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CCTG CLC.2/Alliance A041202 demonstrated superior progression-free survival at 2 years with ibrutinib alone (87%; HR 0.39) or ibrutinib-rituximab (IR 88%; HR 0.38) compared to chemo-immunotherapy with bendamustine-rituximab (BR 74%) in treatment-naïve patients (pts) with chronic lymphocytic leukemia (CLL) who were 65 or older (Woyach NEJM 2018). We hypothesized that ibrutinib-based therapies would be more costly than BR but that costs would be offset by less toxicity and improved quality of life (QOL). We completed a prospective trial-based economic analysis to study the direct medical costs and quality-adjusted benefit associated with ibrutinib-based therapies compared to BR in the Canadian (CDN) subset of patients enrolled in CLC.2/Alliance 041202. All CDN pts were invited to participate in the companion analysis. Health utilities were collected using the EuroQOL EQ-5D and calculated using CDN population valuations (Bansback PLOS One 2012). Resource utilization forms were administered to collect off-protocol health care encounters. The planned analysis was a cost-utility analysis from the perspective of a public healthcare system, examining the costs and outcomes (quality-adjusted life years or QALYs) of ibrutinib-based therapy compared to BR. Unit costs were applied to resource data based on publicly available provincial/national databases; all costs were expressed in 2019 US dollars (1 CDN = 0.75 US dollar). Total and disaggregated direct medical costs are presented descriptively. Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months; derived utilities were used to calculate QALYs. A discount rate for costs and benefits (r=0.05) was applied. The analysis was based on estimation (with bootstrapping) of an incremental cost-effectiveness ratio (ICER) and/or direct medical costs. A total of 55 pts were enrolled; two pts who did not receive any treatment were censored at day 1 and 3 after randomization and excluded from analysis. Of the 53 analysed, pt demographics were well balanced between treatments and were reflective of the entire population: mean age was 71.6 (SD 6.34) in pts receiving ibrutinib alone (n=17), 72.2 (SD 3.85) in pts receiving IR (n=18), and 71.7 (SD 4.1) in pts receiving BR (n=18). A total of 3 pts, one in each arm, had 17p deletion. Progression-free survival at 2 years for CDN pts was 94% (95% CI 65-99%) for ibrutinib, 100% (95% CI 100-100%) for IR, and 72% (95% CI 45-87%) for BR (Figure 1). At 24 months, 1 pt on the BR arm had crossed over to ibrutinib (as per protocol); there was no overall survival difference between the three arms. On-protocol costs (including protocol treatment, ambulatory care, and imaging) and off-protocol costs (including hospitalizations, concomitant medications, and ambulatory care) are highlighted in Figure 2. On-protocol costs were higher for pts receiving ibrutinib (mean $142,001 USD; SD 48,417) and IR ($164,931; SD 46,208) compared to BR ($38,509; SD 10,351), driven by higher drug acquisition costs associated with ibrutinib (list price $6422 for 420mg/30 days). In contrast, off-protocol costs were modestly higher for pts on BR (mean $3050; SD 3812) compared to the ibrutinib ($2460; SD 3863) or IR ($2890; SD 4206); hospitalizations were the key off-protocol cost drivers and were highest for pts on IR and BR. Overall mean costs over the 2-year time horizon were $144,461 (SD 47,910) for pts on ibrutinib, $167,820 (SD 46,830) for pts on IR, and $41,560 (SD 11,849) for pts on BR. Discounted QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR. Given the similar quality-adjusted survival between arms at the time of this analysis, a formal ICER was not calculated. Direct medical costs are substantially higher for pts receiving continuous ibrutinib-based therapies, compared to chemo-immunotherapy of fixed duration, in frontline CLL management; the key cost driver is the cost of ibrutinib. The PFS benefit with ibrutinib-based therapy has not translated into an advantage in quality-adjusted survival to date; further follow-up may be required to demonstrate any cost or QOL benefits associated with fewer progression events for those on ibrutinib. Support: U10CA180821, U10CA180882; U10CA180863 and #704970 CCTG. https://acknowledgments.alliancefound.org ClinicalTrials.gov: NCT01886872 Figure Disclosures Owen: AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Lam:Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Crump:Servier: Consultancy; Kite/Gilead: Consultancy; Roche: Consultancy. Sperlich:Lundbeck Canada: Honoraria. Woyach:Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Hay:Roche: Research Funding; Janssen: Research Funding.

