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Esen, A., and G. Alpay. "Exploring the impact of firm- and relationship-specific factors on alliance performance: Evidence from Turkey." South African Journal of Business Management 48, no. 2 (June 30, 2017): 11–21. http://dx.doi.org/10.4102/sajbm.v48i2.24.
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This study investigates the impact of firm-specific (i.e., alliance orientation and partner selection criteria) and relationship-specific (i.e., strategic fit, cultural fit, and organizational fit) factors on alliance performance and assesses the mediating role of trust in the relationship between relationship-specific factors and alliance performance. Partial least squares analysis is applied to a data set of 106 strategic alliances, including both equity alliances (joint ventures) and non-equity alliances (contractual alliances). The empirical results reveal that alliance orientation and strategic fit lead to superior alliance performance and that cultural fit is positively related to partner trustworthiness. The results have managerial implications regarding how to maximize the positive outcomes of an alliance.
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Coombs, Joseph E., Paul E. Bierly, and Scott Gallagher. "The impact of different forms of IPO firm legitimacy on the choice of alliance governance structure." Journal of Management & Organization 18, no. 4 (July 2012): 516–36. http://dx.doi.org/10.1017/s1833367200000730.
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AbstractWe analyze the effects of four different types of firm legitimacy – managerial, technological, local community legitimacy and business press endorsement – on the choice of alliance governance structure in partnerships with newly public biotechnology firms. We expand current research to differentiate between non-equity, minority equity and joint venture alliance structures. We find that initial public offering of stock (IPO) firms with higher levels of managerial legitimacy and local community legitimacy are more likely to enter into joint ventures than minority equity alliances and non-equity alliances. IPO firms with higher technological legitimacy and business press endorsement are more likely to use a less hierarchical governance structure.
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Coombs, Joseph E., Paul E. Bierly, and Scott Gallagher. "The impact of different forms of IPO firm legitimacy on the choice of alliance governance structure." Journal of Management & Organization 18, no. 4 (July 2012): 516–36. http://dx.doi.org/10.5172/jmo.2012.18.4.516.
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AbstractWe analyze the effects of four different types of firm legitimacy – managerial, technological, local community legitimacy and business press endorsement – on the choice of alliance governance structure in partnerships with newly public biotechnology firms. We expand current research to differentiate between non-equity, minority equity and joint venture alliance structures. We find that initial public offering of stock (IPO) firms with higher levels of managerial legitimacy and local community legitimacy are more likely to enter into joint ventures than minority equity alliances and non-equity alliances. IPO firms with higher technological legitimacy and business press endorsement are more likely to use a less hierarchical governance structure.
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Gudergan, Siegfried P., Timothy M. Devinney, and R. Susan Ellis. "Cooperation and compliance in non-equity alliances." Journal of Business Research 69, no. 5 (May 2016): 1759–64. http://dx.doi.org/10.1016/j.jbusres.2015.10.051.
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Pesch, Robin, and Ricarda B. Bouncken. "The double-edged sword of cultural distance in international alliances." Cross Cultural & Strategic Management 24, no. 1 (February 6, 2017): 33–54. http://dx.doi.org/10.1108/ccsm-03-2016-0065.
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Purpose While previous studies have primarily assumed dysfunctional effects of cultural distance in joint ventures and M&A, this paper elucidates from a positive organizational scholarship perspective how perceived cultural distance can advance firms’ new product development within non-equity alliances. The purpose of this paper is to explain how perceived cultural distance stimulates task discourse that supports alliance partners’ employees in recognizing and applying culture-related differences as complementary problem-solving potentials. Due to a lower integration level in non-equity alliances compared to joint ventures or M&A, this paper assumes that the positive effects outweigh the negative effects of cultural distance. Design/methodology/approach This study applies structural equation modeling to test the hypothesized effects on a sample of 246 international alliances in the manufacturing industry. Findings The analysis mainly supports the hypothesized model and unravels how positive effects can emerge from perceived cultural distance. Practical implications The findings provide managerial implications. Alliance managers should note that cultural distance can have positive and negative effects, and thus it is not a barrier per se in alliances. Firms can benefit from cultural distance if they are able to leverage culture-specific complementarities through task discourse among partners in alliances. Originality/value The manuscript uses a unique data set of 246 international alliances from the global manufacturing industry. The manuscript has not been published elsewhere.
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Reuer, Jeffrey J., and Shivaram Devarakonda. "Beyond Contracts: Governing Structures in Non-Equity Alliances." Academy of Management Proceedings 2012, no. 1 (July 2012): 10448. http://dx.doi.org/10.5465/ambpp.2012.73.
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Reddy, Sabine B., Richard N. Osbom, and Jean-FranVois Hennart. "The Prevalence of Equity and Non-Equity Cross-Border Linkages: Japanese Investments and Alliances in the United States." Organization Studies 23, no. 5 (September 2002): 759–80. http://dx.doi.org/10.1177/0170840602235004.
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Using complementary theories derived from the foreign-entry mode and alliance literatures and two databases on Japanese/US alliances and investments, this study examines the prevalence — a combination of formation and termination — of the full range of investment and cross-border linkage alternatives available to firms. We find that some combinations among the administrative forms, the knowledge flow intent between the partners, and industry-related technology and risk factors were more prevalent than others. Specifically, there were three prevalent combinations consistent with the notions of production efficiency, transaction cost efficiency and learning/adaptation: (1) wholly owned subsidiaries in low R&D-intense industries with the intent of unidirectional knowledge flow; (2) joint ventures in medium R&D-intense industries with reciprocal knowledge flows; and (3) technical agreements with reciprocal knowledge flows in high-tech industries.
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Kumar Muthusamy, Senthil. "Role of context and contest in the structuring of alliance governance." Journal of Strategy and Management 7, no. 2 (May 13, 2014): 172–92. http://dx.doi.org/10.1108/jsma-04-2013-0022.
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Purpose – The alliance governance – whether equity or non-equity based – through which an alliance is governed serves as a mechanism to protect a firm from partner's opportunistic behavior, manage resource dependence and facilitate knowledge sharing. Alliance governance structure also reflects the risk, reward and control that partners perceive in a relationship. In light of the conflicts and instabilities reported in strategic alliances, the purpose of this paper is to examine the interorganizational domain that affects the endurance and continuity of collaboration and explain how the alliance interface contexts determines the structuring of alliance governance. Design/methodology/approach – An empirical examination of 179 strategic alliances, using survey and archival data conducted to test the hypothesized relationship between the choice of governance structure and the complexity of alliance task, balance of power and competitive scope between partners. Findings – A multinomial logistic regression of the hypothesized variables revealed that the complexity of alliance task, balance of power, and competitive scope between partners are significantly related to the mode of alliance governance – whether non-equity, minority-equity, or joint venture. Originality/value – This study makes a significant contribution to the understanding of the relationships between the contextual factors such as the alliance task, power dynamics, and competitive scope that shape the collaboration and structuring of appropriate alliance governance mode. Results of the study provide strong evidence for the hypotheses that the greater the task complexity, and greater the balance of power and scope of competition between partners, the alliance governance tends to be equity or joint venture based. Consistent with recommendations of several organizational scholars that the theory of alliance governance and performance must shift from individual partner firm to interaction domain and interface contexts (Luo, 2002; Gray and Wood, 1991; Oxley and Sampson, 2004), this study integrally examined the dyadic issues such as balance of power, task complexity, and the competitive scope and the dynamic role they play in decisions pertaining to alliance governance. While many extant studies on the choice of alliance governance structure have employed secondary data sources, the study employed data from survey measures (Gulati, 1995; Teng and Das, 2008; Oxley and Sampson, 2004) enhancing the validity of the results.
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Reuer, Jeffrey J., and Shivaram V. Devarakonda. "Mechanisms of Hybrid Governance: Administrative Committees in Non-Equity Alliances." Academy of Management Journal 59, no. 2 (April 2016): 510–33. http://dx.doi.org/10.5465/amj.2012.0098.
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Majocchi, Antonio, Ulrike Mayrhofer, and Joaquin Camps. "Joint ventures or non‐equity alliances? Evidence from Italian firms." Management Decision 51, no. 2 (March 2013): 380–95. http://dx.doi.org/10.1108/00251741311301876.
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Tewari, Manish, Pradip Kumar Ramanlal, Rajesh Kumar, and Soumendra De. "Stock Market Response to Multiple Alliance Announcements." International Journal of Finance & Banking Studies (2147-4486) 9, no. 2 (May 28, 2020): 26–45. http://dx.doi.org/10.20525/ijfbs.v9i2.668.
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We document frequency distribution of 4315 two-party, non-equity alliances undertaken by the U.S. based firms between 1986 and 2015 in 11industries and find that on an aggregate basis, the firms which form multiple alliances based on the exploitation motive are as likely to enter into alliance as the firms that enter into multiple alliances based on the exploration motive. However, we find strong evidence that the firms that enter into alliances on three or more occasions are driven by the exploration motive while, the firms that enter into alliances one and one or two times are driven by the exploitation motive. The average cumulative abnormal returns (ACAR) for all of the three subsamples of firms that undertook one, one or two, and three or more alliances during the time period for this study are all positive but exhibit a declining trend. Firms that are larger in terms of total assets engage more frequently in alliances than smaller firms. Returns to firms that enter into three or more alliances are sensitive to the leverage employed and the likelihood of bankruptcy whereas returns to firms that enter into only one or one or two alliances are affected significantly by the considerations of competitive forces.
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Wang, Yue, and Stephen Nicholas. "The formation and evolution of non-equity strategic alliances in China." Asia Pacific Journal of Management 24, no. 2 (January 31, 2007): 131–50. http://dx.doi.org/10.1007/s10490-006-9034-z.
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Reza Saeedi, Mohammad, Hossein Dadfar, and Staffan Brege. "The impact of inward international licensing on absorptive capacity of SMEs." International Journal of Quality and Service Sciences 6, no. 2/3 (June 10, 2014): 164–80. http://dx.doi.org/10.1108/ijqss-02-2014-0011.
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Purpose – This study aims to examine the impacts of inward international licensing (IIL) on the absorptive capacity (ACAP) of small and medium enterprises (SMEs) in a developing economy. Design/methodology/approach – The study is explorative, qualitative and elaborative in nature. Therefore, a multiple case study was selected and performed as the research strategy. The data were collected from four pharmaceutical SMEs licensed from European pharmaceutical large-scale enterprises. Findings – The results confirm that IIL has a strong effect on acquisition, assimilation, transformation and exploitation as absorptive factors. Furthermore, the results have been enhanced by several contextual factors of ACAP human resources, inter-and intra-firm relationships, internal knowledge and managerial and strategic aspects. These contextual factors have also been influenced by IIL. Originality/value – From the licensee perspective in a developing context, examining the extant literature on non-equity strategic alliances shows that very few studies have empirically examined the impact of this kind of alliance, such as IIL, on SMEs’ ACAP. On this basis, the study provides evidence that non-equity strategic alliances, particularly IIL, enhance SMEs’ capabilities such as ACAP. In other words, to overcome SMEs’ resource limitations and inadequate capabilities, IIL provides opportunities for them to obtain capabilities and critical resources.
