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Piątkowski, Paweł. "STOCK FLOW ADJUSTMENT VS. STABILITY OF POLISH PUBLIC DEBT." PRACE NAUKOWE UNIWERSYTETU EKONOMICZNEGO WE WROCŁAWIU, no. 521 (2018): 131–40. http://dx.doi.org/10.15611/pn.2018.521.13.
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Endriani, Santi. "Konsep Uang: Ekonomi Islam VS Ekonomi Konvensional." Anterior Jurnal 15, no. 1 (December 1, 2015): 70–75. http://dx.doi.org/10.33084/anterior.v15i1.201.
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In Islamic economics, the concept of money is very clear that money is a medium of exchange in muamalah, instead of capital (commodities). That money is objected that are approved by the public as an intermediary tool to hold the exchange or trade. Differences concept of money in Islamic and conventional economics are on the money that is not identical to the capital, the money is public goods, capital is private goods, money is a flow concept, and capital is a stock concept in the concept of money in Islam. While the conventional concept of money in the currency identified with capital money (capital) are private goods. Money (capital) is a flow concept for Fisher, and money (capital) is a stock concept for Cambridge School.
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Fikri, M. Ali, Biana Adha Inapty, and Baiq Rosyida Dwi Astuti. "Direct Current (DC) vs Alternating Current (AC) Financial Transaction Flow in Holding and Non-Holding Companies." Prisma Sains : Jurnal Pengkajian Ilmu dan Pembelajaran Matematika dan IPA IKIP Mataram 10, no. 2 (April 22, 2022): 352. http://dx.doi.org/10.33394/j-ps.v10i2.5090.
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A study on the flow of financial transactions needs to be carried out considering that activities in the financial sector require quick and relevant decisions. The flow of financial transactions in the business world is almost similar to direct current (DC) and alternating current (AC). The phenomenon is that many business people want their funds to be spread outside the company, and some want their funds to only revolve around the company. This study tries to analyze the results of investment flows of funds outside the company and within the company in the scope of the Indonesian capital market. This research is a research using a descriptive approach. The descriptive approach is intended to describe phenomena that occur in the field. The number of sample companies is 175 companies (holding and non-holding). Each company is given a code (code 1 for holding, and code 0 for non-holding), and company data is screened according to research needs on aspects; profit return, stock return, stock price, and profit and loss. Data mining in the field is carried out by researchers by means of secondary data analysis techniques for the capital market through analysis of financial statements from the side of the transaction flow. Then the results of the analysis of the company's flow of funds are processed, compared, and used as the basis for drawing conclusions. The results provide evidence that holding financial flows are more profitable than non-holding according to AC/DC transaction flows. This is in accordance with the risk reduction theory that many developed countries do by controlling the circulation of money only around their country. Theoretically, the results of this study contribute that holding companies have advantages over non-holdings, and practically this research provides a discourse for business people that it is better to run the business alone and not depend on outside parties.
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Vassallo, Paolo, Claudia Turcato, Ilaria Rigo, Claudia Scopesi, Andrea Costa, Matteo Barcella, Giulia Dapueto, Mauro Mariotti, and Chiara Paoli. "Biophysical Accounting of Forests’ Value under Different Management Regimes: Conservation vs. Exploitation." Sustainability 13, no. 9 (April 21, 2021): 4638. http://dx.doi.org/10.3390/su13094638.
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Forest ecosystems are important providers of ecosystem functions and services belonging to four categories: supporting, provisioning, regulating and cultural ecosystem services. Forest management, generally focused on timber production, has consequences on the ability of the system to keep providing services. Silviculture, in fact, may affect the ecological structures and processes from which services arise. In particular, the removal of biomass causes a radical change in the stocks and flows of energy characterizing the system. Aiming at the assessment of differences in stored natural capital and ecosystem functions and services provision, three differently managed temperate forests of common beech (Fagus sylvatica) were considered: (1) a forest in semi-natural condition, (2) a forest carefully managed to get timber in a sustainable way and (3) a forest exploited without management. Natural capital and ecosystem functions and services are here accounted in biophysical terms. Specifically, all the resources used up to create the biomass (stock) and maintain the production (flow) of the different components of the forest system were calculated. Both stored emergy and empower decrease with increasing human pressure on the forest, resulting in a loss of natural capital and a diminished ability of the natural system to contribute to human well-being in terms of ecosystem services provision.
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MATTIUCCI, S., R. CIMMARUTA, P. CIPRIANI, P. ABAUNZA, B. BELLISARIO, and G. NASCETTI. "Integrating Anisakis spp. parasites data and host genetic structure in the frame of a holistic approach for stock identification of selected Mediterranean Sea fish species." Parasitology 142, no. 1 (August 22, 2014): 90–108. http://dx.doi.org/10.1017/s0031182014001103.
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SUMMARYThe unique environment of the Mediterranean Sea makes fish stock assessment a major challenge. Stock identification of Mediterranean fisheries has been based mostly from data on biology, morphometrics, artificial tags, otolith shape and fish genetics, with less effort on the use of parasites as biomarkers. Here we use some case studies comparing Mediterranean vs Atlantic fish stocks in a multidisciplinary framework. The generalized Procrustes Rotation (PR) was used to assess the association between host genetics and larval Anisakis spp. datasets on demersal (hake) and pelagic (horse mackerel, swordfish) species. When discordant results emerged, they were due to the different features of the data. While fish population genetics can detect changes over an evolutionary timescale, providing indications on the cohesive action of gene flow, parasites are more suitable biomarkers when considering fish stocks over smaller temporal and spatial scales, hence giving information of fish movements over their lifespan. Future studies on the phylogeographic analysis of parasites suitable as biomarkers, and that of their fish host, performed on the same genes, will represent a further tool to be included in multidisciplinary studies on fish stock structure.
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Laoh, Lidya Chitra. "Dividend Payout Forecast : Multiple Linear Regression vs Genetic Algorithm-Neural Network." CogITo Smart Journal 5, no. 2 (December 19, 2019): 252. http://dx.doi.org/10.31154/cogito.v5i2.210.252-265.
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This research aims to compare two methods of forecasting, i.e Multiple Linear Regression (MLR) and Genetic Algorithm-Neural Network (GA-NN), in forecasting dividend payout of Indonesian manufacturing company listed on Indonesia Stock Exchange from 2010-2014. Having collected 1384 firm-year observations, the result shows that these two methods could be used to predict dividend payout by considering earnings, free cash flow, growth opportunity, leverage, liquidity and size. This resesarch finds that even though both methods are powerful in prediction, yet in this case, MLR outperforms GA-NN. Keywords : Forecasting, Genetic Algorithm-Neural Network (GA-NN), Multiple Linear Regression (MLR), Dividend Payout Policy , Indonesian Manufacturing Companies
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Senarathne, Chamil W., and Jianguo Wei. "The impact of patent citation information flow regarding economic innovation on common stock returns: Volume vs. patent citations." International Journal of Innovation Studies 2, no. 4 (December 2018): 137–52. http://dx.doi.org/10.1016/j.ijis.2019.02.001.
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Kirchmeier, Delaney R., Alyssa Sheih, Salvatore Fiorenza, Alexandre V. Hirayama, Cassie Chou, Erik Kimble, Jordan Gauthier, et al. "Recombinant CD19 Glycomutant Accurately and Reproducibly Detects CD19-Directed CAR-T Cells By Flow Cytometry." Blood 138, Supplement 1 (November 5, 2021): 1724. http://dx.doi.org/10.1182/blood-2021-148229.
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Abstract Background CD19-directed chimeric antigen receptor (CAR)-modified T cell therapy expansion and persistence in peripheral blood has been shown to correlate with responses against B cell malignances (Hay, Blood, 2018; Ayuk, Blood Adv, 2021). CAR-T cell enumeration is typically achieved through quantitative PCR (qPCR) or flow cytometry (FC). qPCR, however, requires techniques that may not be locally validated and, unlike FC, cannot simultaneously address T cell immunophenotype. Existing FC reagents to detect CD19 CAR-T cells are mostly specific for a given CAR sequence or bind non-specifically to the introduced protein (e.g. Protein A). Utilizing glycosylation data from the structure of CD19(Teplykov, Proteins, 2018), we created a stable, biotinylated CD19 ectodomain glycomutant reagent (gmCD19) that binds to the CD19-directed scFv in CAR constructs and can be detected by FC. Methods The gmCD19 ectodomain (amino acids 21-227, N138Q) was expressed in 293 Freestyle™ cells with a C-terminal 6x Histidine-AviTag™ to facilitate expression, purification, FC detection (with fluorophore-bound streptavidin) and enable tetramer formation. We used FC to determine limit of detection (LoD), defined as the percent of detectable CAR-T cells when spiked into peripheral blood mononuclear cells (PBMC) at known concentrations. We used a CD19-directed CAR-T cell that co-expresses truncated EGFR (EGFRt) to benchmark gmCD19 and compare our reagent with commercially available detection reagents. This was quantitated by Pearson correlation coefficient and Bland-Altman measure of bias - defined as the mean of differences between tests on the same sample. We also tested reagent stability by assessing for decrease in mean fluorescence intensity (MFI) and the percent of CAR-T cells detected after multiple freeze-thaw cycles of the gmCD19 reagent. We compared CAR-T cell detection by gmCD19 with qPCR from actual patient samples treated with axicabtagene ciloleucel (axi-cel) and collected into three different anticoagulants. Results gmCD19 detected as few as 0.25% CAR-T cells by FC and was highly correlated with EGFRt expression (r=0.9993, p<0.0001). When benchmarking gmCD19 with EGFRt expression and comparing gmCD19 quantitation with other commercially available CD19 scFv detection reagents (Acro and BioSwan), gmCD19 showed the least bias (0.04 vs -1.225 and 61.66, respectively), and was the only method that demonstrated statistically significant agreement with EGFRt. Following each freeze-thaw cycle of gmCD19, there was no statistically significant decrease in percent of CAR-T cells detected with only a slight decrease in MFI (~2% decrease per cycle). Detection of axi-cel from patient samples was highly correlated with CAR copy number determined by qPCR, regardless of the anticoagulant in which the patient sample was collected (r=0.9387, 0.9849 and 0.9373 for sodium heparin, sodium citrate and EDTA, respectively) with equivalent coefficients of variation (11.0% vs 11.4% for gmCD19 and qPCR, respectively). Conclusion The availability of multiple CD19-directed CAR-T cell products and the importance of monitoring CAR-T cell expansion and persistence in patients undergoing CAR-T cell therapy creates the necessity for an easily applied, stable, and reliable quantitation FC method. We show that our gmCD19 accurately measures CD19-directed CAR-T cells across a variety of CAR-T cell constructs, including commercially available products. Disclosures Sheih: Umoja Biopharma: Current Employment. Fiorenza: Bristol Myers Squibb: Research Funding; Link Immunotherapeutics: Consultancy. Hirayama: Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Honoraria. Chou: Genentech: Current Employment. Gauthier: Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy. Correnti: Link Immunotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Turtle: PACT Pharma: Consultancy; Amgen: Consultancy; Asher Bio: Consultancy; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; TCR2 Therapeutics: Research Funding; Allogene: Consultancy.
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Rubic-Schneider, Tina, Prithu Sundd, David Ledieu, Déborah Garcia, Jeannine Hehlen, Coline Burnet-Merlin, Benjamin Cochin de Billy, et al. "Characterization of Two Anti-P-Selectin Monoclonal Antibodies (mAbs): Crizanlizumab Shows Comparable or Stronger Effects Versus Inclacumab across Cell Adhesion Assays in Vitro." Blood 138, Supplement 1 (November 5, 2021): 2032. http://dx.doi.org/10.1182/blood-2021-147318.
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Abstract Background: Vaso-occlusive crises (VOCs) are the hallmark of sickle cell disease (SCD) and are associated with significant morbidity and mortality. Crizanlizumab, a first-in-class humanized anti-P-selectin IgG2 mAb, is approved in >40 countries to reduce/prevent VOCs in SCD patients aged ≥16 yrs. Inclacumab, a fully human anti-P-selectin IgG4 mAb, is in clinical development for SCD. In vitro data suggest that inclacumab may show stronger affinity to P-selectin and greater maximal inhibition of cell-cell interactions vs crizanlizumab (Geng et al ASH 2020). Aim: We investigated in blinded experiments whether crizanlizumab and inclacumab can be differentiated in terms of P-selectin binding and inhibition of P-selectin-mediated cell-cell interactions, via 5 different in vitro assays, including testing of blood samples from healthy volunteers and SCD patients. Methods: For both mAbs, we assessed: P-selectin affinity (surface plasmon resonance [SPR]/Biacore assay); inhibition of adhesion of P-selectin-expressing cells to P-selectin glycoprotein ligand-1 (PSGL-1; cell adhesion bioassay); inhibition of platelet aggregation in native blood from healthy volunteers (whole blood impedance aggregometry [WBA] and flow cytometry-based platelet-leukocyte aggregate [PLA] assays); and inhibition of adhesion of SCD patient whole blood or isolated leukocytes to P-selectin-coated substrate under physiologically relevant shear rates in microfluidic systems (flow adhesion bioassays). Results: The SPR/Biacore assay indicated that both mAbs recognize P-selectin with binding affinities of the same order of magnitude, although there was a trend towards higher binding affinity with inclacumab (mean equilibrium dissociation constant [K D ± standard deviation]: 12.4 ± 1.0 nM [crizanlizumab] vs 6.7 ± 0.7 nM [inclacumab]). However, the function-related cell adhesion bioassay revealed a significant difference between the mAbs in their ability to inhibit adhesion of P-selectin-expressing cells to PSGL-1. Crizanlizumab showed stronger inhibition than inclacumab (potency vs crizanlizumab reference standard: 98.0% for the crizanlizumab control sample [95% CI 85.2‒112.7%] and 26.2% for the inclacumab sample [95% CI 20.7%‒32.6%]). Native whole blood samples for WBA and PLA assays were provided by 12 and 10 healthy volunteers, respectively. Blocking of platelet (WBA assay) or platelet-leukocyte aggregation (PLA assay) in whole blood was comparable for crizanlizumab and inclacumab, with a clear trend towards stronger inhibition by crizanlizumab. In the WBA assay, the half maximal inhibitory concentration (IC 50) was twice as high with inclacumab (10.36 μg/mL) as crizanlizumab (5.11 μg/mL); similar data were seen in the PLA assay (Figure 1; IC 50: 4.11 vs 2.81 μg/mL for inclacumab vs crizanlizumab). Blood samples were provided by 9 SCD patients for the flow adhesion bioassays. Dose-dependent inhibition of adhesion of whole blood and isolated leukocytes to P-selectin was seen with both crizanlizumab and inclacumab, with no difference observed between them (Figure 2). A mAb concentration of 10 μg/mL resulted in statistically significant inhibition of adhesion by 60‒75%; further increasing the mAb concentration did not result in stronger inhibition of adhesion beyond this threshold. In relation to the clinically approved crizanlizumab dose (5.0 mg/kg), a concentration of 100 μg/mL corresponds with the maximum plasma concentration (C max) and ~10-15 μg/mL corresponds with the trough concentration (C trough). Conclusions: While the SPR/Biacore data suggested higher P-selectin binding affinity for inclacumab compared with crizanlizumab, there was a stronger inhibition of P-selectin-mediated cell adhesion with crizanlizumab vs inclacumab in other well-characterized functional in vitro assays. In microfluidic flow adhesion bioassays, blockage of cell adhesion from SCD whole blood and leukocytes was comparable for both mAbs. In summary, these data indicate that comparable or stronger blockage of cell adhesion with crizanlizumab vs inclacumab does not require superior P-selectin binding affinity. The data from healthy volunteers will be complemented by data from SCD patients for the WBA and PLA assays. Ultimately, clinical data are required to evaluate potential differences in the profiles and efficacy of crizanlizumab and inclacumab as treatments for SCD patients. Figure 1 Figure 1. Disclosures Rubic-Schneider: Novartis Pharma AG: Current Employment. Sundd: CSL Behring Inc: Research Funding; Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ledieu: Novartis Pharma AG: Current Employment, Current holder of stock options in a privately-held company. Garcia: Novartis Pharma AG: Current Employment. Hehlen: Novartis Pharma AG: Current Employment. Burnet-Merlin: Light Chain Bioscience - Novimmune SA: Current Employment; Novartis Pharma AG: Ended employment in the past 24 months. Cochin de Billy: Novartis Pharma AG: Current Employment. Greutmann: Novartis Pharma AG: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Krӧner: Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2021087050A1. Verneret: Novartis Pharma AG: Current Employment, Current holder of stock options in a privately-held company. Bruederle: Novartis Pharma AG: Current Employment. Gao: Functional Fluidics: Current Employment. Dajee: Novartis: Current Employment.
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Buda, Rocco, Chiara Bedon, and Raffaele Pucinotti. "Retrofit of Existing Reinforced Concrete (RC) Buildings: Steel vs. RC Exoskeletons." Applied Sciences 12, no. 22 (November 13, 2022): 11511. http://dx.doi.org/10.3390/app122211511.
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The existing building stock is largely made up of reinforced concrete (RC) buildings, constructed between the post-World War II period and 1981, and mostly consists of buildings constructed very quickly to meet the great housing demand of this period, and buildings that do not adhere to anti-seismic and energy regulations. Today, after more than fifty years, these buildings have reached the end of their useful life cycle and their maintenance is not sustainable, presenting a series of structural, energy and architectural problems and criticalities. The myriad of possible retrofit interventions currently available for these RC structures drastically reduces when the main requirement for interventions is to avoid operational interruptions to buildings. In this case, an additive structure, operating exclusively from the outside as an exoskeleton, is typically used for achieving appropriate retrofit. In this paper, two solutions are proposed and addressed for the retrofit of an existing RC building in Italy, one through the application of a steel exoskeleton and the other through the application of an RC exoskeleton system. A set of push-over (PO) analyses is carried out to define the performance point of both the original and combined systems. The comparative results of these solutions are then discussed.
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Friedman, J. J. "Vascular sensitivity and reactivity to norepinephrine in diabetes mellitus." American Journal of Physiology-Heart and Circulatory Physiology 256, no. 4 (April 1, 1989): H1134—H1138. http://dx.doi.org/10.1152/ajpheart.1989.256.4.h1134.
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Vascular sensitivity (VS) and reactivity (VR) of hindquarters, totally isolated from rats made diabetic with 45 mg/kg of streptozotocin (STZ), were determined at 1, 2, 4, 8, and 12 wk post-STZ. Age-matched controls received saline injections and were followed for comparable periods. The hindquarters were perfused at constant flow (8-10 ml/min) with a Tyrode-perfluorocarbon (FC-43)albumin-alpha-globulin solution gassed with 95% O2-5% CO2. Tissues were continuously weighed and venous pressure adjusted to maintain an isogravimetric condition. VS and VR were determined from norepinephrine (NE) dose-response curves generated by infusing stock NE (1 mg/ml) at progressively increasing rates (0.004-0.025 ml/min) into a constant tissue perfusion rate (8-10 ml/min) for sufficient time to reach a plateau (2-3 min). Delivered doses ranged from 0.4 to 2.5 micrograms/ml. VR was established as the perfusion pressure reached in response to 2.5 micrograms/ml NE (Pmax). VS was defined as the delivered NE dose that increased perfusion pressure to 50% of Pmax (ED50). VS increased slightly but significantly (P less than 0.01) by 1 wk post-STZ and remained above control throughout the 12-wk post-STZ period. VR also increased significantly (P less than 0.05) by 1 wk post-STZ and remained above control throughout the 12-wk post-STZ period.
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Mendiola, Vincent Louie Ramos, Catherine Ly, Thuy Bui, Jennifer Wang, Jack Rodman, Karrune Woan, Eric Tam, et al. "Superior Outcomes in Hispanic Patients Compared to Non-Hispanic Patients with Ph-Negative Acute Lymphoblastic Leukemia Using the Modified Pediatric-Based University of Southern California Acute Lymphoblastic Leukemia (USC ALL) Regimen for Newly Diagnosed ALL Patients in the Era of Novel Agents; A Retrospective Study." Blood 138, Supplement 1 (November 5, 2021): 3361. http://dx.doi.org/10.1182/blood-2021-150116.
