Journal articles on the topic 'First Philippine Holdings Corporation'

Title – UMW Holdings: sustaining a centennial corporation. Subject area – Strategic Management and Organization Theory and Design. Study level/applicability – Advanced undergraduate and MBA students taking courses in Strategic Management and Organization Theory and Design. Case overview – By the end of 2011, five years short of its centennial anniversary, UMW Holdings was one of the biggest corporations in Malaysia, registering revenues of RM13.5 billion (US$4.5 billion), and net profit after tax of RM1 billion (US$0.33 billion). By that time, it had 110 subsidiaries, operating in four core businesses of automotive assembly and distribution of Toyota lines of products, automotive components and lubricants original equipment manufacturing (OEM) and replacement equipment manufacturing (REM), heavy equipment, and oil and gas drilling service. In September 2011, the company had targeted its Toyota automotive business to contribute to 50 percent of its revenues, while the other 50 percent would come from its other three businesses, by the year 2015. However, as of the first quarter of 2012, Datuk Syed Hisham Syed Wazir, the Group CEO and his management team realized that, at 72 percent, the automotive business was still the main contributor to the Group ' s revenues. As the company ' s Toyota assembly operation was limited exclusively to the Malaysian market, plus in the face of greater competition within the automotive industries, the company needed to set strategies to achieve its 50:50 plan. The case stimulates discussion on strategy formulation of a mature corporation, involved in diversified business portfolio. Expected learning outcomes – Understanding the process of industry analysis, as well as the formulation and implementation of business-level and corporate strategies, enables case analysts to extend the concepts to many business situations. 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.

This decision is the latest of several by arbitral bodies of the International Centre for Settlement of Investment Disputes (ICSID) addressing a claim by Amco Asia Corporation (Amco Asia) against respondent Republic of Indonesia. An ICSID tribunal (First Tribunal) in 1984 rendered an award on the merits in favor of claimant Amco Asia. In 1986 an “ad hoc committee” (Ad Hoc Committee) convened on Indonesia’s request pursuant to Article 52 of the ICSID Convention annulled the 1984 award on the grounds that, with respect to a principal holding, the tribunal had “manifestly exceeded its powers” and “failed to state reasons,” both being grounds for annulment specified in Article 52(1) of the Convention. The Ad Hoc Committee did not disturb certain other holdings of the tribunal. Claimant then resubmitted the dispute, and a second tribunal (Second Tribunal) was constituted pursuant to Article 52(6) of the Convention. The first task of the new tribunal was to determine which holdings of the previous bodies were res judicata and therefore could not be relitigated. The three-member ICSID Second Tribunal held: (1) that holdings of the First Tribunal that had not been annulled by the Ad Hoc Committee were res judicata; (2) that issues as to which the First Tribunal’s holdings had been annulled could be relitigated; and (3) that the Ad Hoc Committee’s reasoning, as distinct from its actual decision of annulment, was not binding on the Second Tribunal.

The history of mining enterprise has recently become an important growth industry in both African and British Commonwealth business history. A number of important multinational mining corporations have in recent years opened their archives on assimilated or restructured parent companies active in overseas enterprise in the first half of this century. In the following essay, Professor Dumett surveys the extensive holdings of the leading British gold mining company in West Africa, the Ashanti Goldfields Corporation.

The article analyzes the scientific views on the concepts of «legal entity» and «corporation» formed in different legal systems, indicating either the identity of these concepts, or their heterogeneity by deducing a number of common and distinct features. Determined that in the Anglo-American legal system, the corporation is seen as a collective term, which should be understood by business associations and nonbusiness capital entities created to meet social objectives. It is proved that in EU law the concept of «corporation» is not identical with that of a legal entity, although a considerable number of types of legal entities are proposed to be included in the list of legal entities. In the countries of the continental legal system (France, Germany, Switzerland, Russia, Ukraine, etc.) the term «corporation» is rarely used in the law. This concept is used mainly in literary sources. Corporations include: various types of companies (full and limited partnerships, joint stock companies and other companies, members of which are limited liability for the obligations of the company), business associations (groups, trade unions, holdings, etc.), cooperatives, leases and state-owned enterprises, as well as various non-economic unions and associations. The main difference between the range of legal entities in the Anglo-American and Continental legal families is that in the first case, the terms «legal entity» and «corporation» are correlated as interchangeable concepts, and in the other case, the possibility of correlation between the concepts of «legal entity» and «corporation» depends on the approach of the legislation of the country to the definition of their organizational and legal forms and the formation in the scientific circles of the criteria for their separation or integration into one or another concept, or the introduction of this concept into the existing legislation of the EU country with a clear list of organizational and legal forms. Therefore, every legal family has their own approaches to the concept of «corporation».

In conducting its business, the corporation stands in corporate ethics and involves many things are about human rights, labor standards or workers, and relationships with the corporate environment. Ideally corporate ethics also puts workers as one form of social responsibility to represent a healthy or not as a company. PT Alpen Food Industry (AFI), a subsidiary of Aice Group Holdings Pte.Ltd Singapore produces Aice ice cream. The company ran into many aspects of ethical and legal (the laws) violations. This paper will discuss ethical violations in the business practices of PT Alpen Food Industry and elaborate on the importance of corporate ethics as a business fence. Furthermore, this paper will be classified in several sub-discussions. First, the ethical dimension approach (ethical behavior) in the corporation. Second, the dynamics in corporate ethics and public relations PT Alpen Food Industry. Third, the unethical business practices of PT Alpen Food Industry. Fourth, provide recommendations on the importance of government regulatory sharpening involved in the business practices of PT Alpen Food Industry to encourage corporate ethics in accordance with the laws and ethical standards of corporate ethics.Keywords: corporate ethics, the laws, labor, industry, regulation ABSTRAKDalam menjalankan bisnisnya, perusahaan terikat dalam etika perusahaan dan melibatkan hal mengenai hak asasi manusia, standar tenaga kerja, dan hubungan dengan lingkungan perusahaan. Idealnya etika perusahaan juga menempatkan pekerja sebagai salah satu bentuk tanggung jawab sosial perusahaan. PT Alpen Food Industry (AFI), anak perusahaan Aice Group Holdings Pte.Ltd Singapura memproduksi es krim Aice mengalami beberapa aspek pelanggaran etika dan hukum (hukum) terutama dalam hal tenaga kerja. Makalah ini akan membahas pelanggaran etika dalam praktik bisnis PT Alpen Food Industry dan menguraikan pentingnya etika perusahaan sebagai pagar bisnis. Selanjutnya, makalah ini akan diklasifikasikan dalam beberapa sub-diskusi. Pertama, pendekatan dimensi etis (perilaku etis) dalam perusahaan. Kedua, dinamika etika perusahaan dan hubungan masyarakat PT Alpen Food Industry. Ketiga, praktik bisnis yang tidak etis dari PT Alpen Food Industry. Keempat, memberikan rekomendasi tentang pentingnya penajaman peraturan pemerintah yang terlibat dalam praktik bisnis PT Alpen Food Industry untuk mendorong etika perusahaan sesuai dengan hukum dan standar etika etika perusahaan.Kata kunci: etika perusahaan, hukum, ketenagakerjaan, industri, regulasi

The date pineapple (Ananas comosus var. comosus) was introduced to Hawaii is not known, but its presence was first recorded in 1813. When American missionaries first arrived in Hawaii in 1820, pineapple was found growing wild and in gardens and small plots. The pineapple canning industry began in Baltimore in the mid-1860s and used fruit imported from the Caribbean. The export-based Hawaii pineapple industry was developed by an entrepreneurial group of California migrants who arrived in Hawaii in 1898 and the well-connected James D. Dole who arrived in 1899. The first profitable lot of canned pineapples was produced by Dole’s Hawaiian Pineapple Company in 1903 and the industry grew rapidly from there. Difficulties encountered in production and processing as the industry grew included low yields resulting from severe iron chlorosis and the use of low plant populations, mealybug wilt that devastated whole fields, inadequate machinery that limited cannery capacity, and lack of or poorly developed markets for the industry’s canned fruit. The major production problems were solved by public- and industry-funded research and innovation in the field and in the cannery. An industry association and industry-funded cooperative marketing efforts, initially led by James Dole, helped to expand the market for canned pineapple. Industry innovations were many and included: selection of ‘Smooth Cayenne’ pineapple as the most productive cultivar with the best quality fruit for canning; identification of the cause of manganese-induced iron chlorosis and its control with biweekly iron sulphate sprays; the use of mulch paper and the mechanization of its application, which increased yields by more than 20 t·ha−1; and the invention of the Ginaca peeler–corer machine, which greatly sped cannery throughput. Nematodes were also a serious problem for the industry, which resulted in the discovery and development of nematicides in the 1930s. As a result, by 1930 Hawaii led the world in the production of canned pineapple and had the world’s largest canneries. Production and sale of canned pineapple fell sharply during the world depression that began in 1929. However, the formation of an industry cartel to control output and marketing of canned pineapple, aggressive industry-funded marketing programs, and rapid growth in the volume of canned juice after 1933 restored industry profitability. Although the industry supported the world’s largest pineapple breeding program from 1914 until 1986, no cultivars emerged that replaced ‘Smooth Cayenne’ for canning. The lack of success was attributed in part to the superiority of ‘Smooth Cayenne’ in the field and the cannery, but also to the difficulty in producing defect-free progeny from crosses between highly heterozygous parents that were self-incompatible. Production of canned pineapple peaked in 1957, but the stage was set for the decline of the Hawaii industry when Del Monte, one of Hawaii’s largest canners, established the Philippine Packing Corporation (PPC) in the Philippines in the 1930s. The expansion of the PPC after World War II, followed by the establishment of plantations and canneries by Castle and Cooke’s Dole division in the Philippines in 1964 and in Thailand in 1972, sped the decline. The decline occurred mainly because foreign-based canneries had labor costs approximately one-tenth those in Hawaii. As the Hawaii canneries closed, the industry gradually shifted to the production of fresh pineapples. During that transition, the pineapple breeding program of the Pineapple Research Institute of Hawaii produced the MD-2 pineapple cultivar, now the world’s pre-eminent fresh fruit cultivar. However, the first and major beneficiary of that cultivar was Costa Rica where Del Monte had established a fresh fruit plantation in the late 1970s. Dole Food Co. and Maui Gold Pineapple Co. continue to produce fresh pineapples in Hawaii, mostly for the local market. All of the canneries eventually closed, the last one on Maui in 2007.