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Beck, John C., Alan B. Larsen, and J. Michael Pinegar. "The wealth effects of non-equity alliances The U.S.-Japanese licensing experience." Pacific-Basin Finance Journal 4, no. 4 (December 1996): 393–408. http://dx.doi.org/10.1016/s0927-538x(96)00005-4.
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Defee, C. Clifford. "Creating Competitive Advantage Using Non-Equity Strategic Alliances: A Small Company Perspective." Supply Chain Forum: An International Journal 7, no. 2 (January 2006): 44–57. http://dx.doi.org/10.1080/16258312.2006.11517168.
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Toon, Mark A., Matthew J. Robson, and Robert E. Morgan. "A value-in-process analysis of relationship interactions in non-equity alliances." Industrial Marketing Management 41, no. 1 (January 2012): 186–96. http://dx.doi.org/10.1016/j.indmarman.2011.11.016.
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Colombo, Massimo G., and Evila Piva. "Knowledge misappropriation risks and contractual complexity in entrepreneurial ventures’ non-equity alliances." Small Business Economics 53, no. 1 (May 7, 2018): 107–27. http://dx.doi.org/10.1007/s11187-018-0062-0.
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Jin, Jun, Max von Zedtwitz, and Li Choy Chong. "Formation of R & D alliances in the Chinese mobile telephony industry." Journal of Chinese Economic and Foreign Trade Studies 8, no. 2 (June 1, 2015): 70–81. http://dx.doi.org/10.1108/jcefts-02-2015-0011.
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Purpose – The purpose of this paper is to investigate how international R & D alliances are formed during industry transition from the point of view of the local Chinese partner. Design/methodology/approach – Review of industry data provided by Chinese Statistical Office coupled with four in-depth case studies. Findings – The nature of the technology, the characteristics of partners and the previous cooperation experience between partners are significantly related to the R & D alliance formation. The research also suggests that during this fast-growing transition period, Chinese local firms preferred non-equity contractual agreements over equity joint venture such as R & D alliance modes, and Chinese local firms favoured American and European multinational corporations (MNCs) as their alliance partners over MNCs from other countries, including the highly developed Japan and Korea. Research limitations/implications – Single-industry focus (telecommunications), and anonymization of cases because of confidentiality of case firms. Single-country focus (China). Practical implications – Firms in China and other emerging countries can improve their technological capability (TC) by choice to facilitate future alliance formation to access and learn the latest technology from their alliance partners, especially during the transition period of an industry and when mature and emerging technologies co-exist. Originality/value – This paper refines alliance theory by focusing on an industry in transition and analyses formation decision factors from the point of view of the smaller domestic partner – usually studies do not differentiate as to industry maturity and inequality between partners.
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Reuer, Jeffrey J., and Shivaram V. Devarakonda. "Does My Partnership Need a Joint Steering Committee?: Governance in Non-Equity Alliances." IESE Insight, no. 36 (March 20, 2018): 23–28. http://dx.doi.org/10.15581/002.art-3134.
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Li, Ning. "Religion, Opportunism, and International Market Entry Via Non-Equity Alliances or Joint Ventures." Journal of Business Ethics 80, no. 4 (July 10, 2007): 771–89. http://dx.doi.org/10.1007/s10551-007-9468-3.
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Lui, Steven S., and Hang-Yue Ngo. "The Role of Trust and Contractual Safeguards on Cooperation in Non-equity Alliances." Journal of Management 30, no. 4 (August 2004): 471–85. http://dx.doi.org/10.1016/j.jm.2004.02.002.
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Paidakaki, Angeliki, and Richard Lang. "Uncovering Social Sustainability in Housing Systems through the Lens of Institutional Capital: A Study of Two Housing Alliances in Vienna, Austria." Sustainability 13, no. 17 (August 30, 2021): 9726. http://dx.doi.org/10.3390/su13179726.
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This paper analyzes social sustainability in the context of urban housing through the lens of institutional capital. It examines how civil society housing actors co-construct bottom-linked governance arrangements by interacting endogenously with peers and exogenously with institutional actors, such as public housing agencies and elected officials, in order to steer, as housing alliances, socially sustainable residential developments. The paper thus offers an answer to the following two research questions: (1) What are internal governance features that characterize such civil society housing alliances? (2) What are their strategies of interaction with institutional actors in order to promote social sustainability and thus counter exclusionary patterns in urban housing systems? Empirical evidences are drawn from two civil society housing alliances in Austria, ‘BAWO’ (a national alliance of homelessness NGOs) and the ‘Initiative Collaborative Building & Living’. During three research stays in Vienna between 2014 and 2020, data was collected through semi-structured interviews and focus groups with leaders and members of housing alliances, interviews with key institutional stakeholders and web research. By reflecting on the institutional and relational character of the two housing alliances and digging out their potential and limitations in promoting different elements of social sustainability, our paper concludes that social sustainability in housing systems can be realized when it is set as a societal ambition sufficiently politicized by major parties involved in housing systems (housing alliances, governmental authorities of all ideological backgrounds, large non-profit housing developers) that collectively guarantee housing affordability and socio-spatial equity for all.
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Wang, An Yu, and Jun Li. "The Cooperative Organizational Modes for Technological Exploitation: Evidence from Chinese Heating Ventilating and Air Conditioning Industry." Advanced Materials Research 129-131 (August 2010): 1394–99. http://dx.doi.org/10.4028/www.scientific.net/amr.129-131.1394.
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The Aim—this paper is to investigate whether there is a certain kind of organizational modes for cooperative technological exploitation. In recent years, an important objective of cooperative R&D alliances built by independent organizations is to explore a new market or to exploit the existing one. Whether the objective can be achieved or not is tightly related to the governing efficiency of the R&D alliance, and the latter in turn depends on the suitable organizational mode. The Method--this paper selects 39 Heating Ventilating and Air Conditioning companies listed in Shanghai and Shenzhen Stock Exchange according to some certain criteria, and collects their collaborative R&D cases since their listing, and then analyzes the impact of technological exploitation objective to the selection of cooperative R&D organizational modes in light of LOGIT model. The result—this paper shows that the equity mode is prior to the non-equity one no matter the R&D alliance is to explore a new market or exploit the existing market.
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Wang, Yue, and Karen Yuan Wang. "Uncovering control mechanisms in contractual joint ventures in China." Corporate Ownership and Control 10, no. 2 (2013): 114–20. http://dx.doi.org/10.22495/cocv10i2art9.
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This paper aims to examine the control mechanisms within CJV non-equity alliances, enhancing our knowledge of one of the most important yet least understood form of foreign investment in China. The findings also help foreign investors to better understand how to use CJVs as an organizational vehicle to enter Chinese market.
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Globerman, Steven, and Bo Bernhard Nielsen. "Equity versus non-equity international strategic alliances involving Danish firms: An empirical investigation of the relative importance of partner and host country determinants." Journal of International Management 13, no. 4 (December 2007): 449–71. http://dx.doi.org/10.1016/j.intman.2007.03.005.
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Vassolo, Roberto S., Jaideep Anand, and Timothy B. Folta. "Non-additivity in portfolios of exploration activities: a real options-based analysis of equity alliances in biotechnology." Strategic Management Journal 25, no. 11 (September 27, 2004): 1045–61. http://dx.doi.org/10.1002/smj.414.
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Garcez, Marcos Paixão, Roberto Sbragia, and Isak Kruglianskas. "FACTORS FOR SELECTING PARTNERS IN INNOVATION PROJECTS – QUALITATIVE EVIDENCES FROM NON-EQUITY BILATERAL ALLIANCES IN THE BRAZILIAN PETROCHEMICAL LEADER." Review of Administration and Innovation - RAI 11, no. 2 (July 2, 2014): 241. http://dx.doi.org/10.5773/rai.v11i2.1292.
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Miranda, Daniela E., Manuel Garcia-Ramirez, Fabricio E. Balcazar, and Yolanda Suarez-Balcazar. "A Community-Based Participatory Action Research for Roma Health Justice in a Deprived District in Spain." International Journal of Environmental Research and Public Health 16, no. 19 (October 2, 2019): 3722. http://dx.doi.org/10.3390/ijerph16193722.
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Addressing health disparities and promoting health equity for Roma has been a challenge. The Roma are the largest disadvantaged ethnic minority population in Europe and have been the victims of deep social and economic injustices, institutional discrimination, and structural antigypsyism over many centuries. This has resulted in a much worse health status than their non-Roma counterparts. Current strategies based on ameliorative and top-down approaches to service delivery have resulted in paradoxical effects that solidify health disparities, since they do not effectively address the problems of vulnerable Roma groups. Following a health justice approach, we present a community-based participatory action research case study generated by a community and university partnership intended to address power imbalances and build collaboration among local stakeholders. This case study involved a group of health providers, Roma residents, researchers, Roma community organizations, and other stakeholders in the Poligono Sur, a neighborhood of Seville, Spain. The case study comprises four phases: (1) identifying Roma health assets, (2) empowering Roma community through sociopolitical awareness, (3) promoting alliances between Roma and community resources/institutions, and (4) building a common agenda for promoting Roma health justice. We highlighted best practices for developing processes to influence Roma health equity in local health policy agendas.
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Gudergan, Siegfried P., Timothy Devinney, Nicole Franziska Richter, and R. Susan Ellis. "Strategic Implications for (Non-Equity) Alliance Performance." Long Range Planning 45, no. 5-6 (October 2012): 451–76. http://dx.doi.org/10.1016/j.lrp.2012.09.002.
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Arora, Soma. "Polaris India International: moving boundaries." Emerald Emerging Markets Case Studies 8, no. 4 (November 8, 2018): 1–28. http://dx.doi.org/10.1108/eemcs-11-2017-0250.
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Learning outcomes To familiarize the students with a process of international expansion within an emerging market scenario encompassing countries such as India, Sri Lanka and a developing country like Kazakhstan. Mostly cases in international marketing are central to developed nations, as that is where the MNCs emerge and grow. In this case study, though Polaris originally is an US-based MNC, the focus lies on Polaris India going international. Hence, it looked at empowering an emerging market for regional development. To provide a situation for choice of entry mode strategies involving strategic alliances and various kinds of non-equity based partnerships. Here there is scope for tremendous learning with reference to institutional voids and market failures prompting a certain mode of entry strategy versus another in international marketing. Though this topic has been researched widely, this case is the first ever tribute to a real-life situation in an emerging market. The case is focussed on experiential marketing as the new tool for sales and communication. This is unique to Polaris, and worth replicating in its internationalization. The crucial question emerged: adaptation of experiential marketing techniques as per local market. Case overview / synopsis This case investigated the process of internationalization for Polaris India, a US-based MNC, making for an interesting study in how emerging markets can become hubs for effective regional market expansion. The case simultaneously explored the concept of experiential marketing in a new light referring to the issue of communication adaptation in international marketing. The company had successfully used Polaris Experience zones as their promotion and distribution tools. The PEZ had weaved its magic on Indian customers to bring about significant positive change to the perception of a brand now extending the brand promise to other emerging markets. Polaris India started as a wholly owned subsidiary of Polaris Industries USA Inc in 2011 with Mr Pankaj Dubey, as the Country Head. Polaris specialized in building world class off-road vehicles and was a global leader in the same. The case study provided an opportunity to discuss behind the scenes role played by channel partners in targeted foreign markets – Sri Lanka and Kazakhstan. In international marketing, strategic alliances are of tremendous significance as a method of entry strategy and the knowledge, depth, expertise can make all the difference to achievement of success in the local market. Polaris despite having to market a product with no readymade market and combating the perceived notion of a super-premium product in emerging markets, managed to weave its own success story. The case is about, how Polaris India went International with its choice of strategic partners and communication tools. Supplementary materials Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes. Subject code Marketing.