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Abstract INTRODUCTION: Hispanic patients with acute lymphoblastic leukemia (ALL) are historically known to have poor outcomes compared to non-Hispanic patients. Our institution, LAC-USC (LA County Hospital/University of Southern California) has shown a complete remission rate of 96% with use of pegasparagase at 2000 IU/m2 using the USC ALL regimen (based on CCG-1882) for patients aged 17-55 years with a 7-year OS of 51% reported in 2014. The modified USC ALL regimen now uses a single dose of cytarabine rather than fractionated doses and uses a single dose 3g/m 2 methotrexate compared to 1g/m 2 (2.5g/m 2 if T-cell) D1, 15 in original USC ALL regimen to improve compliance, while consolidation was increased to six cycles allowing for PEG holidays to improve toxicity (Table 1). Since our institution takes care of a large population of Hispanic patients with ALL, we now report outcomes in Hispanic and Non-Hispanic patients using the modified USC ALL regimen in the era of novel agents like blinatumomab and inotuzumab. METHODS : This retrospective, single institution chart review included adults >18 years old with newly diagnosed Ph-negative ALL (2016-2020). Primary objectives were 3-year over-all survival (OS), event-free survival (EFS), disease-free survival (DFS). Secondary objectives were complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry, descriptive statistics of patients who were stratified into Hispanic and non-Hispanic cohorts and evaluated using Fisher's exact test. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p-value ≤0.05 was significant. RESULTS: 121 Ph-negative patients were reviewed. 87 were Hispanic patients (HP) and 34 non Hispanic patients (NHP). Median ages were 39 and 35 years (p=0.51) and median BMI were 29 and 26.9 kg/m 2 (p=0.42), respectively. There were about equal males and females in HP while NHP had 70.6% males compared to 29.4% females (p=0.076). Both HP and NHP were mainly of the Ph-negative ALL subtype, 50.6% vs 47.1%, followed by Ph-like, 25.4% vs 20.6%, respectively (p=0.884). Majority of the population were unfavorable risk by NCCN karyotypic risk stratification, 55.9% in HP compared to 56.0% in NHP (p=0.99). Over-all, no significant difference between baseline characteristics in both cohorts. After induction 1: CR/CRi was 85.9% in HP and 73.4% in NHP (p=0.09). MRD negativity by flow cytometry in HP was 41.4% compared to 26.4% in NHP (p=0.13). After induction 2: 83% of HP were in CR/CRi compared to 80% in NHP (p=0.99) and MRD negativity by flow was 35.6% in HP compared to 32.4% in NHP (p=0.73). Blinatumomab was given in 33.3% of HP and 32.3% of NHP (p=0.92) while only 5.7% of HP and 2.9% of NHP received inotuzumab (p=0.99). 34.5% of HP underwent allogenic hematopoietic stem cell transplant (allo-HSCT) versus 26.5% in NHP (p=0.40). 3-year OS was 92.2% in HP versus 67.4% in NHP (p=0.004). 3-year DFS was 92.8% in HP versus 60.7% in NHP (p=0.003). 3-year EFS was 54.1% in HP versus 32.3% in NHP (p=0.02) (Table 2). Rate of relapse for HP and NHP were 23.4% vs 29.4% (p=0.74) while rate of mortality for HP and NHP were 7.5% vs 28% (p=0.015), respectively. No clear difference in grade 3/4 PEG toxicities were found in HP and NHP except more hypertriglyceridemia in HP (p=0.019). CONCLUSIONS: We present comparison of outcomes in Hispanic and non-Hispanic patients using our modified USC ALL pediatric-based regimen in an era of novel agents. Our data shows significantly better outcomes in Hispanic patients compared to non-Hispanic patients [OS (92.2% vs 67.4%, p=0.004), DFS (92.8% vs 60.7%, p=0.003) and EFS (54.1% vs 32.3%, p=0.02)]. This study demonstrates that given equal access to care (eg. receiving blinatumomab, allo-HSCT), outcomes in HP with Ph-negative ALL are not worse, but rather superior to those in NHP. Utilization of novel immunotherapy like blinatumomab in the salvage setting to achieve deeper molecular response and increased utilization of haploidentical allo-HSCT have likely contributed to reducing ethnic disparities in Hispanic ALL patients. Future studies are needed to validate these findings with larger patient populations. Figure 1 Figure 1. Disclosures Chaudhary: Oncotartis: Consultancy; Pancella: Consultancy; Moderna: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy . Douer: Jazz: Consultancy; Amgen: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Servier: Consultancy, Speakers Bureau. Yaghmour: Takeda: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.
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Johnson, Ned K., and Jill A. Marten. "Evolutionary Genetics of Flycatchers. II. Differentiation in the Empidonax difficilis Complex." Auk 105, no. 1 (January 1, 1988): 177–91. http://dx.doi.org/10.1093/auk/105.1.177.
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Abstract We used starch-gel electrophoresis to assess variability at 41 genetic loci in 208 individuals from 11 breeding populations of the Western Flycatcher (Empidonax difficilis) complex. Genic variability was substantial in most populations and equivalent to levels found in other avian taxa. A sample of E. d. insulicola from Santa Catalina Island, however, showed reduced heterozygosity and an unusually low percentage of polymorphic loci. We attribute this to a bottleneck at the time of the original colonization. Nei's genetic distances among populations of one taxon ranged from D̄ = 0.0003 (in E. d. difficilis) to D̄ = 0.0033 (in E. d. hellmayri). Intertaxon Nei's D̄ ranged from 0.009 (E. d. insulicola vs. E. d. difficilis) and 0.0149 (E. d. difficilis vs. E. d. hellmayri) to 0.0228 (E. d. insulicola vs. E. d. hellmayri). to 0.0228 (E. d. insulicola vs. E. d. hellmayri). F statistics revealed significant population subdivision within the complex. With Slatkin's rare-allele method we estimated the gene-flow parameter, Nm. Mainland populations experience moderately high gene flow (9.62 immigrants/generation). In contrast, Santa Catalina Island receives an estimated 0.093 immigrants/generation, pointing to very low gene flow and essential genetic isolation. Genetic distances yielded phenograms and distance Wagner trees that provide hypotheses for the relationships and phylogenesis of populations in western North America. The lineage leading to modern E. d. difficilis split from that leading to E. flavescens in the mid-Pleistocene at 866,800 yr BP; the ancestors of modern E. d. difficilis diverged from those of present-day E. d. hellmayri at 248,700 yr BP; and the stock leading to modern E. d. insulicola budded from the lineage that became E. d. difficilis in the late Pleistocene, approximately 187,000 yr BP. Empidonax d. difficilis and E. d. hellmayri nest sympatrically and mate assortatively in the Siskiyou region of northern California. Interbreeding has not been demonstrated conclusively, and we regard these taxa as biologic species. In the absence of a test of sympatry, the well-differentiated form E. d. insulicola of the California Channel Islands cannot be proved to be a biologic species. It is clearly a phylogenetic species, however, in the sense of Cracraft.
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Ungfors, Anette, Niall J. McKeown, Paul W. Shaw, and Carl André. "Lack of spatial genetic variation in the edible crab (Cancer pagurus) in the Kattegat–Skagerrak area." ICES Journal of Marine Science 66, no. 3 (January 18, 2009): 462–69. http://dx.doi.org/10.1093/icesjms/fsn223.
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Abstract Ungfors, A., McKeown, N. J., Shaw, P. W., and André, C. 2009. Lack of spatial genetic variation in the edible crab (Cancer pagurus) in the Kattegat–Skagerrak area. – ICES Journal of Marine Science, 66: 462–469. The stock structure of the edible crab (Cancer pagurus L.) in the Kattegat and Skagerrak was investigated using eight microsatellite DNA loci. Replicate samples, collected 4–6 years apart, were derived from the Kattegat (Grove Bank, 57°N) and the Skagerrak (Lunneviken, 59°N), plus a geographical outgroup sample from the Norwegian Sea (Midsund, 62°N). Genetic differentiation among samples, estimated as global FST = 0.002, was significant (p = 0.03) when the statistical test was based on allele frequencies, but not when based on genotype frequencies. Moreover, all single- and multilocus pairwise tests between samples were non-significant. An analysis of molecular variance, AMOVA, did not reveal significant differentiation between spatial (Kattegat vs. Skagerrak) or temporal (2001/2002 vs. 2006/2007) groups of samples. Power analysis suggested that the loci and sample sizes employed conferred a power of >90% of detecting even low (true FST = 0.002) levels of population structure. Low spatial and temporal genetic structure might be explained by either or both of (i) high levels of contemporary gene flow in the area attributable to adult migration or larval dispersal or both factors taken together, and (ii) patterns of historical gene flow persisting among recently founded large populations.
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Ghorani, E., J. Reading, J. Henry, M. Robert de Massy, R. Rosenthal, V. Turati, A. Furness, et al. "P03.30 Tumur mutations drive dysfunctional T cell differentiation in lung cancer." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A35.1—A35. http://dx.doi.org/10.1136/jitc-2020-itoc7.68.
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BackgroundEffective anti-tumour immunity requires cancer antigen expression, but persistent antigen exposure in chronic viral infections and autoimmunity has a detrimental effect on immune function. This is associated with a decline of early differentiated T cell populations in favour of later differentiated, dysfunctional subsets, resulting in an unfavourable skewing of the immune landscape. It is unknown whether this occurs locally within the antigen rich tumour microenvironment, driving immune failure.Materials and MethodsWe combined tumour infiltrating lymphocyte (TIL) high dimensional flow cytometry, bulk exome and RNA sequencing data from multiregional samples obtained from surgically resected tumours of treatment naive patients with non-small cell lung cancer (NSCLC) amongst the first 100 recruited to the prospective, UK-wide lung TRACERx study. Clonal relationship between T cell populations was determined by T cell receptor (TCR) sequencing. We additionally analysed publically available single T cell RNA sequencing data and bulk RNA sequencing data within TCGA.ResultsT cell differentiation skewing (TDS) occurred amongst TILs in association with tumour mutational burden (TMB). Surprisingly, this was most evident within the CD4 compartment that had a greater abundance of central memory cells expressing the key transcription factor TCF7. Amongst CD4 cells, loss of a PD1-CCR7+ T central memory population was accompanied by gain in abundance of PD1+ populations with exhausted (CD57-ICOShiCTLA4hi) and terminally differentiated effector (CD57+Eomes+) features. TCR sequencing revealed early and dysfunctional differentiated populations to be clonally related and CDR3 clustering analysis showed greater similarity of sequences shared vs. non-shared between subsets, consistent with an antigen driven differentiation process. Similar patterns were observed within the CD8 compartment. Identification of these subsets within single T cell RNA sequencing data revealed shared and distinct functional regulators, suggesting the enhanced effector capability of early compared to dysfunctionally differentiated populations. A validated transcriptional signature of TDS generated using TRACERx samples with paired flow cytometry and RNA sequencing data reflected loss of gene expression downstream of TCF7, and predicted worse survival within TRACERx and multiple TCGA cohorts including lung adenocarcinoma (LUAD).ConclusionsOur finding support a model of neoantigen driven T cell differentiation within the tumour microenvironment that drives the depletion of progenitor-like cells and gain in abundance of dysfunctional subsets, resulting in a loss of immune fitness. Our analysis of transcriptomic data elucidates potential regulatory mechanisms and therapeutic targets within the subsets identified.Disclosure InformationE. Ghorani: None. J. Reading: None. J. Henry: None. M. Robert de Massy: None. R. Rosenthal: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics. F. Consultant/Advisory Board; Modest; Achilles Therapeutics. V. Turati: None. A. Furness: None. A. Ben Aissa: None. S. Kumar Saini: None. S. Ramskov: None. A. Georgiou: None. M. Vila De Mucha: None. I. Uddin: None. T. Ronel: None. R. Salgado: None. T. Lund: None. J. Herrero: None. T. Enver: None. S. Hadrup: None. A. Hackshaw: None. K. Peggs: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics. N. McGranahan,: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics. F. Consultant/Advisory Board; Modest; Achilles Therapeutics. B. Chain: None. C. Swanton: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Pfizer, AstraZeneca, BMS, Roche–Ventana and Boehringer Ingelheim. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; ApoGen Biotechnologies, Epic Bioscience and GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. F. Consultant/Advisory Board; Modest; Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche–Ventana, GRAIL, Medicxi and the Sarah Cannon Research Institute. S. Quezada: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Achilles Therapeutics.
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Claessen, David, Anneke S. de Vos, and André M. de Roos. "Bioenergetics, overcompensation, and the source–sink status of marine reserves." Canadian Journal of Fisheries and Aquatic Sciences 66, no. 7 (July 2009): 1059–71. http://dx.doi.org/10.1139/f09-061.
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One of the hypothesized functions of marine protected areas (MPAs) is to serve as sources of biomass, with biomass spilling over from the reserve into neighbouring, harvested areas. We argue that the net larval flow (from or to the marine reserve) depends on between-area differences in the population-level biomass production rate, whereas the direction of adult flow depends on differences in the biomass standing stock. Hence, an important question is whether population-level biomass production increases (overcompensation) or decreases (undercompensation) with increased per capita mortality. We show that in a consumer–resource context, the source–sink status of an MPA may depend on the details of the individual-level bioenergetics, as well as on the dispersal rates of larvae and adults. We compare two classic bioenergetic models (net-production vs. gross-production allocation). The net-production model predicts that population-level reproduction may increase with mortality (overcompensation), whereas gross-production allocation always results in undercompensation. We show that models often implicitly assume gross-production allocation, thus potentially overestimating the capacity of MPAs to source unprotected areas. We briefly discuss results of two other models (a simplified, logistic model and a size-structured model), suggesting that the relation between overcompensation and the larval sink status of MPAs is general.
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Mendiola, Vincent Louie Ramos, Catherine Ly, Thuy Bui, Jennifer Wang, Jack Rodman, Karrune Woan, Eric Tam, et al. "Outcomes in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia Patients Using Tyrosine Kinase Inhibitors Combined with the Modified University of Southern California (USC ALL) Regimen without Pegaspargase in the Era of Novel Agents; A Retrospective Study." Blood 138, Supplement 1 (November 5, 2021): 4372. http://dx.doi.org/10.1182/blood-2021-150135.
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Abstract Introduction: Prior to the introduction of tyrosine kinase inhibitors (TKIs), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukemia (ALL). We published in 2017 in Br J Haematology our analysis comparing the survival of Ph-Positive (Ph+) and Ph-negative ALL during the period when TKIs were universally available in the United States for Ph+ ALL using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic stem cell transplant (allo-HSCT) to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease (MRD) the best approach is yet to be determined. In this study we present data from our institution with incorporation of TKIs in our modified USC ALL pediatric-based regimen without pegaspargase (PEG) (Table 1). Methods: This retrospective, single institution chart review included adults aged >18 with newly diagnosed Ph+ ALL between 2016 and 2020. Primary objectives were Overall survival (OS) and event-free survival (EFS) at 3 years for Ph+ ALL patients and secondary objectives were rates of complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry and presence of BCR-ABL1 fusion transcript by real time polymerase chain reaction. Descriptive statistics of patients were reported and evaluated using Fisher's exact test. OS and EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant. RESULTS: 26 Ph+ ALL patients were identified. Median age at diagnosis was 42.5 years, with 42.3% males and 57.7% females. Median BMI was 31.1 kg/m 2, 42.3% had hepatic steatosis and 34.6% had CNS disease pre-induction. After induction 1, 91.3% of patients achieved CR/CRi, 8.7% were refractory, and 64.3% were MRD flow negative with 24% of patients with undetectable BCR-ABL1. After induction 2, 94.1% had achieved CR/CRi, 64.3% were MRD flow negative with 44.4% of patients with undetectable BCR-ABL1. After consolidation I, 78.6% were MRD flow negative. 50% of patients had received blinatumomab for MRD flow positivity early in the course and 34.6% underwent allo-HSCT. Of note, 65.4% of patients received Dasatinib only and 30.8% received at least 2 TKIs. Overall, 11.5% had known relapse, 12.5% died. 3-year OS was 83.3% and 3-year EFS was 86.6% (Table 2). When survival was stratified by transplant status, 3-year OS with allo-HSCT was 100% versus 70% without allo-HSCT (p=0.15) and 3-year EFS with allo-HSCT was 100% compared to 77.9% without allo-HSCT (Table 3). CONCLUSIONS: The use of the modified USC ALL regimen without PEG for the treatment of newly diagnosed Ph+ ALL combined with TKI at our institution led to an excellent 3-year OS (83.3%) and 3-year EFS (86.6%). All patients received TKI, half of the patients received blinatumomab and at least one third received allo-HSCT which likely led to higher OS even without PEG. We also observed a trend towards improved OS in recipients of allo-HSCT compared to patients who did not receive allo-HSCT (100% vs. 70%, p=0.15) although statistically not significant, it highlights the role of allo-HSCT in the management of Ph+ ALL patients. Figure 1 Figure 1. Disclosures Chaudhary: TCR2: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Allogene: Current equity holder in publicly-traded company. Douer: Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy; Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Yaghmour: Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.
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Hirayama, Alexandre V., Ye Zheng, Mark R. Dowling, Alyssa Sheih, Tinh-Doan Phi, Delaney R. Kirchmeier, Abby W. Chucka, et al. "Long-Term Follow-up and Single-Cell Multiomics Characteristics of Infusion Products in Patients with Chronic Lymphocytic Leukemia Treated with CD19 CAR-T Cells." Blood 138, Supplement 1 (November 5, 2021): 1749. http://dx.doi.org/10.1182/blood-2021-151571.
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Abstract Introduction Lymphodepletion chemotherapy followed by infusion of autologous T cells engineered to express a CD19-targeted chimeric antigen receptor (CAR) has shown high response rates in relapsed or refractory high-risk chronic lymphocytic leukemia (CLL). Durable remissions were observed, particularly in patients (pts) who achieved minimal residual disease (MRD)-negative (neg) complete response (CR) in the marrow with no detectable malignant clone by IGH sequencing. Here, we present long-term outcomes of CLL pts treated with CD19 CAR-T cell immunotherapy, and single-cell cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analyses of infusion products (IPs) to identify intrinsic T cell characteristics associated with outcomes. Methods Pts were treated on a phase 1/2 clinical trial (NCT01865617) of CD19 CAR-T cell immunotherapy in two cohorts: no ibrutinib (ibr) cohort (No-ibr; ibr discontinued prior to leukapheresis or lymphodepletion) or concurrent ibr cohort (Con-ibr; ibr started at least 2 weeks prior to leukapheresis and continued until at least 3 months after CAR-T cell infusion). Responses were evaluated according to the 2018 International Workshop on CLL (iwCLL) criteria (Hallek et al. Blood 2018). MRD in the marrow was assessed 4 weeks after CAR-T cell infusion using flow cytometry (sensitivity, 10 -4) and IGH sequencing (sensitivity, 10 -6). Multiomics profiling was performed on IPs from 25 pts selected based on distribution of ibr washout time before leukapheresis and clinical response (Table 1). All pts received cyclophosphamide and fludarabine lymphodepletion and 2 x 10 6 CAR-T cells/kg. CD3 + CAR-T cells isolated from IPs underwent CITE-seq (10x Genomics), with generation of gene expression, full-length paired V(D)J, and cell surface protein expression libraries. Differential gene expression (DEG) analyses were performed using Model-based Analysis of Single-cell Transcriptomics (MAST). Blood transcriptome modules were used for Gene Set Enrichment Analysis (GSEA). Results Forty-seven pts (median age, 61 years) with CLL (excluding Richter's transformation without coexisting CLL) received lymphodepletion and CD19 CAR-T cell infusion. Among 29 pts with a pretreatment trackable malignant IGH clone who achieved MRD-neg CR by flow cytometry, at a median follow-up of 23.5 months (interquartile range, 11.0-33.8), the median progression-free survival was 8.5 months (95% confidence interval [CI], 2.9-not reached) for those with a detected post-treatment malignant IGH clone in marrow (n = 11) and could not be estimated (95% CI, 22.2-not reached) in those without a detected post-treatment malignant IGH clone (n = 18; P = .0006; Figure 1A). In the pts without a detected malignant IGH clone 4 weeks after infusion, only 3 (17%) relapsed; 1 died of a myocardial infarction while in ongoing response. We performed multiomics studies on IPs from a selected subset (n = 25) of pts (Table 1) to identify gene expression patterns impacting outcomes. GSEA revealed association with T cell activation, oxidative phosphorylation, transcription initiation and cell cycle modules in IPs of pts who did compared to did not achieve MRD-neg CR (Figure 1B, left), consistent with the hypothesis that CAR-T cell quality is a key determinant of depth and duration of remission in CLL. IPs studied in the multiomics subset were manufactured from pts treated in either the No-ibr or the Con-ibr cohort (Table 1) and our prior data showed a trend towards higher rates of IGH-neg CR in the Con-ibr cohort (85 vs 60%, P = .34). Because ibr administration before leukapheresis might improve CAR-T cell quality and function, we compared IPs of patients in the No-Ibr vs. Con-Ibr cohorts. GSEA revealed that the T cell differentiation via ITK and PKC module was less enriched in IPs of pts in the Con-ibr vs. No-ibr cohort (Figure 1B, right), consistent with ibr-induced inhibition of T cell differentiation as a mechanism for enhanced CAR-T cell quality in the IP. Analyses are ongoing and full results will be presented at the meeting. Conclusion Long-term follow-up confirmed that achieving a malignant IGH-neg response after CAR-T cell therapy is associated with durable remissions in high-risk CLL. Integrated multiomics profiling suggests that CAR-T cell IP quality is a key determinant of MRD-neg CR. Ibr-related inhibition of ITK signaling in T cells can further contribute to the quality of infused CAR-T cells. Figure 1 Figure 1. Disclosures Hirayama: Novartis: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Sheih: Umoja Biopharma: Current Employment. Gauthier: Janssen: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy. Maloney: A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Consultancy; Kite, a Gilead Company, Juno, and Celgene: Research Funding; Juno: Patents & Royalties. Gottardo: Illumina: Consultancy; 10x Genomics: Current holder of stock options in a privately-held company; Ozette Technologies: Current holder of individual stocks in a privately-held company; Modulus Therapeutics: Current holder of individual stocks in a privately-held company. Turtle: PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; AstraZeneca: Consultancy, Research Funding; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Allogene: Consultancy; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board.
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Kreitman, Robert J., Evgeny Arons, Sapolsky Jeffrey, Laura Roth, Hong Zhou, Maryalice Stetler-Stevenson, Wyndham H. Wilson, et al. "Resolution of Hairy Cell Leukemia Minimal Residual Disease by Both BRAF and Clone-Specific Real-Time Quantitative PCR (RQ-PCR) After Treatment with Moxetumomab Pasudotox." Blood 120, no. 21 (November 16, 2012): 2896. http://dx.doi.org/10.1182/blood.v120.21.2896.2896.