Abstract Background: The growth factor receptor bound protein-2 (Grb2) is vital to tumor progression. Prexigebersen (BP1001) is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. Grb2 inhibition suppresses cancer growth and survival. A Phase I/IB single center study (Ohanian, Lancet Haematol 2018) in relapsed/refractory AML patients (pts) demonstrated BP1001 safety up to 90 mg/m2 and demonstrated CR/CRi in 3/6 relapsed/refractory AML pts treated with BP1001 + low dose cytarabine (LDAC) in the Phase IB portion. Based on PK considerations, the recommended Phase II dose was 60 mg/m2. A phase II study was initiated to explore the clinical impact of BP1001 in untreated AML pts considered unsuitable for standard chemotherapy. Methods: This is a multi-center open-label, Phase II study in untreated AML pts to determine the safety and preliminary efficacy of BP1001 (given at 60 mg/m2 over 1-3 h twice weekly for a total of 8 doses over a 28-day cycle) in combination with LDAC (starting after the Day 4 dose, 20 mg twice daily for 10 days). Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Blood samples were taken on Days 1 and 11 to determine BP1001 plasma pharmacokinetics (PK). Results: A total of 25 pts (16 male: 64%) with a median age of 74 years (range, 51-86 years) was treated with at least 1 cycle of BP1001 + LDAC. Sixty-eight percent (17/25) had secondary AML evolved from MDS (n=13) or MPN (n=3) or prior chemotherapy/radiotherapy (n=1). The majority (64%) had adverse-risk (ELN classification); 36% were intermediate-risk. Infusional reactions (IR) (rigors, fevers, or chills) were observed in 20% of pts when the infusion rate was 1 h. IR were mild, controlled with supportive measures, and were not observed when the infusion rate was 2 h. Other AE's were generally consistent with those expected with LDAC and/or AML, including fatigue (64%), diarrhea (24%), neutropenic fever (24%), and pneumonia (20%). The most frequent SAEs were pneumonia (20%) and neutropenic fever (24%). Four pts died within 30 days of treatment (between days 20-27), all of AML-related complications (including intracranial hemorrhage, pneumonia, septic shock, and splenic rupture). Ten pts had documented progressive disease. Two pts withdrew consent after 1 cycle of treatment. Evaluability of efficacy was defined as: receipt of at least 4 cycles of therapy, PD, or CR/CRi prior to 4 cycles. PK data revealed that the Time of maximal observed concentration (Tmax), the mean terminal elimination half-life (t1/2), and the area under the curve from zero to the last quantifiable concentration (AUC(last)) for BP1001 were similar between Days 1 and 11. Tmax of BP1001 was 1.9 vs 2.3 h (day 1 vs 11); t1/2 was 5.2 vs 5.7 h; AUC(last) was 308 vs 275 h*ng/mL. Response: Among 17 fully evaluable pts, 7 pts (41%) demonstrated bone marrow blast reduction, including 5 (29%) who achieved a CR (n=3), CRi (n=1), or morphologic leukemia free state (n=1). Two additional pts demonstrated a ≥50% reduction of bone marrow blasts (from 20% to 9% and from 71% to 8%), including 1 with hematologic improvement of the absolute neutrophil count. The median overall survival (OS) was 5.2 months (range, 0.6-15.2) for all patients. For evaluable patients, the median OS was 6.3 months (0.8-15.2 months). The CRs included: a 74-year old female who achieved CR after 2 cycles of therapy and then received 2 additional cycles followed by a matched-sibling allogeneic transplant. She remained in CR for 10 months before first relapse. A 73-year old female, with AML transformed from MDS, benefited from therapy despite refusal of blood products due to religious objections. Her hemoglobin declined to 4.0 g/dL during therapy but recovered to as high as 9.9 g/dL once in CR after 4 cycles. An 86-year old male achieved CR after 4 cycles of therapy and maintained CR for 3 months before relapse. Conclusions: BP1001 has been safely administered to 25 pts with untreated AML, who were considered unsuitable for standard chemotherapy. Efficacy data are encouraging in a challenging population in which the majority of pts had secondary AML or adverse-risk AML, and compares favorably to the reported CR/CRi/CRp rate with LDAC of 7-13% (Heiblig, Mediterr J Hematol 2016; Kantarjian, J Clin Oncol 2012; Döhner, Blood 2014). A protocol amendment made to optimize BP1001 administration with LDAC and to add a decitabine combination arm is in place. Disclosures Lin: Jazz Pharmaceuticals: Honoraria. Ritchie:Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Craig:Celgene: Research Funding; Novartis: Research Funding; Actinium Pharmaceuticals: Research Funding. Agrawal:Incyte: Speakers Bureau. Pemmaraju:Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; SagerStrong Foundation: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Tari Ashizawa:Bio-Path Holdings, Inc.: Employment, Equity Ownership, Patents & Royalties. Hahne:Bio-Path Holdings, Inc.: Employment. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding. Roboz:Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Cellectis: Research Funding; Roche/Genentech: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Astex Pharmaceuticals: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy.

Abstract Introduction: Cytogenetic abnormalities occur frequently in patients with myelofibrosis (MF) and carry significant prognostic value. A variety of cytogenetic abnormalities have been reported with variable incidence. While the prognostic significance of more common cytogenetic abnormalities is well documented, the prognostic significance of less common abnormalities are difficult to discern due to limiting cohort size. Further, the specific phenotype associated with various cytogenetic abnormalities is less clear. We reviewed our institutional experience in an effort to describe the spectrum of chromosomal abnormalities, assess their correlation with clinical features, and validate their prognostic impact in a cohort of MF patients. Methods: This was a single institution, retrospective study of all patients with a diagnosis of MF who were seen at our center between 2/2001 - 6/2016.We reviewed cases of myelofibrosis in the Moffitt Cancer Center database. Definitions of primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF) and post-polycythemia vera myelofibrosis (post-PV MF) were according to World Health Organization 2016 criteria and the International Working Group for Myeloproliferative Neoplasms, Research and Treatment, respectively. Cytogenetic analysis was documented with preference to date of diagnosis. Overall survival was measured from time of cytogenetic analysis. Results: We identified 312 eligible. Cytogenetic data were available in 278 of 312 (89%) patients. The cohort was 59% male with a median age of 70 years at time of first presentation. PMF comprised 76% of cases with post-PV MF and post-ET MF accounting for 9% and 15% of cases respectively. Cytogenetic analysis was performed within 3 months of diagnosis in 63% and over a year after diagnosis in 24% of patients. Cytogenetic spectrum and frequency is shown in Figure 1. Normal diploid karyotype was present in 55%. The most common cytogenetic abnormality was a deletion of the long arm of chromosome 20 (del 20q), occurring in 39 (14%) cases. Del 20q occurred as an isolated abnormality in 26/39 cases. When occurring in conjunction with other structural abnormalities, it was most often associated with trisomy 9 (6/39). A deletion of the long arm of chromosome 13 (del 13q) was the second most common chromosomal aberration, occurring in 26 (9%) of cases and usually presenting as the sole abnormality (15/26). An extra copy of chromosome 8 (trisomy 8) occurred in 21 (8%) cases and often occurred in conjunction with other cytogenetic abnormalities (11/21). Less common cytogenetic abnormalities included trisomy 9, deletion 7q and deletion 5q, occurring in less than 4% of cases. Monosomal and complex karyotypes accounted for 10% and 8.3% of cytogenetics, respectively. We then assessed relationships between cytogenetic abnormalities and clinical and pathologic features. Del20q was associated with a lower IPSS score (r = -0.18, p = 0.0006). Deletion 13q was associated with older age at presentation (r = 0.14, p = 0.007). Prevalence of trisomy 8 was highest in post-polycythemia vera myelofibrosis (r = 0.14, p = 0.03) and associated with increased peripheral blast percentage (r = 0.16, p < 0.0001). Deletion 5q was associated with decreased hemoglobin (r = -0.13, p = 0.04), transfusion dependence (r = 0.20, p = 0.0009) and conversion to blast phase (r = 0.23, p = 0.0001). Patients with del 20q, del 13q, and trisomy 9 had median overall survival (OS) comparable to patients with a normal karyotype (45 vs 54 months, respectively, p = 0.69). Patients with unfavorable cytogenetic profiles (del 5q, trisomy 8, and chromosome 17 abnormalities) had significantly worse OS when compared to patients with normal diploid karyotype (20 vs 54 months, p = 0.0002) (figure 2). In multivariate regression analysis, controlling for DIPSS, deletion 5q (HR: 0.34 [0.15-0.78]; p = 0.01) and trisomy 8 (HR: 0.35 [0.17-0.73]; p = 0.005) were significantly associated with inferior overall survival. Conclusions: Cytogenetic abnormalities in myelofibrosis provide significant prognostic discrimination in patients with myelofibrosis. Our findings validate the prognostic value of cytogenetics and raise possible heretofore unrecognized clinical associations. Disclosures Lancet: Novartis: Consultancy; Biopath Holdings: Consultancy; Karyopharm: Consultancy; Boehringer-Ingelheim: Consultancy; Quantum First: Consultancy; ERYtech: Consultancy; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Kalo Bios: Consultancy; Baxalta: Consultancy; Amgen: Consultancy. Sweet:Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau.

Abstract Background: Prognostication in MF has historically been based on age, symptoms and hematologic features at presentation. Newer models include cytogenetic and genomic data given their independent prognostic value. In 2014, two prognostic models incorporating gene mutation data were proposed: a "mutation enhanced" IPSS (MIPSS) and a genetics-based prognostic scoring system (GPSS) model; the former using mutation data to enrich standard prognostic inputs, while the latter eschewed classic prognostic inputs for a score comprised solely of cytogenetics, mutation data, and age (Vannucchi, Blood, 2014 and Tefferi, Blood, 2014). In this study, we aimed to validate these risk models as well as propose age-independent models to better capture disease-specific prognosis. Methods: This was a single institution, retrospective study of confirmed MF patients seen between 2/2001 and 6/2016. Definitions of primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF) and post-polycythemia vera myelofibrosis (post-PV MF) were according to World Health Organization 2016 criteria and the International Working Group for Myeloproliferative Neoplasms, Research and Treatment, respectively. Mutation and cytogenetic data were assessed from review of electronic medical record. Prognostic scores were calculated on first presentation to our facility. Survival curves were generated using Kaplan-Meier method and compared using the log-rank test. Results: We identified 103 and 97 patients with available data to calculate MIPSS and GPSS scores respectively. The cohorts were 60% male, with median age 72 years at presentation. The majority of patients had a diagnosis of PMF (80%), with a small component of post-ET MF (13%) and post-PV MF (7%). Assigning scores based on MIPSS, 4% of patients were low-risk (LR), 8% intermediate-1 (IR1), 60% intermediate-2 (IR2), and 28% high-risk (HR). The model successfully differentiated between IR2 and HR with median overall survival (OS) 134 and 26 months, respectively (p = 0.0001) (figure 1A). No significant difference in OS was seen between LR/IR1 groups and IR2 (p = 0.58). Using GPSS, 1% of patients were classified as LR, 13% IR1, 25% IR2, and 61% HR. GPSS performed well in delineating between HR and intermediate risk (combined IR1 and IR2) (median OS 44 vs 134 mo, p = 0.02); however it did not distinguish HR from IR2 (p = 0.09) nor between IR1 and IR2 (p = 0.71) (figure 1B). To more specifically assess disease-specific prognosis and better divide risk scores among our patient population, new models were created. Given that age is a negative risk factor for OS independent of disease state, this input was removed. First, an age-independent MIPSS score was created with four risk groups defined: LR (score 0-0.5), IR1 (score 1-1.5), IR2 (2-3), and HR (score 3.5+). Fifteen percent of patients were classified as LR, 32% IR1, 48% IR2, and 6% HR. This system distinguished significantly between IR2 and HR (median OS 98.0 vs 13.5 mo, p = 0.006), while providing improved differentiation between IR1 and IR2 risk groups (median OS not reached vs. 98 months, p = 0.09) (figure 1C). Next, we aimed to create a truly disease-specific model based on the GPSS. Age was omitted and the impact of SRSF2 mutation was enhanced from 1 point to 1.5 points given its greater weighted impact on OS compared to ASXL1 mutation in our database. Values for other inputs remained consistent with GPSS. Using cytogenetic information (CY) and mutation data (M) as the sole inputs a CYM score was created. This yielded four risk groups defined as LR (0 points), IR1 (1-2.5 points), IR2 (3-5 points) and HR (5.5+ points). Seven percent of patients were classified as LR, 28% IR1, 56% IR2, and 9% HR. This model differentiated between IR2 disease and HR disease effectively (median OS 98 vs 15.2 mo., p < 0.0001). No significant difference was observed between IR1 and IR2 disease (figure 1D). Conclusion: Using previously proposed molecular-based models, we were able to validate their utility in the setting of advanced disease; however, insufficient capture of lower risk categories impaired its validity in that setting. We propose age-independent models to better characterize disease-specific risk in an effort to identify patients who many benefit from allogeneic stem cell transplant and/or clinical trial referral. These models merit testing in larger cohorts with longer follow-up to determine their clinical validity. Disclosures Lancet: Celgene: Consultancy, Research Funding; Amgen: Consultancy; Seattle Genetics: Consultancy; Quantum First: Consultancy; Biopath Holdings: Consultancy; Baxalta: Consultancy; Pfizer: Research Funding; Kalo Bios: Consultancy; Karyopharm: Consultancy; Jazz Pharmaceuticals: Consultancy; ERYtech: Consultancy; Boehringer-Ingelheim: Consultancy; Novartis: Consultancy. Sweet:Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau.

Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and may be the most frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb &lt;10 g/dl on every determination for 12 weeks (wks) or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on rux for ≥6 months with a stable dose for ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, and an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must have received ≥5 cycles of sotatercept to be response-evaluable. Results A total of 53 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty one pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Sixteen TD and 15 non-TD pts received sotatercept alone for a median of 5 (1-67) cycles. Thirteen pts received 0.75 mg/kg and 18, 1 mg/kg. Seven of 24 (29%) evaluable pts responded. Of these, 4 were anemia responses; 3 TD pts achieved TI. Five responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 21 (1-22) days and median duration of response (DOR) 13 (3.9-56.4) months. Seven pts (22.6%) received &lt;5 cycles and were not response-evaluable: 2 proceeded to stem cell transplant (SCT), 2 had logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Three pts continue on study. Reasons for d/c included no response (11), progressive MF (6), SCT (3), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. The median number of cycles was 8 (2-43). Five of 17 (29%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (7-147) days and median DOR 34.6 (3.1-47.9) months. Four pts (19%) received &lt;5 cycles and were not response-evaluable, 1 each due to MF progression, loss of insurance, SCT and pt decision. Five pts remain on study. Reasons for d/c included no response (6), SCT (4), progressive MF (2), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 wks because of early d/c of sotatercept. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was &lt;11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7), limb (bone/muscle/joint) pain (n=3) and headache (1). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 29% both when used alone and in conjunction with a stable dose of rux. A total of 60 pts are planned to be treated on this trial (NCT01712308). Disclosures Bose: Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria. Daver:Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Kadia:Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Cortes:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Novartis: Consultancy, Research Funding. Jain:BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding. Alvarado:Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding. Huynh-Lu:Incyte Corporation: Speakers Bureau. Nguyen-Cao:Incyte Corporation: Speakers Bureau. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding. Kantarjian:Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Janssen: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Amgen: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding.

Abstract Background: SL-401 is a targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies. BPDCN is an aggressive hematologic malignancy of unmet medical need that often presents in bone marrow and skin, and may also involve lymph nodes and viscera. Long-term outcomes after treatment with chemotherapy have been very poor, with median overall survival from diagnosis of ~12 months, highlighting the need for novel therapies. Results from the Phase 2 trial of SL-401 in patients with BPDCN are reported here. Methods:This multicenter, single-arm Phase 2 trial of patients with BPDCN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients with BPDCN or relapsed or refractory (r/r) AML received SL-401 as a daily IV infusion at 7, 9, 12, or 16 ug/kg/day for days 1-5 of a 21 day cycle. In stage 2, patients with BPDCN receive SL-401 at the dose determined in stage 1. Results: As of 7/25/16, 29 patients with BPDCN have received SL-401, including 16 first-line and 10 relapsed/refractory (r/r) adults and 3 pediatric patients (under compassionate use). The 26 adult patients (9+17 in stages 1&2) received SL-401 at 7 ug/kg (n=3 [stage 1]) or 12 ug/kg (n=23 [6+17 in stages 1&2]). The median adult age was 69 years (range: 29-82 years). In stage 1, 12 ug/kg was the highest tested dose for BPDCN; MTD was not reached in BPDCN. Results in AML (r/r) patients will be reported separately. The most common treatment-related AEs, all grades, were transient transaminase elevation (54%) and hypoalbuminemia (38%). Transient thrombocytopenia was also noted (19%). The most common ≥ Grade 3 treatment-related AEs were transient transaminase elevation (42%) and thrombocytopenia (19%). Two stage 1 patients developed capillary leak syndrome (CLS): gr 5 (7 ug/kg) and gr 4 (12 ug/kg). Safety precautions, including monitoring of albumin levels and body weight, were successfully implemented to minimize risk of severe CLS, which has not occurred in patients with BPDCN since adoption. Twenty-one of 26 adult patients were evaluable for response (response assessment from 3 recently treated patients are pending; 1 patient was discontinued for as yet unspecified reasons; and 1 patient treated at 7 ug/kg was not evaluable for response due to AE); median follow-up for evaluable patients was 6.9 months (range: 0.6-17.6 months). An 86% (18/21) ORR was observed in evaluable adult BPDCN patients. ORR in evaluable patients was 100% (14/14) in first-line and 57% (4/7) in r/r BPDCN. Of these, 92% (11/12) of first-line patients treated at 12 ug/kg had a CR (n=8) or clinical CR (CRc: a CR in non-skin organs with gross reduction in cutaneous lesions and residual microscopic skin disease) (n=3). 75% (9/12) of these patients remain progression free for 3+ to 16+ months (ongoing), including 4 patients who remain on SL-401 in remission (for 3+ to 12+ months [up to 16+ cycles], ongoing) and 5 additional patients who experienced a major response on SL-401 (3 CR, 1 CRc, 1 PR) and were then successfully bridged to stem cell transplant (SCT; 3 auto-SCT and 2 allo-SCT) and all remain progression free for 3+ to 16+months (ongoing) since first SL-401 dose. Notably, a patient with r/r BPDCN was recently bridged to allo-SCT following CRc on SL-401. Conclusions: SL-401 demonstrates robust single agent activity in BPDCN, including 86% ORR in all-lines, with multiple CRs, in evaluable patients. Six patients, including 1 r/r patient, have proceeded to SCT after achieving a major response from SL-401, and an additional 7 patients remain on SL-401 for up to 12+ months, ongoing. The SL-401 side effect profile remains manageable, and no unexpected AEs have emerged with increased treatment duration, drug exposure, and patient enrollment. Response duration, progression-free and overall survival data continue to be encouraging and updated data will be presented. Clinical trial information: NCT02113982. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Novartis: Consultancy, Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Lancet:Quantum First: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Biopath Holdings: Consultancy; ERYtech: Consultancy; Karyopharm: Consultancy; Baxalta: Consultancy; Kalo Bios: Consultancy; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Boehringer-Ingelheim: Consultancy; Amgen: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