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Johan, Suwinto. "DETERMINANT EFFICIENCY OF FINANCIAL INSTITUTIONS IN EMERGING MARKET." Jurnal Manajemen dan Pemasaran Jasa 12, no. 2 (October 31, 2019): 165. http://dx.doi.org/10.25105/jmpj.v12i2.4658.
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<p>The aim of this research is to analyze the determinants of non-bank financial institution efficiency. The non-bank financial industry is one of the main contributors to Indonesia economic growth during the last 15 years. The non-bank financial industry will the consumer finance company industry. The panel data used in this research is from 2001-2016.The non-bank financial industry is also measured as one the fastest raising industries in the last 16 years. Thesixmain financial ratios and related industry alliance impact the determinants of finance companies’ efficiency. The financial ratios are firm size, capital structure, equity, asset ratio, income to total assets and cost to total assets. The empirical results show that the determinants of non-bank financial institution are income to total assets and cost to total assets. </p>
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Gonsalves, Christine A., and Kerry R. McGannon. "Constructing women’s heart health and risk: A critical discourse analysis of cardiovascular disease portrayals on Facebook by a US non-profit organization." Journal of Health Psychology 25, no. 13-14 (August 27, 2018): 2317–27. http://dx.doi.org/10.1177/1359105318796187.
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Women’s cardiovascular disease portrayals were explored on Facebook by the US non-profit organization Women’s Heart Alliance and public users in February 2017. Portrayals were explored using critical discourse analysis which also identified subject positions. Women’s cardiovascular disease was constructed within two central discourses: achieving health equity and healthism, with the following subject positions: altruistic fighters, health activists, and compliant patients and consumers. These findings affirmed and resisted problematic forms of cardiovascular disease risk reduction. Recommendations are made using discursive resources and subject positions within social media forms as concrete entry points of resistance and change to raise women’s cardiovascular disease awareness.
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Burkhardt, Kirsten. "Alliance formation as growth opportunity for non-publicly traded companies: a value-added service provided by private equity investors." puntOorg International Journal 1, no. 1 (January 2016): 28–34. http://dx.doi.org/10.19245/25.05.wpn.1.1.6.
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Muhamad Yusuf, Noor Hafizha, Mohamad Shukery Mohamad Shamsudin, Wan Mohd Yaseer Mohd Abdoh, Noor Sharida Badri Shah, and Rozihanim Shekh Zain. "Determinants of Credit Risk: Evidence From Commercial Banks in Malaysia." Jurnal Intelek 16, no. 1 (January 26, 2021): 134–43. http://dx.doi.org/10.24191/ji.v16i1.373.
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The purpose of this study is to determine the relationship between microeconomic factors with credit risk among selected commercial banks in Malaysia. For this purpose, a sample of seven out of 27 commercial banks in Malaysia was selected and the microeconomic factors affecting credit risk with six measurements of return on asset (ROA), bank size, leverage, the ratio of capital, interest income and return on equity (ROE) were examined by applying Panel Regression Fixed Effect (FE) Model for a period 20 years from 1998 to 2017. The scope of the study covers seven selected commercial banks in Malaysia namely: Affin Bank Berhad, Alliance Bank Malaysia Berhad, CIMB Bank Berhad, Hong Leong Bank Berhad, Malayan Banking Berhad, Public Bank Berhad and RHB Bank Berhad. This study is using credit risk proxy by non-performing loan for dependent variable while independent variables that have been selected were returned on asset (ROA), bank size, leverage, the ratio of capital, interest income and return on equity (ROE). The findings of the study managed to reject the null hypothesis for return on asset, bank size, leverage, interest income and return on equity which indicates the five microeconomic variables give a significant relationship with credit risk. There are positive relationships between leverage, interest income and return on equity with credit risk while return on asset, bank size and ratio of capital are negatively related to credit risk. However, the study fails to find any significant relationship between the ratio of capital and credit risk for commercial banks in Malaysia.
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Mims, Alice S., Jessica Kohlschmidt, Uma Borate, Brianna Norris, Taylor Bucy, James S. Blachly, Shelley Orwick, et al. "A Precision Medicine Heirarchical Classification Developed Using Variant Allele Frequency (VAF) for Treatment of Older Patients (Pts) with Acute Myeloid Leukemia (AML): Alliance Clinical Trials in Oncology (Alliance) Historical Patient Control." Blood 132, Supplement 1 (November 29, 2018): 1489. http://dx.doi.org/10.1182/blood-2018-99-116717.
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Abstract Introduction: In contrast to younger pts with AML, those ages 60 years (y) and above often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis. Long-term 10-y event-free survival (EFS) of non-transplanted older AML pts receiving intensive cytarabine/daunorubicin induction (7 and 3) is 2% and the median overall survival (OS) is less than 1 y (Vasu et al., Blood Adv 2018;2:1645-50). Divergent pathogenesis based upon sequentially acquired mutations with targetable founder alterations and recent introduction of new targeted therapies have prompted interest in precision medicine-based treatment of AML. In order to determine if new therapeutic treatment strategies perform better than current standards of care, it is important to understand the historical outcomes for defined genomic groups in older AML pts. Methods: In anticipation of a precision medicine-based trial initiated by the Leukemia and Lymphoma Society (LLS AML Master Study), we designed a precision medicine-based stratification considering "assignment to curative therapy with 7 and 3" for known responsive groups [i.e., core-binding factor (CBF) AML and NPM1-mutated(+)/FLT3-ITD- pts] followed by pts with defined driving cytogenetic aberrations [11q23/MLL-rearranged and TP53 wild-type/complex karyotype (≥3 chromosome abnormalities)] and pts with mutation clone with VAF ≥0.3 by next generation sequencing. For pts not assigned to any genomic group during the initial stratification, a second run-through of the algorithm was performed assessing for a mutation clone with VAF ≥0.2 (Figure 1). The following priority (in order of highest to lowest) was used: CBF-AML, NPM1+/FLT3-ITD-, 11q23/MLL-rearranged, IDH2+, IDH1+, TP53+, TP53 wild-type/complex karyotype, FLT3-ITD+ (both high and low allelic ratios included) or FLT3-TKD+, WT1+ or TET2+, and marker negative (all other karyotypes and mutations not defined by previous grouping). A well-characterized data set of 589 pts aged ≥60 y (range, 60-92) from the Alliance was analyzed to show outcomes of pts within specific genomic groups (Table 1). Identification of a second multi-institutional pt data set is currently on-going to validate these findings. Results: In the Alliance cohort, 516 of 589 (88%) pts were assigned solely based upon cytogenetic group or dominant mutational clone with VAF ≥0.3 and 11 (1%) patients were assigned based off of VAF ≥0.2, thus providing support for this algorithm. The remaining 62 pts were assigned to the marker-negative group. As this algorithm is designed to assign therapy and assess outcome on an intent-to-treat basis, pts who suffered early death (ED), defined as death within 30 days of starting therapy irrespective of cause, were included. Baseline characteristics among groups were similar with the following exceptions: 1) CBF-AML and NPM1+/FLT3-ITD- pts having equal male and female pts with other groups having male predominance; 2) white blood cell counts being highest in NPM1+/FLT3-ITD-, 11q23/MLL-rearranged and FLT3-ITD+ or TKD+ groups; 3) percent of bone marrow blasts were lowest in the TP53+ group. Outcome endpoints are summarized in Table 1. Early death (ED) occurred in 20% of pts, most commonly in TP53+ (41%), IDH1+ (24%) and FLT3-ITD+ or TKD+ (23%) groups. Considering ED, the complete remission (CR) rates were above 50% in the CBF-AML (72%), and NPM1+/FLT3-ITD- (67%) groups, whereas in other groups they ranged between 30% and 50%, except for TP53+ at 17%. The 3-y disease-free survival (DFS) ranged from 0 to 13% for most groups, whereas only NPM1+/FLT3-ITD- (27%) and CBF-AML (30%) pts appeared to gain long-term benefit from 7 and 3. Three-y OS was 0-16% for most groups, except NPM1+/FLT3-ITD- pts at 27% and CBF-AML pts at 33%. Conclusion: Our analysis of a large older AML pt cohort provides evidence of the feasibility of classifying this disease based upon long-term benefit from 7 and 3. We also use cytogenetic/dominant mutation clone identification for precision medicine-based assignment to novel targeted therapies where 7 and 3 lacks impact on long-term outcome. These data can also serve as a historical control population for pts treated as part of the LLS AML Master Study and for other efforts brought forth to advance novel therapies in select genomic groups of older AML pts. Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171 ClinicalTrials.gov Identifiers: NCT00048958 (8461) and NCT00900224 (20202) Disclosures Mims: Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Borate:Agios: Consultancy; Novartis: Consultancy. Stein:Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy. Kolitz:Magellan Health: Consultancy, Honoraria. Wang:Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Levine:Epizyme: Patents & Royalties; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Prelude: Research Funding; Loxo: Consultancy, Equity Ownership; C4 Therapeutics: Equity Ownership; Isoplexis: Equity Ownership; Gilead: Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Imago: Equity Ownership. Druker:Celgene: Consultancy; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Henry Stewart Talks: Patents & Royalties; Millipore: Patents & Royalties; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Monojul: Consultancy; Fred Hutchinson Cancer Research Center: Research Funding; Bristol-Meyers Squibb: Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Oregon Health & Science University: Patents & Royalties; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Ovseiko, P. V., L. Gossec, L. Andreoli, U. Kiltz, L. Van Mens, N. Hassan, M. Van der Leeden, et al. "OP0074 A FRAMEWORK OF POTENTIAL INTERVENTIONS TO ACCELERATE GENDER-EQUITABLE CAREER ADVANCEMENT IN ACADEMIC RHEUMATOLOGY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 39.1–40. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1765.