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Abstract Abstract 2896 Background: Moxetumomab pasudotox is an anti-CD22 recombinant immunotoxin containing truncated Pseudomonas exotoxin which was recently reported to achieve a complete remission rate of 46% in 28 patients with relapsed/refractory hairy cell leukemia (HCL). An additional 20 patients were treated at the highest dose level and are now fully evaluable for response and minimal residual disease (MRD) determinations. RQ-PCR using clone-specific primers and a clone-specific TaqMan probe is capable of detecting one HCL cell in 106normal cells. Recently reported methods to detect the HCL-associated BRAF V600E mutation include pyrosequencing (5–10% sensitivity) and PCR (0.1–0.23% sensitivity). Methods: Moxetumomab pasudotox was administered to 16 patients at 5–40 ug/Kg every other day for 3 doses (QODx3) and to 32 patients at 50 ug/Kg QODx3, via 1–16 (median 4) cycles per patient at 4-week intervals. Complete remission (CR) required resolution of cytopenias and elimination of HCL in the blood and marrow by standard microscopy, but MRD could be present by flow cytometry of blood or bone marrow aspirate (BMA) or immunohistochemistry (IHC) of the bone marrow biopsy (BMBx). Blood and marrow from patients were also tested by PCR using consensus primers. When immunoglobulin (Ig) rearrangements could be cloned, RQ-PCR using clone-specific primer and probe was performed. To detect MRD by the BRAF V600E mutation, BRAF quantitative PCR (BRAF-qPCR) was performed on cDNA samples, using mutant-specific primer, and SYBR-Green detection followed by melting point analysis. MRD testing for BRAF-qPCR, unlike clone-specific RQ-PCR, did not require prior cloning of the Ig rearrangement. Results: All 198 cycles of moxetumomab administered to 48 patients were evaluable for toxicity and response. No dose limiting toxicity was observed, although 2 patients as previously reported had a grade 2 hemolytic uremic syndrome with transient grade 1 platelet and creatinine abnormalities. Of the 48 HCL patients at all dose levels, there were 26 (54%) CRs, with an overall response rate (ORR) of 88%. Of 32 at 50 ug/Kg QODx3, there were 19 (59%) CRs with an ORR of 91%. Of these 19 CRs, 11 (58%) achieved MRD negativity by repeated flow cytometry of both BMA and blood and IHC of BMBx. Flow cytometry of the BMA was the most sensitive conventional test of MRD. Of the 9 CRs at 50 ug/Kg QODx3 evaluable by clone-specific RQ-PCR of blood, 5 negative were also flow-negative, and 4 positive were also flow-positive (p=0.008). BRAF-qPCR on cDNA from limiting dilutions of BRAF V600E+ Colo-205 cells into BRAF wild-type cells achieved consistent detection at 1:105dilution (0.001%). Of 10 flow-negative CRs at 50 ug/Kg QODx3 evaluated by BRAF-qPCR, all 10 (100%) were BRAF-qPCR negative, including 4 which were nonevaluable by RQ-PCR due to inability to clone the Ig rearrangements prior to treatment. Currently 12 (63%) of the 19 CRs at 50 ug/Kg QODx3 are ongoing at 6–47 (median 21) months, including 10 (91%) of 11 MRD-negative vs 2 (25%) of 8 MRD+ CRs (p=0.006). Conclusions: Moxetumomab pasudotox is active in relapsed and refractory HCL and has a safety profile supporting further development for this disease. Retreatment on this trial could not necessarily be extended to achieve MRD-negative BMAs or molecular remission by RQ-PCR using sequence-specific or BRAF primers. However, these tests might be useful in the future to guide retreatment, optimize CR durability and possibly eradicate the HCL clone in selected patients. This summary contains investigator reported data. This study was sponsored by MedImmune, LLC, and supported by NCI's Intramural Research Program and the Hairy Cell Leukemia Research Foundation. Disclosures: Kreitman: NIH: Co-inventor on the NIH patent for Moxetumomab Pasudotox, Co-inventor on the NIH patent for Moxetumomab Pasudotox Patents & Royalties. Off Label Use: Moxetumomab Pasudotox is an experimental agent for CD22+ hematologic malignancies. FitzGerald:NIH: Coinventor on the NIH patent for Moxetumomab Pasudotox, Coinventor on the NIH patent for Moxetumomab Pasudotox Patents & Royalties. Fei:AstraZeneca: Stock, Stock Other; MedImmune, LLC: Employment. Ibrahim:AstraZeneca: Stocks, Stocks Other; MedImmune: Employment. Pastan:NIH: Coinventor on NIH patent for moxetumomab pasudotox, Coinventor on NIH patent for moxetumomab pasudotox Patents & Royalties.
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White, Susan. "Amazon and Whole Foods: adventures in grocery shopping." CASE Journal 16, no. 2 (April 27, 2020): 115–53. http://dx.doi.org/10.1108/tcj-11-2018-0118.
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Theoretical basis This case focuses on valuation using various methods to price a firm. Students attempting this case should know the basics of how to value a company using discounted cash flow, comparable multiples and comparable transactions. Students will need to calculate the weighted average cost of capital using comparable companies and the capital asset pricing model and determine differences in value created by an acquisition vs a leveraged buyout (LBO). The case also discusses qualitative issues in mergers, such as fit between target and acquirer, integration issues, potential high debt from LBO. Research methodology This case was library-researched, using Amazon and Whole Foods public filings and business press papers. Case overview/synopsis Whole Foods Markets received a buyout offer from Amazon. Whole Foods could solicit offers from other firms, including firms more directly in the grocery business. Whole Foods also considered a management buyout or purchase by a private equity firm. Whole Foods had underperformed, with a falling stock price and reduced profitability. Amazon’s bid was attractive, a premium of about 40 per cent over Whole Foods’ pre-merger stock price. Whole Foods also wanted to consider issues such as culture. Whole Foods’ strategy was to sell organic foods at premium prices, while Amazon was a retail discounter with a largely online business. Complexity academic level This case is appropriate for graduate students at the end of their introductory course or for graduate or undergraduate students in a corporate finance elective, particularly a merger/restructuring elective. The case has been used in an advanced undergraduate finance elective, with a team presenting the case to the class, with remaining students in the class required to write case summaries and questions for the presenting group.
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Chadha, Saurabh, and Anil K. Sharma. "Determinants of capital structure: an empirical evaluation from India." Journal of Advances in Management Research 12, no. 1 (May 5, 2015): 3–14. http://dx.doi.org/10.1108/jamr-08-2014-0051.
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Purpose – The purpose of this paper is to study the key determinants of capital structure for Indian manufacturing firms and which theory implications, i.e. trade off vs pecking order are more applicable in current Indian manufacturing sector scenario. Design/methodology/approach – A sample size of 422 listed Indian manufacturing companies on Bombay Stock Exchange has been considered to do the empirical evaluation. A ten year period from 2003-2004 to 2012-2013 and annual financial standalone data have been considered for study. Ratio analysis and panel data approach have been applied to perform the empirical evaluation. Total debt to total capital and total debt to total assets are used as the proxy for firm financial leverage. Findings – It was empirically found that size, age, asset tangibility, growth, profitability, non-debt tax shield, business risk, uniqueness and ownership structure are significantly correlated with the firm financial leverage or key determinants of capital structure in Indian manufacturing sector. Also, other variables like dividend payout, liquidity, interest coverage ratio, cash flow coverage ratio (CFCR), India inflation and GDP growth rate are empirically found to be insignificant to determine the capital structure of Indian manufacturing sector. There is no single theory implications, i.e. trade off vs pecking order which can explain the capital structure nature of Indian manufacturing sector and rather it is a mix of both the theories. Originality/value – The findings of the study would enhance the literature on capital structure and is significant for the Indian manufacturing firm’s decisions as it includes the most recent data and covers the period of both pre- and post-recession of 2008-2009.
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Jesuraj, Nithya J., Julie M. Cole, Felipe Bedoya, Steven B. Wells, Guokui Qin, Sean Kevlahan, Marcela V. Maus, and Andrew J. Ball. "A Novel Phase-Change Hydrogel Substrate for T Cell Activation Promotes Increased Expansion of CD8+ Cells Expressing Central Memory and Naive Phenotype Markers." Blood 128, no. 22 (December 2, 2016): 3368. http://dx.doi.org/10.1182/blood.v128.22.3368.3368.
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Abstract Introduction For chimeric antigen receptor T cell-based (CAR-T) and engineered T cell receptor (TCR) immunotherapies, T cell expansion methods and phenotype/s of transplanted T cells may heavily influence clinical outcomes. Much current focus is on the potential of defined CD4+/CD8+ T cell populations vs bulk, and on the potential superiority of CAR-T cells from naïve (TN) or central memory (TCM) versus effector memory (TEM) cells. Many commercial T cell activation and expansion methods utilize rigid magnetic beads bound to antibodies against CD3 and CD28 as substrates. These methods are often associated with high costs and licensing restrictions for clinical and commercial applications. Additionally, de-beading processes can be highly complex and inefficient, adding additional time, costs and risks. It has been shown that substrate rigidity influences T cell expansion and phenotype. We hypothesized that a novel phase-change substrate could modulate expanded T cell phenotype/s and address de-beading challenges. Methods An alginate-based phase-change hydrogel was synthesized and coated onto magnetic beads to form hydrogel-coated particles of approximately 10 µm diameter. This hydrogel, in the presence of chelating agents, rapidly dissolves, enabling removal magnetic bead removal. The coated particles were conjugated with streptavidin (SA) and bound to biotinylated antibodies against CD3 (OKT3) and CD28 (28.2) to form CD3/CD28 hydrogel particles (CD3/CD28-HP). Human CD3+ T cells from peripheral blood were seeded (Day 0) at 1x10E6 cells/mL in 24 well plates (n=3) in complete RPMI medium supplemented with IL-2. To each well, 25 µL of CD3/CD28-HP were added per 0.5x10E6 cells in a single stimulation. Media addition or change of culture vessel occurred each 2-3 days. Following expansion, chelating agent was added and magnetic beads removed. Flow cytometry was used to assess cell viability and expression of phenotypic markers including CD3, CD4, CD8, CD45RA and CCR7. ELISA was used to measure secretion of IL-2, IL-4, and IFNγ. Residual magnetic beads were counted via hemocytometer. Results CD3/CD28-HP promoted significant T cell expansion of 0.3, 1.4, 2.4, 4.8 and 6.6 population doublings (PD) by Days 2, 5, 6, 9, and 13 respectively (p<0.01-p<0.001 vs Day 0). Similarly, CD3/CD28-HP-induced expansion in a separate lab using a different T cell donor yielded 4.7 PD by Day 9 (p<0.001 vs Day 0). Phenotypic markers were assessed on Days 6 and 13. Expansion using CD3/CD28-HP led to significantly more CD8+ cells and significantly fewer CD4+ cells versus the starting population on both days (p<0.05-p<0.001). When compared to a commercially available magnetic CD3/CD28 bead product, CD3/CD28-HP produced a significantly larger CD8+ population on Days 6 (p<0.05)and 13 (p<0.001), and a smaller population of CD4+ T cells on Day 13 (p<0.01). CD3/CD28-HP-based expansion significantly increased the percentage of CD3/CD45RA expressing T cells compared with the magnetic bead-based product on Day 6 (p<0.05). Also, on Day 6, T cells expanded using CD3/CD28-HP showed increased CD8/CD45RA/CCR7 expression when compared to T cells expanded with the commercial magnetic bead product (p<0.05). Cytokine secretion was assessed on Days 6 and 13. Cells expanded using both expansion methods secreted IL-2, IL-4, and IFNγ, with no significant differences in secretory function observed between expansion methods. Following de-beading of expanded cells, cell recovery was 96% for the CD3/CD28-HP-expanded cells and 93% for cells expanded using commercial magnetic bead-based expansion product. Additionally, in de-beaded cells, fewer residual magnetic particles were present in the CD3/CD28-HP-expanded population than in cells expanded via the commercial magnetic bead-based expansion product. Conclusions These data demonstrate the utility of a novel phase-change hydrogel system to efficiently induce T cell proliferation, promote expansion of functional T cells expressing markers associated with CD8+, TN and TCM phenotypes, and to separate expanded cells efficiently from magnetic beads. In future studies, we will determine if T cells expanded using this method show increased stemness and persistence in in vivo models, and further explore the possibilities of this novel system for rapid expansion and recovery of specific T cell subtypes. Disclosures Jesuraj: Quad Technologies: Employment, Other: stock options. Cole:Quad Technologies: Employment, Other: Stock Options. Wells:Quad Technologies: Employment, Other: Stock Options. Qin:Quad Technologies: Employment, Other: Stock options. Kevlahan:Quad Technologies: Employment, Equity Ownership. Maus:Novartis: Patents & Royalties: related to CTL019, Research Funding. Ball:Quad Technologies: Employment, Other: Stock Options.
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Fidai, Shiraz, Madina Sukhanova, Brian C. H. Chiu, Y. Lynn Lynn Wang, Wendy Stock, Peter A. Riedell, Sonali M. Smith, Elizabeth Hyjek, and Girish Venkataraman. "TP53 Aberrations By FISH in CLL and Complex Karyotype at Transformation Predict for Worse Outcome in Diffuse Large B-Cell Lymphoma - Richter Transformation: A Single Institution Series of 75 DLBCL-RT Cases." Blood 132, Supplement 1 (November 29, 2018): 2984. http://dx.doi.org/10.1182/blood-2018-99-112242.
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Abstract Background: Richter transformation (RT), also known as Richter syndrome, is a rare complication of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that has an aggressive clinical course and unfavorable prognosis. The majority of these transformations occur in the form of diffuse large B-cell lymphoma (DLBCL), and less frequently in the form of prolymphocytic leukemia (PLL), or classical Hodgkin lymphoma (cHL). We examined a series of RT cases with available CLL/SLL data diagnosed at our institution between 2000 and 2018 to identify clinical/biologic characteristics associated with adverse outcome. Design: After searching our pathology archives between the years 2000-2018, we identified a total of 83 RT cases: 75 DLBCL-RT (including 7 PLL-RT) and 8 cHL-RT. For the purposes of this study, we focused only on DLBCL-RT cases. All clinical, demographic, and pathologic data including cytogenetics (karyotype and FISH), immunohistochemistry (IHC), and flow cytometry were collected. Data points included age, gender, CLL/SLL histology (typical vs. atypical), CD5, CD38, ZAP-70 status, CLL karyotype, FISH [chromosomes 11q (ATM), trisomy 12, 13q, 14 (IGH), 17p(P53)]. In addition, time to transformation (months), site of transformation, transformation biopsy characteristics (germinal center vs. non-germinal center, CD5 status, along with MYC and BCL2 IHC status), and karyotype at transformation were collected. For the current analysis , karyotype and FISH data were dichotomized into (complex vs. non-complex) or (abnormality present vs. absent) respectively. Limited CLL treatment data was also collected but details on performance status, stage and IPI at transformation were not available. The clinical end point was overall survival (OS) determined as age at the time of transformation to death due to any cause, censoring patients without an event at last follow-up. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards regression models. Data analyses were performed using Stata®11. Results: Among DLBCL-RT patients, the median age at transformation was 66 years (range: 43-95). 87% of cases had antecedent CLL with a typical phenotype (CD5+, CD23+, FMC7-), 66% of CLL cases expressed CD38 (flow > 20% positivity) and 77% were positive for ZAP-70 (IHC). There was no correlation between CD38 expression and ZAP-70 (p=0.7). Fifty-three percent of the CLL cases harbored a complex karyotype. The most frequent abnormalities detected by FISH were TP53 aberrations (39%), followed by del13q (37%), Trisomy 12 (33%), IGH breaks (21%) and 11q/ATM deletion (17%). Transformation occurred at median of 59 months (0-352 range) after CLL diagnosis. DLBCL-RT was non-germinal center B-cell phenotype in 85% (n=27) of cases, with variable expression of CD5 (61%), p53 (50%), MYC (83%) and BCL2 (90%). EBER was infrequent at transformation (4%; n=23). Among DLBCL-RT, a total of 29 patients died at a median of 6 months (0-58 months) after RT diagnosis. In univariate analysis, age at transformation, type of CLL (typical vs. atypical), site (nodal vs. extranodal), CLL CD38 or ZAP-70 expression did not impact survival outcome. Only TP53 aberrations by FISH in antecendent CLL (p=0.02) (Figure 1) and the presence of complex karyotype at transformation were associated with adverse survival outcome (p=0.004) (Figure 2). MYC and/or BCL2 genetic alterations at transformation did not impact outcome. In a multivariable Cox model including both CLL TP53 aberrations and complex karyotype at transformation, only complex karyotype at transformation is weakly associated with outcome (p=0.09; hazard ratio 0.14 [0.015-1.36]; 95% CI) although this analysis is limited by the number of available patients with complete data (n=17). Conclusion: DLBCL-RT from an underlying CLL has a poor survival outcome and only TP53 alterations in the CLL and complex karyotype at transformation impacted survival. Figure. Figure. Disclosures Stock: Jazz Pharmaceuticals: Consultancy. Riedell:Bayer: Consultancy, Speakers Bureau; Novartis: Consultancy; Kite Pharmaceuticals: Consultancy, Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria.
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P., Afsheena, and Shijin Santhakumar. "Timeliness and persistence of conservative earnings in an emerging market." Journal of Financial Reporting and Accounting 18, no. 3 (June 10, 2020): 483–503. http://dx.doi.org/10.1108/jfra-12-2018-0116.
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Purpose The asymmetric effect of conservatism on earnings and its other components serves as a contrivance to incorporate transparency and timeliness in financial reporting. This study aims to explore cash flow-return association, which provides insight into the accruals’ contribution that traverses through conservatism-earnings persistence liaison and its associated effects on stock returns. Design/methodology/approach The study used asymmetric timeliness (AT) model and two firm-year measures, namely, C-Score and conservatism ratio, to capture conservatism. The firm-year measures of conservatism, in addition to the AT measure, facilitate a better understanding of the persistence of reported earnings that branch out the study from the existing literature. Further, the study used panel regression analysis to evaluate the timeliness and persistence of earnings under the conservative approach with a sample of Indian corporate data from 2000 to 2017. Findings The findings of the study reveal that conservative earnings are less persistent and the accruals recognize bad news timelier than good news. The unfavorable change in earnings shows a lower earnings response coefficient in contrast to favorable earnings variations. However, the appropriate loss recognition nature of conservative reporting has little or no influence on stock returns in an emerging market such as India. Research limitations/implications Accounting conservatism is a captivating feature accounting information, especially pertinent to many decision-makers. Thus, the study has implications for the investors while evaluating the adverse and positive changes in accounting earnings; also, the results are helpful for the standard setters in ongoing debate related to accounting conservatism vs fair evaluation. The present study focuses exclusively on ex-post conservatism, while the ex post and ex ante conservatism are having a significant role in accounting practices. Future research on the differential effects of ex post and ex ante conservatism on accounting information in an emerging market, is worth promising. Originality/value The study reveals the first Indian evidence on accounting conservatism and earnings persistence relationship, which would bring a different dimension to investors’ perception in evaluating the characteristic variations of reported earnings. The findings add value to the accounting standard setters concerning the asymmetric verification as Indian Accounting standards are on the verge of convergence with International Financial Reporting Standards (IFRS).
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Kumar, Alok. "Dynamic Style Preferences of Individual Investors and Stock Returns." Journal of Financial and Quantitative Analysis 44, no. 3 (June 2009): 607–40. http://dx.doi.org/10.1017/s0022109009990020.
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AbstractThis study shows that individual investors systematically shift their preferences across extreme style portfolios (small vs. large, value vs. growth). These preference shifts are influenced by past style returns and earnings differentials, and advice from investment newsletters, but are unaffected by innovations in macroeconomic variables or shifts in expectations about future cash flows. Furthermore, investors’ dynamic style preferences influence returns along multiple dimensions: i) the contemporaneous relation between style returns and style-level preference shifts is strong, ii) there is weak evidence of style return predictability, and iii) the correlations among stocks within a style increase when investors move into or out of the style with greater intensity. Overall, the results indicate that stock categorization influences investors’ portfolio decisions and stock returns.
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Karol, Seth E., Thomas Alexander, Amit Budraja, Stanley Pounds, Kristin E. Canavera, Lei Wang, Joshua Wolf, et al. "Venetoclax in Combination with High-Dose Chemotherapy Is Active and Well-Tolerated in Children with Relapsed or Refractory Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 178. http://dx.doi.org/10.1182/blood-2019-127716.
