolled (median age 70 years, 54.0% female, 49.2% given intravenous recombinant tissue-type plasminogen activator before thrombectomy). Rate of modified Thrombolysis in Cerebral Infarction 2b to 3 postprocedure was 87.8% (95% CI, 85.3%–90.4%). First pass and postprocedure rates of modified Thrombolysis in Cerebral Infarction 2c to 3 were 41.5% and 66.2%, respectively. At 90 days, 55.8% (95% CI, 51.9%–59.7%) had modified Rankin Scale score 0 to 2, and all-cause mortality was 15.5% (95% CI, 12.8%–18.3%). Conclusions: Using Penumbra System for frontline mechanical thrombectomy treatment of patients with large vessel occlusion–acute ischemic stroke in a real-world setting was associated with angiographic, clinical, and safety outcomes that were comparable to prior randomized clinical trials with stringent site and operator selection criteria. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03464565.

Abstract: We developed an epitope selection method for the design of MHC targeting peptide vaccines. The method utilizes predictions for several clinical checkpoint filters, including binding affinity, immunogenicity, antigenicity, half-life, toxicity, IFNγ release, and instability. The accuracy of the prediction tools for these filter variables was confirmed using experimental data obtained from the Immune Epitope Database (IEDB). We also developed a graphical user interface computational tool called ‘PCOptim’ to assess the success of an epitope filtration method. To validate the filtration methods, we used a large data set of experimentally determined, immunogenic SARS-CoV-2 epitopes, which were obtained from a meta-analysis. The validation process proved that placing filters on individual parameters was the most effective method to select top epitopes. For a proof-of-concept, we designed epitope-based vaccine candidates for squamous cell carcinoma, selected from the top mutated epitopes of the HRAS gene. By comparing the filtered epitopes to PCOptim’s output, we assessed the success of the epitope selection method. The top 15 mutations in squamous cell carcinoma resulted in 16 CD8 epitopes which passed the clinical checkpoints filters. Notably, the identified HRAS epitopes are the same as the clinical immunogenic HRAS epitope-based vaccine candidates identified by the previous studies. This indicates further validation of our filtration method. We expect a similar turn-around for the other designed HRAS epitopes as a vaccine candidate for squamous cell carcinoma. Furthermore, we obtained a world population coverage of 89.45% for the top MHC Class I epitopes and 98.55% population coverage in the absence of the IFNγ release clinical checkpoint filter. We also identified some of the predicted human epitopes to be strong binders to murine MHC molecules, which provides insight into studying their immunogenicity in preclinical models. Further investigation in murine models could warrant the application of these epitopes for treatment or prevention of squamous cell carcinoma.

Abstract: Introduction Dozens of secondary mutations in BCR-ABL have been identified in CP-CML patients (pts) whose disease becomes resistant to imatinib. Four TKIs (dasatinib, nilotinib, bosutinib and ponatinib) are potentially available as second (2L) or later line treatment, but no comprehensive clinical dataset or validated preclinical methodology exists to inform the choice of therapy based on BCR-ABL mutation status. While an extensive clinical dataset is available that describes response rates observed with dasatinib 2L treatment according to the specific BCR-ABL mutation present at baseline (eg cytogenetic response rates based on at least 10 pts available for 15 mutants), minimal data are available for the other TKIs, including, nilotinib and, especially, bosutinib and ponatinib. 1A generally more practicable approach is to compare sensitivities of BCR-ABL mutants to each TKI based on in vitro assessments. We have previously compared the in vitro potencies of all approved BCR-ABL TKIs against 21 BCR-ABL mutants, with preliminary results suggesting that TKI potency in vitro could be related to clinical efficacy if clinical pharmacokinetic parameters, and functional effects of protein binding, were taken into account. 2However, confirmation that this, or an alternative, methodology can produce reliable associations between in vitro data and clinical efficacy across all TKIs requires a more extensive clinical dataset than is currently available. To address this gap, we sought to leverage the combined resources of multiple institutions to collect outcome data for all available TKIs being used 2L in CP-CML pts who had a single BCR-ABL mutation detected at baseline. Uniform inclusion criteria were used to enhance the chance that the mutant BCR-ABL clone is the predominant driver of disease, so clinical outcomes could be optimally associated with preclinical data. Here we describe the design and initial results of this effort. Methods De-identified data were collected retrospectively based on chart review of appropriately consented pts. Key inclusion criteria include chronic phase disease being treated 2L and the presence of a single BCR-ABL mutation detected by Sanger sequencing. Additional demographic data collected include the 1L TKI and cytogenetic and molecular response status at