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Background:A growing number of professional societies in clinical and medically related disciplines investigate evidence, make recommendations, and take action to advance gender equity. Evidence on women’s advancement and leadership in the context of the European Alliance of Associations for Rheumatology, EULAR, is limited [1].Objectives:The objective of the EULAR Task Force on Gender Equity in Academic Rheumatology was to establish the extent of the unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology and develop a framework to address this through EULAR and Emerging EULAR Network (EMEUNET).Methods:Potential interventions to accelerate gender-equitable career advancement in academic rheumatology were gathered from a narrative review of the relevant literature, expert opinion of a multi-disciplinary Task Force (comprised of 23 members from 11 countries), data from the surveys of EULAR scientific member society leaders, EULAR and EMEUNET members, and EULAR Executive Committee members. These interventions were rated by Task Force members, who ranked each according to perceived priority on a five-point numeric scale from 1 = very low to 5 = very high.Results:A framework of 29 potential interventions was formulated, which covers six thematic areas, namely, EULAR policies, advocacy and communication, EULAR Congress and associated symposia, training courses, mentoring/peer support, and EULAR funding (Figure 1).Figure 1.A framework of potential interventions with the levels of priority, mean and standard deviation (SD)Conclusion:The framework provides structured interventions for accelerating gender-equitable career advancement in academic rheumatology.References:[1]Andreoli L, Ovseiko PV, Hassan N, et al. Gender equity in clinical practice, research and training: Where do we stand in rheumatology? Joint Bone Spine 2019;86(6):669-72.Acknowledgements:The task force is grateful to EULAR for funding this activity under project number EPI 024.Disclosure of Interests:None declared
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Dulisse, Brian, Xiaoyan Li, Julie A. Gayle, Richard L. Barron, Frank R. Ernst, Kenneth J. Rothman, Jason C. Legg, and James A. Kaye. "Clinical and Economic Burden During Hospitalizations Among Cancer Patients with Febrile Neutropenia: Evidence From U.S. Hospitals, 2007–2010." Blood 120, no. 21 (November 16, 2012): 239. http://dx.doi.org/10.1182/blood.v120.21.239.239.
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Abstract Abstract 239 Background: Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy that often requires hospitalization. Published burden-of-illness estimates for FN-related hospitalizations were either based on clinical practice more than a decade ago (Caggiano et al Cancer 2005, Kuderer et al Cancer 2006) or derived from small samples (Schilling et al Exp Ther Med 2011). Methods: A retrospective cohort study was conducted to provide updated estimates using 2007–2010 hospital discharge data from a database maintained by Premier and containing service records of over 400 geographically diverse hospitals. It is one of the largest hospital databases in the U.S. The study population included adult patients with 1 of 6 tumor types (breast, lung, colorectal, ovarian cancers; non-Hodgkin lymphoma [NHL]; and Hodgkin lymphoma), discharge diagnoses of neutropenia (ICD-9 code 288.0x) with fever or infection, and receipt of intravenous antibiotics. The average hospitalization cost, case fatality rate, and average length of stay (LOS) associated with each patient's first FN-related hospitalization (index hospitalization) were computed with associated 95% confidence intervals (CIs) for all tumor types combined and stratified by tumor type. Detailed costs and resource utilization components within index hospitalizations were also examined and tallied. Tumor-type-specific multivariate linear regressions (for costs and LOS) and logistic regressions (for mortality) were conducted to assess the effect of infection types and comorbidities on study outcomes, adjusting for other patient and hospital characteristics. FN-related 30-day readmission rates after index hospitalizations were also estimated. All cost measures reflected actual direct costs to hospitals and were adjusted to 2010 dollars. Results: Hospitalization with FN was identified in 16,273 cancer patients. The mean (SD) age was 63 (14) years; 49% were aged ≥65 years; and 60% were female. Hospitalization costs and clinical outcomes of index hospitalizations varied by tumor type and by discharge status (Table). For all tumor types combined, 19% of patients were treated in an intensive care unit (ICU) setting during index hospitalizations, with average LOS of 5.2 days spent in ICU. The estimated models identified certain infection types and comorbidities as potential risk factors for inpatient mortality and predictors of higher economic burden. Of note, breast cancer patients with diagnosed septicemia/bacteremia (N=656) had average costs that were $5,664 (95% CI: $4,233–$7,095) higher than those with other infections (N=2,623), average LOS that was 1.7 days (95% CI: 1.0–2.3) longer, and a higher case fatality rate (risk ratio [as approximated by odds ratio]: 4.12, 95% CI: 2.6–6.5), after adjusting for other observed potential confounders. Higher average costs were also observed in NHL patients with diagnosed renal disease (N=1,263) than in those without renal disease (N=4,174) (adjusted difference: $10,408, 95% CI: $8,391–$12,425). The FN-related 30-day readmission rate after index hospitalization was 5.9% for all tumor types combined. The rate was 9.9% for NHL and 8.6% for Hodgkin lymphoma, higher than that in patients with other tumor types (2.3%–4.1%). Conclusions: FN-related hospitalizations among cancer patients are expensive, resource-intensive, and associated with considerable mortality risk. Substantial differences in the clinical and economic burden of FN exist depending on tumor types, infection types, and comorbidities. Disclosures: Dulisse: Premier healthcare alliance: Employment. Li:Amgen Inc.: Employment, Equity Ownership. Gayle:Premier healthcare alliance: Employment. Barron:Amgen Inc.: Employment, Equity Ownership. Ernst:Premier healthcare alliance, which contracted with Amgen to conduct this study.: Employment. Rothman:Dr. Rothman is an employee of RTI Health Solutions, an independent non-profit research organization that does work for government agencies and pharmaceutical companies.: Employment. Legg:Amgen Inc.: Employment, Equity Ownership. Kaye:RTI Health Solutions (a business unit of RTI International): Employment.
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McCarthy, Philip L., Paul Richardson, Vera Suman, Miranda Cooper, Owain Saunders, Sujith Dhanasiri, Sergio Giralt, Kenneth Anderson, Edward Stadtmauer, and Sarah A. Holstein. "Survival Analysis from the CALGB Study of Lenalidomide Maintenance Therapy in Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplantation Adjusted for Crossover (Alliance 100104)." Blood 132, Supplement 1 (November 29, 2018): 4737. http://dx.doi.org/10.1182/blood-2018-99-113001.
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Abstract Background: The phase 3 double-blind, CALGB/Alliance 100104 study assessed the efficacy and safety of lenalidomide (LEN) or placebo maintenance therapy until relapse in post-autologous stem cell transplantation (ASCT) patients with newly-diagnosed multiple myeloma (NDMM). Interim analyses demonstrated superiority for LEN versus placebo for time to progression (TTP), thus meeting the primary TTP endpoint of the trial. The study was unblinded in December 2009 and, based on the TTP and overall survival (OS) benefit observed with LEN, patients in the placebo arm (who had not yet progressed) at the time of unblinding were given the option of crossing over to receive LEN. Data have been reported for a follow-up of 91 months based on the planned intention to treat (ITT) analysis, yielding a TTP hazard ratio (HR) 0.57 and an OS difference of HR 0.61 (Holstein SA, et al. Lancet Haematol. 2017;4:e431-42). Crossover to active treatment enabled patients to benefit from LEN maintenance and collection of additional efficacy and safety data; however, crossover can confound the estimates of OS for longer follow-up. We report the results of an analysis adjusted for crossover, thus aiming to provide a more accurate estimate of the survival benefit achieved with LEN maintenance therapy. Methods: Results are reported for an analysis based on an updated data cutoff, post-October 2016. The rank-preserving structural failure time model (RPSFTM) was considered the most appropriate method to adjust for crossover (Robins JM, Tsiatis AA. Commun Stat Theory Methods. 1991;20:2609-31). This method requires that the assumption that the treatment effect is the same for patients who receive LEN at randomization as those who receive LEN as crossover treatment is not violated; a landmark analysis was performed to explore this. The iterative parameter estimation (IPE; Branson M, Whitehead J. Stat Med. 2002;21:2449-63) algorithm was used as validation. Both the RPSFTM and IPE analyses assume a residual LEN effect after discontinuation (base case). Results: A total of 76 NDMM patients who had not progressed, as determined by central adjudication, crossed over from placebo to LEN and were included in the analysis. The landmark analysis of OS from the date of unblinding indicated that the treatment effect for the crossover versus the non-crossover placebo group was HR 0.57 (95% confidence interval [CI] 0.29-1.15) (Figure). This also provided a measure of the benefit of LEN maintenance in patients who started maintenance therapy after the trial-specified 90-100 day window post-ASCT (median 11.5 months post-randomization; range 3.2-51.0 months). Adjustment for crossover using the RPSFTM or IPE resulted in an increase in the relative treatment effect of LEN maintenance (vs placebo) on OS from 30.8 months for the ITT analysis (HR 0.61; 95% CI 0.47-0.81) to 40.1 months (HR 0.52; 95% CI 0.36-0.73) for the RPSFTM analysis and 38.8 months (HR 0.52; 95% CI 0.37-0.74) for the IPE analysis (Table). Results were consistent across the two methods. Discussion: This analysis was performed on an updated version of the data set reported in the Holstein article. Once we adjusted for crossover, depending on the methodology used, there was an additional gain of ~40 months of OS. Previously, a pre-planned, pooled meta-analysis of 3 studies that included CALGB/Alliance (McCarthy PL, et al J Clin Oncol. 2017;35:3279-89) indicated that the OS gain was 2.5 years; however, our analysis from the CALGB study alone shows that LEN maintenance may provide a survival benefit of > 3 years. In diseases where prolonged follow-up is required to demonstrate survival benefits, allowing patients to crossover to active treatment may be important to facilitate this. However, the results should be analyzed appropriately to enable assessment of the value of the therapy. As this analysis indicates, the value of active treatment may be underestimated if adjustment for crossover is not performed. In conclusion, the data reported here provide further insight into the survival benefits of LEN maintenance therapy post-ASCT and support guideline recommendations to offer LEN maintenance therapy to all patients post-ASCT. Support: U10CA180821, U10CA180882, U10CA180820; ClinicalTrials.gov Identifier: NCT00114101. Disclosures McCarthy: Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Cooper:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Saunders:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Dhanasiri:Celgene: Employment, Equity Ownership. Anderson:Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Walker, Christopher J., Junke Wang, Alyssa I. Clay-Gilmour, Krzysztof Mrózek, Deedra Nicolet, Christopher C. Oakes, Jessica Kohlschmidt, et al. "Meta-Analysis of Genome-Wide Association Studies of Acute Myeloid Leukemia (AML) Patients Identifies Variants Associated with Risk of 11q23/KMT2A-Translocated and Core-Binding Factor (CBF) AML and Suggests a Role for Transcription Elongation in Leukemogenesis." Blood 136, Supplement 1 (November 5, 2020): 29–30. http://dx.doi.org/10.1182/blood-2020-141653.