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Introduction: Venetoclax (VEN) is a potent and selective inhibitor of BCL-2. It has demonstrated activity in adults with acute myeloid leukemia (AML) in combination with low-dose cytarabine (<100mg/m2/day) and hypomethylating agents. Here, we report safety and activity of VEN in combination with intermediate- and high-dose cytarabine with or without idarubicin in children and young adults with relapsed or refractory AML. Methods: VEN was given daily for 28 days and chemotherapy was started on day 8, or earlier in cases of disease progression. Dosages of VEN and chemotherapy were escalated separately using a rolling-six design. Response to the VEN window was determined using total peripheral blood blast count or, in a subset of patients, bone marrow blast percentage as determined by flow-cytometry based minimal residual disease (MRD). Pharmacokinetics of VEN both as a single agent and in combination with chemotherapy were measured in a subset of patients treated at the maximum tolerated combination dose of VEN. Response to therapy was determined using bone marrow evaluation between days 29-50 of therapy. All patients received antimicrobial prophylaxis, typically with levofloxacin and micafungin. Azoles were prohibited during VEN administration. Results: Thirty-six patients aged 2-22 years were enrolled. All dose levels were tolerated. The recommended phase 2 dose of VEN in combination with high-dose cytarabine with or without idarubicin was 360 mg/m2 daily (max 600mg). One patient (treated with 240mg/m2 of VEN and intermediate-dose cytarabine) experienced a dose-limiting toxicity due to delayed count recovery and one patient died of recurrent colitis (at dose level 3) which first occurred during prior therapy and was deemed unrelated to VEN. Patients experienced a mean of 2.4 non-hematologic grade 3+ toxicities, with infections including culture-negative febrile neutropenia, sepsis, and colitis the most common toxicities. Patient-reported quality of life was similar at study entry and at the completion of cycle 1 and was within normal limits in most patients. Among 22 patients receiving VEN with high-dose cytarabine ± idarubicin, 14 (64%) achieved a complete response (CR) or complete response with incomplete count recovery (CRi). Response to the VEN window was associated with end of cycle 1 response; 13/15 (87%) patients with a greater than 80% reduction in peripheral blasts achieved a partial response (PR; 3) or CR/CRi (10). In contrast, only 8/15 (53%) patients with less than an 80% reduction in blasts responded to combination therapy (7 CR, 1 PR). Window response to VEN was associated with BH3 dependence as determined by cytochrome c release from leukemia cells in a flow-cytometry based assay. 5 of the 6 (83%) patients with primary BCL-2 dependence had a >80% reduction in blasts; the single patient with a poor response had a change to BCL-XL dependence at the end of cycle 1. In contrast, 4 of the 6 (66%) patients with primary BCL-XL dependence had a <80% reduction in blasts; the 2 patients with a >90% reduction had secondary BCL-2 dependence. None of the 4 patients with FLT3-ITD or point mutations responded as determined by end of cycle 1 marrow. VEN levels were consistent across weights and ages and similar to levels seen in adults. The levels were similar between patients who did and did not receive idarubicin (mean AUC24 38.3 ± 32.7 vs. 47.3 ± 22.9 μg•h/mL). Conclusion: VEN combined with high-dose cytarabine or high-dose cytarabine and idarubicin was well tolerated and effective in children and young adults with relapsed or refractory AML. Enrollment continues to refine estimates of response rate. VEN window response is associated with BH3 dependence and end of cycle 1 response rates. Targeting BCL-XL or FLT3 may improve response to combination therapy. Table Disclosures Karol: Abbvie: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study.. Alexander:AbbVie: Other: travel funding. Salem:AbbVie: Employment, Other: Stock/stock options. Palenski:Abbvie: Employment, Other: Stock/ stock options. Opferman:AbbVie: Research Funding. Rubnitz:AbbVie: Research Funding.
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Zeidan, Amer M., Jan Philipp Philipp Bewersdorf, Vanessa Hasle, Ethan G. Thompson, Daniel Lopes de Menezes, Shelonitda Rose, Isaac Boss, and Brian Fox. "Immune and Epigenetic Landscape of TP53-mutated Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes (HR-MDS)." Blood 138, Supplement 1 (November 5, 2021): 3371. http://dx.doi.org/10.1182/blood-2021-146329.
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Abstract Introduction: Mutations in TP53 occur in 10% of patients (pts) with AML and HR-MDS and have been associated with worse outcomes and an immunosuppressive phenotype. To define the immune and epigenetic landscape in TP53-M advanced myeloid neoplasms (MN), we compared data from 61 pts with HR-MDS or AML with TP53 mutations (TP53-M) to 143 TP53 wildtype (TP53-WT) pts who were followed prospectively with serial samples in a well-annotated clinical trial in which all pts received hypomethylating agent (HMA)-based therapy. Methods: The FUSION trial (NCT02775903) was a large, randomized phase 2 study comparing azacitidine (AZA) monotherapy with AZA + anti-PD-L1 antibody durvalumab in 2 separate cohorts of previously untreated unfit AML and HR-MDS pts (Zeidan A et al, ASH 2019). Responses were classified by IWG 2003 and 2006 criteria for AML and MDS, respectively. Survival was estimated using Kaplan-Meier techniques. Samples from peripheral blood (PB) and bone marrow (BM) were obtained at baseline and serially on trial. A 38-targeted mutation analysis was performed at Munich Leukemia Laboratory. Only level 1 pathogenic TP53 mutations with variant allele frequency (VAF) ≥2% were included. DNA methylation was assessed using Illumina's Infinium Human Methylation EPIC methylation array. Immunophenotyping and immune checkpoint expression was performed using flow cytometry. Gene expression profiles were studied by RNA-sequencing. Results: Of 129 AML and 84 HR-MDS pts enrolled in FUSION trial, 37 had TP53-M AML, 88 TP53-WT AML, 24 TP53-M HR-MDS, and 55 TP53-WT HR-MDS pts. The average VAF for TP53 mutations were 37%, and 90% had ≥10% VAF. TP53-M AML pts were more likely to have poor-risk cytogenetics, therapy-related disease, and lower BM blast percentage compared to TP53-WT AML pts. TP53-M HR-MDS were more likely to have secondary MDS, very poor risk cytogenetics by IPSS-R, and very high risk IPSS-R score. There were no statistically significant differences in overall response rate (ORR) between TP53-M and TP53-WT pts (AML cohort: ORR: 35.1% [95% CI: 21%-53%] vs. 34.1% [CI: 26%-45%]; HR-MDS cohort: ORR: 41.7% [CI: 23%-63%] vs. 60% [CI: 46%-73%]). Median OS was 8.1 [95% CI: 5.4 - 13] months (mos) among TP53-M AML pts and 16.6 [95% CI: 13 - 21] mos for TP53-WT AML pts [Figure 1A]. Median OS was 9.8 [95% CI: 9.3 - 20+] mos for TP53-M HR-MDS pts and 23.5 [95% CI: 12 - 25+] mos for TP53-WT HR-MDS pts [Figure 1B]. Global DNA methylation was independent of TP53 mutation status in both AML (global methylation score x10^5: TP53-M: 4.9 [SD: 0.23] vs TP53-WT: 4.8 [SD: 0.33]; p=0.35) and HR-MDS pts (global methylation score: TP53-M: 4.8 [SD: 0.20] vs TP53-WT: 4.7 [SD: 0.25]; p=0.24) at baseline. DNA methylation changes after one cycle of AZA treatment were similar in both cohorts (AML: TP53-M:4.4 [SD: 0.38] vs TP53-WT: 4.5 [SD: 0.41, p=0.33]; HR-MDS: TP53-M: 4.3 [SD: 0.35] vs TP53-WT: 4.3 [SD: 0.36]; p=0.52). In RNA sequencing (Figure 2), TP53-M pts had higher expression of T-cell genes (e.g. IL7R) in both AML and HR-MDS compared to TP53-WT pts. Compared to TP53-WT pts, IFN alpha signature genes were reduced only in TP53-M AML pts but were increased in TP53-M HR-MDS pts. PD-L1 (CD274) expression was correlated with the T-cell gene signature and had a higher expression in TP53-M samples. TP53-M pts showed lower expression of tumor associated genes (e.g. CD34) consistent with the tumor cell percentages seen by BM flow cytometry. However, in gene set enrichment analysis, MYC target genes, MTORC1, and E2F were enriched in TP53-M samples consistent with the higher expression of proliferation genes (e.g., MKI67). In the bone marrow flow cytometry of AML pts, more T-cells were seen in TP53-M pts (Figure 3A), and PDL1 positive tumor cells were trending higher in TP53-M pts while the total abundance of tumor cells was slighter higher in TP53-WT (Figure 3B). Discussion: We confirm here that achieving a response to AZA therapy in AML or HR-MDS pts is not impacted by presence of TP53 mutations, however as expected median OS was substantially shorter among TP53-M pts for both AML and HR-MDS. In analyzing the epigenetic landscape, there were no differences in baseline global DNA methylation by TP53 status. RNA sequencing showed enrichment of T-cell genes and PD-L1, and an increase in gene expression of proliferation genes in TP53-M pts. Taken together, these findings support the presence of immunosuppressive microenvironment among TP53-M pts with advanced MN. Figure 1 Figure 1. Disclosures Zeidan: Janssen: Consultancy; Jasper: Consultancy; Epizyme: Consultancy; Acceleron: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; BioCryst: Other: Clinical Trial Committees; Astex: Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; ADC Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; Agios: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Aprea: Consultancy, Research Funding; Ionis: Consultancy; Astellas: Consultancy. Hasle: Bristol Myers Squibb: Current Employment. Thompson: Bristol Myers Squibb: Current Employment. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boss: Bristol Myers Squibb: Current Employment. Fox: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.
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Soumerai, Jacob D., Anthony R. Mato, Ahmet Dogan, Venkatraman Seshan, Erel Joffe, Kelsey Flaherty, Jason Carter, et al. "Zanubrutinib, Obinutuzumab, and Venetoclax in Chronic Lymphocytic Leukemia: Early MRD Kinetics Define a High-Risk Patient Cohort with Delayed Bone Marrow Undetectable MRD and Earlier Post-Treatment MRD Recurrence." Blood 138, Supplement 1 (November 5, 2021): 3753. http://dx.doi.org/10.1182/blood-2021-150961.
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Abstract Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11], PPV 100% [21/21], NPV 79% [11/14]. As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p<0.001; Figure) despite shorter treatment duration. We did not observe differences in posttreatment MRD kinetics based on IGHV status or high-risk genetics. Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.
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Hidalgo-Lopez, Juliana E., Gail J. Roboz, Brent Wood, Michael Borowitz, Elias J. Jabbour, Kelly Velasco, Ehab Elkhouly, et al. "Heterogeneity of Minimal/Measurable Residual Disease (MRD) Practices in Adult B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) in the United States." Blood 138, Supplement 1 (November 5, 2021): 4478. http://dx.doi.org/10.1182/blood-2021-144353.
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Abstract Background: MRD testing in BCP-ALL is critical for appropriate patient management, but little is known regarding sample acquisition and testing heterogeneity across clinical practice settings. These factors may impact the quality and reliability of MRD assessment. Methods: Thirty-minute online surveys were conducted in May 2021 with hematologists/oncologists (HEME/ONCs) in the United States in both academic (acad) and community (comm) settings. Respondents were licensed physicians board certified in oncology and/or hematology who treated ≥2 BCP-ALL patients/year or ≥10 patients in the past 5 years, with over 25% of time spent in the clinical setting; pediatric HEME/ONCs were excluded. Survey enrollment is ongoing, with interim results presented here; a related survey for pathologists (PATHs) is underway. Results: HEME/ONC respondents (acad n=40, comm n=57, from 29 states) had been practicing as specialists for a median of between 11-15 years (choices were ranges, eg 6-10, 11-15, min-max was 1-34 years), and typically spent over 75% of their time in the clinic; 94% of respondents had ≥5 BCP-ALL patients/year and 92% ordered MRD tests for ≥5 patients/year. Typical timepoints for MRD testing included the end of induction/suspected complete remission, the end of consolidation, and at suspected disease progression; testing after the end of consolidation was infrequent in both groups (Table). Testing for MRD at the end of consolidation was notably more frequent in the academic setting. In both settings, the HEME/ONC ordering the MRD test generally also performed the bone marrow collection procedure (acad: 78%, comm: 56%). Resources consulted on bone marrow collection best practices included UpToDate (21%), ASH and ASCO (13%), NCCN guidelines (13%), and hematology/oncology journals. About half of practices had defined institutional protocols for bone marrow collection (acad: 55%, comm: 47%), nearly all of which were developed internally. The amount of bone marrow sample collected showed high variability, ranging from 1-10 draws (median=3) and 1-30 mL sample per draw (median=5 mL). While 49% of HEME/ONCs performed <5 draws and extracted ≤6 mL per draw, 22% collected 10 mL/draw, and 10% collected 20 mL/draw; the remaining 18% reported >5 draws and/or >6 mL per draw. In both settings, the first pull was identified and labeled in 35% of procedures; in those cases, the first-pull samples were used primarily for MRD testing in 60% of cases as recommended by NCCN guidelines (vs for morphology assessment and cytogenetic studies). HEME/ONCs typically relied on the expertise of pathologists to choose MRD testing methodology.Survey results indicate that external labs (both national clinical reference labs and commercial labs) were most commonly used for MRD assessments (63%); comm HEME/ONCs were more likely to use external reference labs and acad HEME/ONCs were more likely to use in-house labs. When asked to estimate the frequency with which different MRD methods were used, mean responses were 54% flow cytometry and 40% next-generation sequencing. While all HEME/ONCs indicated that MRD results were presented clearly in lab reports, there was a desire to include more guideline information about MRD interpretation and BCP-ALL treatment. Conclusion: Interim results identified broad heterogeneity in clinical practices affecting sample collection for MRD assessment in Ph- BCP-ALL in the US, indicating several opportunities for harmonization of routine MRD assessment in BCP-ALL. These opportunities include optimization of bone marrow sample collection techniques (volume/draw and identification/use of first pull for MRD), timing/frequency of specimen collection, serial MRD surveillance after consolidation, MRD method chosen, and standardizing reports to include guideline information. There were gaps in awareness of FDA-approved methods of MRD testing for BCP-ALL. Initiatives supporting provider education and harmonization of best practices from professional guideline committees/organizations are needed to optimize outcomes of BCP-ALL patients. Figure 1 Figure 1. Disclosures Hidalgo-Lopez: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Roboz: Janssen: Research Funding; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Borowitz: Amgen, Blueprint Medicines: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Velasco: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Elkhouly: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Adedokun: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Zaman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Iskander: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding.
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Nastiti, Pambayun Kinasih Yekti, Apriani Dorkas Rambu Atahau, and Supramono Supramono. "THE DETERMINANTS OF WORKING CAPITAL MANAGEMENT: THE CONTEXTUAL ROLE OF ENTERPRISE SIZE AND ENTERPRISE AGE." Business, Management and Education 17, no. 2 (October 9, 2019): 94–110. http://dx.doi.org/10.3846/bme.2019.10409.
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Purpose – working capital management plays a vital role in determining the continuity of enterprises’ business activities. Enterprises should manage their working capital efficiently to avoid excessive working capital investments and at the same time, to maintain their liquidity. This study aims to examine the determinants of working capital management and to test the different effects of the determinants of working capital management based on enterprise size and enterprise age. Research methodology – the sample consists of 117 manufacturing enterprises listed at the Indonesian Stock Exchange for the years 2010–2017. Panel data regression was used to test the hypothesis. Findings – the findings reveal that sales growth and economic growth determine working capital management. However, the effects of the determinants of working capital management differ depending on enterprise size and enterprise age. Specifically, economic growth is the only determinant that exhibits different effects on working capital management between different enterprise size and enterprise age subsamples. Meanwhile, besides economic growth, capital expenditure, and operating cash flow are the other enterprise-specific determinants that exhibit different effects on working capital management between the two enterprise age subsamples. Research limitations – this study only measures enterprise size with total assets. Thus, we advise future studies to complement this proxy with other measures such as market value and the listing size criterion (main board vs development board). Further, it is necessary to analyse the non-linear relationship between leverage and working capital management to explain the positive effect of leverage on working capital management. Practical implications – the empirical results suggest that manufacturing enterprises must focus more on their sales growth because it affects their ability to manage their working capital efficiently. Besides, younger manufacturing enterprises need to shorten their cash cycles that are longer relative to old enterprises. Originality/Value – no previous studies have analysed the determinants of working capital management based on enterprise characteristics, especially enterprise size and age. Specifically, in the scientific literature, enterprise size and enterprise age mainly act as the dependent variables.
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Alhumaid, Muhned, Georgina S. Daher-Reyes, Aaron D. Schimmer, Andre C. Schuh, Anne Tierens, Caroline J. McNamara, Dawn Maze, et al. "Prognostic Role of Multiparameter Flow Cytometry-Based Measurable Residual Disease Assessment in Patients with Acute Myeloid Leukemia Harboring DNMT3A/TET2/ASXL1 Mutation." Blood 136, Supplement 1 (November 5, 2020): 8–9. http://dx.doi.org/10.1182/blood-2020-138862.
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BACKGROUND: Multiparameter flow cytometry (MFC) has increasingly been used for measurable residual disease (MRD) assessment in patients with acute myeloid leukemia (AML), while next-generation sequencing (NGS)-based MRD monitoring tool is in clinical development for its application. Clonal hematopoiesis (CH), in which leukemia-associated somatic mutations gene are present in individuals with no apparent hematologic disease, adds a challenge in the detection of MRD. In patients with AML, CH could be potentially pre-leukemic, while persistent mutations in DNMT3A, TET2 orASXL1 (DTA) in remission marrow are usually removed from the analysis of residual leukemic cells. However, reports suggest that persistent DTA mutations in remission may be correlated with an increased relapse risk. In the patients with DTA mutations, the use of NGS for MRD monitoring is limited or modified due to the presence of CH clone in the remission marrow. We evaluated whether MFC-MRD can be adjunctive to predict the risk of AML relapse in this population of 221 patients with DTA mutation (DNMT3A (n=123), ASXL1 (n=56) or TET2 (n=100). METHODS: The present study evaluated long-term outcomes in AML patients who achieved first complete remission (CR1) and compared outcomes according to MFC-based MRD status (was defined as negative if patients achieved 0.1 or less) assessed at the time of CR1. A total of 435 patients diagnosed with AML and treated with induction chemotherapy between 2015 and 2018 were included. MFC-MRD was assessed in 336 patients in CR1 (77%). NGS was performed using samples obtained at the time of initial diagnosis and used for mutational subgroup classification. Overall survival (OS) was calculated as the date of CR1 to the date of death and censored on the date of the last follow-up. Relapse-free survival (RFS) was defined as the time from the date of CR1 to the date of relapse or death from any cause. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated considering competing risk. The Kaplan-Meier method using a log-rank test and a multivariate Cox proportional hazard model was used for analyses of time-to-event endpoints. For CIR and NRM, Gray test was performed for the risk factors and the Fine-Gray model was adopted for the multivariate model. RESULTS: According to the MFC-MRD status, i.e., the group with positive MRD (MRDpos; n=118, 35%) vs. those with negative MRD (MRDneg; n=218, 65%), we evaluated OS, RFS, and CIR. The MFC-MRDneg group showed better OS at 2 years 67.0% than the MFC-MRDpos group 40.7% (p<0.001). The MFC-MRDneg group also showed a higher RFS rate at 2 years (58.7%) than the MFC-MRDpos group (40.6%) (p=0.001). The CIR was higher in the MFC-MRDpos group, 26.9%, than in the MFC-MRDneg group 21.1%, but with borderline statistical significance (p=0.083). NRM was slightly higher in the MFC-MRDpos group, 32.5%, than in the MFC-MRDneg group, 20.2%, but with borderline statistical significance (p=0.057). We divided the groups according to the number of induction treatment courses, AML type, cytogenetics risk, and age (<60 vs ≥60), and compared OS, RFS, CIR and NRM between MFC-MRDpos vs MRDneg groups, which showed that MFC-MRD is relevant for risk stratification regardless of above-mentioned clinical variables Tab1. Also, we evaluated MFC-MRD status at CR by mutational profile subgroup. Long-term outcomes such as OS, RFS, CIR or NRM were compared by the mutational subgroup. It consistently showed a trend of superior OS, RFS and lower risk of CIR in patients with MFC-MRDneg compared to MFC-MRDposTab1. Of interest, in the subgroup of patients carrying any DTA mutations (n=221), those with MFC-MRDneg (n=103) showed better OS (HR 1.61 [1.01-2.55%]; p=0.042), RFS (HR 1.66 [1.06-2.61%]; p=0.026) and CIR (HR 1.99[1.03-3.83%]; p=0.04) compared to those MFC-MRDpos (n=64; Fig 1). Multivariate analysis confirmed that the MFC-MRDneg is an independent prognostic factor in patients with DTAmutwith respect to OS: MFC-MRDpos (HR 1.63, p=0.04) and age (≥60; HR 2.04, p=0.008) for OS; for RFS, MFC-MRDpos (HR 1.71, p=0.02) and age (≥60; HR 2.32, p= 0.001); for CIR, MFC-MRDpos (HR 2.31, p=0.01) and HCT (HR 0.14, p=<0.001). Conclusion: These findings suggest that in AML patients with DTAmut, MFC-MRD status at the time of remission assessment can be a tool for MRD assessment when NGS-based MRD assessment is limited. Further study is strongly warranted to reach a clearer conclusion with multiple cohorts. Disclosures Schimmer: Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria; Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock . Tierens:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees. McNamara:Novartis: Honoraria. Maze:Pfizer: Consultancy; Novartis: Honoraria; Takeda: Research Funding. Gupta:Pfizer: Consultancy; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding.
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Murphy, Tracy, Stanley W. K. Ng, Ian King, Tong Zhang, Andrea Arruda, Narmin Ibrahimova, Jaime O. Claudio, et al. "Inferior Outcomes with a High LSC17 Score Can be Improved with Flag-IDA." Blood 136, Supplement 1 (November 5, 2020): 35–36. http://dx.doi.org/10.1182/blood-2020-138943.
