Abstract: Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy. While central nervous system (CNS) relapse in DLBCL is uncommon, it is usually fatal. As many relapses are parenchymal, systemic high-dose methotrexate (HDMTX) has largely replaced intrathecal methotrexate as CNS prophylaxis in high risk patients (historically characterised using IPI score/number of extranodal sites) in Australia. However, the efficacy of HDMTX in this context remains undetermined, can be associated with nephrotoxicity, myelosuppression and hepatotoxicity and necessitates the use of significant hospital resources for administration and monitoring. The German high-grade non-Hodgkin lymphoma study group (DSHNHL) prognostic model separates patients with DLBCL into 3 risk groups for CNS disease based on a score derived from 6 factors. The aims of this study were to evaluate the toxicity of HDMTX, and describe outcomes in HDMTX and non-HDMTX patients according to the DSHNHL model. Methods: 150 patients diagnosed with DLBCL between 2004 and 2014, initially treated with RCHOP-like chemotherapy and given or not given HDMTX for CNS prophylaxis were identified by pharmacy records at two teaching hospitals. Patient records were retrospectively reviewed for HDMTX toxicity, CNS disease risk factors as specified in the DSHNHL model and CNS relapse. All surviving patients had at least a year of follow-up. The toxicity parameters of 28 HDMTX patients was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4, up to 30 days from the date of the last dose of HDMTX. Statistical analysis was performed using STATA Data Analysis and Statistical Software version 13. Analysis involved Fisher's exact test for categorical variables and Mann-Whitney U test for continuous variables. A p-value was statistically significant if it was equal to or less than 0.05. Results: 28 patients with DLBCL selected to receive HDMTX were planned for 2 doses. All initial doses were administered at a concentration of 3g/m2 except for 2 patients who had a first dose of 1.5g/m2. Two of 28 patients received only one dose, and 3 had their second dose reduced, all due to renal impairment. 20 of 28 patients (71%) did not experience nephrotoxicity and no patient progressed to grade 4 or 5 renal toxicity. Myelosuppression was the most common toxicity, with anaemia grade 3-4 in 1 (4%), grade 3 and 4 neutropenia in 8 and 3 (but with febrile neutropenia in only one case) and grade 3-4 thrombocytopenia in 2 (7%) patients. 24 of 28 HDMTX patients and 122 non-HDMTX had sufficient data available for the 6 components of the DSHNHL model. Comparison of the DSHNHL model score for HDMTX and non-HDMTX patients showed no significant difference in the distribution of scores (p-value 0.478). No patient had all 6 factors. Fourteen (58%) HDMTX and 66 (54%) non-HDMTX patients were categorized as low risk (score 0 to 2), 8 (33%) HDMTX and 31 (25%) non-HDMTX were intermediate risk (score 3) and 2 (8%) HDMTX and 25 (20%) non-HDMTX were high risk (score 4 to 6) according to the DSHNHL model. The 2 (of 24) HDMTX patients who relapsed in the CNS had DSHNHL model scores of 1 and 3. Of the 122 non-HDMTX patients, 3 relapsed in the CNS, all with intermediate or high risk disease. Conclusions: HDMTX was well-tolerated by patients, therefore can safely be administered as CNS prophylaxis under current hospital protocols. Application of the DSHNHL prognostic model identifies a different population of candidates for CNS prophylaxis compared to historical risk factors and may lead to better patient selection for this intervention. Disclosures Hawkes: Merck Serono: Research Funding; BMS: Other: travel expenses, Research Funding; Takeda: Other: travel expenses.

Abstract: Older people are often admitted for rehabilitation to improve walking, yet not everyone improves. The aim of this study was to determine key factors associated with a positive response to hospital-based rehabilitation in older people. Methods This was a secondary data analysis from a multisite randomized controlled trial. Older people (n= 198, median age 80.9 years, IQR 76.6- 87.2) who were admitted to geriatric rehabilitation wards with a goal to improve walking were recruited. Participants were randomized to receive additional daily physical therapy focused on mobility (n = 99), or additional social activities (n = 99). Self-selected gait speed was measured on admission and discharge. Four participants withdrew. People who changed gait speed ≥0.1 m/s were classified as ‘responders’ (n = 130); those that changed 〈 0.1m/s were classified as ‘non-responders’ (n = 64). Multivariable logistic regression explored the association of six pre-selected participant factors (age, baseline ambulation status, frailty, co-morbidities, cognition, depression) and two therapy factors (daily supervised upright activity time, rehabilitation days) and response. Results Responding to rehabilitation was associated with the number of days in rehabilitation (OR 1.04; 95% CI 1.00 to 1.08; p = .039) and higher Mini Mental State Examination scores (OR 1.07, 95% CI 1.00 – 1.14; p = .048). No other factors were found to have association with responding to rehabilitation. Conclusion In older people with complex health problems or multi-morbidities, better cognition and a longer stay in rehabilitation were associated with a positive improvement in walking speed. Further research to explore who best responds to hospital-based rehabilitation and what interventions improve rehabilitation outcomes is warranted. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613000884707; ClinicalTrials.gov Identifier NCT01910740 .