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The first three authors contributed equally. The last three authors share senior authorship. Background: Although there has been an increased recognition of the contribution of germline variants to development of myeloid neoplasms, only two large-scale case-control genome-wide association studies (GWASs) have been conducted to identify variants that predispose to AML. Importantly, these studies were dedicated to AML predisposition in general, without investigation of molecularly distinct AML subtypes. Thus, we performed the first dedicated meta-analysis combining the two GWASs to investigate predisposing variants to cytogenetic AML subsets characterized by recurrent translocations and inversions. Methods: Two sets of adult de novo AML patients treated on Alliance for Clinical Trials in Oncology (Alliance) protocols, and two sets of adult de novo AML patients reported to CIBMTR (2000-11) from DISCOVeRY-BMT cohorts were compared with four sets of population-matched non-leukemic individuals of European ancestry. Illumina Infinium arrays were used for genotyping. The haplotype reference consortium was used for imputation and comparisons were performed using SNPtest and METAL with fixed-effects, for CBF-AML (n=251, including t(8;21), n=115; inv(16), n=136) and AML with 11q23/KMT2A translocations (n=177). Blood or bone marrow samples from subsets of these patients and additional AML patients with other cytogenetic abnormalities were used for total transcriptome RNA sequencing with Illumina instruments. Results: Two risk loci reached genome-wide significance in AML patients with 11q23/KMT2A translocations (Fig 1A). The most significant single nucleotide polymorphism (SNP) in the 4q21.3 risk locus, rs17668899[A] (P = 2.32 x 10-8, odds ratio [OR] = 3.92 [2.43-6.32]) is in intron 6 of the AFF1 gene (also called AF4) (Fig 1B), within an enhancer that interacts with the AFF1 transcription start site (Fig 1C, left). KMT2A-translocated AML patients with the risk allele had higher blast expression of AFF1 compared to those homozygous for the non-risk allele, although the trend did not reach significance (Fig 1D). Notably, AFF1 encodes a subunit of the super-elongation-complex (SEC) that acts as Pol II-associated master regulator of global transcription elongation. AFF1 is a common translocation partner of KMT2A in patients with acute lymphoblastic leukemia with t(4;11)(q21;q23), and is required for KMT2A-mediated leukemogenesis. We observed significantly higher AFF1 expression in both KMT2A-translocated AML and cytogenetically normal (CN) AML compared to CBF-AML (Fig 1E). The suggested role of AFF1/SEC is consistent with recent studies showing an important role for DOT1L, H3K79 methylation, and transcriptional elongation in NPM1-mutant AML (the most common subtype of CN-AML). Outcome analysis showed higher expression of AFF1 associated with shorter disease-free (DFS) in patients < 60 years treated on Alliance studies (hazard ratio [HR] = 1.36, P=0.04; Fig 1F). The second KMT2A-translocated AML risk locus was located at 22q13.31, and the most significant SNP was rs62231468[A] (P = 4.95 x 10-9, OR = 3.25). rs62231468 is immediately 5' of the LDOC1L gene (a retrotransposon GAG-related gene, also called RTL6), and analysis of expression quantitative trait loci (eQTL) showed association of rs62231468[A] with higher LDOC1L expression, consistent with its location in an active enhancer (Fig 1C, right). The association between rs62231468[A] and higher LDOC1L expression was validated in leukemic blast expression from a set of 449 AML patients of any cytogenetic subset (Fig 1G). Notably, higher LDOC1L expression was associated with shorter DFS and overall survival (OS) in Alliance patients < 60 years (DFS, HR = 1.25, P=0.03; OS, HR = 1.46, P<0.001; Fig 1H-I). Analysis of patients with CBF-AML identified rs71568004[C] as more common in CBF-AML patients compared to controls (P = 3.84 x 10-8 , OR = 3.05 [2.05-4.53]). This SNP is ~50kb 5' of the MARCKS gene located at 6q21, but genomic context analysis did not reveal any clear associations with MARCKS expression. Conclusions: Our first assessment of risk alleles for cytogenetic subsets of AML identified two novel independent risk loci associated with 11q23/KMT2A-translocated AML, and one risk locus associated with CBF-AML. These data suggest an important, subtype-specific role for transcriptional elongation in AML and that functional studies of retro transposition elements should be undertaken in leukemogenesis. Figure Disclosures Walker: Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy. Powell:Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Kolitz:Pfizer: Membership on an entity's Board of Directors or advisory committees; Magellan: Membership on an entity's Board of Directors or advisory committees. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. McCarthy:Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding. Stone:AbbVie: Consultancy, Research Funding; Actinium: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Arog: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Biolinerx: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Takeda: Consultancy; Daiichi-Sankyo: Consultancy; Elevate: Consultancy; Gemoab: Consultancy; Janssen: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Stemline: Consultancy; Syndax: Consultancy; Syntrix: Consultancy; Syros: Consultancy. Byrd:Trillium: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Acerta Pharma: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau. Eisfeld:Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy.
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DeAngelo, Daniel, Wendy Stock, Stephen Petersdorf, Shaw-Ling Wang, Angela Volkert, Erik Vandendries, and Anjali Advani. "Weekly Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 2612. http://dx.doi.org/10.1182/blood.v120.21.2612.2612.
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Abstract Abstract 2612 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antitumor agent. CD22 is expressed on a majority of B-cell acute lymphoblastic leukemia (ALL). An initial study suggested INO efficacy and tolerability in ALL (Lancet Oncol 2012;13:403-11). Objectives: The current phase 1, multicenter, dose-escalation study was performed to optimize the INO dose and schedule (weekly dosing) based on safety, efficacy, and pharmacokinetic data in CD22+ relapsed or refractory ALL. The safety and efficacy of INO at the recommended dose and schedule will subsequently be further evaluated in a 12-patient (pt) expanded cohort. Methods: Eligible pts were aged ≥18 y with CD22+ ALL (defined as ≥20% blasts CD22+ by flow cytometry) refractory to initial induction or in relapse (≥first relapse), with no evidence of central nervous system disease. INO was administered in 28-d cycles (see Table), with a maximum of 6 cycles. The final dose was to be determined based on both toxicity (ie, rate of dose-limiting toxicities [DLT] at each dose level) and evidence of efficacy using the EffTox V2.10 software (Biometrics 2004;60:684–693). Adverse event (AE) severity was assessed per CTCAE V3 with DLTs defined as any of the following INO-related events during Cycle 1: grade ≥4 non-hematologic toxicity; prolonged myelosuppression (absolute neutrophil count [ANC] <500/μL or platelets <25,000/μL in bone marrow) with no evidence of leukemia persisting >45 d from last dose; grade 3 non-hematologic toxicity persisting >7 d from the last dose; grade ≥3 elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin persisting >7 d; or any toxicity resulting in permanent INO discontinuation. Weekly teleconferences with investigators were used to assess toxicity. Complete response (CR) was defined as <5% bone marrow blasts with absence of peripheral blasts, ANC ≥1,000/μL, platelets >100,000/μL, and no extramedullary disease; incomplete CR (CRi) was similar but permitted ANC <1,000/μL and/or platelets ≤100,000/μL. Results: We report preliminary data for 13 pts (see Table), with a median duration of follow-up of 147 d (range, 30–188 d). Median age was 56 y (range, 23–65 y), and 69% of pts were male. Five (39%) pts were in salvage 1, 2 (15%) were in salvage 2, and 4 (31%) were in salvage ≥3. Two pts had prior allogeneic stem cell transplant. Three (23%) pts were Ph+ and 7 (54%) pts had circulating blasts at baseline; median baseline WBC was 2.01×103/mm3 (range, 0.5–29.11×103/mm3). The single DLT observed to date was transient grade 4 elevated lipase occurring at INO dose level 3. The most frequent (≥10% of pts) treatment-related AEs were thrombocytopenia (31%, all grade 3/4), neutropenia (15%), and elevated ALT (15%). Treatment-related elevated AST and alkaline phosphatase were each reported for 8% of pts. Reported dose delays were due to thrombocytopenia (n = 3), neutropenia (n = 2), elevated LFT (n = 2), bacteremia, increased blood creatinine, periorbital cellulitis, and QTc prolongation (n = 1 each). Fourteen serious AEs were reported for 9 pts, including 2 cases each of febrile neutropenia and septic shock. Responses were observed across all INO doses explored to date (see Table). The preliminary response rate was 82% (9/11 evaluable pts), including 36% of pts with a CR and 45% with a CRi. Median time to response was 43 d (range, 28–56 d). Six of 9 (67%) pts who achieved CR/CRi also achieved minimal residual disease (<1 blast out of 104 mononuclear cells by flow cytometry). Seven pts discontinued treatment, including 1 each due to disease progression and an AE (acute renal failure, not treatment related), and 5 pts who proceeded to transplant. Four deaths were reported, including 1 due to disease progression and 3 due to sepsis occurring within 30 d after stem cell transplantation. Conclusions: INO had a safety profile consistent with prior reports, characterized by hematologic, gastrointestinal, and hepatic events and infection. The remarkable response rate of 82% for single-agent INO in this relapsed/refractory population warrants further exploration in CD22+ ALL. Updated results will be presented at the meeting. Disclosures: Stock: Tau for work done through the CALGB/ALLIANCE: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Volkert:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. Advani:Pfizer Inc: Consultancy, Honoraria, Research Funding.
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Cairns, David, Charlotte Pawlyn, Kara-Louise Royle, Phillip Best, Jenny Bird, Stella Bowcock, Kevin Boyd, et al. "Frailty-Adjusted Therapy in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (FiTNEss): A UK Myeloma Research Alliance Study, Myeloma XIV." Blood 134, Supplement_1 (November 13, 2019): 3153. http://dx.doi.org/10.1182/blood-2019-126207.
Full textAbstract:
Background Transplant non-eligible (TNE) myeloma patients are a very heterogeneous group that is not well-defined on the basis of age alone, but rather by the interplay of age, physical function, cognitive function and comorbidity better defined as 'frailty'. The International Myeloma Working Group (IMWG) has published a scoring system for myeloma patient frailty that predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). It has been proposed to be useful in determining the feasibility of treatment regimens and appropriate dose reductions but has not been validated prospectively. We hypothesize that by defining subgroups of patients based on the IMWG frailty score, and guiding up-front dose adjustments we can personalize therapy to improve treatment tolerability and therefore short-term outcomes, along with quality of life. In addition we plan to compare the use of single agent immunomodulatory (IMiD) based maintenance therapy with an IMiD and proteasome inhibitor maintenance doublet to try and improve long-term outcomes for patients. Study Design and Methods Myeloma XIV (NCT03720041) is a phase III, multi-center, randomized controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRd), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (IR) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant. The trial outline is shown in Figure 1. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomized (R1) on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomization (R2) on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians are blinded to maintenance allocation. The primary objectives of the study are to determine: Early treatment cessation (within 60 days of randomization) for standard versus frailty-adjusted up-front dosingProgression-free survival (PFS, from maintenance randomization) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (IR) The secondary objectives of the study include determining: progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, overall survival (OS), overall response rate (ORR), treatment compliance and total amount of therapy delivered, toxicity & safety including the incidence of Second Primary Malignancies (SPMs), Quality of Life (QoL), cost-effectiveness of standard versus frailty-adjusted up-front dosing of IRd and cost-effectiveness of IR versus R. Exploratory analyses include the association of molecular subgroups with response, PFS and OS. Seven hundred and forty participants will be enrolled into the trial at R1 to give 80% power to demonstrate a difference in early cessation and ensure that at least 478 participants remain and are randomized at R2 (based on attrition rates in our previous study Myeloma XI). At R2 478 patients will give us 80% power to detect an eight month difference in PFS between R and IR. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Royle:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Best:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Bowcock:Takeda: Honoraria, Research Funding. Boyd:Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Drayson:Abingdon Health: Consultancy, Equity Ownership. Henderson:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty adjusted dosing. Ixazomib and lenalidomide combination as maintenance.
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Zettl, Florian, Friederike Braulke, Marita Ziepert, Andreas Viardot, Christoph Kahl, Gabriele Prange-Krex, Agnieszka Korfel, et al. "Rituximab and Bendamustine for First-Line Treatment of Frail or Elderly Patients with Aggressive B-Cell Lymphoma: Final Results of the Prospective Phase-II Brenda Trial of GLA (German Lymphoma Alliance)." Blood 134, Supplement_1 (November 13, 2019): 4073. http://dx.doi.org/10.1182/blood-2019-122948.