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Introduction: Acute myeloid leukemia (AML) is driven by a subpopulation of leukemia stem cells (LSCs), which possess properties such as quiescence and self-renewal that are linked to therapy resistance and relapse. The LSC17 score was derived from genes differentially expressed between functionally validated LSC+ and LSC- fractions from 78 AML patients and is strongly associated with survival and response to standard therapy. A critical advantage of the LSC17 test over cytogenetic and molecular analysis is its rapid turnaround time (24-48h on a NanoString platform), providing clinicians with a rapid and powerful tool for upfront risk stratification. We have developed a clinical assay for the LSC17 score validated in a CAP/CLIA-lab setting. Methods: We conducted a prospective, multicenter validation and feasibility study to test the prognostic value of the LSC17 assay under real-world conditions in AML patients treated with curative intent. Patients with a possible new diagnosis of AML were eligible. Patients with a confirmed diagnosis of acute promyelocytic leukemia were excluded from analysis. Standard prognostic markers including cytogenetics, molecular studies and targeted sequencing using a standard AML panel were performed in parallel to the LSC17 score. Treatment was administered according to physician preference, based on patient history and results of standard prognostic assays, when available. Survival data was censored on June 14th, 2020. Results: 381 patients were recruited to the study between June 2016 and March 2020. 4 patients were excluded for quality control reasons (one sample had insufficient RNA and three samples failed quality control checks). 103 were excluded as they had alternative diagnoses. 84 patients were excluded because they did not receive intensive chemotherapy. LSC17 scores ranged from 0 to 1.25, and were classified as high or low according to the median score of 0.51 from a previously validated reference cohort (Ng et al, Nature 2016). Of the 190 patients included in this analysis, 84 had a low LSC17 score and 106 had a high LSC17 score. The median age was 61 years (range 18-79); 86 (45%) were female. When stratified according to ELN 2017 criteria, 48 (27%), 51 (29%), and 77 (44%) patients had favorable, intermediate, and adverse risk disease, respectively. Low LSC17 score was associated with normal cytogenetics (high vs low, 33% vs 58%; P <0.01) and low molecular risk disease (normal cytogenetics, NPM1 mutated, FLT3-ITD wildtype; high vs low, 4% vs 30%; P <0.01). High LSC17 score was associated with poor risk cytogenetics (high vs low, 41% vs 11%; P <0.01), myelodysplasia-related changes (high vs low, 36% vs 10%; P <0.01), and adverse risk by ELN criteria (high vs low, 66% vs 18%; P <0.01). We first considered response to induction chemotherapy (Table 1). 141 patients had standard induction chemotherapy with 3+7, 40 had Flag-IDA and 9 had CPX-351. High score patients had inferior responses to 3+7 with only 59% achieving complete remission (CR) after 1 cycle of chemotherapy compared to 96% of low score patients; responses for LSC17 high score patients were better in the Flag-IDA group with 80% achieving CR after 1 cycle. When considering overall CR rates after 2 cycles of induction, patients with a high LSC17 score were less likely to achieve CR (high vs low, 87% vs 98%; P=0.02). However, this difference was predominantly observed in patients treated with 3+7 (87% vs 99% CR rate in high vs low score patients, respectively); response rates to Flag-IDA were not significantly different between the 2 groups. Measurable residual disease (MRD) monitoring by flow cytometry was performed at the time of CR in 135 (71%) patients enrolled at Princess Margaret Cancer Centre. Patients with a high LSC17 score were significantly more likely to have MRD compared to low score patients (46% vs 10% respectively, P <0.0001). The initial poor response to 3+7 observed in high score patients was associated with worse survival compared to low score patients (Figure 1) (HR 1.8, P=0.09). Survival of high and low score patients treated with Flag-IDA was similar (HR 1.5, P=0.43). Conclusion: AML patients with a high LSC17 score have inferior outcomes following 3+7 induction chemotherapy. The LSC17 score should be considered as a tool to identify and stratify high-risk patients to alternative upfront therapies such as Flag-IDA. A risk adapted study is planned to validate these results. Disclosures Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Maze:Novartis: Honoraria; Takeda: Research Funding; Pfizer: Consultancy. McNamara:Novartis: Honoraria. Schimmer:Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria. Leber:Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tierens:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees. Wang:Trilium therapeutics: Patents & Royalties: There is an existing license agreement between TTI and University Health Network and J.C.Y.W. may be entitled to receive financial benefits further to this license and in accordance with UHN's intellectual property policies. .
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Kucukal, Erdem, Aaron Wolfe, Ryan Kocevar, Lalitha V. Nayak, Samuel Sowemimo-Coker, John Zak, Laurel Omert, and Umut A. Gurkan. "Hypoxic Storage of Red Blood Cells: Assessment of Adhesion Properties Using a Standardized Endothelium-on-a-Chip Microfluidic Platform." Blood 138, Supplement 1 (November 5, 2021): 1072. http://dx.doi.org/10.1182/blood-2021-151270.
Full textAbstract:
Abstract Background: Blood transfusions are routine medical procedures in which stored blood or blood products (i.e., red blood cells, RBCs) are given to the patient to prevent adverse health outcomes due to acute or chronic anemia. The current regulations require RBCs to be stored at 4 ºC not more than 42 days before a transfusion. However, RBCs undergo extensive rheological changes during storage and may contribute to complications associated with transfusion. Hemanext has recently introduced an innovative storage system to ameliorate such storage lesions, in which RBCs are stored in a hypoxic environment, and thus they are exposed to much lower oxidative stress during storage. In this study, we report the changes in adhesion properties of stored RBCs to human endothelial cells following a 42-day storage in normoxia vs hypoxia, using a standardized endothelialized microfluidic platform: Endothelium-on-a-chip. Methods: Two units of 1-day old blood type O positive leukocyte reduced RBCs in additive solution were pooled and divided into equal aliquots (300mL each) A and B. Unit A was stored under conventional normoxic storage condition at 4°C for 42 days. Unit B was deoxygenated so that the percent oxygen saturation of the hemoglobin was less than 20%. The deoxygenated RBCs were stored in an oxygen impermeable storage bag for 42 days at 4°C. Adhesion levels were tested at the beginning (baseline, Week 1) and the end of the storage period (Week 6). To conduct the adhesion experiments, human umbilical vein endothelial cells (HUVECs) were first cultured within microfluidic channels under flow for at least 48 hours. Next, the HUVECs were treated with 40 µM heme for 4 hours at 37 ºC [1]. RBCs were centrifuged to remove the storage buffer and resuspended in basal cell culture medium (EGM, Lonza, Morristown, USA) supplemented with 10 mM HEPES at a hematocrit of 40%. A 15 µl of RBC solution was then injected over heme-activated HUVECs at a shear stress of 1 dyne/cm 2 followed by a 10-minute rinse with fresh basal culture medium to remove non-adherent RBCs. At the end of the experiment, adherent erythrocytes were manually quantified. Control experiments were conducted with non-activated HUVECs. Results: We found that RBCs that were stored under conventional normoxic condition displayed higher adhesion to heme-activated HUVECs than hypoxic condition as illustrated in Figure 1A and 1B. The baseline adhesion levels (Week 1) to non-activated HUVECs (control) were negligible (Fig. 1C, normoxia: 13±6; hypoxia: 18±10, p>0.05) while both cell populations had considerable adhesion levels to heme-activated HUVECs at baseline (Fig. 1C, normoxia: 372±59; hypoxia: 335±37). Following a 6-week storage, adhesion of RBCs stored in normoxia to heme-activated HUVECs was higher compared to those stored in hypoxic conditions while the p-value was not significant, which was likely due to the limited sample size (Fig. 1C, 1782±519 vs 594±55, p=0.08, N=3). These results suggest that storage-mediated RBC adhesion to heme-activated HUVECs may be ameliorated by the novel hypoxic-storage condition. Discussion: This study showed a decrease in the adhesion of hypoxic RBCs to heme-activated HUVECs when compared to conventionally stored RBCs for transfusion. This result suggests that hypoxic RBCs may reduce the risk of developing vaso-occlusion (VOC) after RBC transfusion in patients such as in sickle cell disease where adhesion to heme-activated HUVECs has been implicated in the pathogenesis of VOC [1]. Acknowledgements: This work was funded by Hemanext. The authors would like to thank the Ohio Third Frontier Technology Validation and Start-up Fund (TVSF) and National Science Foundation Phase-I Small Business Technology Transfer (STTR) award, which supported this work in part. Stored RBCs were donated by Hemanext. Reference: 1. Kucukal, E., et al., American Journal of Hematology, 2018. 93(8): p.1050-1060 Figure 1 Figure 1. Disclosures Kucukal: BioChip Labs: Current Employment, Patents & Royalties. Kocevar: BioChip Labs: Current Employment. Nayak: BioChip Labs: Current Employment. Sowemimo-Coker: Hemanext: Current Employment. Zak: BioChip Labs: Current Employment, Current holder of stock options in a privately-held company; XaTek: Current Employment, Current holder of stock options in a privately-held company; TecTraum Inc: Current Employment, Current holder of stock options in a privately-held company. Omert: Hemanext: Current Employment. Gurkan: Biochip Labs: Patents & Royalties; Hemex Health, Inc.: Current Employment, Patents & Royalties; Dx Now Inc.: Patents & Royalties; Xatek Inc.: Patents & Royalties.
34
Kantarjian, Hagop M., Wendy Stock, Ryan D. Cassaday, Daniel J. DeAngelo, Elias Jabbour, Susan M. O'Brien, Matthias Stelljes, et al. "Efficacy and Safety Outcomes in the Phase 3 INO-Vate Trial By Baseline CD22 Positivity Assessed By Local Laboratories." Blood 134, Supplement_1 (November 13, 2019): 1344. http://dx.doi.org/10.1182/blood-2019-122097.
Full textAbstract:
Introduction: Inotuzumab ozogamicin (InO) is a CD22-directed antibody-calicheamicin conjugate. Patients (pts) with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) treated with InO vs standard of care chemotherapy (SC) had significantly better response, and improved survival in INO-VATE (NCT01564784). Based on central laboratory assessment, this favorable benefit-risk profile of InO was independent of leukemic blast CD22 positivity (≥90% vs <90%) and CD22 receptor density (quantified as Molecules of Equivalent Soluble Fluorochrome, quartile analysis). As CD22 is usually assessed in local labs in clinical practice, this study uses INO-VATE data to investigate the relationship between baseline CD22 positivity assessed by local labs and the efficacy and safety of InO vs SC. Methods: Adult pts (≥18 yrs) with R/R CD22-positive (based on local or central lab results) ALL in salvage 1 or 2 were randomized to InO (n=164) or SC (n=162) (details: NEJM 2016;375:740-53). InO starting dose was 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1; 0.5 mg/m2 on Days 8 & 15 of a 21-28-day cycle for ≤6 cycles) and reduced to 1.5 mg/m2/cycle for pts with complete remission (CR) or CR with incomplete hematologic recovery (CRi). SC included fludarabine/cytarabine [Ara-C]/granulocyte colony-stimulating factor, Ara-C plus mitoxantrone, or high-dose Ara-C. CD22 positivity (% of leukemic blasts expressing CD22) was measured at screening by flow cytometry or immunohistochemistry. Efficacy (CR/CRi, minimal residual disease [MRD, assessed in central labs] among responders, overall survival [OS], progression-free survival [PFS], and duration of remission [DoR]) and safety outcomes were analyzed by CD22 positivity quartiles, Quartile 1 (Q1) having the lowest and Q4 the highest CD22 positivity. Data cutoff: 04Jan2017. P-values are 1-sided. Results: Baseline CD22 positivity per local lab was available for 152 pts per arm. CD22 positivity (%) was comparable between treatment arms for each quartile; median (range) was 21.9 (1.0-39.4) for InO vs 23.9 (0.0-39.0) for SC in Q1, 55.5 (40.0-68.9) vs 56.3 (40.0-66.0) in Q2, 84.0 (70.0-92.0) vs 84.0 (70.0-92.9) in Q3, and 98.0 (93.0-100.0) for both arms in Q4. CR/CRi rates showed no difference among quartiles in the InO (P=0.5906) or SC arm (P=0.2061), and were significantly higher with InO vs SC for all quartiles (Q1: 81.6% vs 41.2%, P=0.0002; Q2: 68.4% vs 36.8%, P=0.0029; Q3: 73.2% vs 27.0%, P<0.0001; Q4: 77.1% vs 20.9%, P<0.0001) (Figure). MRD negativity rates in responders were also higher with InO vs SC and the differences in the lower quartiles (Q1-Q3) were significant (Q1: 87.1% vs 50.0%, P=0.0121; Q2: 69.2% vs 21.4%, P=0.0048; Q3: 66.7% vs 30.0%, P=0.0486; Q4: 77.8% vs 55.6%, P=0.1930) (Figure). PFS, DoR, and OS were longer with InO vs SC. The benefit of InO over SC was more evident in the higher quartiles (Q2-4); hazard ratio (97.5% Cl) was 0.44 (0.31-0.61) for PFS, 0.53 (0.31-0.88) for DoR, and 0.71 (0.52-0.99) for OS (Table). Cytopenias were the most common ≥grade 3 adverse events in the InO arm, with similar rates across the quartiles (Q1-Q4: neutropenia: 52.6%, 47.4%, 39.0%, and 48.6%; thrombocytopenia: 34.2%, 44.7%, 46.3%, and 31.4%; febrile neutropenia: 15.8%, 28.9%, 29.3%, and 34.3%). Rates of ≥grade 3 infections were 21.1%, 26.3%, 36.6%, and 31.4% for Q1-Q4. In InO-treated pts, rates of ≥grade 3 hyperbilirubinemia were similar for the lower quartiles (Q1-Q3: 5.3%, 7.9%, and 2.4%; 11.4% for Q4); rates of ≥grade 3 veno-occlusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS) within 2 years of randomization regardless of causality were 13.2%, 7.9%, 7.3%, and 17.1% in Q1-Q4, respectively; 3 grade 5 VOD/SOS events occurred in Q1, 2 in Q4, and 0 in Q2 and Q3. Conclusions: In general, the results showed improvement in measures of efficacy for InO over SC that was comparable across all 4 CD22 positivity quartiles per local lab assessments. For DoR, PFS, and OS, there was a suggestion of greater benefit for pts in higher CD22 positivity quartiles treated with InO, though these analyses are limited by the small sample size. These trends are in alignment with those previously presented for central lab CD22 positivity and receptor density (Blood 2017;130[Suppl 1]:1272). Overall, InO demonstrated a favorable benefit/risk profile for pts with R/R B cell precursor ALL independent of local lab CD22 positivity. Disclosures Kantarjian: Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Novartis: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; BMS: Research Funding; Immunogen: Research Funding. Stock:Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees. Cassaday:Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. DeAngelo:Celgene: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Takeda Pharmaceuticals: Consultancy; Abbvie: Research Funding; Shire: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Blueprint: Consultancy, Research Funding; Pfizer: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. O'Brien:Sunesis: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Eisai: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; Alexion: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Aptose Biosciences, Inc: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Amgen: Consultancy; Regeneron: Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Celgene: Consultancy. Stelljes:Novartis: Honoraria; MDS: Consultancy; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Wang:Pfizer: Employment, Equity Ownership. Paccagnella:Pfizer: Employment, Equity Ownership. Nguyen:Navigate BioPharma Services, Inc., a Novartis Subsidiary: Employment; Novartis: Equity Ownership. Sleight:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Neuhof:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Advani:Amgen: Research Funding; Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy.
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Yilmaz, Musa, Hagop Kantarjian, Nicholas J. Short, Marina Konopleva, Tapan M. Kadia, Courtney D. DiNardo, Gautam Borthakur, et al. "Hypomethylating Agent (HMA) Therapy and Venetoclax (VEN) with FLT3 Inhibitor "Triplet" Therapy Is Highly Active in Older/Unfit Patients with FLT3 Mutated AML." Blood 138, Supplement 1 (November 5, 2021): 798. http://dx.doi.org/10.1182/blood-2021-154143.
Full textAbstract:
Abstract Introduction Internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations (m) in FLT3 occur in about 30% of the patients (pts) with newly diagnosed AML. FLT3m are associated with a higher risk of relapse and inferior overall survival (OS). Outcomes remain poor in older/unfit pts with FLT3m AML; with expected median OS of 8-12 months with combinations of low intensity chemotherapy (LIC) with FLT3 inhibitors (FLT3i) or with venetoclax (VEN) [Ohanian et al. AJH, 2018; Konopleva et. al. ASH, 2020). In this current study, our goal was to analyze outcomes in newly diagnosed older/unfit pts with FLT3m AML treated with LIC + FLT3i (doublet regimen) vs. LIC + VEN + FLT3i (triplet regimen) on clinical trials at our institution. Methods We identified 87 older or unfit adult pts with newly diagnosed FLT3-m (ITD and/or TKD) AML treated on FLT3i-based LIC clinical trials between 6/2012-3/2021 (Figure 1). All pts had at least two or more bone marrow (BM) assessments including at baseline, end of the first cycle of therapy, and/or later during therapy. MRD assessments were performed by in-house multicolor flow cytometry (MFC) (sensitivity of 10 -4) and multiplex polymerase chain reaction (PCR) (sensitivity of 10 -2-10 -3) for ITD and D835. Results Of the 87 pts with newly diagnosed FLT3m AML, 60 (69%) and 27 (31%) received doublet and triplet regimens, respectively. Baseline clinical characteristics, including age, WBC, organ function, cytogenetics, ECOG PS and molecular aberrations, were generally similar between patients treated with doublet vs triplet (Table 1). Of the 60 pts who received LIC (HMA 83%, LDAC-based 17%) + FLT3i doublets, 44 (73%) received a first-generation FLT3i (36 sorafenib, 8 midostaurin) and 16 (27%) second-generation FLT3i (quizartinib). Our analysis showed no statistically significant difference in CR/CRi and FLT3-PCR or MFC negativity rates in patients treated with first or second-generation FLT3i based LIC doublets (Figure 2A). There was no statistically significant OS difference between patients treated with first- vs. second-generation FLT3i doublet regimens (P=0.19). In the triplet group, 12 (44%), 10 (37%), 4 (15%) and 1 (4%) pts received gilteritinib, sorafenib, quizartinib and midostaurin combined with HMA-VEN, respectively. Triplet HMA-VEN-FLT3i was associated with significantly higher CR/CRi (93% vs 70%, P=0.02), FLT3-PCR (96% vs 54%, P<0.01), and MFC negativity (83% vs 38%, P<0.01) rates than doublet regimens (Figure 2B). The 60-day mortality was similar between triplet vs doublet; 7% (n=2) vs 10% (n=6), respectively. The median follow-up time was shorter in the triplet arm than in the doublet arm: 12 vs. 63 months (p<0.01). The median OS was better with the HMA-VEN-FLT3i triplets compared with the HMA-FLT3i doublets (not reached (NR) vs 9.5 months, P<0.01). The median OS in patients treated with triplets vs second-generation FLT3i doublets vs first-generation FLT3i doublets was NR vs 15.7 vs 8.7 months (P<0.01) (Figure 3). 8 (29%) and 6 (10%) pts went to SCT after triplet vs doublet, respectively. A landmark analysis at 4-month (n=50) demonstrated that pts who received ASCT in CR1 had superior OS than patients who did not receive ASCT in CR1 ( NR vs 19 months, P=0.01). Conclusions First- and second-generation FLT3i-based doublet regimens were associated with comparable response rates and survival of 9-16 months in older adults with newly diagnosed FLT3 mutated AML. The HMA-VEN-FLT3i combination significantly improved CR/CRi rates, FLT3-PCR and MFC MRD rates as well as OS, without increasing early mortality in this retrospective analysis. These findings suggest the need for prospective validation of HMA-VEN-FLT3i triplets in older/unfit AML. Figure 1 Figure 1. Disclosures Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Precision Biosciences: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: AstraZeneca: Consultancy; Astellas: Research Funding; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria. Konopleva: Ascentage: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Cellectis: Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support. Kadia: AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; GSK: Consultancy. Pemmaraju: LFB Biotechnologies: Consultancy; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Clearview Healthcare Partners: Consultancy; Affymetrix: Consultancy, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; MustangBio: Consultancy, Other; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Jain: Bristol Myers Squibb: Honoraria, Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding; Beigene: Honoraria; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Janssen: Honoraria; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Andreeff: Medicxi: Consultancy; Senti-Bio: Consultancy; Amgen: Research Funding; Syndax: Consultancy; Oxford Biomedica UK: Research Funding; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Glycomimetics: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company. Ravandi: AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Daver: Abbvie: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Astellas: Consultancy, Research Funding; Hanmi: Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.
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Cui, Lu, Cristabelle De Souza, Tristan Lerbs, Jessica Poyser, Maryam Kooshesh, Atif Saleem, Kerri Rieger, et al. "Selective Targeting of Immune Modulatory Proteins to Mitigate Fibrosis and Inflammation in Sclerodermatous Graft-Vs-Host Disease." Blood 138, Supplement 1 (November 5, 2021): 644. http://dx.doi.org/10.1182/blood-2021-151223.