Background: The minimal or measurable residual disease (MRD) status post induction-consolidation is widely accepted as major surrogate endpoint that correlates with outcome in adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, the optimal time-points of MRD assessment at complete remission (CR) or later during consolidation and its impact on outcome remain unclear. Methods: We performed a retrospective chart review of 419 newly diagnosed adult patients with Philadelphia negative B-cell ALL who received treatment at the M.D. Anderson Cancer Center between 01/2000 and 01/2015 (Figure 1). Overall, 394 of 419 (94%) patients achieved CR. Two hundred and fifteen patients (51%) had available MRD assessment (by multicolor flow cytometry) at CR (1st time-point: median 24 days) and first post-CR MRD assessment (2nd time-point: median 3.6 months), and constitute the current studied cohort. MRD responses were stratified as MRD negative (undetectable), low-positive (≤0.1%), and high-positive (>0.1%). Results: The median age for the study cohort (n=215) was 37 years (range 15-86), and 17% (n=37) had unfavorable cytogenetic profile, such as complex karyotype (n=9), KMT2A (MLL) rearrangement (n=14), and low hypodiploidy/near triploidy (n=14) (Table 1). At first time-point (1TP), 148 patients (68%) were MRD negative and 67 (32%) were positive (Figure 2). Of the 148 patients with negative MRD at 1TP, 147 (99%) maintained it through second time-point (2TP). Fourteen of 16 (88%) patients with low-positive MRD and 33 of 51 (64%) with high-positive MRD at 1TP became MRD negative at 2TP. Patients who were MRD negative at both time-points, early MRD responders, had the 3-year event-free survival (EFS) and overall survival (OS) rates of 65% and 76%, respectively (Table 2). Patients with improved MRD status from positive to negative, late MRD responders, had lower 3-year EFS and OS rates, 42% and 58%, respectively (Figure 3, p<0.01). The 3-year EFS and OS rates were the lowest (16% and 49%, respectively) in patients with persistent MRD at both time points (p<0.01). Multivariate analysis showed that older age, KMT2A (MLL) rearrangement, and MRD positivity at 1TP only correlated with worse survival (Table 3). Conclusion: The early achievement of MRD negative CR is a strong predictive for survival. Innovative combinations of conventional chemotherapy and targeted agents that induce early MRD eradication may have the potential to improve cure rates in adult ALL. Disclosures Kantarjian: Daiichi-Sankyo: Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Loghavi:GLG Consultants: Consultancy; AlphaSights: Consultancy; MDACC: Employment. Cortes:BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Wierda:Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding. Jain:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding. Verstovsek:Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. O'Brien:Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Regeneron: Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Eisai: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Amgen: Consultancy; Kite: Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Aptose Biosciences, Inc: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Astellas: Consultancy. Jabbour:Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Introduction: The use of 2G TKIs in patients with CP-CML who have failed ≥1 2G TKIs is not associated with durable responses; there is limited clinical evidence to support that switching to alternate 2G TKI therapy improves long-term clinical outcomes for these patients. Patients with resistant and intolerant CP-CML with substantial prior 2G treatment demonstrated deep, lasting responses to PON in the pivotal PACE trial. A post hoc modeling analysis of the data from PACE suggested a relationship between dose and safety events (including arterial occlusive events [AOEs]). The OPTIC trial was designed to prospectively evaluate response-based PON dosing regimens with the aim of optimizing its efficacy and safety in patients with CP-CML; the interim analysis (IA) demonstrated clinically manageable safety and AOE profiles with response-based PON dosing regimens. The combined PACE and OPTIC trials comprise the largest patient population in a post-2G TKI setting. We present the efficacy and safety outcomes of these patients over time. Methods: PACE (NCT01207440) evaluated PON in patients with refractory CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). OPTIC (NCT02467270) is a multicenter, randomized Phase 2 trial characterizing the safety and efficacy of PON over a range of 3 starting doses (45, 30, or 15 mg/day); patients with CP-CML receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR-ABL1IS. Data from patients with CP-CML in PACE (n=254) and the 45-mg starting dose cohort (45 mg→15 mg) in OPTIC (n=92) who have been treated with ≥1 2G TKI are presented; OPTIC data are from the IA. Efficacy data includes molecular responses (measured using polymerase chain reaction and performed at the same central lab for both studies) and survival outcomes over time. Safety data, including treatment-emergent AOE rates following adjudication, are also presented. Results: A combined 350 PON-treated patients from the PACE and OPTIC trials who have received ≥1 prior 2G TKI were analyzed; efficacy results are summarized in Table 1. The ≤1% BCR-ABL1IS response rates increased over time and ranged from 42% to 52% in the OPTIC IA 45-mg starting dose cohort and in PACE. Progression-free survival and overall survival were 52% and 73%, respectively, in PACE (up to 5 years) and 81% and 93%, respectively, at the OPTIC IA (up to 2 years) (Table 1). Serious treatment-emergent adverse event (AE) and AOE rates (including exposure-adjusted AOE rates) were lower in OPTIC IA with a response-adjusted dosing regimen compared with PACE (Table 2). Propensity score analyses comparing AOE incidence among all patients in OPTIC vs PACE demonstrate that the relative risk for adjudicated AOEs is 64% lower in OPTIC when compared with PACE after adjusting for baseline differences, duration of exposure, and total PON dose received. Analyses on responses by mutation status also will be presented. Conclusions: In this analysis, comprising the largest patient population of CP-CML patients in a post-2G TKI setting, ponatinib shows high response rates and robust survival outcomes in patients who have failed 2G TKIs. With the response-adjusted dosing regimen in OPTIC (starting at 45 mg and reducing to 15 mg upon response), efficacy outcomes were consistent with that of PACE, while the overall incidences of AOEs and serious treatment emergent-AEs were lower; exposure-adjusted AOEs during the first 2 years were also lower. The ongoing OPTIC study is also evaluating lower starting doses of ponatinib (30 and 15 mg) and primary analysis of this study will provide a refined understanding of the benefit:risk profile of the 3 starting doses of ponatinib in CP-CML patients. Disclosures Kantarjian: Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Jazz: Research Funding. Deininger:Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; SPARC: Research Funding; DisperSol: Consultancy; Leukemia & Lymphoma Society: Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Galena: Consultancy, Honoraria, Other; Pfizer: Honoraria, Other, Research Funding; Ariad: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Other, Research Funding. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria. Apperley:Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; BiolineRx: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Arog: Research Funding. Chuah:Pfizer: Other: Travel, Research Funding; Korea Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. DeAngelo:Jazz: Consultancy; Autolos: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Forty-Seven: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy; Glycomimetics: Research Funding; Pfizer: Consultancy; Shire: Consultancy; Incyte Corporation: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; MSD: Research Funding. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Pinilla Ibarz:Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; TG Therapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Talpaz:IMAGO: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Srivastava:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding.

Abstract Background: Somatic mutations occur frequently in patients with MF and have been shown to correlate with clinical presentation and outcome. Newer prognostic models integrate molecular data to better identify high-risk patient populations. We attempted to characterize the mutational landscape and correlate mutations with clinical presentation, response to treatment and outcomes. Methods: This was a single institution, retrospective study of patients with a diagnosis of MF seen at our center between 2/2001 and 6/2016. Somatic mutation data was assessed in patients who had undergone next generation sequencing with targeted myeloid panels at the time of referral to our center. Gene classes were defined as previously reported in the literature (Patnaik, Blood Cancer J, 2016). Results: We identified 104 eligible MF patients (median age at diagnosis 72 years; 60% males). The cohort was comprised of PMF (80%), post-PV MF (14%) and post-ET MF (7%) patients. DIPPS-plus risk score was high in 27% of patients, intermediate-2 in 41%, intermediate-1 in 28%, and low in 4%. Frequencies of driver mutations were 65% for JAK2V617F, 16% for CALR (14/17 type 1 or type 1-like)and 8% for MPL with 11% of patients classified as "triple-negative." The frequencies of mutations were 34% for TET2, 42% ASXL1, 12% EZH2, 19% IDH1/IDH2, 11% DNMT3, and 23% SRSF2 (figure 1). All other mutational frequencies occurred in less than 10% of patients. No somatic mutations were seen in 12%, 1 mutation in 22%, 2 mutations in 22%, 3 mutations in 20%, and 4+ mutations in 24%. When grouped in terms of gene function, 45% had a mutation in an epigenetic regulation gene (TET2, DNMT3, IDH1/2), 46% in a gene involved in histone modification/chromatin regulation (ASXL1, EZH2), 41% in a splicing gene (SF3B1, SRSF2, U2AF1, ZRSR2), 30% in a signal transduction gene (KRAS, NRAS, CBL, FLT3, RUNX1, SETBP1), and 7% in a DNA damage response gene (TP53 and PHF6). Mutations in a single gene group were seen in 33% of patients, with 27% having mutations in 2 classes, 16% in 3 classes, and 9% involving 4 separate gene classes. Mutations in epigenetic regulatory genes correlated with increased monocyte count (p = 0.03) and transformation to blast phase (BP) (p = 0.04). Mutations in genes involved in histone modification correlated with increased number of immature myeloid cells (p = 0.001), decreased hemoglobin (p = 0.02), thrombocytopenia (p = 0.009), increased LDH (p = 0.02), increased DIPSS and DIPSS+ (p = 0.002 and 0.001) and were more likely to be transfusion dependent (OR: 3.67 [1.47-9.04]; p = 0.007). Splicing machinery mutations correlated with older age at presentation (p = 0.002). Mutations in signal transduction genes correlated with increased monocyte count (p = 0.006), increased peripheral blasts (p = 0.02) and BP transformation (p = 0.001). ASXL1 was associated with a better response to erythropoiesis-stimulating agents (p = 0.04). The number of individual mutations and affected gene classes correlated with age at diagnosis (p = 0.01 and 0.007). CALR mut MF was associated with improved overall survival (OS) as compared to JAK2V617F or MPLmut MF (HR 0.38 [0.17-0.85], p = 0.02). Triple-negative MF had inferior 2-yr survival of 65% as compared to 83% in JAK2/MPL mutated MF. SRSF2 mutations were associated with inferior OS (HR: 2.99 [1.03-8.69]; p = 0.04), whereas ASXL1 had a trend towards inferior OS (HR 2.09 [0.90-4.84]; p = 0.09. In multivariate regression analysis, controlling for DIPSS, SRSF2 remained significantly associated with OS (p = 0.02). An increased number of somatic mutations was associated with worse OS (HR 1.21 [1.03-1.43], p = 0.02) as was an increased number of affected gene classes. Conclusion: Somatic mutations correlate with clinical features of MF and few carry prognostic significance. SRSF2 mutations have prognostic effects independent of currently utilized risk scores, while the impact of ASXL1 was less clear and potentially captured in standard risk models. Additionally, we showed that mutation burden holds prognostic significance both in terms of quantity of mutations as well as number of affected classes. Disclosures Lancet: Amgen: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Kalo Bios: Consultancy; Jazz Pharmaceuticals: Consultancy; Biopath Holdings: Consultancy; ERYtech: Consultancy; Pfizer: Research Funding; Quantum First: Consultancy; Boehringer-Ingelheim: Consultancy; Baxalta: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy. Sweet:Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Karyopharm: Honoraria, Research Funding. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Although the JAK1/2 inhibitor RUX provides significant benefits to patients with myelofibrosis (MF), activation of non-JAK pathways could lead to therapeutic resistance, suggesting a need for rationally developed therapeutic combinations. We hypothesized that the combination of RUX and AZA would target distinct clinical and pathological manifestations of MF, resulting in synergistic efficacy. Updated phase II study results are presented in this abstract. Methods: This is a single-arm Phase II trial of RUX in combination with AZA for pts with MF. Eligible pts included adults >18 years with newly diagnosed or previously treated (excluding previous therapy with RUX or AZA) MF with int-1, int-2, or high risk according to the DIPSS criteria. RUX at 15-20 mg orally twice daily (BID) was given alone in 28 day cycles for the first 3 cycles. AZA was added from cycle 4 onwards at 25 mg/m2 days 1-5, and could be gradually up-titrated to 75 mg/m2 days 1-5 over subsequent cycles if clinically indicated. AZA could be initiated prior to cycle 4 in pts with proliferative disease or high bone marrow blasts. The primary objective was to determine the response rate per the IWG MRT 2013 criteria. Secondary objectives included safety and tolerability. Results: 60 pts were enrolled (58 evaluable, 2 too early) between May 2013 and June 2019. Pt characteristics are in Table 1. The median age was 66 years (range, 46-87). Forty pts (67%) had int-2/high DIPSS score, 9 (15%) had ≥10% blasts. JAK2V617Fwas detected in 35 pts (58%). Among 44 pts with comprehensive molecular panel, 21 (48%) had additional mutations (ADD mut), with the most frequent being ASXL1 and TET2 (8 pts each, 18%; Table 1), followed by IDH, TP53 and DNMT3A. AZA was given to 53 pts (88%), with 6 (11%) pts initiating AZA earlier than cycle 4. Median (med) follow-up was 35 months (range, 1-70+) with a med of 26 cycles (range, 1-70) administered. 20 pts (33%) are still on RUX AZA therapy, with a med of 47 cycles (range, 1-70), including 7 pts who have received >65 cycles. Twenty nine (48%) and 16 (30%) pts required RUX and AZA dose reduction and/or treatment interruption, respectively. Med dose of RUX was 15 mg BID (range, 5-25). Among 58 evaluable pts, 43 (74%) achieved IWG-MRT 2013 objective response (OR) on study (Table 2), with a med time to response of 2.0 months (range, 0.7-19.0). Among 43 pts with baseline splenomegaly ≥5 cm, 30 (70%) and 25 (58%) had palpable spleen reduction ≥50% at any time on study and at week 24, respectively. Thirty percent of responses (13/43), including responses in spleen (10/30), occurred only after the addition of AZA (Table 2). Med time to response after the addition of AZA was 4.0 months (range, 0.5-17.0). Median overall survival (OS) was not reached, with 1-year and 3-year OS rates of 89% and 66%, respectively. Improvement in bone marrow morphology (fibrosis, collagen and/or osteosclerosis), was noted in 21 (61%) of 35 sequentially evaluated patients (Figure 1, bone marrow improvements at 24 months and at any time on a study). The med time to response was 12.0 months (range, 6.0-18.0), and responses have been sustained in all but 1 patient. Updated results will be presented at the meeting. The med duration of responses (DoR) was not reached for OR, ≥50% spleen length reduction, or symptom response. Patients with ≥1 ADD mut appeared to have shorter DoR spleen (≥50% spleen length reduction) than those with no ADD mut; 47 months vs NR (p=0.05). Patients with TP53 and IDH1/2 mutation had shorter DoR (DoR [OR] 18.5 and 13.0 months, respectively) than those with no ADD mut, ASXL mut, or any other single ADD mut (DoR [OR] 46.0, 45.0 months and NR). The most common possibly therapy related non-hematological adverse events (AEs) were infections (28%) and constipation (11%). Significant hematological AEs included grade III-IV anemia (37%), neutropenia (18%) and thrombocytopenia (27%), these were transient and did not require therapy interruption in most cases. Only 4 pts discontinued therapy due to drug-related AEs (cytopenia in 4 pts). Table 3 summarizes AEs on study. Conclusion: Concomitant RUX with AZA appears safe and effective. Myelosuppression was manageable with only 4 pts (7%) requiring study discontinuation due to cytopenias, a similar rate to single agent RUX in phase III trials (7-9%). A 2013 IWG-MRT objective response and ≥50% spleen reduction were achieved in ≥ 70% of pts at any time on study; and responses appear durable. The study is ongoing (NCT01787487). Disclosures Verstovsek: Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation: Research Funding; Kartos: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Borthakur:Agensys: Research Funding; Novartis: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; PTC Therapeutics: Consultancy; AstraZeneca: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Cyclacel: Research Funding; Bayer Healthcare AG: Research Funding; Incyte: Research Funding; BMS: Research Funding; GSK: Research Funding; AbbVie: Research Funding; NKarta: Consultancy; Janssen: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo:celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; syros: Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria. Ravandi:Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Jazz Pharma: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Ariad: Research Funding.