baseline. Clinical outcome data collected include whether specific cytogenetic (MCyR or CCyR) and/or molecular (MR1, MR2, MMR) responses were achieved on 2L TKI treatment. To facilitate integration of data across multiple institutions, we examined the concordance between cytogenetic and molecular response outcomes. Univariate and multivariate regression will be used to examine associations between clinical responses and in vitro data. Results Results are reported as of July 24, 2015, based on data compiled from 157 pts who met all of the inclusion criteria (collected from 5 of the more than 10 institutions participating in this study). The median duration of prior TKI treatment was 3.0 years, with the vast majority of pts having received imatinib 1L (154 pts). Pts had 37 unique mutations at baseline, with the most common being T315I (N=19), M244V (N=18), M351T (N=13), G250E (N=12), and F359V (N=12). Cytogenetic and/or molecular response data were available for all 157 pts according to treatment 2L with dasatinib (N=81), nilotinib (N=61), ponatinib (N=14), and bosutinib (N=1). The use of MR2 as a surrogate for CCyR was examined in 121 pts evaluable for this comparison: 59 pts achieved both MR2 and CCyR, 58 achieved neither, and 4 achieved MR2, but not CCyR. MR2 demonstrated 100% sensitivity and 93.5% specificity at determining CCyR in the interim data. Conclusion A broad collaborative effort has been successfully initiated to greatly expand the available clinical data relating response outcomes to TKI treatment in CP-CML pts according to baseline mutation status. Analysis of a substantially expanded clinical dataset and the association with preclinical data will be presented. References: 1. Baccarani, M., et al, Molecular monitoring and mutations in chronic myeloid leukemia: how to get the most out of your tyrosine kinase inhibitor. Am Soc Clin Oncol Educ Book, 2014: p. 167-75. 2. Gozgit, M.J., et al., Comprehensive Analysis of the In Vitro Potency of Ponatinib, and all Other Approved BCR-ABL Tyrosine Kinase Inhibitors (TKIs), Against a Panel of Single and Compound BCR-ABL Mutants. ASH, 2013: p. Abstract: 3992. Disclosures Rivera: ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Branford:BMS: Honoraria, Research Funding; ARIAD Pharmaceuticals Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Nicolini:Novartis: Honoraria, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; BMS: Other: Travel/Accommodations/Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARIAD: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting or Advisory Role, Speakers Bureau. Pritchard:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time/Part-time Employee & Stock Shareholder (self-managed). Gozgit:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Milojkovic:Pfizer: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; BMS: Honoraria; Novartis: Honoraria. Muller:ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding; BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding; Novartis: Honoraria, Other: Consulting or Advisory Role, Research Funding. Deininger:Novartis: Other: Consulting or Advisory Role, Research Funding; Celgene: Research Funding; ARIAD Pharmaceutical Inc.: Other: Consulting or Advisory Role; Incyte: Other: Consulting or Advisory Role; BMS: Other: Consulting & Advisory Role, Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Pfizer: Other: Consulting or Advisory Role. Heinrich:MolecularMD: Other: Consulting or Advisory Role; MolecularMD: Other: Stock/Shareholder; Onyx: Other: Consulting or Advisory Role; Novartis: Other: Expert Testimony; Blueprint Pharmaceuticals: Consultancy, Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceuticals Inc.: Consultancy, Other: Consulting or Advisory Role, Research Funding; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; Pfizer: Consultancy, Other: Consulting or Advisory Role; BMS: Research Funding; Bayer: Research Funding. Soverini:Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Baccarani:BMS: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses, Speakers Bureau; ARIAD Pharmaceuticals Inc.: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Cortes:Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding. Etienne:Novartis: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses, Speakers Bureau; ARIAD Pharmaceuticals Inc.: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Abstract: Background: Some previous studies in Ph+ ALL suggested that T315I mutations of the ABL1 KD are present in many pts prior to tyrosine kinase inhibitor (TKI) treatment. However, these reports used RT-PCR to generate complementary DNA (cDNA) prior to analysis, which may introduce random errors and lead to false positive results. We hypothesized that ultrasensitive DS of genomic DNA (gDNA) would more accurately detect low-level pretreatment ABL1 mutations in Ph+ ALL because it does not rely upon error prone RT-PCR. Methods: DS compares the nucleotide sequences of each strand of double-stranded molecules, improving the accuracy of conventional next-generation sequencing by more than 10,000-fold. DS of exons 4-10 of ABL1 was performed to an average molecular depth of 〉 10,000x. A mixture of known ABL1 variants at varying low variant allelic frequencies (VAFs) versus a negative control were used to determine sensitivity