PURPOSE The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy (RT) for small-cell lung cancer (SCLC). Because of the relevance of this topic to ASCO membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations. METHODS The ASTRO guideline on RT for SCLC was reviewed for developmental rigor by methodologists. Then, an ASCO Expert Panel reviewed the content and the recommendations. RESULTS The ASCO Expert Panel determined that the recommendations from ASTRO guideline on RT for SCLC, published in June 2020, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed ASTRO guideline on RT for SCLC with a few discussion points. RECOMMENDATIONS Recommendations addressed thoracic radiotherapy for limited-stage SCLC, role of stereotactic body radiotherapy in stage I or II node-negative SCLC, prophylactic cranial radiotherapy, and thoracic consolidation for extensive-stage SCLC. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Abstract Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 “don't eat me” signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

AbstractIntroductionAdvances in the care of cancer patients have resulted in increased survival. The proximal femur is a common site for metastatic disease, often requiring surgical intervention. Tranexamic acid (TXA) has proven to be safe in elective and traumatic femoral hemiarthroplasty; however, its use has not been investigated in oncologic patients.MethodWe reviewed 66 patients (37 males) with a mean age of 64 ± 3 years undergoing a hemiarthroplasty for metastatic disease in the femoral neck. A total of 22 (33%) patients received intraoperative TXA. Primary outcomes included postoperative blood loss, intraoperative and postoperative transfusion requirement, and postoperative complications.ResultsThere was no difference in the baseline characteristics between the TXA and non‐TXA groups. When comparing the TXA and non‐TXA groups, there were no differences in 72 h postoperative blood loss between groups (1.21 L vs. 1.33 L, p = 0.61), percentage of patients requiring transfusion (36.4% vs. 36.4%, p = 1.0), or the incidence of postoperative complications including venous thromboembolism (14% vs. 11%, p = 0.70) and pulmonary embolism (0% vs. 5%, p = 1.0).ConclusionOncology patients are a high‐risk population for thromboembolic events. This initial study supports the safe use of TXA intraoperatively in femoral hemiarthroplasty performed for metastatic disease.

AbstractBackgroundTau deposition is a key biological feature of Alzheimer’s disease (AD) that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau accumulation while others are more resistant. The recent availability of tau positron emission tomography (tau‐PET) provides an opportunity to test the hypothesis that genetic factors are associated with differential tau deposition.MethodsWe performed a genome‐wide association study (GWAS) of tau‐PET on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.4% cognitively unimpaired) from the population‐based Mayo Clinic Study of Aging. Following genotyping with the Illumina GSA array and standard quality control, 515,206 single nucleotide polymorphisms (SNPs) were tested for association with entorhinal cortex 18F‐flortaucipir tau‐PET burden using linear regression under an additive genetic model and covarying for age and sex.ResultA genome‐wide significant association was identified for rs75546066, an intergenic SNP on chromosome 9 between MED27 (mediator complex subunit 27) and NTNG2 (netrin G2), with the minor (A) allele associated with lower tau burden (p=2.85 x 10‐8, β=‐0.48). Linkage disequilibrium and public expression quantitative trait loci (eQTL) data suggested a functional relationship between rs75546066 and NTNG2, the latter of which is highly expressed in the brain. In addition to this novel finding, three SNPs within MAPT (microtubule‐associated protein tau) displayed nominal associations to tau‐PET burden, including rs3785883 (p=0.04, β=0.07) which was previously associated with higher cerebrospinal fluid tau in an independent cohort. No associations with tau‐PET burden were identified for the APOE (apolipoprotein E) ɛ4 or ɛ2 alleles or for genotyped SNPs previously associated with AD in large case‐control studies.ConclusionTo our knowledge, this study represents the first reported neuroimaging GWAS of tau pathology. Our findings confirm the association of MAPT with tau burden and nominate the rs75546066‐NTNG2 locus as a novel potential protective influence against tau pathology which warrants further functional characterization. Our data also supports the inference that tau accumulation may have a genetic architecture distinct from APOE and other known AD susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting models.