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS). However, the expression of PD-1 and PD-L1 was found to be increased in CD34 positive cells from patients with MDS (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with its ligands PD-L1 and PD-L2. A phase 1b, multicohort study of pembrolizumab in advanced hematologic malignancies revealed that a small number of patients with higher-risk MDS had long-term survival and no immune-mediated adverse events (Garcia-Manero G, Blood 2016). We report updated results from a phase II clinical trial evaluating the safety and clinical activity of the combination of azacitidine and pembrolizumab in previously-untreated patients with higher-risk MDS. Methods: Adult patients with untreated intermediate-1- or higher-risk disease by the International Prognostic Scoring System (IPSS) with adequate renal and hepatic function and no prior stem cell transplantation, active autoimmune disease, or immunodeficiencies were eligible for the study. Patients received azacitidine 75 mg/m2 intravenously (IV) or subcutaneously daily for 7 days every 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 21 days thereafter independent of the azacitidine dosing schedule. The endpoints were overall response rate, survival, and safety. The criteria for early trial termination included an overall response rate (ORR) &lt; 20%, incidence of grade 3-4 adverse events (AEs) &gt; 30%, poor adherence to protocol and regulatory requirements, severe and adverse drug reactions, and plans to modify or discontinue development of the study drug. Clinical trial information: NCT03094637. Results: At data cut-off (July 2020), 17 therapy-naïve patients have been enrolled and treated with frontline combination azacitidine and pembrolizumab with a median follow-up time of 13.8 months and 5 patients continuing on treatment in cycles 4-28. The median age of patients treated is 71 years (range 36-82), and additional patient characteristics are depicted in Figure A. The overall response rate is 80%, with 3 patients reaching complete remission (CR), 4 patients attaining marrow CR (mCR), 4 patients exhibiting mCR with either hematologic improvement of platelets (HI-P) or erythrocytes (HI-E), and 1 patient demonstrating HI-E. Out of the 12 responders, 7 patients have normal cytogenetics, 1 has del(7q), 1 has del(5q), and 1 has complex karyotype. The most frequently observed mutations in these individuals are TET2 in 5 patients, ASXL1 and SRSF2 in 4 patients each, and RUNX1 and TP53 in 3 patients each. Overall survival was not reached in the frontline HMA + immunotherapy cohort (Figure B). Treatment was overall well-tolerated. The most common treatment-related adverse events (all grades) observed were arthralgias (40%), pneumonia (33%), nausea (27%), and skin rash (27%). One patient died in the first 60 days while receiving treatment from the unrelated cause of ventricular fibrillation. Conclusions: In this phase II trial, preliminary data suggest that combining azacitidine and pembrolizumab was relatively safe and well-tolerated in patients who had never received prior therapy. Though overall survival was not yet reached with the current follow-up time, combination therapy may have antitumor activity in these patients. Figure 1 Disclosures Borthakur: Abbvie: Research Funding; Jannsen: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Treadwell Therapeutics: Consultancy; Cyclacel: Research Funding; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Research Funding; Polaris: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; GSK: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cortes:Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding. DiNardo:MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Alvarado:BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding. Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; CTI BioPharma: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Jain:Pfizer: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Immunogen: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS), but the survival of patients after failure of HMA therapy is poor at approximately 4 to 6 months. Expression of PD-1 and PD-L1 was increased in CD34 positive cells from patients with MDS with further upregulation following HMA therapy and HMA failure (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2. A phase Ib, multicohort study of pembrolizumab in advanced hematologic malignancies showed a small number of patients with long-term survival and no immune-mediated adverse events in the higher-risk MDS cohort (Garcia-Manero G, Blood 2016). We report updated results from an ongoing phase II clinical trial evaluating the safety and clinical activity of azacitidine and pembrolizumab in patients with higher-risk MDS. Methods: Adult patients with intermediate-1- or higher-risk disease by the International Prognostic Scoring System (IPSS) with adequate renal and hepatic function and no prior stem cell transplantation, active autoimmune disease, or immunodeficiencies were eligible for the study. Patients were divided into two cohorts: those who were treatment-naïve and those who had not responded to, progressed on, or relapsed after HMA therapy. Patients received azacitidine 75 mg/m2 intravenously (IV) or subcutaneously daily for 7 days every 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 21 days thereafter independent of the azacitidine dosing schedule. The endpoints were overall response rate, survival, and safety. The criteria for early trial termination included an overall response rate (ORR) < 20%, incidence of grade 3-4 adverse events (AEs) > 30%, poor adherence to protocol and regulatory requirements, severe and adverse drug reactions, and plans to modify or discontinue development of the study drug. Clinical trial information: NCT03094637. Results: At data cut-off (July 2019), 35 patients have been enrolled and 30 patients treated with combination azacitidine and pembrolizumab with a median follow-up time of 10.7 months and 10 patients continuing on treatment in cycles 1-16. Twenty patients were enrolled in the HMA failure cohort and 10 patients in the treatment-naïve MDS cohort. Overall responses rates were 30% in the HMA failure cohort and 70% in the HMA therapy-naïve cohort. In the HMA failure cohort, 2 patients achieved complete remission (CR), 2 patients attained marrow CR (mCR), and 2 patients showed hematological improvement of platelets (HI-P). In the previously untreated MDS cohort, 2 patients reached CR, 2 patients had mCR, 2 patients exhibited mCR with HI-P, and 1 patient demonstrated HI-P. The most frequently observed mutations in the 13 responding patients were ASXL1 and TET2 in 4 patients each and DNMT3A and TP53 in 3 patients each. Six of the responders had normal cytogenetics, 1 had del(20q), and 2 had complex karyotype. Overall survival was 5.9 months in the HMA failure cohort and 12.9 months in the HMA naïve cohort. Treatment was overall well-tolerated. The most common treatment-related adverse events (all grades) were neutropenia (37%), myalgias/arthralgias (20%), constipation (17%), and elevated alanine aminotransferase levels and injection site reactions (13%). Three patients died in the first 60 days while receiving treatment from the unrelated causes of cardiac arrest from ventricular fibrillation, septic shock and multiorgan failure, and fungal pneumonia. Conclusions: In this ongoing phase II trial, preliminary data suggest that azacitidine and pembrolizumab was relatively safe and well-tolerated. Combination therapy may have antitumor activity in patients who failed HMA, though no significant improvement in overall survival was observed. Disclosures Borthakur: FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AbbVie: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Xbiotech USA: Research Funding; Strategia Therapeutics: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Bayer Healthcare AG: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Cyclacel: Research Funding; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; Agensys: Research Funding; Oncoceutics: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Eli Lilly and Co.: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Daver:Astellas: Consultancy; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Forty-Seven: Consultancy; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Cortes:Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding. DiNardo:agios: Consultancy, Honoraria; syros: Honoraria; medimmune: Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Bose:Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Jain:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Jazz Pharma: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Astex: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; BMS: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS), but the survival of patients after failure of HMA therapy is poor at approximately 4 to 6 months. Expression of PD-1 and PD-L1 was increased in CD34 positive cells from patients with MDS with further upregulation following HMA therapy and HMA failure (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2. A phase 1b, multicohort study of pembrolizumab in advanced hematologic malignancies showed a small number of patients with long-term survival and no immune-mediated adverse events in the higher-risk MDS cohort (Garcia-Manero G, Blood 2016). We report final results from a phase II clinical trial evaluating the safety and clinical activity of azacitidine and pembrolizumab in patients with higher-risk MDS after failure of hypomethylating agent therapy. Methods: Adult patients with intermediate-1- or higher-risk disease by the International Prognostic Scoring System (IPSS) with adequate renal and hepatic function and no prior stem cell transplantation, active autoimmune disease, or immunodeficiencies were eligible for the study. For this HMA failure cohort, patients had to not respond to, progress on, or relapse after at least 6 cycles of HMA therapy. Patients received azacitidine 75 mg/m2 intravenously (IV) or subcutaneously daily for 7 days every 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 21 days thereafter independent of the azacitidine dosing schedule. The endpoints were overall response rate, survival, and safety. The criteria for early trial termination included an overall response rate (ORR) &lt; 20%, incidence of grade 3-4 adverse events (AEs) &gt; 30%, poor adherence to protocol and regulatory requirements, severe and adverse drug reactions, and plans to modify or discontinue development of the study drug. Clinical trial information: NCT03094637. Results: At data cut-off (July 2020), 20 patients with HMA failure have been enrolled and treated with combination azacitidine and pembrolizumab with 2 patients continuing on treatment in cycles 30 and 33. The median age of patients treated is 74.5 years, and additional patient characteristics are shown in Figure A. The overall response rate is 25%, with 1 patient achieving complete remission (CR), 2 patients attaining marrow CR (mCR), and 2 patients showing hematological improvement of platelets (HI-P). One of the responders has normal cytogenetics, 1 has del(20q), 1 has del(5q), and 1 has complex karyotype. The most frequently observed mutations in the 5 responding patients are ASXL1 and SETBP1 in 2 patients each. Interestingly, the patient on treatment in cycle 33 has 2 separate TP53 mutations and continues to have stable disease with sustained transfusion independence. With a median follow-up time of 27.9 months, the overall survival is 6.1 months (Figure B). Treatment is overall well-tolerated. The most common treatment-related adverse events (all grades) observed are neutropenia (40%), pneumonia (35%), constipation (30%), and febrile neutropenia (25%). Two patients died in the first 60 days while receiving treatment from the unrelated causes of septic shock and fungal pneumonia. Conclusions: This phase II trial suggests that the combination of azacitidine and pembrolizumab was relatively safe and well-tolerated in patients who had previously failed HMA therapy. Though no significant improvement in overall survival was observed, combination therapy may have antitumor activity in certain HMA failure patients, resulting in sustained responses in some high-risk individuals. Figure Disclosures Borthakur: PTC Therapeutics: Consultancy; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Incyte: Research Funding; AstraZeneca: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Novartis: Research Funding; PTC Therapeutics: Research Funding. Daver:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Immunogen: Research Funding; Merus: Research Funding; Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding. DiNardo:MedImmune: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Calithera: Research Funding; Novartis: Consultancy; Jazz: Honoraria; Takeda: Honoraria. Jabbour:Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding. Alvarado:FibroGen: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Jain:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Ascentage: Research Funding; BMS: Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding.