Full textAbstract:
Introduction For patients (pts) with aggressive B-cell lymphoma immunochemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) represents the standard of care with curative intention. For elderly pts a dose-reduced R-mini-CHOP protocol is feasible. No standard of care exists for frail or very old (>80 yrs) pts not eligible for CHOP-like treatment. Here we present the final results of the prospective DSHNHL-phase-2 trial for old or frail pts receiving Rituximab/Bendamustine (RB) for 1st-line treatment of aggressive B-cell lymphoma. Our goal was to determine feasibility, toxicity of the BR regimen in this pt cohort, and to determine which pts groups might potentially benefit from this reduced-intensity approach. Methods The open-label, multicenter, prospective, non-randomized phase-II trial "Subcutaneous Rituximab and Intravenous Bendamustine in very Elderly Patients or Elderly Medically Non Fit Patients ("Slow Go") with Aggressive CD20-positive B-cell Lymphoma" (B-R-ENDA, DSHNHL 2010-1, EudraCT 2010-024004-98) included all pts aged ≥81 yrs or 61-80 yrs and elevated CIRS >6, not qualifying for R- CHOP, with histologically confirmed CD20+aggressive lymphoma of any Ann Arbor-stage and IPI score, and ECOG <4 as determined during or after a prephase treatment. During run-in-phase, 20 pts received a prephase treatment of Prednisolone 100mg p.o. d-7 to -1, followed by Rituximab 375mg/m² i.v. on d-3, again followed by 7 cycles of Rituximab 375mg/m² i.v. on d1,q21 and 6 cycles of Bendamustine 90mg/m² i.v. on d1 and 2,q21. After a safety analysis, subsequent pts received prephase treatment with Rituximab 375mg/m² i.v. followed by 7 cycles of subcutaneous (s.c.) Rituximab 1400mg on d1,q21 and bendamustine as above. Primary endpoints were 2-year-progression-free survival (PFS) for efficacy (expected at 30-50% in the >80 yr cohort), and treatment-associated deaths, frequency of grade 3/4 adverse events and SAEs, adherence to the protocol, complete and partial remission rate, rate of primary progression and relapse, and quality of life assessed by geriatric assessment and EORTC-QLQ-C30 for feasibility. Results: From 2012 to 2016, 68 pts (22 male, 46 female) were recruited in 24 centers into the trial and included into this intent-to-treat analysis (ITT). The median age was 81 yrs with 21% of pts older than 85 yrs. The median CIRS score was 8 and 72% had a CIRS >6. The IPI was >2 in 59% of pts. The patient population was per protocol divided into two subgroups: pts 61 to 80 yrs old and medically non-fit (29 pts) and pts older than 80 yrs (39 pts). For the 61 to 80 yrs old medically non-fit patients median age was 77 yrs (64-80), median CIRS score was 10 (2-22), IPI was > 2 in 76% of pts, 66% of pts had stage 3 or 4 disease, and ECOG was >1 in 52% of pts. For the subgroup of pts > 80 yrs, median age was 84 yrs (81-95), median CIRS score was 7 (1-17), IPI was > 2 in 46% of pts, 51% of pts had stage 3 or 4 disease, and ECOG was >1 in 23% of pts. 49% of pts received the complete treatment as planned (61-80 yrs: 38%; >80 yrs: 56%). Reasons for early termination of treatment were PD in 15% (17%; 13%) and toxicity in 24% (24%; 23%) of pts. 29% 95% Confidence interval 19-42% of pts (38%; 23%) had grade 3-5 infections. Treatment related mortality was 15% (17%; 13%). Overall response rate (ORR) was 41% (28%; 51%) with 31% CR (10%; 46%). Median observation time was 29 months for EFS, PFS and OS. 2-yrs EFS was 23% (10%; 37%), PFS was 40% (32%; 45%), OS was 42% (37%; 46%). In a multivariate analysis adjusted for IPI factors elevated LDH and ECOG >1 constituted the most significant risk factors for poor outcome. Conclusions: We describe a frail patient cohort with a median CIRS score of 8, with 72% pts with a CIRS >6, considerable comorbidities and a high percentage of high-risk IPI. The primary efficacy endpoint (2 yr PFS > 80 yrs 45%) was met; for R-mini-CHOP, this was reported at 47% (Peyrade et al., Lancet Haemat, 2011). The IPI predicts outcome in the >80 yrs cohort reliably. The RB regimen is active even in very elderly and frail pts up to 90 yrs of age. Therefore, in pts not eligible for full- or reduced dose R-CHOP treatment, it represents a tolerable and efficient alternative, albeit with a limited curative potential preferably in IPI low/intermediate-risk pts. Biomarker, comorbidity and QoL data will be analysed subsequently. Disclosures Zettl: Roche: Other: travel grants, Research Funding; Mundipharma: Research Funding. Viardot:Kite/Gilead: 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; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korfel:Mundipharma: Consultancy, Research Funding. Dreyling:Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: scientific advisory board; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Acerta: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Illmer:Roche: Other: travel support. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Poeschel:Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support; Astra Zeneca: Other: Travel support. Truemper:Takeda: Consultancy, Research Funding; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy.
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Shadman, Mazyar, Ajay K. Gopal, Stephen D. Smith, Ryan C. Lynch, Chaitra S. Ujjani, Cameron J. Turtle, Adam Greenbaum, et al. "CD20 Targeted CAR-T for High-Risk B-Cell Non-Hodgkin Lymphomas." Blood 134, Supplement_1 (November 13, 2019): 3235. http://dx.doi.org/10.1182/blood-2019-125102.
Full textAbstract:
Background: Chimeric antigen receptor T-cells (CAR-T) targeting CD19 have shown clinical efficacy in high-risk B-cell lymphomas, which has led to approval of 2 such therapies (axicabtagene ciloleucel and tisagenlecleucel) for large B-cell lymphoma after 2 lines of treatment. Despite the promising results, complete remission (CR) is achieved in ~ 50% of patients, and with longer follow-up progression-free survival is around 40%. Therefore, finding effective treatments for high-risk B-NHLs remains an unmet need. CD20 is a proven therapeutic target for B-Cell Non-Hodgkin Lymphomas (B-NHL), supported by previously approved naked and radiolabeled anti-CD20 monoclonal antibodies and a number of studies investigating novel bispecific antibodies targeting this antigen. CD20-targeted CAR-T is another potential adoptive immunotherapy option that could be utilized in combination or sequentially before or after CD19 CAR-T, depending on efficacy. Here, we present our ongoing phase I/II clinical trial investigating safety and efficacy of CD20 CAR-T for high-risk B-NHLs (NCT03277729). Methods: MB-106 is a fully human third-generation CD20 targeted CAR-T with both 4-1BB and CD28 costimulatory domains. In the phase I portion of the study we use a continual reassessment method dose escalation design to find the maximally tolerated dose. Lymphodepletion (LD) chemotherapy consists of fludarabine and cyclophosphamide. Patients (pts) will undergo a mandatory biopsy before LD to confirm the diagnosis and CD20 expression. A repeat research biopsy will be done between 10-16 days after CAR-T infusion (Figure 1). Except for the first patient of each dose cohort, treatment is given in the outpatient setting (Fred Hutch/Seattle Cancer Care Alliance) and pts will only be admitted to the University of Washington Medical Center if clinically indicated after CAR-T infusion. Response to treatment will be assessed on day 28 using Lugano criteria. Patients with relapsed or refractory CD20 positive B-NHL are eligible, including but not limited to DLBCL, primary mediastinal lymphoma, follicular lymphoma or other indolent histologies, and mantle cell lymphoma. Prior treatment with CD19 CAR-T is permitted as long as there is evidence of B-cell recovery in peripheral blood (≥ 20 B cells/µl) as a functional test to rule out persistent CD19 CAR-Ts. Patients need to meet standard organ function criteria and have adequate blood counts (ANC >750, Hb >8.5, Plts >50,000). Patients with significant neurologic conditions, active CNS lymphoma, or need for systemic immunosuppressive therapy are excluded from the study. Disclosures Shadman: Mustang Bio: Research Funding; Verastem: Consultancy; Genentech: Consultancy, Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Research Funding; Sound Biologics: Consultancy; TG Therapeutic: Research Funding; Acerta Pharma: Research Funding; Sunesis: Research Funding; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Research Funding; Astra Zeneca: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. Smith:Pharmacyclics: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Portola Pharmaceuticals: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Incyte Corporation: Research Funding; Seattle Genetics: Research Funding; Denovo Biopharma: Research Funding. Lynch:Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; T.G. Therapeutics: Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Humanigen: Other: Ad hoc advisory board member; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Kite/Gilead: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member. Yeung:Pfizer: Research Funding; OBI Pharmaceutical: Research Funding; Merck: Consultancy; DiaCarta: Consultancy. Sersch:Mustang Bio: Employment. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Till:Mustang Bio: Patents & Royalties, Research Funding.
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Ustun, Celalettin, Jennifer Le-Rademacher, Hai-Lin Wang, Megan Othus, Zhuoxin Sun, Brittny Major, Mei-Jie Zhang, et al. "Allogeneic Hematopoietic Cell Transplantation (HCT) Vs. Non-HCT Consolidation Therapies in Acute Myeloid Leukemia (AML) Patients 60-75 Years of Age in First Complete Remission (CR1): An Alliance (A151509), SWOG, ECOG-ACRIN and CIBMTR Study." Blood 132, Supplement 1 (November 29, 2018): 2170. http://dx.doi.org/10.1182/blood-2018-99-118383.
Full textAbstract:
Abstract Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials. Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times. Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively. Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p <0.0001) relative to CT (figure 1A). Treatment-related mortality (TRM) was worse after HCT in the first 9 months (HR=2.8, CI: 1.5 -5.2, p=.0009), while relapse was less frequent beyond 9 months after treatment (HR = 0.42, CI: 0.29 to 0.61, p<.0001). Despite higher early TRM, HCT recipients went on to manifest superior OS [5 year OS: HCT 29% (24-34%), CT 13.8% (9 -22%)] (Figure 1A). The benefit of HCT for survival after 9 months was more prominent in those with unfavorable cytogenetics (Figure 1B). Multivariate analysis for OS showed no statistically significant effect of age or performance status, while unfavorable cytogenetics were detrimental (HR=1.74, p<.0001). Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. Disclosures Ustun: novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.
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Wieduwilt, Matthew J., Jun Yin, Meir Wetzler, Geoffrey L. Uy, Bayard L. Powell, Jonathan E. Kolitz, Michaela Liedtke, et al. "A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Transplantation for Adults with Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Final Results of Alliance/CALGB Study 10701." Blood 132, Supplement 1 (November 29, 2018): 309. http://dx.doi.org/10.1182/blood-2018-99-120029.