Abstract: Background: Novel strategies are needed to improve upon the 60% cure rate of upfront R-CHOP in advanced DLBCL. Single-agent immune checkpoint inhibition (ICI) has limited efficacy in heavily pre-treated DLBCL (response rate & lt;10%, Ansell JCO 2019), potentially due to residual immunocompromise from prior therapy. Frontline ICI, given when host immunity is relatively intact, may improve these outcomes. Concurrent ICI with R-CHOP is safe (Smith BJH 2020) but corticosteroid-related immunosuppression may negate ICI efficacy. These factors, along with evidence that ICI sensitises non-Hodgkin lymphoma to subsequent chemotherapy (Carreau BJH 2020), support a sequential treatment strategy. Avelumab (Av) is an anti-PDL1 monoclonal antibody with antibody dependent cell cytotoxicity (ADCC) activity which acts synergistically with rituximab (R) in vitro. We report the results of a phase II single arm study assessing safety of 1st line sequential AvR induction, R-CHOP & Av maintenance for DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage II-IV DLBCL and no active autoimmune disease were treated with AvR induction x2 cycles q2-weekly (Av 10mg/kg IV + R 375mg/m2 IV), followed by R-CHOP21 x 6 cycles then Av 10mg/kg x 6 cycles q2-weekly if in complete metabolic response (CMR) post R-CHOP. The primary endpoint was the rate of grade 3/4 immune-related adverse events (irAE). Secondary endpoints included overall response rate (ORR), failure free survival (FFS), overall survival (OS) and overall toxicity. Response was determined centrally by PET-CT (Lugano 2014 criteria). CMR rates by PET-CT post AvR induction and post C2 R-CHOP were exploratory endpoints. Genomic analysis was performed including next generation sequencing (NGS) based sequence variant detection, copy number analysis and structural variant detection. Results: 28 pts were enrolled from Dec 2017 to Oct 2019. Key baseline characteristics included median age 54 yrs (range 20-79); stage III/IV disease 68%; elevated LDH 61%; IPI ≥2 25%. Histology included 21 DLBCL NOS (75%; 14 GCB, 7 non-GCB by Hans algorithm), 6 primary mediastinal B-cell lymphoma (PMBCL; 21%) and 1 EBV positive DLBCL (4%). The study met its pre-specified primary endpoint of G3/4 irAE & lt;30%. Grade 3/4 irAEs included hepatitis (n=1) and rash (n=2). G1/2 irAEs occurred in 71% (20/28) as follows: rash 53%, liver dysfunction 26%, hyper/hypothyroidism 29% and diarrhoea 21%. 79% had G3/4 toxicity, predominantly haematological, related to RCHOP with febrile neutropenia/infection in 28% of pts. ORR post R-CHOP was 89% (all CR) (Figure 1). The ORR to 2 cycles of induction AvR was 60%, including 6 CMR (21%) across all diagnostic/histologic subgroups (n=1 PMBCL, n=2 non-GCB DLBCL, n=3 GCB DLBCL; Figures 1 and 2). Six pts (21%) progressed during AvR induction (with 1 pt completing only 1 x AvR cycle); all subsequently responded to R-CHOP. With a median follow-up of 16 months, 1-year FFS was 76% and OS 89%. Treatment was discontinued early in 5 pts; 2 during R-CHOP due to progressive disease and 3 during Av maintenance (n=1 immune hepatitis; n=1 pulmonary embolism initially reported as pneumonitis; n=1 progressive disease). Alterations in the CD274/PDCDLG2 locus were identified by NGS in 3 of 27 evaluable pts (n=2 PMBCL, n=1 EBV+ DLBCL). Full genomic analysis to identify factors associated with response will be presented. Conclusion: Sequential AvR induction, R-CHOP and Av maintenance in pts with newly diagnosed DLBCL is feasible with a manageable toxicity profile and a high CR rate. Responses to AvR alone were higher than expected based on the relapsed/refractory population and may suggest superior efficacy of ICI in the frontline setting. These results support ongoing sequential studies of immune priming with PD1/PDL1 inhibition prior to R-CHOP in DLBCL. Acknowledgements: Merck KgA for avelumab plus funding. Tour de Cure Scott Canning Early Career Grant (E Hawkes) and Wilson Centre for Lymphoma Genomics for biomarker testing. Disclosures Hawkes: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Merck Sharpe & Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; takeda: Speakers Bureau; Merck KgA: Research Funding. Chong:Merck Serono: Research Funding; Bristol-Myers Squibb: Research Funding; Hutchison Medipharma: Research Funding; Bayer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Servier: Research Funding; Isofol: Research Funding. Blombery:Novartis: Consultancy; Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria. Barraclough:Roche: Other: Conference sponsorship. Keane:Celgene: Honoraria, Other: Travel; BMS: Research Funding; Roche: Honoraria, Other: Travel, Speakers Bureau; MSD Oncology: Honoraria, Other: Travel; Gilead: Honoraria, Other: Travel, Speakers Bureau. Fong:Pfizer: Honoraria; Astellas: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody. Inhibition of the PD1/PDL1 pathway stimulates anti-tumour immunity.