Introduction: Tyrosine kinase inhibitors (TKIs) are an effective therapy for pts with CML. However, resistance to treatment driven by point mutations in the ABL kinase domain, particularly the T315I mutation, represents a clinical challenge. The T315I mutation confers resistance to all approved ATP-competitive TKIs except ponatinib (PON) and is associated with significantly worse clinical outcomes. PON use, however, is limited in many patients by its safety profile. Asciminib has a distinct mechanism of action and is the first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor. Asciminib demonstrated clinical activity in heavily pretreated CML pts with or without mutations, with promising efficacy in pts with T315I, including those resistant to/intolerant of (R/I) PON. Methods: This phase 1 study enrolled adults with CML in chronic phase (CP) or accelerated phase (AP) R/I ≥ 2 TKIs; pts with T315I were eligible after receiving ≥ 1 TKI if no other effective therapy was available. Pts with uncontrolled cardiovascular conditions were excluded. Pts with T315I were assigned to varying dose levels in phase 1, and 200 mg twice daily (BID) was selected for cohort expansion. Here, we report updated efficacy and safety results in pts with T315I who received 200 mg BID (data cutoff: April 2, 2020). Results: A total of 52 pts with T315I received asciminib 200 mg BID. At the data cutoff, treatment was ongoing in 35/52 pts (67.3%); 17 (32.7%) discontinued treatment, a majority of whom (10 [19.2%]) discontinued due to physician's decision, mainly for unsatisfactory response (Table 1). Of pts still on treatment, 31/35 (88.6%) received treatment for &gt; 48 wk. The median duration of exposure was 68.4 wk (range, 2-175 wk) and median dose intensity was 399.0 mg/day (range, 188-400 mg/day). Among evaluable pts not in major molecular response (MMR) at baseline, 23/49 (46.9%) achieved MMR and 21 of these responders were still in MMR at the time of data cutoff; 40.8%, 42.9%, 44.9%, and 46.9% had MMR by 24, 48, 72, and 96 wk, respectively. The Kaplan-Meier-estimated rate of durable first MMR among pts who achieved MMR was 87% (95% CI, 68.4-100.0) at 96 wk and remained unchanged until 144 wk. The median time to MMR was 12.1 wk (range, 4-84 wk). By 24 wk, 57.1% of PON-naive pts and 28.6% of PON-pretreated pts achieved MMR (Table 2). Three additional pts achieved MMR after 24 wk: 2 PON naive and 1 PON pretreated. The estimated cumulative MMR rate at 60 wk increased to 66% and 32% in PON-naive and PON-pretreated pts, respectively (Figure). Among 26 pts who did not achieve MMR, 3 had additional mutations (E255K, E355G, F359I) at baseline and 6 acquired new mutations after baseline (F359I [n = 2], A337T/F359V, M351T, M244V, E453Q). Among 2 pts who lost MMR, 1 acquired a new F359V mutation. Among evaluable pts without MMRat baseline, 13/49 (26.5%) and 10/49 (20.4%) achieved MR4 and MR4.5, respectively. Treatment-related adverse events (AEs) were reported in 45/52 pts (86.5%) and were mainly mild in severity; grade ≥ 3 AEs were reported in 17/52 pts (32.7%). All-grade serious AEs were reported in 12 pts (23.1%), with 2 (3.8%) deemed treatment related. No on-treatment deaths were reported. On-treatment AEs leading to discontinuation were reported in 4 pts (7.7%; disease progression, grade 2 thrombocytosis, grade 3 lipase elevation, and grade 4 pancytopenia, 1 pt each). Dose reductions and interruptions (excluding dosing errors) were reported in 21 (40.4%) and 22 (42.3%) pts, respectively (reduction and/or interruption in 29 pts total); they were mainly due to AEs (13 [25.0%] and 18 [34.6%] pts, respectively). The most frequent any-grade AEs of special interest (occurring in ≥ 10% of pts) were gastrointestinal toxicity (48.1%), hypersensitivity (26.9%), myelosuppression (25.0%), pancreatic toxicity (25.0%), hepatotoxicity (23.1%), thrombocytopenia (21.2%), hemorrhage (17.3%), leukopenia (15.4%), and edema and fluid retention (13.5%). Ischemic stroke and peripheral arterial occlusive disease were each reported in 1 pt; both pts had underlying cardiovascular disease. Conclusions: Asciminib 200 mg BID monotherapy continued to demonstrate a favorable safety profile and clinical efficacy in pts with CML-CP/AP harboring the T315I mutation, with durable MMR seen in almost half of the patients. Asciminib is a promising therapeutic option for pts with CML-CP/AP with T315I, including those for whom PON treatment has failed. Disclosures Cortes: Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Telios: Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Hochhaus:Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Janssen:MSD: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Roche: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Takeda: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steegmann:Novartis: Honoraria, Other: Speaker; Bristol-Myers Squibb: Honoraria, Other: Speaker; Incyte: Honoraria, Other: Speaker; Pfizer: Honoraria, Other: Speaker. Heinrich:Novartis: Consultancy, Patents & Royalties: Patent on treatment of GIST licensed to Novartis; Blueprint Medicines: Consultancy; Deciphera: Consultancy, Speakers Bureau. Talpaz:IMAGO: Consultancy; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Etienne:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Deininger:Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fusion Pharma: Consultancy; Novartis: Consultancy, Other, Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC: Research Funding; Pfizer: Honoraria, Other, Research Funding; DisperSol: Consultancy; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; Leukemia & Lymphoma Society: Research Funding; Ariad: Consultancy, Honoraria, Other; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding. le Coutre:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Lang:Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Aimone:Novartis: Current Employment. Polydoros:Novartis: Current Employment, Current equity holder in publicly-traded company. Cacciatore:Novartis: Current Employment. Stenson:Novartis: Current Employment. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Introduction Second-generation FLT3i demonstrated composite CR rates (CRc) of 45-55% in pts with relapse/refractory (R/R) FLT3-mutated AML in phase II/III (ADMIRAL, QUANTUM-R) trials. However, &gt;85% of pts treated in these trials were prior FLT3i naïve as these trials enrolled most of their pts prior to midostaurin approval. The response rates to sequential FLT3i exposure remain poorly defined. The goal of this analysis was to provide benchmark response rates to second and even potentially third sequential FLT3i exposures. Methods We retrospectively reviewed adult pts with FLT3-mutated AML treated between Jan 2006 and Dec 2019 at our institution. Single agent FLT3i, FLT3i-based combinations with cytotoxic chemotherapy (CCT) and with low intensity therapy (LIT) (hypomethylating agent or low-dose cytarabine based combinations) were included. Cohort 1 (Figure 1A) included pts who received first FLT3i-based therapy in the "frontline induction" followed by post-induction FLT3i-based salvage therapies. Cohort 2 (Figure 1B) included pts who received their first FLT3i-based therapy in "salvage" followed by sequential FLT3i based therapies in subsequent salvages. Results A total of 239 pts with FLT3-ITD and/or FLT3-D835 mutated AML who received FLT3i based treatments were identified (Table 1). Cohort 1 - First FLT3i exposure in frontline setting In frontline pts who received a FLT3i (cohort 1), the CRc rates with the first "induction" (n=56), and post-induction salvage: second (n= 32) and third FLT3i-based (n= 8) therapies, were 77%, 31%, and 25% respectively (Table 2A). The median overall survival (OS) with the first, second and third FLT3i-based therapies were 16.7 months, 6.0 months, and 1.4 months, respectively. Cohort 2 - First FLT3i exposure in salvage setting In pts receiving a FLT3i-based therapy for the first time in a R/R AML setting (i.e. no FLT3i with induction) (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n=183), second (n=89), and third/fourth (n=29) sequential FLT3i-based therapies, respectively (Table 2B). Single-agent versus Combination FLT3i-based therapies In cohort 1, in the post-induction salvage setting, the CRc rates with single-agent FLT3i (n=21) versus combinations (n=19) were 19% versus 42%, respectively. (Table 2A). In cohort 2, the CRc rates with single-agent FLT3i (n=82) versus FLT3i-based combinations (n=101) in first FLT3i exposure were 34% versus 53%, respectively, and with single agent FLT3i (n=63) versus FLT3i-based combinations (n=55) in the second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively (Table 2B). The median OS with the first FLT3i-based therapy in salvage AML was 5.4, 10.4, and 9.9 months with single-agent, LIT, and CCT FLT3i-based therapies, respectively (P&lt;0.001) (Figure 2A). Median OS with the second FLT3i-based therapy exposure in salvage AML was 2.8, 5.3, and 4.7 months, with single-agent, LIT, and CCT FLT3i-based therapies, respectively (P=0.174) (Figure 2B). Impact of Minimal Residual Disease at CRc in Cohort 2 In the salvage AML (cohort 2), 104 of 301 achieved CRc, and 84 of 104 (80%) of these pts had serial FLT3-ITD/TKD PCR checked on the bone marrow at baseline and at CRc. Pts who achieved MRD negativity by FLT3-PCR had improved OS (16.3 versus 8.5 months, P=0.04) and event free survival (EFS) (12.2 versus 3.3 months, P&lt;0.001) (Figure 3A-B). Achievement of MRD-negativity by MFC at CRc was however not associated with a significant impact on OS (9.8 vs 10.7 months, P=0.55) nor EFS (4 vs 3.4 months, P=0.19). Conclusion The CRc rates and median OS dropped with sequential FLT3i exposure, from induction to post-induction salvage (cohort 1) and sequentially in subsequent salvages (cohort 2). FLT3i combinations demonstrated improved CRc rates and improved OS compared with single agent FLT3i's in all similar FLT3i exposure settings. Achievement of MRD negativity by FLT3-PCR improved OS in R/R setting. These data provide benchmark expectations in the "post-midostaurin" and now "post-gilteritinib" era for clinical trials evaluating combinations of FLT3i's with chemotherapy, hypomethylating agents, venetoclax, and triplets of hypomethylating agents with venetoclax and FLT3i's in R/R FLT3-AML, a majority of whom will have received one or more prior FLT3 TKI therapies. Disclosures Yilmaz: Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Kadia:Pfizer: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; JAZZ: Honoraria, Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Jazz: Honoraria; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; MedImmune: Honoraria; Syros: Honoraria; Takeda: Honoraria. Borthakur:Incyte: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; Treadwell Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Cyclacel: Research Funding. Konopleva:Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; Agios: Research Funding; AstraZeneca: Research Funding; Kisoji: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Merck: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Pemmaraju:Plexxikon: Research Funding; Cellectis: Research Funding; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Incyte Corporation: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Cortes:Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian:Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Ravandi:AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: BOS is approved for patients (pts) with Philadelphia chromosome-positive (Ph+) CML resistant/intolerant to prior therapy and pts with newly diagnosed Ph+ CP CML. Approval of first-line BOS was based on the primary results from the phase 3 BFORE trial, which showed superior efficacy vs imatinib (IMA) in the modified intent-to-treat (ITT) population (pop; Ph+ with e13a2/e14a2 transcripts) after ≥12 mo of follow-up. We report the final efficacy and safety results from the BFORE trial after 5 y of follow-up. Methods: In the open-label BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive BOS (n=268) or IMA (n=268; 3 untreated), both at 400 mg once daily. Efficacy was assessed in the ITT pop (all randomized pts). Long-term secondary endpoints included duration of response (DOR), on-treatment event-free survival (EFS) and overall survival (OS). Safety was assessed in the safety pop (all treated pts). This final analysis was based on an April 17, 2020 last pt last visit (June 12, 2020 database lock), 5 y (240 weeks) after the last enrolled pt. Results: At study completion in BOS and IMA arms, respectively, 59.7% and 57.4% were still on treatment, 86.6% and 86.2% completed 5 y on study. Median duration of treatment and time on study was 55.2 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 394 (39-583) vs 400 (189-765) mg/d. Cumulative major molecular response (MMR) rate by 60 mo was higher with BOS vs IMA (73.9% vs 64.6%), as was cumulative molecular response (MR)4 (58.2% vs 48.1%) and MR4.5 rate (47.4% vs 36.6%; Table). Among evaluable pts, more pts in the BOS arm achieved BCR-ABL1 ≤10% at 3 months (Table); cumulative MMR by 60 mo was higher in pts with transcripts ≤10% vs &gt;10% in both treatment arms (BOS, HR 2.67 [95% CI, 1.90-3.75]; IMA, HR 3.12 [2.19-4.45]). Pts in the BOS arm achieved responses earlier than pts in the IMA arm; cumulative incidence function for MMR, MR4 and MR4.5 was higher with BOS vs IMA (HR [95% CI]: MMR 1.34 [1.10-1.64], MR4 1.34 [1.07-1.69], MR4.5 1.41 [1.09-1.83]). Among responders, duration of MMR was similar for BOS and IMA (Table). Superior MRs with BOS vs IMA were consistent across Sokal risk groups, with the greatest difference seen in pts with high Sokal risk (Table). On-treatment transformations to accelerated/blast phase (AP/BP) occurred in 6 (AP 3; BP 3) BOS- and 7 (AP 6; BP 1) IMA-treated pts. No transformation occurred after the 24-mo follow-up. In all, 18 BOS- vs 25 IMA-treated pts had EFS events. There were no differences in EFS between treatment arms; cumulative incidence of on treatment progression/death at 60 mo was 6.7% for BOS vs 9.3% for IMA (Table). The 60-mo OS rates were similar (94.5% and 94.6%; Table); 14 BOS- and 14 IMA-treated pts died during the study period: 3 and 4 were CML-related, 0 and 1 were due to adverse events (AEs) related to study treatment. The most common reasons for permanent discontinuation were AEs (25.0% vs 12.5%) and lack of efficacy (4.9% vs 16.2%). Treatment-emergent AEs (TEAEs) occurred in 98.9% of pts in each arm; most common (&gt;30%) were diarrhea (75.0%), nausea (37.3%), thrombocytopenia (35.8%) and increased alanine aminotransferase (ALT; 33.6%) with BOS, and diarrhea (40.4%), nausea (42.3%) and muscle spasms (30.6%) with IMA. Most TEAEs occurred during the first year of treatment. Grade 3/4 TEAEs occurred in 73.5% of BOS- vs 57.0% of IMA-treated pts; most common (&gt;5%) were increased ALT (20.9%) and lipase (13.4%), thrombocytopenia (14.2%), increased aspartate aminotransferase (10.4%), diarrhea (9.0%) and neutropenia (7.5%) with BOS, and neutropenia (13.6%), thrombocytopenia (6.0%), anemia (5.7%) and increased lipase (5.7%) with IMA. No individual AE led to discontinuation in &gt;5% of pts. The most frequent AEs leading to permanent treatment discontinuation were increased ALT (4.9%) with BOS vs thrombocytopenia (1.5%) with IMA; 1.5% vs 1.1% of pts discontinued due to diarrhea. Conclusions: At 5 y, first-line BOS continued to show superior efficacy vs IMA; BOS-treated pts achieved earlier and deeper molecular response. An improvement in MR with BOS was demonstrated across Sokal risk groups, with the greatest benefit vs IMA observed in Sokal high-risk pts. Long-term AEs were generally manageable, and consistent with previous reports and the known safety profiles of both drugs. These results confirm the use of BOS as a standard of care in pts with newly diagnosed CP CML. Disclosures Brümmendorf: Takeda: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Merck: Consultancy; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding. Cortes:Astellas: Research Funding; Arog: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Immunogen: Research Funding; Telios: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis: Consultancy, Research Funding. Milojkovic:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Clark:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Ariad/Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, 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. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Garcia-Gutiérrez:Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Other: Travel, Research Funding; Korea Otsuka Pharmaceutical: Honoraria. Kota:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Ariad: Honoraria; Incyte: Honoraria; Xcenda: Honoraria. Lipton:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Rousselot:Incyte: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Mauro:Sun Pharma/SPARC: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Hochhaus:MSD: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hurtado Monroy:Incyte: Consultancy; Pfizer: Consultancy. Leip:Pfizer: Current Employment, Current equity holder in publicly-traded company. Purcell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Yver:Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira:Pfizer: Current Employment, Current equity holder in publicly-traded company. Deininger:Gilead Sciences: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Other; SPARC: Research Funding; DisperSol: Consultancy; Pfizer: Honoraria, Other, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galena: Consultancy, Honoraria, Other.