Full textAbstract:
Abstract Dasatinib with corticosteroid yields high complete remission (CR) rates in Ph+ ALL with minimal induction death. Optimal post-remission therapy is not known. We report a prospective study evaluating dasatinib/dexamethasone induction then consolidation with reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), autologous HCT (autoHCT), or chemotherapy alone (chemo), followed by dasatinib-based maintenance. Methods: We conducted a phase II, 3-arm, non-randomized trial (NCT01256398, Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171) at 17 US centers with primary objectives to determine 3-year overall survival (OS) and disease-free survival (DFS) of adults ≥18 years (yrs) old with untreated Ph+ ALL treated with dasatinib/dexamethasone induction, CNS prophylaxis with systemic and intrathecal methotrexate, consolidation with alloHCT, autoHCT, or chemo, then dasatinib maintenance. Induction (Course I) used dasatinib 140 mg orally daily and dexamethasone 10 mg/m2/day orally or IV days 1-7. If ≤20% lymphoblasts in marrow at Day 15, Course II continued dasatinib with 7 days of dexamethasone. If >20% lymphoblasts, patients (pts) also received vincristine and daunorubicin. Pts not in CR/CRi received a second induction (Course III) with dasatinib, cyclophosphamide, vincristine, daunorubicin, and dexamethasone. CNS prophylaxis (Course IV) used dasatinib, IV vincristine and IV, oral, and intrathecal methotrexate. Course V consisted of HCT or chemo. Pts 18-70 yrs old underwent RIC alloHCT if they had a HLA-matched donor; otherwise they underwent autoHCT. AlloHCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 IV once on day -2. GVHD prophylaxis with tacrolimus began day -2. Pts undergoing autoHCT received etoposide 10 mg/kg/day (age >65, 5 mg/kg/day) CIV for 4 days and cytarabine 2 g/m2 (age >65, 1 g/m2) IV every 12 hours for 8 doses then G-CSF for mobilization. AutoHCT conditioning was melphalan 100 mg/m2/day IV on days -2 and -1. Pts >70 yrs old or unable to undergo HCT received etoposide/cytarabine alone. Dasatinib maintenance (Course VI) began day 30 of Course V and continued for 12 months and until 2 consecutive negative BCR-ABL1 RT-PCR assays 3 months apart or relapse. BCR-ABL1 isoform and ABL1 kinase domain (KD) mutation determination were done locally. Results: From 12/15/2010 to 11/14/2014, 64 eligible pts enrolled. Median age was 60 yrs (22-87); median WBC 23.2 x 103/μl (0.3-454). The dominant BCR-ABL1 isoform was p190 in 59%, p210 in 17%, and not reported in 23%. The CR rate was 97% with no induction deaths. Fifty-five pts completed CNS prophylaxis (Course IV). Twenty pts underwent protocol-specified alloHCT, 7 autoHCT, and 9 chemo. Nine pts underwent off-study alloHCT and 5 skipped Course V. Dasatinib maintenance was tolerable with 72%, 80%, and 80% receiving >50% of planned maintenance doses in alloHCT, autoHCT, and chemo arms, respectively. With a median follow up of 48 months (37-78) for survivors, 3-yr OS and DFS were 55% (median OS 45 months) and 43% (median DFS 30 months), respectively. For pts undergoing consolidation with protocol-specified alloHCT, autoHCT, or chemo, 3-yr OS was 75%, 71%, and 55% respectively with median OS not reached (NR) for all groups. DFS at 3-yrs was 55%, 43%, and 46% respectively. Median DFS for alloHCT was 42 months vs 15 months for autoHCT and 34 months for chemo (Log-Rank P=0.4). Outcomes were similar with inclusion of off-study alloHCT and chemo patients skipping Course V. Relative to p190 BCR-ABL1 isoform, p210 was associated with shorter median OS (NR vs 16 months, P=0.04) and median DFS (35 months vs 10 months, P<0.0001). Three-year DFS was 9% with p210. Relapse occurred in 23 pts with 5 CNS relapses reported, one isolated. Relapse occurred in 25% of alloHCT, 43% of autoHCT, and 37% of chemo pts. T315I mutation in ABL1 KD was detected in 6 of 8 marrow relapses (75%). One isolated CNS relapse had no ABL1 KD mutations. Conclusions: Dasatinib and dexamethasone followed by alloHCT, autoHCT, or chemo yield similar 3-yr survival comparable to approaches using intensive induction chemotherapy. Pts with the p210 BCR-ABL1 isoform had dismal outcomes and may benefit from alternate approaches. T315I mutation was the major cause of relapse and should be addressed in future studies. Disclosures Wieduwilt: Amgen: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria. Liedtke:Caelum: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Research Funding; Genentech/Roche: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBirdBio: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Devine:Kiadis Pharma: Consultancy. Larson:BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.
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Lynch, Ryan C., Victor A. Chow, David G. Maloney, Cameron J. Turtle, Mazyar Shadman, Chaitra S. Ujjani, Ryan D. Cassaday, et al. "Low Achievement of End of Life Quality Measures in Large B-Cell Lymphoma Patients Who Progressed after CD19-Specific CAR-T Cell Therapy." Blood 134, Supplement_1 (November 13, 2019): 413. http://dx.doi.org/10.1182/blood-2019-124857.
Full textAbstract:
Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA-approved in patients with relapsed or refractory large B-cell lymphomas and can lead to long-term remissions in 35-40% of patients. Outcomes in patients who progress after CAR T-cell therapy is poor, with a median overall survival (OS) of 5.3 months with few long-term survivors (Chow et al. AJH 2019). Achieving quality end of life (EOL) care for patients with hematologic malignancies has been a challenge, and widespread consensus on what are acceptable metrics is lacking (Odejide et al JCO 2016). EOL care among large B-cell lymphoma patients who progressed after CAR-T cell therapy has not been previously examined. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance since 2011 who subsequently progressed and ultimately died were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. We also examined a similar cohort of chemorefractory large B-cell lymphoma patients who did not receive CAR T-cell therapy and later died of their disease (Smith et al. AJH 2019). EOL metrics including death in an acute care facility, transfusion or hospice admission within 7 days of death, lymphoma treatment (excluding steroids) within 14 days of death, ED visit, and hospitalization, or ICU admission within 30 days of death were abstracted from medical records under IRB approval. We also analyzed data based on death ≤90 days or > 90 days after CAR T-cell therapy or date determined chemorefractory in the cohort receiving non-CAR T-cell treatments. Statistical analyses were descriptive, with univariate analyses performed between the subsets mentioned above. P-values were calculated using Fisher's Exact test for categorical variables, and Wilcoxon Rank Sum test for continuous variables. Results: We identified 49 patients who progressed after CD19-specific CAR T-cell treatment and subsequently died, and 31 patients with chemorefractory DLBCL who did not receive CAR T-cells. 37 of 49 post-CAR patients, and 17 of 31 chemorefractory patients had adequate data for analysis. Baseline characteristics were balanced between the two groups except that post-CAR patients had more median prior therapies (4 (range 1-9) vs. 3 (range 2-3), p = 0.005). There was no significant difference in EOL measures between the post-CAR and chemorefractory subsets. While few patients received chemotherapy (8.1% vs. 11.8%) or oral therapy (10.8% vs. 17.6%) within 14 days of death, there were high rates of ED visits and hospitalizations (73.0% vs. 82.4%), as well as hospice enrollment within 7 days of death (43.8% vs. 50.0%). When we stratified post-CAR patients by death ≤ 90 days vs > 90 days after progression, we found that late death was associated with increased rates of ICU stays within 30 days of death (55.0% vs. 11.8%, p = 0.014), hospice enrollment within 7 days of death (73.3% vs. 17.6%, p = 0.004), death in an acute care facility (45.0% vs. 11.8%, p = 0.036), and inability to meet all EOL measures (95.0% vs. 64.7%, p = 0.033). No significant differences were seen in chemorefractory patients when stratified by time of death. Conclusions: Patients who succumb to refractory DLBCL received aggressive care at the EOL, including high rates of ED/hospital visits and ICU stays near death, whether treated with CAR T-cell therapy or alternative treatments at our center. In particular, patients with death more than 90 days after relapse from CAR T-cell therapy rarely achieved standard EOL measures. While these data require validation in other cohorts, improvements in EOL care and planning appear critical in the setting of refractory DLBCL. Disclosures Lynch: Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Takeda Pharmaceuticals: Research Funding. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Turtle:Humanigen: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member; T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member. Shadman:Sunesis: Research Funding; Atara Biotherapeutics: Consultancy; TG Therapeutic: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding; Sound Biologics: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; Celgene: Research Funding; ADC Therapeutics: Consultancy. Ujjani:AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding; Genentech: Honoraria; Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy. Cassaday:Merck: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy. Smith:Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol-Myers Squibb (spouse): Research Funding.
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Röllig, Christoph, Michael Kramer, Maria Gabrecht, Mathias Hänel, Regina Herbst, Ulrich Kaiser, Norbert Schmitz, et al. "Randomized Comparison of Intermediate-Dose Cytarabine Plus Mitoxantrone (IMA) Versus Standard-Dose Cytarabine Plus Daunorubicin (DA) for Induction Therapy in AML Patients >60 Years. Results from the SAL 60+ Trial." Blood 126, no. 23 (December 3, 2015): 222. http://dx.doi.org/10.1182/blood.v126.23.222.222.
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Abstract Background: Most patients (pts) diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy in medically fit pts is still the standard practice and a prerequisite for long-term survival, elderly pts have a higher risk of treatment related morbidity and lower remission rates than younger AML pts. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML pts (Niederwieser et al., Blood 2002, abstr. 1337). We present the mature final results of a randomized-controlled trial comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA). Patients and Methods: In the 60+ trial of the Study Alliance Leukemia (SAL), AML pts >60 years and medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). All pts in CR after DA received intermediate-dose cytarabine plus amsacrine (MAMAC) as consolidation treatment, whereas pts in CR after IMA were consolidated with standard-dose cytarabine plus mitoxantrone (2+5). Primary study endpoint was the CR rate with an expected difference of 15% in favor of IMA. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: Between February 2005 and October 2009, 852 pts were screened for study inclusion and 485 pts started study treatment, of which 241 pts were randomized for treatment arm A (DA) and 244 for treatment arm B (IMA). The median age was 69 years. Pt characteristics were equally distributed between the two arms. According to a strict definition, all patients with early death, study drop-out, or failed remission assessment were categorized as being not in CR. The CR rate amongst all 485 pts treated in the study was 47%. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). If all first CRs were taken into account including those achieved after trial discontinuation, the CR rates after DA versus IMA induction were 55% versus 64% (p=0.043). Separate analyses addressing age, cytogenetics, de novo AML, NPM1 and FLT3-ITD confirmed higher CR rates after IMA induction throughout these subgroups. Six-week mortality was 14% in both arms. The median duration of ≥ grade 3 neutropenia was 23 days after DA I and 25 days after IMA (p=0.031). The median duration of thrombocytopenia ≥ grade 3 was 16 versus 20 days after DA I and IMA I, respectively (p<0.001). The incidences of non-hematologic toxicities were not significantly different except for a higher incidence of liver toxicity (odds ratio IMA/DA = 0.52; p=0.001) and gastrointestinal symptoms (OR IMA/DA = 0.62; p=0.041) after DA. In the course of treatment, 11 pts in each arm (5%) received allogeneic stem cell transplantation. After a median follow-up of 66 months, RFS curves are superimposable in the first year with a similar median RFS of 11 months and 10 months after DA and IMA, respectively. However, a separation of RFS curves developed with longer follow up, resulting in 1-year RFS rates of 45% versus 46%, but 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS for all randomized pts was 10 months in both arms; 1-year and 3-year OS rates were 45% and 19% after DA versus 44% and 19% after IMA (p=0.513). Conclusion: The results indicate that elderly AML pts benefit from a dose escalation of cytarabine in induction therapy by significantly higher CR rates and similar toxicity compared to a standard 7+3 approach. In our trial, this did not translate into a survival advantage, most likely due to differences in consolidation treatment of the respective treatment arms. In combination with an effective consolidation strategy such as high-dose cytarabine or allogeneic transplantation, our current results favor the use of intermediate dose cytarabine in induction for pts with a curative AML treatment approach. Figure 1. CR rates depending on induction treatment Figure 1. CR rates depending on induction treatment Disclosures Einsele: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Platzbecker:Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Ehninger:Cellex GmbH: Equity Ownership.