Full textAbstract:
Abstract Chronic graft-vs-host disease (cGVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HCT) in patients. This debilitating condition is characterized by chronic inflammation, cell-mediated and humoral immunity, and ultimately tissue fibrosis. There is currently little or no understanding of the molecular pathogenesis of chronic cGVHD resulting in poor effective treatment strategies. Sclerodermatous GVHD (sclGVHD) is one of the more severe forms of cGVHD associated with poor prognosis and low sensitivity to immune suppressive therapy. Methods: To address the current gap in knowledge pertaining to the underlying pathophysiology of sclGVHD we used single cell RNA sequencing analyses on fresh patient biopsy specimens. In vivo studies were carried out by sub lethal irradiation of BALB.k recipients which underwent HCT from miAg-mismatched AKR/J donors. Recipient sclerodermatous-tissues were analyzed using FACS, IHC and IF staining. Human studies were conducted on (i) Primary samples from patients with severe sclGVHD using tissue microarrays (TMA) by Immuno-histofluorescence (IHF) and IF. (ii) Dermal fibroblasts from sclGVHD samples were subjected to ATACseq and ChiPseq CRISPR-Cas9 JUN deletion. (iii) Also, dermal fibroblasts from human scl-GVHD were implanted under the kidney capsule of NSG mice to study the effects of inhibiting pro-fibrotic pathways in vivo. Results: We show for the first time that in a mouse model of sclGVHD (male), recipients of female T-cell replete grafts developed severe scleroderma with massive skin thickening and collagen deposition. Fibroblasts strongly expressed JUN, which is part of AP-1, a transcription factor involved in the acute phase response that regulates gene expression in response to stimuli from cytokines, growth factors and pathogens. We have previously demonstrated JUN as a key player in the molecular pathogenesis of other fibrotic diseases (Wernig G et al. PNAS 2017, Cui et al. Nature comm. 2020, Lerbs et al. JCI i 2020). Likewise, CD47, an immune checkpoint protein that prevents removal of Mϕ, was strongly co-expressed in fibroblasts in sclGVHD - but not in the control mice (Fig A+B). Here we show that (i) In humans, (n = 45 sclGVHD patients), there is a strong expression and activation of JUN and CD47 in dermal fibroblasts which was not observed in control samples. Mixed inflammatory infiltrates were dominated by Mϕ and granulocytes. (ii) Isolated primary fibroblasts from fresh human sclGVHD skin biopsies analyzed for chromatin accessibility across the genome by ATAC-seq showed wide open accessibility to the JUN promoter, IL-6 promoter and CD47 enhancer and promoter indicating that they play a critical role in regulating the pathogenesis of sclGVHD. In contrast, normal fibroblasts displayed only minimal accessibility to the JUN promoter. We further validated our data using CRISPR-Cas9 knock-down studies on sclGVHD fibroblasts and show that the IL-6 promoter, enhancer and promoter of CD47 are regulated by JUN, with JUN deletion resulting in significant decrease in the promoter binding accessibility to IL-6 and CD47 (Fig C). Further, JUN activity appears to regulate key members of the Hh signaling pathway (GLI1, PTCH1 and PTCH2), as their chromatin accessibility was decreased with JUN deletion. These correlative findings were confirmed by JUN ChIP seq, an assay that identifies binding sites of DNA-associated proteins. (iii) To test our findings in vivo we established xenograft models of primary human sclGVHD by implanting cells under the kidney capsule of NSG mice.All treatments (except placebo) resulted in decreased fibrosis (Fig D), presumably by blocking the activation of JUN (pJUN) and its profibrotic downstream pathway members IL-6 and pSTAT3, as assessed by phospho flow. Conclusion: In our studies we demonstrate that in established SclGVHD, combinatorial therapy consisting of anti-CD47 antibody together with IL6 blockade has the highest potential to translate into a therapeutic intervention given its ability to be more effective than currently used antifibrotic and anti-inflammatory agents in clinic. The findings from our study are significant because we show an important mechanism underlying SclGVHD onset, identify a novel genetic signature that can be targeted, describe a new mouse model and a clinical assay that has a high throughput readout and suggest a treatment regimen for patients. Figure 1 Figure 1. Disclosures Arai: Magenta Therapeutics: Research Funding. Shizuru: Forty seven Inc: Other: Inventor on a patent licenses by Forty Seven. Forty seven was acquired by Gilead in 2020; Jasper Therapeutics, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Chair of scientific advisory board.
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Morodomi, Yosuke, Roberto Aiolfi, Eric Won, Sachiko Kanaji, Paul Schimmel, Zaverio M. Ruggeri, and Taisuke Kanaji. "Sca-1 As a Marker of Stress-Induced Thrombopoiesis in Mice." Blood 134, Supplement_1 (November 13, 2019): 1068. http://dx.doi.org/10.1182/blood-2019-127446.
Full textAbstract:
Introduction: It has been shown that megakaryocytes (MKs) can develop from a subset of MK-biased hematopoietic stem cells (HSCs). We also demonstrated that an active form of tyrosyl tRNA synthetase (YRS) has ex-translational activities that stimulate rapid platelet production in thrombocytopenic mice. Remarkably, YRS stimulates the development of MKs expressing the stem cell marker, Sca-1, and the monocyte/macrophage marker, F4/80. Thus, we hypothesized that YRS treatment mimics stress-induced megakaryopoiesis and Sca-1 may be a marker for MKs/platelets derived from MK-biased HSCs under inflammatory stress conditions. Accordingly, YRS does not induce Sca-1+ MKs in type I interferon (IFN-I) receptor knockout mice, suggesting a role of IFNs in the induction of Sca1+ MKs. Methods: We used a transgenic mouse strain expressing EGFP under the transcriptional regulatory elements of the Sca-1 gene (Sca-1-EGFP Tg) as a sensitive marker of Sca-1+ MKs. To compare transcriptional profiles, we sorted from mouse bone marrow (BM) EGFP+F4/80+CD41+mGPIbα+ and EGFP-F4/80-CD41+mGPIbα+ cells - representing Sca-1+ MKs and Sca-1- (conventional) MKs, respectively - and performed RNA-Seq analysis. To investigate the mechanism of Sca-1+ MK induction, mouse BM cells were treated with a synthetic TLR7 agonist and MKs were analyzed by flow cytometry. To elucidate the role of Sca-1+ MKs in thrombopoiesis, we infected Sca-1-EGFP Tg mice with lymphocytic choriomeningitis virus (LCMV) Armstrong strain, and analyzed the percentage of EGFP+ platelets and expression of IFN-stimulated genes. Results: We found that expression of MK-specific mRNAs is ~10-fold higher in Sca1+ than Sca1- MKs. As shown in Figure 1A, Sca1+ MKs highly expressed myeloid-related genes (Mpo, Elane, and Ctsg) and stem cell-related genes (Cd34 and Kit); in contrast, Sca1- MKs highly expressed erythroid lineage genes, consistent with origin from a common megakaryocyte-erythroid progenitor (MEP). Expression of IFN-stimulated genes, such as Ifitm1/2/3, is upregulated in Sca-1+ MKs, suggesting the involvement of IFN-I signaling in Sca-1+ MK induction. TLR7 typically recognizes single-stranded viral RNA and stimulates IFN-I production. When Sca-1-EGFP Tg BM cells were cultured in the presence of Gardiquimoid (1 µg/ml), a synthetic TLR7 agonist, Sca1- MKs were reduced and Sca1+ MKs were markedly increased compared to control vehicle treatment (9442 ± 1465 vs 4201 ± 1100). Notably, the proportion of high-ploidy cells was greater in Sca1+ thanSca1- MKs. Moreover, when Sca-1-EGFP Tg mice were infected with LCMV, which cause IFN-I-dependent thrombocytopenia, the percentage of EGFP+ platelets was markedly increased on day 3 (40.0 ± 3.7%) and peaked at day 7 (89.2 ± 5.4%) post-infection as compared to before (3.0 ± 1.0%) (Figure 1B), with 100-fold increase in the EGFP mean fluorescence intensity. Expression of Ifitm3 in platelets was also increased at day 10 post-infection. These results are consistent with our original hypothesis that YRS mimics inflammatory stress conditions and Sca1+ MKs are induced as a consequence of TLRs activation and IFN-I signaling. Conclusions: Our findings indicate that TLR7 activation and IFN-I signaling shift MK generation from Sca-1- to Sca-1+ progenitors, which rapidly develop to high-ploidy Sca-1+ MKs that may accelerate recovery from thrombocytopenia. Accordingly, under inflammatory stress conditions, such as viral infection, the majority of circulating platelets originate was from Sca-1+ MKs. The high expression of Ifitm proteins, which are known to inhibit cellular entry by viruses, in Sca-1+ MKs/platelets may contribute to their role in host defense. Disclosures Aiolfi: MERU-VasImmune, Inc: Other: Stock option. Kanaji:MERU-VasImmune, Inc: Other: Stock option. Schimmel:aTyr Pharma: Consultancy, Equity Ownership, Patents & Royalties. Ruggeri:MERU-VasImmune Inc.: Equity Ownership, Other: CEO and Founder. Kanaji:MERU-VasImmune, Inc: Other: Stock option.
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Brown, Patrick A., Lingyun Ji, Xinxin Xu, Meenakshi Devidas, Laura Hogan, Michael J. Borowitz, Elizabeth A. Raetz, et al. "A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children's Oncology Group Study AALL1331." Blood 134, Supplement_2 (November 21, 2019): LBA—1—LBA—1. http://dx.doi.org/10.1182/blood-2019-132435.
Full textAbstract:
First relapse of B-ALL in children and AYAs is a vexing clinical problem with high rates of subsequent relapse and death using conventional treatment approaches. This is especially true in patients with early relapse [high risk (HR), defined as marrow relapse <36 months from diagnosis or isolated extramedullary relapse <18 months from diagnosis] and those with late relapse and minimal residual disease (MRD) of ≥0.1% at the end of re-induction chemotherapy [intermediate risk (IR)]. Allogeneic hematopoietic stem cell transplant (HSCT) is considered the treatment of choice for this population, but many relapsed patients are not able to proceed to HSCT due to adverse events (AEs) from chemotherapy and/or inability to achieve the MRD-negative second remission known to be associated with optimal HSCT outcomes. The CD3-CD19 BiTE® blinatumomab has single agent efficacy in relapsed/refractory B-ALL (pediatrics and adults) and MRD-positive B-ALL (adults), and a favorable toxicity profile. The primary aim of this study was to compare disease-free survival (DFS) of HR/IR first relapse B-ALL patients aged 1-30 years randomized following re-induction chemotherapy (Block 1 of UKALLR3/mitoxantrone arm) to receive either two intensive chemotherapy blocks (Blocks 2 and 3 of UKALLR3; Control Arm A) or two 4-week blocks of blinatumomab, each followed by one week of rest (Blina cycles 1 and 2; Experimental Arm B). Patients with ≥25% marrow blasts after Block 1 were ineligible for randomization. After randomized therapy, patients on both arms proceeded to HSCT. Secondary aims included comparisons of the following between Arms A and B: AEs, MRD response (by flow cytometry, central lab), overall survival (OS) and ability to proceed to HSCT. During a planned interim analysis (data cut-off 6/30/19) by the Data Safety and Monitoring Committee, the HR/IR randomization was stopped early. While the improvement in DFS for Arm B did not cross the predefined superiority threshold at the time of interim analysis, the combination of improved DFS, superior OS, lower toxicity, and superior MRD clearance for Arm B relative to Arm A was judged to provide sufficiently compelling evidence to establish a new standard of care. A total of 208 HR/IR patients were randomized (Arm A: 103, Arm B: 105). Baseline characteristics were comparable between arms (Table 1). With median follow up of 1.4 years, the intent-to-treat (ITT) 2-year DFS (% ± standard error) was 41.0 ± 6.2% for Arm A vs. 59.3 ± 5.4% for Arm B (p=0.05, 1-sided per pre-specified statistical plan)(Figure 1A). The ITT 2-year OS was 59.2 ± 6.0% for Arm A vs. 79.4 ± 4.5% for Arm B (p=0.005, 1-sided)(Figure 1B). Among patients with detectable MRD (≥0.01%) at the completion of Block 1 chemotherapy, the proportion that achieved undetectable MRD (<0.01%) after Block 2 (Arm A) vs. Blina cycle 1 (Arm B) was 21% vs. 79% (p<0.0001)(Table 2). The rates of MRD response were similar with Block 3 or Blina cycle 2 (Table 2). Post-induction toxic deaths occurred in 4 patients on Arm A (all infections) vs. none on Arm B (p=0.05). Relative rates of CTCAEv4 grade ≥3 febrile neutropenia, infections, sepsis and mucositis were strikingly higher for Block 2/3 (Arm A) vs. Blina cycle 1/2 (Arm B): 44%/46% vs. 4%/0%, 41%/61% vs. 10%/11%, 14%/21% vs. 1%/2%, and 25%/7% vs. 0/1% respectively (p<0.001 for all comparisons except mucositis for Block 3 vs. Blina cycle 2, p=0.16). For Arm B, the rate of selected blinatumomab-related AEs in cycle 1/2 were: Cytokine release syndrome (CRS) 22%/1% (grade ≥3 1%/0%); seizure 4%/0% (1%/0%); other neurotoxicity (e.g., cognitive disturbance, tremor, ataxia, dysarthria) 14%/11% (2%/2%). All blinatumomab-related AEs fully resolved. The rate of patients successfully proceeding from randomization to HSCT (data cut-off 9/30/19) was strikingly different between arms. On Arm A, only 45% (44 of 98 who received randomized therapy) proceeded to HSCT. On Arm B, 73% (75 of 103 who received randomized therapy) proceeded to HSCT (p<0.0001). In conclusion, for children and AYA patients with HR/IR first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as post-reinduction consolidation prior to HSCT, resulting in fewer and less severe toxicities, higher rates of MRD response, greater likelihood of proceeding to HSCT and improved disease-free and overall survival. Patients remain in follow up, and prospectively defined analyses of longer-term outcomes will be forthcoming. Disclosures Brown: Jazz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Borowitz:Beckman Coulter: Honoraria. Raetz:Pfizer: Research Funding. Zugmaier:Amgen: Employment, Other: holds stock, Patents & Royalties: & other intellectual property. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Pulsipher:Medac: Honoraria; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Lecture. Hunger:Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Jazz: Honoraria; Novartis: Consultancy. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Investigational use of blinatumomab
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Bourreau, Jean-Pierre, Hamid S. Banijamali, and Cyril E. Challice. "Modification of excitation–contraction coupling in cat ventricular myocardium following endocardial damage." Canadian Journal of Physiology and Pharmacology 71, no. 3-4 (March 1, 1993): 254–62. http://dx.doi.org/10.1139/y93-040.
Full textAbstract:
Damage to endocardial endothelium (denudation of the superficial tissue) by brief exposure to a 100-μL bolus of detergent (Triton X-100, 1% by volume stock) decreased the twitch force of papillary muscle (and trabeculae) by ~ 30% to a new but steady level without changes in resting tension. The decline in twitch force was evident immediately after the addition of Triton. Modification of the action potential measured from the contracting tissue appeared only later, when the change in contraction was already well established (i.e., after ~ 2 min). Action potential shortened in duration at 50% repolarization by ~ 100 ms and increased in plateau amplitude, although the latter increase was not always observed. A similar treatment procedure applied to strips of ventricular wall with the endocardium exposed to the superfusion solution resulted in a substantial decrease in action potential duration (~ 110 ms). In contrast, treatment of strips of epicardial layers of ventricular walls (with epicardial side facing the superfusion solution) did not produce a similar result. In β-stimulated (1 μM isoproterenol) and partially depolarized preparations (with 20 mM KCl), with intact endocardium, electrically evoked contractions were followed by aftercontractions, which were suppressed following Triton treatment. Action potentials in a depolarizing medium also shortened in duration (~ 50 ms), although following a delay (2–3 min). The decay to steady state of postextrasystolic potentiated beat was slower after endocardial damage than under control conditions. This suggested an increased Ca2+ recirculation through the sarcoplasmic reticulum between two consecutive beats (35% before Triton vs. 45% after Triton). Finally, in a medium containing 3 μM ryanodine, Triton treatment of the endocardial endothelium failed to induce any effect on either twitch force or action potential. Prolonged exposure to Triton X-100 (by a slow flow or high concentration) induced only deteriorating effects leading to substantial rise in the resting tension and generation of contractures and abbreviated action potentials with depressed plateau. These observations are consistent with the hypothesis that a modification in the sarcoplasmic reticulum function may, at least in part, be responsible for the observed changes in contractile function of the myocardium following endocardial damage with Triton treatment.Key words: endocardial endothelium, sarcoplasmic reticulum, ventricle, myocardial contraction.
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Lachowiez, Curtis, Courtney D. DiNardo, Kiyomi Morita, Ken Furudate, Feng Wang, Tomoyuki Tanaka, Sa A. Wang, et al. "Longitudinal Next Generation Sequencing Reveals the Clonal Hierarchy of IDH Mutated Clones and Impact on Survival in NPM1 Mutated AML." Blood 138, Supplement 1 (November 5, 2021): 607. http://dx.doi.org/10.1182/blood-2021-148971.
Full textAbstract:
Abstract Background: NPM1 mutations (NPM1 +) occur in ~30% of acute myeloid leukemia (AML), often with co-occurring mutations including isocitrate dehydrogenase mutations (IDH +). Previous studies suggest early acquisition and expansion of IDH1/2 mutations (IDH1 +/IDH2 +) prior to NPM1 + development increase relapse risk. Yet the clonal hierarchy of NPM1 +/IDH + AML, dynamics of IDH + during therapy, and predictive value of IDH1 +/2 + in NPM1 + AML in response to standard intensive (IC) or venetoclax-based (VEN) treatment is less studied. Methods: We identified 71 patients with newly diagnosed NPM1+ AML (index cohort). Longitudinal molecular assessment of bone marrow samples at diagnosis, remission, and relapse was performed using next-generation sequencing (NGS) of genes frequently mutated in AML. Clonality within each sample was inferred using variant allele frequency (VAF) of individual mutations compared with NPM1 +(co-dominant: VAF difference of < 10%; sub-clonal: VAF ≥10% lower). Measurable residual disease (MRD) was assessed using flow cytometry (FC) (MRD FC; lower limit of sensitivity 10 -3-10 -4) and NGS. To validate findings in the index cohort, clinical and genomic data were collected from a publicly available dataset of 39 patients with NPM1 + AML who underwent single cell DNA sequencing (scDNAseq) at our institution. Categorical and continuous variables were assessed using the fisher exact test and the Wilcoxon rank sum test, respectively. Adjustment for multiple comparisons utilized the Benjamini-Horchberg procedure. Time-to-event outcomes were assessed by the log-rank method. Results: Median patient age was 64 years (range 19-84). Thirty-eight patients (54%) received IC (IC: n=30, IC+VEN: n= 8); 33 (46%) received lower-intensity therapy (lower-intensity: n= 6, lower-intensity+VEN: n=27). Common co-occurring mutations at diagnosis included DNMT3A (62%), FLT3 (52%), TET2 (27%), IDH2 (23%), IDH1 (18%), PTPN11 (18%), and NRAS (17%). SRSF2, IDH2, TET2, ASXL1, and DNMT3A mutations preceded or were co-dominant with NPM1 +, while NRAS, PTPN11, and FLT3 mutations were sub-clonal. IDH1 +was sub-clonal in 40% of cases (Fig. 1A). In the scDNAseq cohort IDH1 + was sub-clonal in 40% (n=3/8); IDH2 + preceded NPM1 +in 75% (n=9). Compared with IDH1 +, IDH2 + was more likely to precede or be co-dominant with NPM1 + (95% vs. 60%, p-value: 0.017). DTA (DNMT3A, TET2, ASXL1) mutations were detected more often in remission versus IDH + (88% vs. 55%, p-value: 0.01). Persistent IDH1 + and IDH2 + were identified in 36% (n=4) and 73% (n=11) of patients. Concurrent MRD FC confirmed clearance of the previous AML clone in 100% of patients, with a pre-leukemic/CH immunophenotype identified in 50% and 80% of cases with persistent IDH1 +or IDH2 +, respectively Patients with IDH + often developed new or persistent mutations in remission compared with patients with wild-type IDH(54% vs. 12%, p-value <0.001), including splicing mutations (SRSF2, U2AF1, ZRSR2, SF3B1: 25% [n=7]) and emergent TET2 mutations (14% [n=4]). Despite persistence of these mutations in remission, 100% achieved MRD FC negativity and all remain in remission, however 80% had a a CH phenotype detectable by FC. Patients with NPM1 +/IDH + compared with NPM1 +/IDH - AML in complete remission (N=91) had improved event-free (EFS; median 65 vs. 28 months, p-value: 0.002) and overall survival (OS; median 82 months vs. NR, p-value: 0.02) (Fig. 1B and C), largely driven by NPM1 +/IDH2 + cases, and patients receiving IC. No survival difference was observed based on clonal hierarchy of IDH + (clonal vs sub-clonal) compared with NPM1 + or persistent IDH + in remission with concurrent clearance of NPM1 + and MRD FC. FLT3 mutations were identified at similar frequencies in the NPM1 +/IDH +and NPM1 +/IDH - groups (50% vs. 53%, p-value: 0.84; ITD: 81% vs. 69%, p-value: 0.49), and a similar number of patients receiving VEN (48% vs.43%, p-value: 0.38). Conclusion: IDH1 + and IDH2 + develop at differing timepoints during leukemogenesis in NPM1 + AML. IDH2 + frequently precedes NPM1 and persists in remission, while IDH1 + is more often sub-clonal and cleared in remission. Persistent IDH1 + or IDH2 + frequently correlate with detection of a CH phenotype by MFC in remission, and in the absence of NPM1 + and MRD FC do not influence relapse. Improved EFS and OS was observed with NPM1 +/IDH + AML, identifying a molecular subgroup associated with favorable outcomes to both VEN and IC treatment regimens Figure 1 Figure 1. Disclosures DiNardo: Foghorn: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Wang: Stemline Therapeutics: Honoraria. Kadia: Ascentage: Other; AstraZeneca: Other; Liberum: Consultancy; Genfleet: Other; Pfizer: Consultancy, Other; Astellas: Other; Novartis: Consultancy; BMS: Other: Grant/research support; Jazz: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other. Daver: Gilead Sciences, Inc.: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Short: NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria. Khoury: Angle: Research Funding; Kiromic: Research Funding; Stemline Therapeutics: Research Funding. Konopleva: F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Agios: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; KisoJi: Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding. Ravandi: AbbVie: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Takahashi: Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy.
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Zhang, Bo, Prajish Iyer, Meiling Jin, Elisa Ten Hacken, Zachary Cartun, Kevyn Hart, Laura Z. Rassenti, et al. "Expression of Sf3b1-K700E accelerates the Development of Chronic Lymphocytic Leukemia in a Del(13q) Murine Model." Blood 136, Supplement 1 (November 5, 2020): 4–5. http://dx.doi.org/10.1182/blood-2020-139096.