and specificity of DS. DS of ABL1 was performed on 64 pts with newly diagnosed Ph+ ALL prior to receiving frontline hyper-CVAD plus a TKI (imatinib, n=5; dasatinib, n=38; ponatinib, n=21). DS was also performed on cDNA samples from RT-PCR to assess the RT-induced error rate. On RNA from relapse samples, the KD (codons 221 through 500) of BCR-ABL1 was sequenced by the Sanger method, using a nested PCR approach, with a detection limit of 10-20%. Results: A total of 115 pretreatment ABL1 mutations were detected by DS, with ≥1 mutation detected in 47/64 pts (73%). These mutations were generally present at very low levels (median VAF 0.008% [range, 0.004%-0.649%]). Eleven TKI resistance (TKI-R) mutations (10% of all detected mutations) were identified by DS in 7 pts (Table 1). Eighteen pts (28%) relapsed; however, none of the pts with TKI-R mutations relapsed, despite 5 pts receiving a TKI at least intermediately resistant to the detected mutation. Using Sanger sequencing, TKI-R mutations were detected at relapse in 9 pts (T315I, n=6; F317I, V229L and V338G, n=1 each). None of these TKI-R mutations was detected by DS in pretreatment samples. Together, these results suggest that low-level pretreatment ABL1 KD mutations are not clinically meaningful in Ph+ ALL. To validate the DS methodology, we examined its sensitivity and specificity using 6 gDNA samples containing ABL1 KD mutations (9 different SNVs, including 6 TKI-R) mixed with control gDNA from a healthy young individual for predicted VAFs of 1/250 to 1/25,000. Mutations were identified by DS with 100% sensitivity down to VAF 〈 5.6x10-5, with high precision (r2=0.93 for detected vs. predicted VAF; Figure 1). None of the spiked-in mutations were detected in the negative control (100% specificity). In the control samples, the background mutation frequency of ABL1 was ~5x10-7. Using a null model of random distribution of mutations in normal samples at this frequency, there was no significant difference in the proportion of TKI-R mutations detected with DS versus the expected background frequency, suggesting that there is no biased detection of TKI-R mutations by DS. To assess whether cDNA may be susceptible to artefactual mutations induced by RT steps, DS was performed on cDNA from 6 pts in whom no pretreatment ABL1 KD mutation was detected by DS. cDNA generated by RT had a 50-100x increased mutation frequency relative to the normal gDNA samples (Figure 2). False TKI-R mutations were observed in all cDNA samples (ranging from 11-16 TKI-R variants per sample). Overall, the fraction of TKI-R variants relative to total variants detected was significantly higher in all 6 cDNA samples compared to the negative control. Conclusion: DS had 100% sensitivity and specificity for detection of TKI-R mutations in ABL1. In contrast, RT-generated cDNA increased mutation frequency by 50- to 100-fold, suggesting that RT-based methods may falsely assess the presence of TKI-R mutations. Prior to TKI treatment, DS detected ABL1 mutations at a rate similar to healthy controls, and even in cases when a low-level TKI-R mutation was detected by DS, there was no association with relapse. Together, these findings suggest that pretreatment ABL1 mutations in Ph+ ALL are due to random age-related mutagenesis and do not represent clinically meaningful subclones that contribute to relapse. The superior accuracy of DS compared to RT-PCR has broad implications in the detection of low-level mutations across cancers, which may allow for early interventions to target emerging resistant subclones. Disclosures Short: Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Kantarjian:Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Ravandi:Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Agios: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ablynx: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding. Garcia-Manero:Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Pratt:TwinStrand Biosciences: Employment. Williams:TwinStrand Biosciences: Employment. Valentine:TwinStrand Biosciences: Employment. Salk:TwinStrand Biosciences: Employment. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

Abstract: COVID-19–related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19. Methods This was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection. With a doubly robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT). Results Of a total of 15,128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19; of those, 5,848 (38.7%) patients received IVT-only and 9,280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted OR 1.53; 95% CI 1.16–2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20–2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23–1.99), 24-hour mortality (OR 2.47; 95% CI 1.58–3.86), and 3-month mortality (OR 1.88; 95% CI 1.52–2.33). Patients with COVID-19 also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26–1.60). Discussion Patients with AIS and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non–COVID-19 patients receiving treatment. Current available data do not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in patients with COVID-19 or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis. Trial Registration Information The study was registered under ClinicalTrials.gov identifier NCT04895462.