Background: The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) are Philadelphia negative myeloid neoplasms with overlapping clinicopathological features of both MPNs and MDS. Ruxolitinib (RUX), a JAK 1/2 inhibitor is FDA approved for primary myelofibrosis. The hypomethylating agents, azacitidine (AZA) and decitabine, are approved for MDS. The independent activity of RUX and AZA in patients with MPNs and MDS, respectively, and their non-overlapping toxicity profiles suggest that the combination of these two agents administered sequentially and at lower doses may be tolerable and efficacious in patients with MDS/MPNs. Herein we present updated results from a Phase II trial. Methods: This is a single-arm Phase II trial of RUX in combination with AZA for patients (pts) with MDS/MPNs. Eligible pts included adults > 18 years with newly diagnosed or previously treated (excluding previous therapy with RUX or AZA) MDS/MPNs with intermediate-1, intermediate-2, or high risk according to the DIPSS criteria for PMF. RUX at 15-20 mg orally twice daily was to be given alone in 28 day cycles for the first 3 cycles. AZA was to be added from cycle 4 onward at 25 mg/m2 days 1-5, and could be gradually up-titrated to 75 mg/m2 days 1-5 over subsequent cycles if clinically indicated. AZA could be initiated prior to cycle 4 in pts with proliferative disease or high bone marrow blasts. The primary objective was to determine the response rate per the 2015 IWG MDS/MPN response criteria. The secondary objective was to determine the safety and tolerability of the combination therapy. Results: Forty-five pts were enrolled between May 2013 and June 2019. The median age was 68 years; 64% were ≥65 years, 77.7% were int-2 or high risk by DIPPS. Twenty one (46.6%) pts had splenomegaly and 16 (35.5%) pts had EUMNET MF-2 or MF-3. JAK2V617F mutation was present in 16 pts (35.5%). Thirteen pts had pre-therapy BM blasts >5%. The pts. characteristics are in Table 1. Fourty three pts were evaluable for response at the time of this report. AZA was given to 41/45 pts (91.1%), with 26 (63%) pts initiating the AZA before cycle 4 due to increased of bone marrow blast or proliferative disease. After a median follow-up of 30.8 months (mo), 19 pts are still alive. 24 pts (56%) achieved an objective IWG 2015 response. The median time to IWG response was 1.8 mo (0.4-5.5). A ≥50% palpable spleen length reduction was seen in 64% (9/14) of evaluable pts with a median time to response of 1.0 mo. 8/13 (62%) evaluable pts achieved a BM blast reduction to <5%. Specific responses are listed in Table 2. No significant difference in JAK2 mutation status (p=0.215) or frequency of splenomegaly (p=0.298) was noted between responders and non-responders. The most common possibly related non-hematological adverse events were grade I-II constipation (22.2%), nausea (15.5%) and pain (15.5%). Significant possibly related hematological AEs included grade III-IV anemia (35.5%), neutropenia (22.2%) and thrombocytopenia (53.3%), these were usually transient and only 2 pts had to discontinue protocol therapy due to cytopenias. All possibly related adverse events are listed in Table 3. Five pts progressed to AML, with a median time to progression of 13.8 mo. Overall, the median OS was 25.4 mo with 1-year and 3-year OS rates of 86% and 40%. Pts with MDS/MPN-U had a better median OS compared with CMML and aCML (31.8 mo vs. 16 mo vs. 1.5 mo; p=0.009). Figure 1 depicts OS by diagnosis. The 1-year and 3-year OS rates for pts with MDS/MPN-U were 100% and 46%, respectively. The median duration of response was 8.35 mo (range 2.1-14.6 mo).The median OS of 31.8 mo among MDS/MPN-U pts compares favorably to a median OS of 16.1 mo from the previously published historical cohort of MDS/MPN-U patients treated with AZA alone (N = 36) at our institution (DiNardo C et al, Leukemia 2014). Conclusions: RUX in combination with AZA was safe and effective and may be a therapeutic option to consider, especially in pts with MDS/MPN-U. Transient grade III-IV myelosuppression was frequently seen, but only 2 pts (4.4%) required treatment discontinuation, which is similar to discontinuation rates with single agent RUX in MF in COMFORT studies (8-9%). Overall response rate was 56%. Additionally 63% BM remissions were noted among pts with ≥5% blast at baseline. The clinical trial is still recruiting (NCT01787487) and focussed on enrolling MDS/MPN-U pts. Disclosures Kantarjian: BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Astex: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cortes:Merus: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Pemmaraju:novartis: Consultancy, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; cellectis: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AbbVie: Research Funding; Bayer Healthcare AG: Research Funding; GSK: Research Funding. Wierda:GSK/Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Pharmacyclics LLC: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding. Daver:Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Ruxolitinib a JAK1/2 is approved for the treatment of MF and PV HMA decitabine and azacitidine are approved for MDS This trial is combining azacitidine and ruxolitinib in MDS/MPNs