Full textAbstract:
RNA splicing factor SF3B1 is one of the most recurrently mutated genes in chronic lymphocytic leukemia (CLL), but expression of this mutation alone in murine B cells does not result in CLL. This gene mutation is often subclonal and associated with poor survival. How this mutation impacts CLL progression remains elusive. Since SF3B1 mutation frequently co-occurs with chromosome 13q deletion (del(13q)), and mice with deletion of the Minimal Deleted Region (MDR) of del(13q) develop indolent CLL, we therefore asked whether co-expression of Sf3b1 mutation can accelerate the onset of CLL in this murine model. If so, how does Sf3b1 mutation mechanistically contribute to CLL. To this end, we first crossed mice carrying conditional knock in allele Sf3b1-K700E and mice with conditional knockout of MDR. We then bred the offspring with CD19-Cre mice to generate cohorts of mice which have B cell-specific homozygous deletion of MDR with (DM) or without (MDR-MT) heterozygous Sf3b1-K700E. We monitored the onset of CLL by tracking of circulating B220+CD5+ CLL-like cells from peripheral blood with flow cytometry, starting at the age of 6-months and ending by 24-months. We detected CLL-like disease in 24% (6 of 25) of DM and 7.4% (2 of 27) of MDR-MT mice with disease presence in the spleen, bone marrow and lymph node, confirmed by flow cytometry and immunohistochemistry. The increased frequency of CLL in DM mice indicated that Sf3b1-K700E could accelerate CLL (Pearson Chi-Square 2-sided, p=0.098). To elucidate how Sf3b1 mutation contributes to increased CLL penetrance, we performed integrated RNA sequencing (RNA-seq) and TMT proteomics analysis with splenic B cells derived from DM mice with and without CLL. We found that genes involved in MYC, cell cycle checkpoints and mTORC1 pathways are upregulated and enriched at both the RNA and protein levels when we compared DM-CLL cells to their DM B cell counterparts, indicating these cellular processes are involved in the onset of CLL. To further define the role of Sf3b1-K700E mediated alternative splicing in the activation of these pathways, we first identified candidate splicing isoforms (nfatc1, braf, depdc5, tsc2) through computational analysis of RNA-seq data and then validated the isoforms in an independent cohort of samples (n=3,). Functional annotation of how exactly these isoforms impact CLL is ongoing. Importantly, we also observed gene upregulation of mTORC1 pathway in human CLL cells with SF3B1 mutation and del(13q) when compared with normal B cells. We next asked whether DM CLL cells are sensitive to inhibition of mTORC1 pathway and RNA splicing inhibition in vitro. We exposed DM B and CLL cells to either Temsirolimus (Tem, mTORC1 inhibitor), or H3B8800 (H3B, SF3B1 inhibitor) alone or in combination for 24 hours and then measured the cell viability with CellTiter-Glo assay. When compared to DMSO control, both Tem and H3B single treatments significantly inhibited the survival of DM CLL cells, but not DM B cells (all groups vs control, unpaired t test, p<0.01). Furthermore, an additive effect was observed in DM CLL cells when 1nM of H3B was combined with Tem treatment (IC50: 1.2nM vs. 135.2uM, unpaired t test p<0.001). We then tested the effects of both drugs in vivo using NSG mice engrafted with DM CLL cells. Mice treated with combination of Tem (15mg/kg, i.p, 5 days) and H3B (4mg/kg, gavage, 5 days) had a lower CLL burden in peripheral blood in comparison to either the single treatment or no drug treatment group (all groups vs. comb, p≤0.001). Furthermore, the combination treatment increased the survival of NSG mice engrafted with CLL cells compared to control (median survival: control vs. comb 15 vs. 34 days, log rank p<0.001). Importantly, when we exposed human CLL cells with both del(13q) and sf3b1 mutation (DM-CLL, n=3), or with del(13q) alone (n=2), or normal B cells (n=4) to the combination treatment in vitro, DM-CLL cells showed the highest sensitivity to the treatment (DM-CLL vs. all groups, p<0.05), suggesting that SF3B1 mutation may accelerate CLL with del(13q) through modulating RNA splicing and mTORC1 pathway. Our study demonstrates that expression of Sf3b1-K700E could accelerate the development of CLL based on MDR deleted murine model through alternative RNA splicing and mTORC1 activation. This finding supports the use of an mTORC1 inhibitor together with RNA splicing inhibitor in the subset of CLL patients with both SF3B1 mutation and del(13q). Disclosures Kipps: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; VelosBio: Research Funding; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Wu:BionTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding.
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Hines, Patrick C., Xiufeng Gao, Andrew Herppich, Wendy Hollon, Meera B. Chitlur, Janet L. Kwiatkowski, and Michael Tarasev. "Ex Vivo Evaluation of Red Blood Cell Adhesion and Whole Blood Thrombosis in Pyruvate Kinase Deficiency." Blood 138, Supplement 1 (November 5, 2021): 923. http://dx.doi.org/10.1182/blood-2021-149744.
Full textAbstract:
Abstract Introduction Pyruvate Kinase Deficiency (PKD) is an inherited glycolytic enzymopathy that is characterized by a life-long chronic hemolytic anemia with severe comorbidities. Hypercoagulability due to increased platelet activity caused by nitric oxide sequestration by cell free hemoglobin has been well-described not just in PKD, but in other hemolytic anemias as well, such as e.g., sickle cell disease (SCD). Hypercoagulability is often accompanied by a cascade of pathophysiological events leading to cell oxidative damage, endothelial activation, and changes in both cell stability and adhesive properties. Increased red blood cell (RBC) adhesion and hypercoagulability may impair microvascular blood flow. Despite these well-recognized rheological changes that are similar to those that occur in other hemolytic anemias, the relationship between baseline erythrocyte adhesion and thrombosis potential have not been well-studied in PKD. Methods 10 PKD subjects and 5 healthy controls were recruited under the IRB-approved protocol from Wayne State University. Flow adhesion of whole blood to vascular cell adhesion molecule-1 (FA-WB-VCAM) was performed by flowing whole blood (1:1 dilution) through a microfluidic channel for 3 minutes (1 dyne/cm 2 shear stress, 1.67Hz pulse frequency). Flow adhesion avidity of the whole blood sample to VCAM-1 (FAAv-WB-VCAM), representing the strength of the RBC-VCAM-1 adhesive interactions, was assessed by quantifying adhesion following sequential increase in shear (5, 10, 20 dyne/cm 2). Thrombin generation assay was conducted using platelet poor plasma with and without thrombomodulin and microparticles (MP) as previously published [1]. Clotting time - reported as lag time (LT), time to peak (ttPeak) and peak height (velocity and amount of net thrombin production), and endogenous thrombin potential (ETP), representing number of substrates potentially convertible by thrombin, were measured. Significance was at p < 0.05. Results FA-WB-VCAM at baseline sample hematocrit was significantly elevated (Figure 1) in PKD subjects (808±377 cells/mm², n=10) compared to healthy controls (6±4 cells/mm², n=4) and even to our previously reported steady state levels in sickle cell samples (290±50 cells/mm² [2]. Thrombin generation profiles were similar between PKD subjects and healthy controls with the exception of the thrombin generation index (PPP+TP/PPP)*100ETP that was significantly (p<<0.01) elevated in citrated plasma of PKD subjects (92.9±6.8) as compared to healthy controls (68.6±11.9). For PKD subjects, FA-WB-VCAM correlated significantly with platelet counts (R²=0.81, p<0.05), and FAAv-WB-VCAM was negatively correlated with platelet (P=0.03, R 2=0.5), but not with erythrocyte-derived microparticles (MP). Platelet-derived MP strongly correlated with thrombin generation (ETP, p<0.01, R 2=0.76) but not with LT or ttPeak of thrombin generation. Red blood cell MP were significantly (p=0.02) decreased in splenectomized patients (200±170, n=7) vs. non-splenectomized subjects (2090±1860, n=3). LT and ttPeak were significantly longer in PKD subjects with thrombosis history than without. Conclusions PKD subjects in this study had elevated RBC adhesive properties similar to that observed in SCD, confirming that pathologic RBC membrane damage resulting in increased adhesion is a common feature of hemolytic anemias. The hemoglobin level of 7.8±1.1 g/dL (mean±SD) for PKD patients was within 6 to 11 g/dl range of hemoglobin levels typical for SCD. There was no significant difference in any other measured parameters (thrombin generation, adhesion avidity, microparticles data). Thrombin generation in PKD subjects was not consistent with hypercoagulability. Based on these observations, pathologic RBC adhesion may be both a novel a mechanism driving hypercoagulability in individuals with PKD. Further studies to determine whether RBC-modifying therapies may decrease thrombosis risk in PKD are warranted. 1. Zia A, Callaghan MU, Callaghan JH, et al. Hypercoagulability in adolescent girls on oral contraceptives - global coagulation profile and estrogen receptor polymorphisms. Am J Hematol, 2015;90:725-31 2. Pittman DD, Hines PC, Beidler D, et al. Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) by patient-reported outcomes, actigraphy, and biomarkers. Blood. 2021;137(15):2010-20 Figure 1 Figure 1. Disclosures Hines: Functional Fluidics: Current holder of stock options in a privately-held company. Gao: Functional Fluidics: Current Employment. Herppich: Functional Fluidics: Ended employment in the past 24 months. Kwiatkowski: Imara: Consultancy, Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Bioverativ: Research Funding; Vertex: Research Funding; Silence Therapeutics: Consultancy; bluebird bio: Consultancy, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Chiesi: Research Funding; CRISPR: Research Funding. Tarasev: Functional Fluidics: Current holder of stock options in a privately-held company.
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Koller, Paul, Rima M. Saliba, Celina Ledesma, Gabriela Rondon, Uday Popat, Amin M. Alousi, Rohtesh S. Mehta, et al. "Allogeneic Hematopoietic Cell Transplantation May Improve Long-Term Outcomes in Patients with Ph-like Acute Lymphoblastic Leukemia with CRLF2 Overexpression." Blood 134, Supplement_1 (November 13, 2019): 4598. http://dx.doi.org/10.1182/blood-2019-130645.
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Introduction: Philadelphia (Ph) like acute lymphoblastic leukemia (ALL) is a high risk subtype of ALL, with the majority of patients overexpressing CRLF2; CRLF2 overexpression is associated with particularly poor outcomes (Jain, Blood, 2017). To date, the efficacy of hematopoietic cell transplantation (HCT) in these patients is unknown. Methods: In this retrospective study, we evaluated patients with CRLF2 overexpressed ALL who received or did not receive HCT. CRLF2 status was identified via FISH or multi-parameter flow cytometry. We identified 55 patients treated at our institution from 1992-2019 who had CRLF2 overexpression at diagnosis and achieved a first complete remission (CR1). To account for potential survival bias in the HCT group, outcomes between the two groups were compared in a landmark analysis starting at 3 months since CR1. Results: Baseline characteristics and treatment outcomes are described in Table 1. The median age was 32 years and 34 years, respectively, for HCT vs. non-HCT groups. In both groups, patients received high-intensity induction therapy with or without asparaginase. Patients who did not receive HCT were more likely (63%) to have been diagnosed prior to 2013, whereas all those treated with HCT were diagnosed after 2013. This difference reflects a change in practice at our institution after the description of CRLF2 overexpression as a poor prognostic factor. Median peripheral blood platelet count (102 k/uL vs 46 k/uL, p=0.02) and bone marrow blasts (76% vs 91%, p=0.02) at diagnosis were different between the HCT and non-HCT groups, respectively. In the HCT group, the majority of patients underwent myeloablative conditioning (n= 11, 79%) with a matched donor (n=9, 64%). With a median follow up of 26 months from CR1 in both groups, landmark analysis showed a trend for lower 3-year progression rate (25% vs 66%, HR=0.3, p=0.08) and improved progression-free survival (PFS) (51% vs 22%, HR=0.6, p=0.3) and overall survival (OS) (59% vs 35%, HR=0.6, p=0.3) in the HCT versus non-HCT groups. The median PFS was 16 months for the non-HCT group, and has not been reached for the HCT group. In the HCT group, PFS appears to have reached a plateau at 14 months, with 6 of 14 patients remaining alive in remission at a median follow-up of 24 months (range 17-41). Conclusions: CRLF2 overexpression in ALL is associated with a high rate of progression. Allogeneic HCT is beneficial against relapse, showing a trend for improved PFS and OS.A larger sample size and longer follow up is needed to confirm these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Bioclinical: Consultancy; Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Jain:BMS: Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Kantarjian:Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding. Konopleva:Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Agios: Research Funding; Calithera: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; 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; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Amgen: Research Funding; Jazz: Consultancy.
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Loh, Mignon L., Richard C. Harvey, Charles G. Mullighan, Stephen B. Linda, Meenakshi Devidas, Michael J. Borowitz, Andrew J. Carroll, et al. "A BCR-ABL1-Like Gene Expression Profile Confers a Poor Prognosis In Patients with High-Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From Children's Oncology Group (COG) AALL0232." Blood 118, no. 21 (November 18, 2011): 743. http://dx.doi.org/10.1182/blood.v118.21.743.743.
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Abstract Abstract 743 We have previously identified a subset of National Cancer Institute (NCI)-HR B-cell precursor (BCP) ALL patients with a gene expression profile similar to that of BCR-ABL1 ALL (BCR-ABL1-like ALL (Mullighan, N Engl J Med 2009; den Boer, Lancet Oncology 2009; Harvey, Blood, 2010, and unpublished data) and poor outcome on the COG P9906 trial, which was limited to a selected subset of HR BCP ALL patients. These cases are BCR-ABL1-negative but commonly have deletion or mutation of IKZF1. Up to half of these cases harbor rearrangements, deletions and/or mutations activating cytokine receptors and tyrosine kinase signaling (e.g. CRLF2 and activating JAK1/2 mutations), although the kinase-activating mutations in many cases remain unknown. In this analysis, we have assessed the prognostic significance of this BCR-ABL1-like signature in an unselected cohort of BCR-ABL1 negative BCP ALL patients consecutively enrolled on COG AALL0232. This phase 3 trial utilized a 2×2 factorial design comparing dexamethasone (DEX) versus prednisone (PRED) during induction, and high dose methotrexate (HD-MTX) versus Capizzi methotrexate (C-MTX) during interim maintenance 1 (IM-1). We recently reported improved event free survival (EFS) for patients receiving HD-MTX versus C-MTX (Larsen, J Clin Oncol 29: 6s, 2011) and for DEX versus PRED among patients <10 years old randomized to HD MTX (Winick, J Clin Oncol 29: 586s, 2011). We used two algorithms, Recognition of Outliers by Sampling Ends (ROSE) and Predictive Analysis of Microarrays (PAM), to define 66 of 565 (ROSE) and 81 of 572 (PAM) patients as BCR-ABL1-like. Event-free survival (EFS) for BCR-ABL1-like cases was inferior to that of non-BCR-ABL1-like cases, irrespective of the clustering algorithm used to identify them, with 5-yr EFS rates of 63.1±7.2% vs. 84.9±2.0% (p<0.0001) for ROSE clustering and 62.6±6.9% vs. 85.8±2.0% (p<0.0001) for PAM. These differences were maintained regardless of randomized treatment arm. We next examined variables that contributed to outcome in patients who displayed the BCR-ABL1-like signature, identified either by ROSE or PAM. Older (≥ 10 years) BCR-ABL1-like patients were significantly more likely to have an initial white blood count greater than 100,000/ul (ROSE: p< 0.001, PAM: p< 0.001). Interestingly, older females with the BCR-ABL1-like signature had superior EFS compared to males (4-yr EFS for ROSE: 73. ±9.8% vs. 43.0 ±10.3%, p=0.02; 4-yr EFS for PAM: 69. ±10.2% vs. 43. ±9.4%, p=0.04). In a multivariate COX regression analysis of the entire cohort that included identification of BCR/ABL1-like by PAM (HR 1.88, p=0.011), the other significant predictors of poor outcome were the presence of minimal residual disease (MRD) ≥ 0.01% in the bone marrow as measured by flow cytometric methods on day 29 (HR 3.09, p < 0.0001) and the presence of hypodiploidy (HR 3.14, p=0.027). In a COX model including identification of BCR/ABL1-like by ROSE (HR 1.65, p=0.053), other significant factors were day 29 MRD positivity (HR 3.26, p<0.0001), age ≥ 10 years (HR 1.61, p=0.047), presenting white blood cell count > 100,000/ul at diagnosis (HR 1.62, p=0.047), and hypodiploidy (HR 3.0, p=0.034). In summary, the BCR-ABL1-like gene expression profile identified a subset of unselected BCP ALL patients using two different clustering algorithms that was strongly associated with a high rate of treatment failure, even with the best available therapy recently identified in COG AALL0232. The prognostic significance of these gene signatures was also independent of other known risk factors. Ongoing work to determine the genetic and biochemical landscape that contribute to this phenotype will hopefully yield new approaches to treatment for these BCR-ABL1-like patients in order to improve outcome. Disclosures: Borowitz: BD Biosciences: Research Funding. Wood:BD Biosciences: Research Funding. Hunger:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speaker's children own stock in BMS.
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Tian, Linjie, Ana Paucarmayta, Rustin Lovewell, Karla Maloveste, Junshik Hong, Carly Hedgepath, Kwang Woon Kim, et al. "A Novel Lair-1 Antibody Selectively Targets Acute Myeloid Leukemia (AML) Stem Cells." Blood 138, Supplement 1 (November 5, 2021): 3413. http://dx.doi.org/10.1182/blood-2021-147656.
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Abstract Extensive research has led to recent approval of novel therapies such as mylotarg, venetoclax, glasdegib and CC486, and small molecule inhibitors against actionable mutations such as ivosidenib (IDH1), enasidenib (IDH2), gliteritinib and midostaurin (FLT3) in AML. However, the mainstay of treatment in AML remains unchanged since the 1970s. There is a significant unmet need for AML patients that fail to respond to or relapse after standard-of-care (SOC) treatments including allogeneic stem cell transplantation and targeting actionable mutations. In addition, a large fraction of SOC patients invariably relapse due to persistence of chemotherapy-resistant leukemia stem cells (LSCs) or immune evasion. Therefore, identification of unique therapies that preferentially target elusive LSCs and promote immune responses to AML to prevent relapse are highly sought after. Unlike, targeting acute lymphoblastic leukemia (ALL) with CD19 or CD22 with various modalities, when developing AML therapies, it is of paramount importance to differentiate LSCs from hematopoietic stem cells (HSCs) to lessen or abolish unavoidable cytopenias. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an immune checkpoint receptor on T cells and myeloid cells that delimits immune cell activation through binding to endogenous collagen ligands. In addition, LAIR-1 is universally expressed on AML blasts and may sustain AML survival signals. We demonstrated using multi-color flow cytometry that LAIR-1 is highly expressed in AML blasts (n=9 of 9) and that LAIR-1 expression in LSCs (markers: CD34 +CD38 -CD90 -CD45RA +/- or CD34 -CD117 +CD244 +/-) is high compared with negligible expression of LAIR-1 in HSCs (markers: CD34 +CD38 -CD90 +CD99 -) (n=3) (Figure 1). Based on these findings, we hypothesized that a LAIR-1 monoclonal antibody (mAb) would disrupt LAIR-1 mediated survival signaling and preferentially target LAIR-1 expressing AML LSCs and blast cells but not HSCs. To test this, we developed a novel LAIR-1 targeting mAb with a functional human IgG 1 isotype that blocks LAIR-1 binding to its ligands (including collagens, complement component C1q, MBL and SP-D) To characterize the anti-leukemic effect of the LAIR-1 mAb we performed an in vitro antibody dependent cell cytotoxicity (ADCC) assay with LAIR-1 expressing AML cells (MOLT4 and MV-4-11). Compared with isotype control, the LAIR-1 mAb significantly increased leukemia cell death (MV411 = 17% above isotype, and MOLT4 = 29.24% above isotype at 15 µg/ml), suggesting that the LAIR-1 mAb confers ADCC activity against LAIR1 + AML cells (Figure 2). To elucidate if the LAIR-1 mAb has a direct signaling effect on LAIR-1 + AML cells, a colony forming unit assay using primary AML cells was carried out. Interestingly, the LAIR-1 mAb inhibited colony formation by AML CD34 + cells (40-60% decreased compared with isotype control, N=4), but not normal CD34 + cells. These data suggests that our LAIR-1 mAb stimulated LAIR-1 signaling that inhibits LSC self-renewal. We then tested the in vivo anti-leukemia effect of the mAb in cell line derived xenograft (CDX) models (immune deficient mice transplanted with MV-4-11 expressing luciferase). In vivo bioluminescence imaging indicated that the LAIR-1 mAb significantly inhibited in vivo AML growth (91% reduction of total flux)(Figure 3). A significant increase in cell death was observed in the presence of the mAb in the blood (47%), spleen (89.4%) and bone marrow (27.6%). Similar to the anti-leukemic effect in CDX AML models, the LAIR-1 mAb significantly suppressed in vivo growth of AML patient derived xenografts (5 different primary AML donors) (10-90% human CD33 + AML cells in isotype control treatment vs 0.5-5% CD33 + AML cells in anti-LAIR-1 treatment, N=3) (Figure 4), while minimally impacting normal immune cells. Taken together, our studies suggest that the LAIR-1 mAb we generated is a novel AML immunomedicine that preferentially eradicates AML LSCs and blasts while preserving healthy HSCs through disruption of AML survival signals and clearance of AML through ADCP and ADCC. Additional studies are currently evaluating if this novel LAIR-1 mAb has other mechanisms of action that contribute to overall in vivo activity, including reduction of AML niche implantation, regulation of bone marrow homing and regulation of anti-tumor immunity. Figure 1 Figure 1. Disclosures Tian: NextCure: Ended employment in the past 24 months. Paucarmayta: NextCure: Current Employment. Lovewell: NextCure: Current Employment. Maloveste: NextCure: Current Employment. Copeland: NextCure: Current Employment. O'Neill: NextCure: Current Employment. Patel: NextCure: Current Employment. Liu: NextCure: Current Employment, Current holder of stock options in a privately-held company. Myint: NextCure: Current Employment, Current holder of stock options in a privately-held company. Langermann: NextCure: Current Employment, Current holder of stock options in a privately-held company. Flies: NextCure: Current Employment, Current holder of stock options in a privately-held company. Kim: Nextcure: Research Funding.