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Stasik, Sebastian, Jan Moritz Middeke, Michael Kramer, Christoph Rollig, Alwin Krämer, Sebastian Scholl, Andreas Hochhaus, et al. "EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 1528. http://dx.doi.org/10.1182/blood-2018-99-114421.
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Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.
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Cowan, Andrew J., Philip Stevenson, Ted A. Gooley, Shani L. Frayo, George R. Oliveira, Stephen D. Smith, Damian J. Green, et al. "Results of a Phase I-II Study of Fenretinide and Rituximab for Patients with B-Cell Lymphomas." Blood 126, no. 23 (December 3, 2015): 2728. http://dx.doi.org/10.1182/blood.v126.23.2728.2728.
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Abstract Background: Despite improved treatment options, indolent non-Hodgkin lymphoma (NHL) and Mantle Cell Lymphoma (MCL) remain incurable for most patients. Fenretinide (4-hydroxy(phenyl)retinamide; 4-HPR), an orally bioavailable synthetic retinoid, has been shown to induce apoptotic cell death in a variety of tumor types, presumably via intratumoral induction of oxygen free radicals. Our group has shown single-agent fenretinide anti-B-NHL activity as well as synergy with anti-CD20 antibody therapy when tested in vitro (Shan et al Clin Cancer Res. 2001) and in human xenograft models (Gopal et al, Blood 2004). These preclinical data support the first trial to evaluate this strategy of fenretinide and rituximab in patients with B-cell malignancies. Here we report results from a phase I-II study evaluating the safety and efficacy of fenretinide with rituximab for indolent NHL and MCL. Methods: This was an open-label, phase I/II study conducted at the Fred Hutchinson Cancer Research Center (FHCRC) and Seattle Cancer Care Alliance, Seattle, WA (ClinicalTrials.gov identifier: NCT00288067). The study was approved by the institutional review board at FHCRC and written informed consent was obtained from all patients. Major eligibility criteria included: CD20 positive lymphoid malignancy, radiographically measurable disease, ECOG PS ²2, and adequate organ function. The phase I portion evaluated the safety of dosing single agent fenretinide at 900 mg/m2 PO BID for days 1-5 of a 7 day cycle and allowed de-escalation for excess toxicity. The phase II portion added 375 mg/m2 IV rituximab weekly on weeks 5-9 then every 3 months. All patients could remain on therapy until disease progression or unacceptable toxicity. Response assessment occurred approximately every 3 months. Correlative studies included fenretinide pharmacokinetics, serum retinol concentrations, and evaluation of tumor expression of BCL-2 family proteins. Response was scored by standard criteria (Cheson 1999). Results: Thirty-two patients enrolled in the study: 7 patients in phase I, and 25 patients in phase II. The median age was 64 years (range, 40 - 78), 81% were male, and the median number of prior therapies was 1 (range, 0 - 10) with 22 (69%) having received prior rituximab and 8 (25%) with rituximab-refractory disease. Histologies included 13 CLL/SLL, 10 follicular (FL), 7 mantle cell (MCL), 1 lymphoplasmacytic, and 1 marginal zone. No dose limiting toxicities were observed in the phase I portion, and 900 mg/m2 was the dose level delivered in combination with rituximab for the phase II component. The most common treatment-related adverse events (AE) of any grade were reversible night blindness (n=18, 56%), other eye disorders (n=17, 53%), rash (n=12, 38%), and photosensitivity (n=8, 25%). The most common treatment related AEs of grade 3 or higher included: maculopapular rash, night blindness, and decreased lymphocyte count. Three patients (9%) discontinued treatment early due to toxicity (rash-2, GI toxicity-1). One patient with MCL in the phase I portion experienced stable disease (SD) lasting 35 months. In the phase II portion of the study, 5 (20%) patientÕs disease responded (Figure), with 2 (8%) achieving complete remission (both SLL/CLL), and 3 (12%) achieving partial remission (2 FL, 1 MCL). In addition 16 (64%) patients had SD. The median progression-free survival was 9 months (range, 6 - 31 months), and the median overall survival was not reached (range, 33 months to not reached). Median time to progression of responders was 14.5 months. The one-month median peak and trough concentrations of fenretinide were 11.45 µM and 2.5 µM, respectively. Correlative studies assessing Bcl-2, BAX, and apoptosis in the 13 patients with circulating tumor cells were not able to associate these data with response, or survival. Discussion: In this phase I/II study, the combination of fenretinide and rituximab was well tolerated with predictable, reversible toxicities with up to 4.5 years of continuous therapy. Though the ORR was modest (20%), the majority had of patients had disease control (ORR + SD=84%) which lasted for > 6 months. Further study of this novel combination should focus on identifying the subset of B-NHL that is most likely to respond or the rational addition of other agents to augment these anti-tumor effects. Figure 1. Figure 1. Disclosures Pagel: Actinium Pharmacetuicals, Inc.: Equity Ownership. Gopal:Merck: Research Funding; Emergent/Abbott: Research Funding; Cephalon/Teva: Research Funding; BioMarin: Research Funding; Sanofi-Aventis: Honoraria; Millenium: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Piramal: Research Funding; Biogen Idec, BMS: Research Funding.
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Herold, Sylvia, Thoralf Stange, Matthias Kuhn, Ingo Roeder, Christoph Röllig, Gerhard Ehninger, and Christian Thiede. "Targeted Resequencing of MLL-PTD Positive AML Patients Reveals a High Prevalence of Co-Ocurring Mutations in Epigenetic Regulator Genes." Blood 124, no. 21 (December 6, 2014): 1035. http://dx.doi.org/10.1182/blood.v124.21.1035.1035.
Full textAbstract:
Abstract Background Partial tandem duplication mutations of the Mixed Lineage Leukemia gene (MLL-PTD) can be found in about 10% of patients with AML, especially in patients with normal karyotype AML. The mutation generates a self-fusion within the N-terminal part of MLL and has been shown to be leukemogenic in mouse models. In patients, the presence of the mutation is associated with poor prognosis. Little is known on the molecular profile of patients with MLL-PTD and on the cooperating mutations. In order to identify accompanying molecular alterations, we performed whole exome sequencing (WES) of eight AML patients harbouring MLL-PTD mutations. Based on the observed alterations we then designed a custom amplicon panel and performed targeted resequencing in a cohort of 90 MLL-PTD mutated AML patients. Materials and Methods All patients included in this analysis were treated in prospective treatment protocols of the Study Alliance Leukemia (SAL). To enrich for malignant cells and to obtain germline reference material (T-cells), FACS sorting was performed on viable cells banked at diagnosis. After whole genome amplification of the primary DNA, whole exomes were enriched (TruSeq chemistry; Illumina), and paired-end sequenced using Illumina HiSeq2000 2x100 bp runs. Resulting data were mapped against human genome (Hg19). Only somatic single nucleotide variants (SNVs) were included in the final analysis. Based on the SNVs identified by whole exome sequencing (WES), a custom amplicon panel (TruSeq Custom Amplicon, TSCA, Illumina) for targeted resequencing was designed. The assay included either the entire coding region or mutational hot spots of 56 genes (Fig.1). In total, 700 targets were amplified in a single reaction for each patient and paired end sequenced on a MiSeq NGS system (Illumina). Paired end reads were BWA mapped against targeted regions and data analysis was done using the Sequence Pilot software package (JSI Medical Systems) with a 20% variant allele frequency (VAF) mutation calling cutoff. Only non-synonymous variants not specified as SNP in the db137 database and predicted as deleterious (Provean) were included in the final analysis. All variations were confirmed by Sanger sequencing. Results WES of eight MLL-PTD (7/8 FLT3-ITD negativ) patients revealed a total 490 SNVs (range 13-254 per patient). Most frequently mutated genes were DNMT3A, IDH1/2 and TET2. Somatic mutations were also found in genes rarely mutated in AML, such as ATM, GNAS, TET1 and EP300. Based on the WES-data, 90 MLL-PTD patients were screend for a panel of 56 genes using the TSCA assay, which revealed in total of 169 mutations. 18 genes were not found to be mutated and in 8 patients, no co-occurring mutations were identified. Due bad assay performance EP300, EZH1, JAK3, MLL2, MLL3 and NOTCH1 were excluded from the data analysis. Here again, the most frequently mutated genes were DNMT3A (34.4%), IDH1 (20.0%), IDH2R140 (18.9%), IDH2R172 (7.9%), TET2 (16.7%) and FLT3 (11.3%). Mutations were less frequently found in RUNX1 (8.9%) and ASXL1, SMC1A, U2AF1 (5.6% each) (Fig. 1). In addition to these known genes, most prevalent mutations were found in ATM (8.9%) as well as DNMT3B and TET1 (4.4% each). Overall, we oberserved a low frequency of mutations in typical class 1 genes such as NRAS, KRAS and FLT3, which was lower than reported in the TCGA data set. Conclusions This analysis in a large set of patients with MLL-PTD mutations did not reveal any new and specific individual mutation present in patients with this alteration. Instead, our finding of a very high prevalence of alterations in epigenetic regulator genes, found in more than 85% of patients with MLL-PTD, strongly argues for a particular disease biology in these patients. These findings might also implicate that treatment based on demethylating agents or histone-deacetylase inhibitors might be especially attractive in patients with MLL-PTD. Figure 1: Figure 1:. Distribution of mutations in MLL-PTD patients The assay included either the entire coding region or mutational hot spots of the following 56 genes; ASXL1, ATM, BCOR, BRAF, CBL, DDR1, DNMT1, DNMT3A, DNMT3B, EIF4A2, EP300, ETV6, EZH1, EZH2, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KDM4A, KDM5A, KDM5C, KDM6A, KIT, KRAS, MET, MLL, MLL2, MLL3, NOTCH1, NOTCH4, NPM1, NRAS, PDGFRA, PDGFRB, PHF6, PTEN, PTPN11, RAD21, RUNX1, SF3A1, SF3B4, SMC1A, SMC3, SMC4, TET1, TET2, TP53, U2AF1 and WT1. Disclosures Thiede: AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other.