Abstract: The ischemic penumbra may be classical, with complete annular configuration around the infarct core, or nonclassical with a more fragmented pattern. We tested the hypotheses that these penumbral patterns may: be associated with specific predictive factors, influence infarct growth and clinical outcome, and influence the effect of tissue plasminogen activator (t-PA). Methods— Using the EPITHET/DEFUSE data set, in which patients received alteplase or placebo 3 to 6 hours poststroke, perfusion-weighted imaging and diffusion-weighted imaging images were analyzed. These mismatch patterns were defined as “classical” or “nonclassical.” Multivariate analysis was used to identify variables associated with mismatch patterns, the effect of t-PA, as well as the relationship between mismatch patterns, infarct growth, and clinical outcomes. Results— We included 158 patients (median age, 74 years; median National Institute of Health Stroke Scale score, 12). Multivariate analysis indicated that the factors associated with classical mismatch pattern type were large mismatch volume ( P 〈 0.001) and cortical infarct location ( P =0.036). Infarct growth, clinical outcome, and the efficacy of t-PA were not statistically different between patterns. Conclusions— Coregistered mismatch volume and cortical location of infarction were the important factors associated with presence of the classical mismatch pattern. The lack of effect of the type of mismatch patterns on infarct growth, clinical outcomes, or the benefit of t-PA would suggest that mismatch topography is less important during the hyperacute phase of ischemic stroke than during subacute phase.

Abstract: Background and purpose: The ECASS 3 study demonstrated efficacy of intravenous thrombolysis up to 4.5h after stroke onset. It has been hypothesized that some patients have tissue at risk and an acceptably low hemorrhage risk beyond 4.5h. Imaging based selection may help identify these patients for late reperfusion therapies. No randomized data have shown efficacy of tPA or reperfusion later than 4.5h after onset. We analysed the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) data to assess the effect of treatment and reperfusion on attenuation of infarct growth in the 4.5 to 6 hour time window. Methods: Patients were randomized to placebo or tissue plasminogen activator (tPA) between 4.5-6h from stroke onset (without using imaging selection criteria). Pre-treatment DWI and day 90 T2-weighted lesion volumes (average of manually outlined lesions by 2 independent raters) were compared to assess the influence of tPA and reperfusion on absolute and relative infarct growth. Day 3 volume was used when day 90 data was missing. The effect of tPA on reperfusion was also assessed. Good clinical outcome was defined as a National Institute of Health Stroke Scale (NIHSS) at day 90 0-1 or improvement ≥ 8 from baseline. Good functional outcome was defined as modified Rankin Scale (mRS) 0-2. Results: Of 69 patients treated 4.5-6hrs hours after stroke onset, infarct growth could be assessed in 63. The median relative growth was significantly lower in the tPA group compared to placebo (0.94 vs 1.68, p=0.025). There was a nonsignificant trend towards lower absolute growth (-0.17mL vs 9.56mL, p=0.069). Reperfusion markedly reduced relative (0.80 vs 1.89, p 〈 0.001) and absolute infarct growth (-2.49mL vs 39.50mL, p 〈 0.001). Reperfusion was more likely in the tPA group (57.7 vs 25.0% p=0.026) and was associated with better clinical and functional outcomes (86.4% vs 28.1% p 〈 0.001 and 72.7 vs 34.4% p=0.012). Conclusion: Thrombolysis after 4.5 hours reduced infarct growth and increased the rate of reperfusion. The strong positive effect of reperfusion on clinical and functional outcomes in this later time window is evidence of persisting salvageable ischemic penumbra. This supports continuing efforts to extend the treatment window for reperfusion therapies.