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Mostafa, Wael. "The relative information content of cash flows and earnings affected by their extremity." Managerial Finance 40, no. 7 (June 3, 2014): 646–61. http://dx.doi.org/10.1108/mf-06-2013-0128.
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Purpose – Many studies examine the relative information content of earnings and cash flows from operations. Most studies find that earnings have higher information content than cash flows. An interesting question that follows is whether these findings hold after controlling the extremity of earnings and cash flows. The purpose of this paper is to examine the relative information content of earnings and cash flows in the following four different cases: first, moderate earnings vs moderate cash flows, second, extreme earnings vs moderate cash flows, third, moderate earnings vs extreme cash flows, and fourth, extreme earnings vs extreme cash flows. Design/methodology/approach – To assess the relative information content of earnings and cash flows for each of the four cases mentioned above, the authors compare the explanatory power for regression of returns on unexpected earnings relative to regression of returns on unexpected cash flows. Therefore, the author compares the adjusted R2 of the model with earnings variables and the model with cash flows variables using Vuong's test, that examines the statistical significance of the difference between adjusted R2s of the rival (non-nested) models, and interpret a statistically higher adjusted R2 as an indicator for higher relative information content. Findings – The results show that: first, when both earnings and cash flows are moderate, earnings are more highly associated with stock market price changes than cash flows, second, when both earnings and cash flows are extreme, earnings also have greater relative information content than cash flows, third, when the extremity differs between earnings and cash flows, the moderate variable is superior to the other extreme variable in explaining security returns. These results suggest that earnings are definitely more value relevant than cash flows. However, only in cases when cash flows from operations are moderate and earnings are extreme, cash flows possess higher information content than earnings. Practical implications – The explanatory power for stock returns will be higher for earnings or cash flows depending on which is more highly persistent. This result reverses the conventional finding of the superiority of earnings over cash flows in explaining security returns. Originality/value – In contrast to previous studies, the authors control for the extremity of earnings and cash flows when evaluating the relative information content of earnings and cash flows from operations.
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Casu, Carla, Rea Oikonomidau, Yatrik Shah, Elizabeta Nemeth, Tomas Ganz, Brian MacDonald, and Stefano Rivella. "Concurrent Treatment with Minhepcidin and Deferiprone Improves Anemia and Enhances Reduction of Spleen Iron in a Mouse Model of Non-Transfusion Dependent Thalassemia." Blood 124, no. 21 (December 6, 2014): 748. http://dx.doi.org/10.1182/blood.v124.21.748.748.
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Abstract Individuals affected by non-transfusion-dependent thalassemia (NTDT) develop severe ineffective erythropoiesis that causes a number of serious clinical morbidities, such as chronic anemia, splenomegaly and systemic iron overload requiring chelation therapy. In NTDT, low hepcidin levels caused by ineffective erythropoiesis result in increased iron absorption which may in turn exacerbate erythroid cell damage, apoptosis and ineffective erythropoiesis. Minihepcidins (MH) are short peptide mimetics that reproduce the iron restrictive effects of hepcidin. Using a mouse model of NTDT (Hbbth3/+), we previously showed that MH-induced iron restriction significantly reduced erythroid cell damage, leading to reduced ineffective erythropoiesis and improved anemia. Accumulation of tissue iron was significantly diminished in MH treated animals. In clinical settings, use of MH for the treatment of NTDT would likely be concomitant with oral chelation therapy. Therefore we conducted studies in the (Hbbth3/+) mouse to evaluate whether the concurrent use of the oral iron chelator deferiprone (DFP) and MH would alter a) the hematological benefit of MH or b) the tissue iron reduction benefit of DFP. MH may improve the efficacy of DFP by reducing dietary iron absorption, thus increasing net reduction in tissue iron. Studies were performed in six week old mice using MH M004, which reduces cell surface expression of ferroportin with an EC50of 9.7 nM and causes >80% reduction in serum iron at a dose of 7.5 mg/kg in the rat. M004 (2.65 mg/kg) or vehicle control was administered twice weekly by subcutaneous injection for six weeks. Half of the mice in each group had free access to water containing DFP (1.25 mg/mL). Treatment with MH alone produced a profile of hematological changes resulting in a significant increase in circulating hemoglobin of 1.6 g/dL. Flow cytometry studies of bone marrow erythroid populations from MH-treated animals demonstrated an increase in the relative proportion of mature erythroid cells, reduced apoptosis and reduced levels of ROS. Parameters of erythrocyte damage (red cell distribution width, red cell morphology, red cell survival time) were improved and an increase in peripheral red cell number was observed. Reticulocyte count and spleen size were both reduced, reflecting improved erythropoietic efficiency. In separate studies in Hbbth3/+ mice that also expressed a hypoxia induced luciferase-reporter gene, treatment with MH resulted in reduction of tissue hypoxia. Mice treated with DFP alone showed no hematologic improvement compared to vehicle control whereas mice treated with MH and DFP together showed similar hematologic benefit as mice treated with MH alone (Hb increase of 2.3 g/dL versus control). Both DFP and MH administered separately caused a reduction in total liver iron compared to vehicle controls but the different was only statistically significant in MH treated animals. When administered concurrently, the combination of DFP and MH caused a further non-significant reduction compared to either agent alone. Although spleen iron/g wet weight was increased by MH, reflecting the iron-sequestering effect of hepcidin, total spleen iron was not significantly increased because spleen size was also reduced. DFP was equally effective in reducing spleen iron/g wet weight with or without concurrent MH treatment. However total spleen iron was non-significantly reduced (-35%) in DPF-treated mice compared to vehicle controls (1,435 ± 627 µg (mean ± SEM) vs 2,210 ± 213 µg) but a larger, statistically significant reduction in spleen iron was observed in MH + DFP treated mice compared to MH alone (-50%, 1,258 ± 414 vs 2,531 ± 246, p<0.05). In conclusion, the beneficial hematological effects of MH treatment in this model of NTDT remained even during concurrent treatment with DFP. DFP had no hematological benefits when used as a single agent, reflecting the inability of iron chelators to cause clinically meaningful iron restriction. Reduction in tissue iron by DFP was either unaffected or enhanced by concurrent treatment with MH. The improved effect of DFP on spleen iron burden in the presence of MH may reflect the complementary effects of these agents to increase iron excretion and reduce dietary iron absorption respectively. Enhancement of the clinical efficacy of iron chelators may be an important benefit of MH therapy in addition to the observed increase in circulating hemoglobin. Disclosures Casu: Isis Pharmaceuticals, Inc.: Employment; Merganser Biotech LLC: Employment. Nemeth:Merganser Biotech LLC: Stockholders Other. Ganz:Merganser Biotech LLC: Stockholders Other. MacDonald:Merganser Biotech LLC: Employment, Equity Ownership. Rivella:bayer: Consultancy, Research Funding; merganser Biotech LLC: Consultancy, Research Funding, Stock options, Stock options Other; isis Pharmaceuticals, Inc.: Consultancy, Research Funding.
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Fisher, Jack, Christopher J. Walker, Peter Johnson, Mark S. Cragg, Francesco Forconi, Yosef Landesman, Salim I. Khakoo, and Matthew D. Blunt. "Selinexor Enhances NK Cell Activation Against Lymphoma Cells Via Downregulation of HLA-E." Blood 138, Supplement 1 (November 5, 2021): 2411. http://dx.doi.org/10.1182/blood-2021-144836.
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Abstract Introduction: Natural killer (NK) cells are powerful immune effectors which induce direct cytotoxicity, promote adaptive immune responses and mediate antibody dependent cellular cytotoxicity (ADCC). Enhancement of NK cell activity against cancer is currently the focus of intense research efforts and strategies include CAR-NK, stimulatory antibodies, cytokines and checkpoint inhibitors. Upregulation of exportin-1 (XPO1) is common in human cancers and high expression is negatively associated with survival in various cancers including diffuse large B cell lymphoma (DLBCL). Targeted inhibition of XPO1 by the selective inhibitor selinexor leads to cancer cell death via accumulation of tumour suppressor proteins in the nucleus, dysregulation of growth regulatory proteins and blockade of oncogene protein translation. The therapeutic efficacy of XPO1 inhibition has led to FDA approval of the oral XPO1 inhibitor selinexor for the treatment of multiple myeloma and DLBCL. The effect of selinexor on NK cell activity has not previously been investigated and was therefore addressed in this study. Methods: The B lymphoma cell lines JeKo-1, SU-DHL-4 and Ramos were incubated with selinexor (50-2000nM) for 18 hours before analysis. Flow cytometry was used to assess cell surface expression of activating and inhibitory ligands for NK cells. For NK based assays, peripheral blood derived NK cells were isolated from healthy donors and incubated with IL-15 (1ng/ml) overnight prior to co-culture with target lymphoma cells for a further 4 hours. Cytotoxicity was assessed using propidium iodide staining of target cells and degranulation of NK cells was assessed by measurement of CD107a. Whole blood samples from colorectal cancer patients (n=11) at pre-treatment and 3 weeks post selinexor monotherapy were assessed by flow cytometry for CD45+CD3-CD19-CD56+ NK cells. Results: Selinexor pre-treatment of target lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4 (2.2 Fold increase, p<0.01), JeKo-1 (2 Fold increase, p<0.01) and Ramos (1.7 Fold increase, p<0.01) cells. In accordance with this, selinexor pre-treatment of target cells also increased the activation of NK cells against SU-DHL-4, JeKo-1 and Ramos cells as measured by CD107a expression in both CD56 bright and CD56 dim NK cell sub-groups. To identify the mechanism behind this, we measured expression of activating and inhibitory ligands for NK cells on SU-DHL-4 cells after incubation with selinexor. No significant changes in expression of activating ligands (MICA/B, ULBP-2/5/6, ULBP-1, Vimentin, B7H6, CD54) were evident. In contrast, selinexor significantly (p<0.001) reduced the surface expression of HLA-E on SU-DHL-4 cells by 50%. Selinexor mediated downregulation of HLA-E was also evident in Ramos (60% reduction, p<0.001) and JeKo-1 cells (20% reduction, p<0.01). HLA-E binds the ITIM containing receptor NKG2A, a key inhibitory receptor for NK cells and subsets of T cells. In accordance with this, selinexor pre-treatment of SU-DHL-4 cells selectively increased NKG2A+ NK cell activation (p<0.01) following co-culture. To examine the effect of selinexor on NK cells in patients, we assessed the proportion of NK cells in the peripheral blood of 11 colorectal cancer patients at pre-treatment and three weeks post selinexor monotherapy. % NK cells of CD45+ peripheral blood lymphocytes following treatment with selinexor was increased 2-fold (Median 5% pre-treatment vs 10% post selinexor). In addition, increased abundance of the less mature and less cytotoxic CD56 bright subset of NK cells was associated with poor response to therapy (Median 4% responders (n=3) vs 20% non-responders (n=8)). Larger patient datasets are required to confirm these effects and this analysis is currently ongoing. The effect of selinexor on NK cells in patients with lymphoma is also currently under investigation. Conclusions: The NKG2A:HLA-E axis is a novel immune checkpoint target and our data identifies that selinexor sensitises lymphoma cells to NK cell mediated killing via disruption of this interaction. In addition, we provide initial evidence that NK cells may be associated with clinical response to selinexor. This data indicates that NK cells may contribute to the therapeutic efficacy of selinexor and that selinexor may synergise with NK cell targeted therapies for the treatment of lymphoma. Disclosures Walker: Karyopharm Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Johnson: Morphosys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Bristol-Myers: Honoraria; Epizyme: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Novartis: Honoraria; Takeda: Honoraria; Oncimmune: Consultancy; Janssen: Consultancy. Cragg: BioInvent International: Consultancy, Research Funding; GSK: Research Funding; UCB: Research Funding; iTeos: Research Funding; Roche: Research Funding. Forconi: Novartis: Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Gilead: Research Funding. Landesman: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Blunt: Karyopharm Therapeutics: Research Funding.
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Scarfò, Irene, Kathleen M. E. Gallagher, Mark B. Leick, Michael C. Kann, Justin Budka, Bharat Sowrirajan, Kim Nguyen, Rhine R. Shen, Adrian Bot, and Marcela V. Maus. "Effects of Prior Exposure to Tec Kinase(BTK/ITK) Inhibitors on Kte-X19 Products." Blood 138, Supplement 1 (November 5, 2021): 3849. http://dx.doi.org/10.1182/blood-2021-146941.
Full textAbstract:
Abstract Introduction: Frequent and durable responses were recently reported in relapsed or refractory (R/R) mantle cell lymphoma (MCL) patients treated with KTE-X19, an autologous CD19-targeted chimeric antigen receptor-engineered T-cell (CAR-T) product (Wang et al. N Engl J Med. 2020). Most patients enrolled had received at least one line of Tec kinase inhibitor prior to KTE-X19 manufacturing, either in the form of ibrutinib, a Bruton's tyrosine kinase (BTK) and Inducible T cell kinase (ITK) inhibitor, or acalabrutinib, a more selective BTK inhibitor. Pharmacokinetic expansion of KTE-X19 was higher in ibrutinib-treated patients relative to acalabrutinib-treated patients. We previously showed that prolonged exposure to ibrutinib enhanced T cell effector function and proliferation in patients with CLL (Fraietta et al, Blood, 2016). To assess the impact of Tec kinase inhibitor on KTE-X19 products and downstream clinical outcomes, we examined the phenotype, transcriptional profile and cytokine production of KTE-X19 infusion products and post-infusion lymphocytes from patients with R/R MCL treated on the Zuma-2 study. Study Design and Methods: We evaluated biospecimens from MCL patients who enrolled on the Zuma-2 clinical trial (NCT02601313) and who were previously treated with ibrutinib (n=14) or acalabrutinib (n=6). Samples analyzed consisted of KTE-X19 CAR T products and peripheral blood mononuclear cells (PBMC) collected 7 days after infusion. Lymphocytes were assessed for CAR expression, T cell phenotype, transcriptional profile and cytokine production. In addition, CAR T cell phenotypes and cytokines were profiled following co-culture of KTE-X19 with CD19 + Toledo cells (DLBCL). Results: Flow cytometric analysis of KTE-X19 demonstrated similar distributions of CD4+ and CD8+ T cells and comparable frequencies of central and effector memory populations in the CAR+ T cells derived from patients with prior exposure to ibrutinib vs. acalabrutinib. T helper subset analysis trended towards enrichment of Th1/Th17 populations within the CAR+ CD4+ cells of the ibrutinib cohort. This finding was further supported by transcriptional profiling of sorted CAR+ T cells from infusion products, where Th1/Th17, Jak/STAT and activation-related genes were enriched in the cohort with prior ibrutinib exposure. In addition, the Th1 phenotype was more frequent in PBMC of ibrutinib-exposed patients (8/14) compared to acalabrutinib-exposed patients (1/4). Interestingly, a shift from a central memory-dominant product towards an effector memory phenotype was observed in peripheral CD4+ and CD8+ CAR T cells in the ibrutinib cohort, whereas acalabrutinib post-infusion CAR T cells maintained a central memory phenotype. In vitro stimulation of KTE-X19 CAR-T infusion products with tumor cells resulted in a significant enrichment of the Th1 population in patients who had received ibrutinib compared to those that received acalabrutinib (p=0.0058). Following stimulation, CAR-T cells from the acalabrutinib cohort produced higher levels of Th2 cytokines, including IL-4, IL-5, and IL-13 as well as GM-CSF compared to the ibrutinib cohort. Conclusions: Analysis of KTE-X19 infusion products and day 7 post-infusion PBMC demonstrated that CAR T cells from patients with prior ibrutinib exposure have a Th1 predominant phenotype, suggesting that ibrutinib but not acalabrutinib promotes Th1 differentiation and effector function, potentially through the inhibition of ITK. Furthermore, our data suggest that inhibition of non-BTK targets such as ITK may play a role in driving a Th17 phenotype. Prior exposure to ibrutinib may increase CAR T cell effector function to a greater extent than exposure to acalabrutinib to enhance clinical outcome in patients with MCL. Disclosures Budka: Kite Pharma: Current Employment. Sowrirajan: Kite Pharma: Current Employment. Nguyen: Kite Pharma: Current Employment. Shen: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties; Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Maus: Agenus: Consultancy; Arcellx: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Atara: Consultancy; Bayer: Consultancy; BMS: Consultancy; Cabaletta Bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; In8bio (SAB): Consultancy; Intellia: Consultancy; GSK: Consultancy; Kite Pharma: Consultancy, Research Funding; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Novartis: Consultancy; Tmunity: Consultancy; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company.
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Mandato, Elisa, Yanbo Sun, Vignesh Shanmugam, Il-Kyu Choi, Kyle T. Wright, Robert A. Redd, Lee N. Lawton, et al. "Genetic Perturbation of CD70/CD27 Co-Stimulation Promotes the Development of Bcl6-Driven Diffuse Large B-Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 713. http://dx.doi.org/10.1182/blood-2021-153533.
Full textAbstract:
Abstract Multiple co-stimulatory and co-inhibitory pathways modulate T-cell dependent anti-tumor immune responses in lymphoid malignancies. We recently defined the recurrent genetic alterations and associated substructure of diffuse large B-cell lymphoma (DLBCL), including five distinct clusters (1-5), and identified potential genetic bases for immune evasion [Nature Medicine 2018; 24:679-690]. In our series, 26% of tumors had inactivating somatic mutations or copy loss of CD70 and likely disruption of CD70/CD27 co-stimulation. CD70 and CD27 are homotrimer type II and homodimer type I transmembrane proteins and members of the TNF and TNF receptor superfamilies, respectively. CD70 is transiently expressed on certain normal B-cell and dendritic cell populations upon activation and constitutively expressed on multiple B-cell tumors. CD70 activation of CD27 + T cells promotes antigen-dependent T-cell expansion and immune surveillance of normal and malignant B cells. Patients with germline deficiencies of either CD70 or CD27 have an increased incidence of EBV-associated lymphoid malignancies, underscoring the importance of this co-stimulatory pathway. In our series, CD70 alterations were most common in Cluster 1 DLBCLs, which also exhibited recurrent BCL6 chromosomal translocations. The co-occurrence of CD70 and BCL6 genetic alterations was noteworthy because of the established role of CD8 + T-cell dependent immune surveillance in murine models of Bcl6-driven DLBCL [Nature Medicine 2014; 20:283-290]. To assess the consequences of Cd70 deficiency and perturbed CD70/CD27 co-stimulation on Bcl6-driven lymphomagenesis, we crossed the previously described Bcl6tg/+ and Cd70-/- mice to generate Cd70-/-; Bcl6tg/+ animals. In the aging cohorts, Cd70-/-; Bcl6tg/+ mice were more likely than Bcl6tg/+ animals (or the Cd70-/- or wild-type [WT] groups) to be euthanized for symptoms before the study endpoint (18 months [mo]) (5 of 18 Cd70-/-; Bcl6tg/+ euthanized for symptoms prior to the first of 9 Bcl6tg/+). Additionally, significantly greater total numbers and percentages of Cd70-/-; Bcl6tg/+ mice, in comparison to Bcl6tg/+ or Cd70-/- animals, were euthanized for symptoms (64% Cd70-/-; Bcl6tg/+ vs. 29% Bcl6tg/+, p=0.005 and 64% Cd70-/-; Bcl6tg/+ vs. 11% Cd70-/-, p=0.002). Almost all euthanized Cd70-/; Bcl6tg/+ and Bcl6tg/+ micehad massively enlarged spleens infiltrated with histopathologically confirmed DLBCLs characterized by clonal Ig gene rearrangements. Our findings indicate that genetic perturbation of Cd70 accelerates the onset and significantly increases the incidence of Bcl6-driven DLBCL. To characterize potential differences in the anti-tumor immune responses in Cd70-/-; Bcl6tg/+ and Bcl6tg/+ mice (and Cd70-/- and WT controls), we also harvested spleens from 6 animals in each of the aging cohorts at predetermined intervals (2, 6, 14 and 18 mo). We analyzed the composition of splenic-cell suspensions by flow cytometry and evaluated the intact splenic architecture and morphology with expert hematopathologists (VS, KW and SR). At 14 and 18 mo, spleens from WT and Cd70-/- animals were largely normal in appearance and size. In contrast, spleens from 14 and 18 mo Bcl6tg/+ and Cd70-/-; Bcl6tg/+ mice exhibited disordered architecture and abnormal pre-malignant lymphoid proliferation with expanded white pulp including morphologically and immunophenotypically aberrant B cells of small to large size and increased infiltrating T-cells. Additionally, significantly higher fractions of splenic CD8 + T cells from 14 and 18 mo Bcl6tg/+ and Cd70-/-; Bcl6tg/+ animals expressed the CD69 activation marker and exhibited terminal differentiation, consistent with an ongoing anti-tumor immune response. Interestingly, Bcl6tg/+ animals had significantly higher percentages of splenic TCRβ + T cells at the earlier time point (14 mo) with delayed-onset splenomegaly (at 18 mo), which is in marked contrast to the Cd70-/-; Bcl6tg/+ mice that had significantly lower percentages of splenic TCRβ + T cells at the earlier time point (14 mo) and early-onset splenomegaly (14 mo). These findings suggest that the initial T-cell mediated immune response was more effective in Bcl6tg/+ than Cd70-/-; Bcl6tg/+ animals. Taken together, our data indicate that genetic perturbation of CD70/CD27 co-stimulation limits the development of an effective anti-tumor immune response in Bcl6tg/+-driven DLBCL. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Rodig: Affimed: Research Funding; Bristol-Myers-Squibb: Research Funding; Merck: Research Funding; Immunitas: Membership on an entity's Board of Directors or advisory committees; KITE/Gilead: Research Funding. Shipp: Bristol Myers Squibb: Research Funding; Immunitas Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; Merck: Research Funding; Abbvie: Other: Institution: Research Grant/Funding; Bayer: Other: Institution: Research Grant/Funding.