AbstractBackgroundUsing an objective mathematical algorithm to assess corticolimbic involvement of neurofibrillary tangle pathology, we identified three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Typical AD brains were representative of the expected patterns of hippocampal and cortical involvement as outlined by Braak tangle stage. In contrast, we discovered an extreme phenotype that exists outside of the Braakian‐concept of neurofibrillary tangle patterns. Hippocampal sparing AD cases demonstrate unexpected sparing of the hippocampus relative to severely involved association cortices and limbic predominant AD cases demonstrate inundation of the hippocampus relative to mildly involved association cortices. Using these AD subtypes, our objective was to leverage our understanding of disease spectrum to uncover transcriptomic changes that underlie selective vulnerability of the hippocampus in AD.MethodWe performed RNA‐sequencing in 40 neuropathologically diagnosed AD cases (10 HpSp, 20 Typical and 10 Limbic) and 15 controls to uncover gene expression changes associated with phenotype differences allowing us to prioritize 44 genes for further exploration. Validation with NanoString and quantification with digital pathology were performed in an expanded cohort of 158 AD cases (36 HpSp, 79 Typical and 35 Limbic) and 32 controls. We quantified digital pathology measures of early tangle pathology (CP13), mature tangle pathology (Ab39), amyloid‐β (33.1.1). In addition, we measured cellular markers for microglia (CD68), endothelia (CD34), and astroglia (GFAP). Deep learning based prediction models were employed, which nominated the SLC38A2 gene as a predictor of AD.ResultThe SLC38A2 gene was originally prioritized in our RNA‐sequencing data based upon differential expression between controls and typical AD. We observed upregulation of SLC38A2 in all AD subtypes. RNA‐seq gene expression measures validated well with NanoString for SLC38A2 (R=0.97, p<0.001). Regression analysis identified early tangle (p=0.011) and late tangle measures (p=0.026) as significant predictors of gene expression, but not amyloid measures (p=0.74). Microgliosis approached significance (p=0.052), but with no contribution from endothelial cell burden (p=0.17) or astrogliosis (p=0.58). Age approached significance (p=0.06), but not sex (p=0.88) or APOE‐ε4 status (p=0.10).ConclusionOur data supports consideration of intra‐disease divergence with regard to case stratification and may reveal genes previously masked by heterogeneity of cohorts.

ObjectiveThe objective of this study was to describe clinical features, [18F]‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB).MethodsThis is a clinicopathologic case‐control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA‐DLBD. We analyzed clinical features and compared FDG‐PET metabolism in LPA‐DLBD to an independent group of patients with clinical pDLB and regional α‐synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB‐DLBD).ResultsAll patients with LPA‐DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA‐DLBD, LPA‐Alzheimer's disease (LPA‐AD), and LPA‐frontotemporal lobar degeneration (LPA‐FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA‐DLBD patients. Seventy‐five percent of the patients with LPA‐DLBD showed a parietal‐dominant pattern of hy pometabolism; LPA‐FTLD – temporal‐dominant pattern, whereas LPA‐AD showed heterogeneous patterns of hypometabolism. LPA‐DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA‐DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α‐synuclein burden in the middle frontal and inferior parietal cortices compared to DLB‐DLBD.InterpretationWhereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α‐synuclein‐associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520–533

(1) Background: Arthrofibrosis is a common cause of patient debility and dissatisfaction after total knee arthroplasty (TKA). The diversity of molecular pathways involved in arthrofibrosis disease progression suggest that effective treatments for arthrofibrosis may require a multimodal approach to counter the complex cellular mechanisms that direct disease pathogenesis. In this study, we leveraged RNA-seq data to define genes that are suppressed in arthrofibrosis patients and identified adiponectin (ADIPOQ) as a potential candidate. We hypothesized that signaling pathways activated by ADIPOQ and the cognate receptors ADIPOR1 and ADIPOR2 may prevent fibrosis-related events that contribute to arthrofibrosis. (2) Methods: Therefore, ADIPOR1 and ADIPOR2 were analyzed in a TGFβ1 inducible cell model for human myofibroblastogenesis by both loss- and gain-of-function experiments. (3) Results: Treatment with AdipoRon, which is a small molecule agonist of ADIPOR1 and ADIPOR2, decreased expression of collagens (COL1A1, COL3A1, and COL6A1) and the myofibroblast marker smooth muscle α-actin (ACTA2) at both mRNA and protein levels in basal and TGFβ1-induced cells. (4) Conclusions: Thus, ADIPOR1 and ADIPOR2 represent potential drug targets that may attenuate the pathogenesis of arthrofibrosis by suppressing TGFβ-dependent induction of myofibroblasts. These findings also suggest that AdipoRon therapy may reduce the development of arthrofibrosis by mediating anti-fibrotic effects in joint capsular tissues.