Abstract: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. Methods: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. Results: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0–61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. Conclusions: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.

Abstract: Although chronic kidney disease (CKD) is associated with worse stroke outcomes, data regarding the influence of CKD on intravenous thrombolysis outcomes are scarce. We sought to assess the efficacy and safety of intravenous thrombolysis for acute ischemic stroke with unknown onset time in patients with CKD. Methods: Patients with an acute stroke of unknown onset time from the EOS trials (Evaluation of Unknown Onset Stroke Thrombolysis) collaboration were evaluated using an individual patient-level database of randomized controlled trials comparing intravenous thrombolysis with placebo/standard treatment. CKD was defined as baseline estimated glomerular filtration rate of 〈 60 ml/min/1.73m 2 Mixed-effect logistic-regression analysis was performed to evaluate treatment effects. A favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. Results: Baseline data on renal function were available for 688 of 843 patients. Of these, CKD was present in 146 (21%), including 69 of 351 patients receiving alteplase and 77 of 337 patients receiving placebo/standard treatment. Overall, treatment with alteplase was associated with higher odds of favorable outcome, and CKD did not modify the treatment effect ( P interaction =0.834). A favorable outcome was observed in 31 of 69 (46%) patients with CKD in the alteplase group and in 28 of 77 (36%) patients with CKD in the control group (adjusted odds ratio, 1.19 [95% CI, 0.55–2.58] ). Among patients with CKD, symptomatic intracranial hemorrhage occurred in 2 patients (3%) in the alteplase group but in none of the controls ( P =0.133). At 90 days, death was reported in 3 patients (4%) in the alteplase group compared with 2 patients (3%) in the controls ( P =0.539). Conclusions: The present analysis indicates that the benefit of alteplase does not differ between stroke patients with unknown onset time with and without CKD, although the statistical power was lacking to confirm the efficacy in subgroups. This study only applies to mild-to-moderate or predialysis CKD.

Abstract: Several methods for conducting power analysis of studies with outcomes across the full ordinal modified Rankin Scale are proposed in the literature. No systematic comparison of accuracy, agreement, and sensitivity to small changes in hypothesized effect sizes for these methods is available. Our aim is to conduct such a systematic comparative analysis and to introduce a comprehensive freely available online tool to facilitate appropriate power analyses for ordinal outcomes. METHODS: We performed simulation studies utilizing the control arm modified Rankin Scale distributions from the AVERT (A Very Early Rehabilitation Trial), EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits), and HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) studies, as well as a uniform distribution, in combination with hypothetical treatment effects. We systematically evaluated published power formulas for Ordinal Logistic Regression and Tournament Methods (generalized odds ratio; Win Probability; Win Ratio; and Wilcoxon-Mann-Whitney U test). We also developed an online and downloadable Shiny R app facilitating sample size calculation for, and ordinal analysis of, modified Rankin Scale data. RESULTS: Power formulas for Tournament Methods performed well, while the formula for ordinal logistic regression was inaccurate. Tang’s Wilcoxon-Mann-Whitney U test sample size formula exhibited the highest accuracy. All methods, including ordinal logistic regression, had almost identical empirical power for a given sample size. All power methods exhibited sensitivity to small changes in hypothesized effect size. The developed freely available online app supports analytical and visualization requirements for all investigated methods for power and statistical analyses of ordinal modified Rankin Scale outcomes. CONCLUSIONS: As Tournament Method sample size formulas are assumption-free and accurately calculate power, stroke researchers should use these methods when designing studies with outcomes measured on the full or partially collapsed modified Rankin Scale as well as other ordinal scales, even if they intend to use ordinal logistic regression for analysis. Conducting sensitivity analyses of the effect size assumptions are essential for appropriate sample size estimation. Our developed tool supports both of these recommendations ( https://www.thembc.com.au/tournamentmethods ).