Background: Low-dose hypomethylating agents (HMAs) (azacitadine or decitabine) are safe and effective in patients with myelodysplastic syndromes (MDS). The aims of this study are to report the long-term follow-up of the phase 2 study of azacitidine or decitabine in lower-risk MDS and to identify specific populations of patients with lower-risk MDS who may benefit from early intervention with HMA therapy. Methods: Patients with previously untreated MDS or chronic myelomonocytic leukemia with low or intermediate-1 risk by the international prognostic scoring system (IPSS) were randomized with a Bayesian response-adaptive design, and received either decitabine 20 mg/m2 daily or azacitidine 75 mg/m2 daily on days 1-3 every 28-day cycle. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Overall survival (OS) was defined as the time duration from the start of therapy to the date of death from any cause or the date of last follow-up, whichever came first. A linear mixed effect model with fixed and random effect was assessed for the longitudinal repeated measurements of the percentage of blasts in bone marrow during the study treatment. Multivariate Cox regression analysis was performed to identify prognostic factors for survival after variable selection with a P-value cutoff of 0.250 by univariate analysis. Historical comparison was performed to identify subgroups of patients who had benefit from HMA therapy. Results: Between November 12, 2012 and February 15, 2016, 113 patients were enrolled and treated with a median follow-up of 59 months: 73 (65%) patients were treated with decitabine and 40 (35%) were treated with azacitadine (Table 1; Figure 1). The median time from MDS diagnosis to the first date of therapy was 1.4 months (range, 0.2-49.8) and 0.9 months (range, 0.3-62.5) in the decitabine and azacitidine groups, respectively (P=0.052). The overall response rate was 67% and 48% in the decitabine and azacitidine groups, respectively (P=0.042); among 59 patients with baseline transfusion dependency, 19 (32%) achieved transfusion independence [decitabine, 16/39 (41%); azacitidine, 3/20 (15%); P=0.039]. The linear mixed effect model showed the equivalent longitudinal estimation of the percentage of blasts during the study (azacitadine vs. decitabine: P=0.989; estimate, -0.015; 95% CI, -2.325 - 2.295) (Figure 2). The median OS were 30 months and 37 months in the azacitadine and decitabine, respectively (P=0.625); the 5-year OS rates were 32% and 33%, respectively. By MD Anderson low-risk prognostic scoring system (MDA-LR-PSS), the median OS were not reached, 34 months, and 28 months in the low-, intermediate-, and high-risk groups, respectively (P&lt;0.001); the 5-year OS rates were 52%, 38%, and 22%, respectively (Figure 3). Multivariate analysis identified prior history of cytotoxic chemotherapy or radiation (P=0.002; hazard ratio [HR], 2.665; 95% confidence interval [CI], 1.436-4.944), transfusion dependency (P=0.016; HR, 2.023; 95% CI, 1.143-4.944), mutations in DNMT3A (P=0.006; HR, 4.266; 95% CI, 1.509-12.062), TP53 (P&lt;0.001; HR, 5.594; 95% CI, 2.198-14.234), U2AF1 (P=0.018; HR, 2.263; 95% CI, 1.153-4.442), and complete response to HMA therapy (P&lt;0.001; HR, 0.295; 95% CI, 0.154-0.568) as prognostic factors for survival. Type of HMA therapy was not prognostic factor for survival by univariate analysis (P=0.625; HR, 0.891; 95% CI, 0.559-1.418). When compared with a historical control cohort of 648 patients with low/intermediate-1 risk IPSS not treated with frontline HMAs, the survival improvement with low-dose HMA was notable in the high-risk cohort by MDA-LR-PSS (P=0.014; HR, 0.597; 95% CI, 0.396-0.900). Conclusion: Low-dose HMA therapy can achieve transfusion independency in transfusion-dependent patients with lower-risk MDS, and can improve survival compared to historical data in patients with high-risk features by the MDA-LR-PSS. Disclosures Sasaki: Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy. Jabbour:Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Kadia:Ascentage: Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; BMS: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Astellas: Research Funding; Astra Zeneca: Research Funding; Cellenkos: Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Jannsen: Research Funding; Treadwell Therapeutics: Consultancy; BioLine Rx: Research Funding; GSK: Research Funding; Novartis: Research Funding; PTC Therapeutics: Research Funding; PTC Therapeutics: Consultancy; Abbvie: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Incyte: Research Funding; BioTherix: Consultancy; BioLine Rx: Consultancy; Cyclacel: Research Funding; Curio Science LLC: Consultancy. Pemmaraju:DAVA Oncology: Honoraria; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; AbbVie: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria. Cortes:Immunogen: Research Funding; Merus: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado:BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding.

Background: The survival of patients with chronic myeloid leukemia (CML) in chronic phase (CP) is approaching that of general population particularly in patients who achieved cytogenetic and/or molecular response. However, a proportion of patients on tyrosine kinase inhibitors (TKIs) develop intolerance and/or resistance, and required subsequent TKI therapy. The aims of this study is to evaluate the outcome of patients with CML-CP treated with third-line TKI therapy. Methods: We performed a retrospective review of patients with CML-CP or accelerated phase (AP) who received a third-line TKI therapy at out institution. Overall survival was calculated from the start of TKI therapy until death from any cause at any time. Univariate and backward multivariate Cox regression was performed to identify prognostic factors for survival after variable selections by a p value cutoff of 0.250 by univariate analysis. Time to stem cell transplant during the third-line TKI therapy was handled as a time-dependent variable. Results: Between March 2005 and November 2015, 178 patients who received 1 third-line TKI therapy were included in the analysis: 65 (64%) patients nilotinib; 63 (35%) dasatinib; 22 (12%) ponatinib; 15 (8%) imatinib; and 13 (7%) bosutinib. Patient characteristics are described in Table1. Among 22 patients on ponatinib, 21 (95%) patients had prior history of resistance to second-generation TKIs. Overall, the median follow-up was 73 months (range, 0.6-175.2) without significant difference by TKI therapy (P=0.260); nilotinib, 78 months; dasatinib, 73 months; ponatinib, 100 months; imatinib, 64 months; bosutinib, 72 months. The median time from the diagnosis of CML-CP to third-line TKI therapy was 58 months (range, 2.96-195.7). Among 178 patients, 164 (92%) patients received imatinib as the first TKI therapy; 7 (4%), nilotinib; 3 (2%), dasatinib; and 4 (2%), ponatinib. Eighty-nine (50%) received dasatinib as the second TKI therapy; 64 (36%), received nilotinib; 15 (8%), bosutinib; 6 (3%), imatinib; and 4 (2%), ponatinib. Among 154 evaluable patients, 90 (58%) molecular response 4.5 (MR4.5) (BCR-ABL1 ≤0.0032% [IS]); 9 (5%) molecular response 4 (MR4) (BCR-ABL1 ≤0.01% [IS]); 16 (9%) major molecular response (MMR) (BCR-ABL1 ≤0.1% [IS]) 13 (7%), BCR-ABL1 ≤1% (IS); and 26 (15%) had no response. Of the 178 patients 81 (45%) discontinued TKI therapy due to intolerance and/or resistance. The median duration of the third-line TKI therapy was 9 months (range, 1.0-86.9). Overall, the median survival was not reached with a 5-year survival rate of 69% (Figure 1). The 5-year survival rates were 57%, 68%, and 80% in patients who received imatinib, second-generation TKIs, and ponatinib, respectively (P=0.45). These 5-year survival rates were 38%, 56%, and 84%, respectively among patients with previous history of resistance to second-generation TKIs (dasatinib, nilotinib, or bosutinib) during the frontline and/or second-line TKI therapy. The median survival were 36 months, 75 months, not reached, respectively (P=0.100). Backward multivariate analysis identified age (P&lt;0.001; hazard ratio [HR], 1.052; 95% confidence interval [CI], 1.027-1.077), the progression to AP at the time of third-line TKI therapy (P=0.008; HR, 3.278; 95% CI, 1.364-7.875), previous history of resistance to a second-generation TKI therapy (P=0.018; HR, 2.280; 95% CI, 1.155-4.504), and stem cell transplant during the third-line TKI therapy (P=0.001; HR, 9.099; 95% CI, 2.452-33.768) as adverse prognostic factors for survival. In contrast ponatinib therapy as the third-line TKI was the only prognostic factor for favorable survival (P=0.047; HR, 0.364; 95% CI, 0.134-0.986). Conclusion: Third-line TKI therapy can achieve an optimal response with long-term survival in patients with CML-CP/-AP. In patients with previous history of resistance to second-generation TKIs, ponatinib is an optimal TKI associated with favorable survival. Allogeneic stem cell transplant should be deferred till patients fail ponatinib therapy. Disclosures Sasaki: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria. Kadia:Novartis: Honoraria; Cyclacel: Research Funding; Astellas: Research Funding; Pulmotec: Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Cellenkos: Research Funding; Celgene: Research Funding. Yilmaz:Daicho Sankyo: Research Funding; Pfizer: Research Funding; Pint Pharma: Honoraria. DiNardo:ImmuneOnc: Honoraria; Novartis: Consultancy; Calithera: Research Funding; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; MedImmune: Honoraria. Pemmaraju:Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Incyte Corporation: Honoraria; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria; Plexxikon: Research Funding; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Cellectis: Research Funding; MustangBio: Honoraria. Cortes:Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Immunogen: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; BMS: Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding.

I welcome you with most significant pleasure and honour to the Volume 1 Issue 4 of Indian-Pacific Journal of Accounting and Finance. In this Issue 4, the emphasis is placed on accounting, taxation, business administration, corporate governance and risk management, accounting regulation and financial reporting, and accounting. In the first paper entitled “Board Characteristics, Corporate Performance and CEO Turnover Decisions: An empirical study of listed Non-financial Companies”, Mr Yahya Uthman Abdullahi (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia), Dr. Rokiah Ishak (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia) and Dr. Norfaiezah Sawandi (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia) examine the influence of board characteristics and corporate performance on CEO turnover decisions using a sample of 144 firms from non-financial companies listed on the Nigerian Stock exchange between the periods of 2011 to 2015. The study adopts agency and resource dependency theories to support its objectives and applies a logistic regression statistical technique to analyse the results. The results show that board nominating committee has a significant positive relationship with CEO turnover and board gender diversity has a negative influence on CEO turnover. Also, the study also finds that poor corporate performance leads to CEO turnover. In concurring with the findings, the study suggests to the government to enact legislation on gender quota for more women appointment on the board of the corporation to better the performance of the firm, and as well to enhance the monitoring role of the board. In the second paper with the caption “Factors affecting the productivity of IRBM Field Tax Auditor: A Case Study in Malaysia”, Mr Sabin Samitah (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia), Prof Dr Kamil Md Idris (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia) and Dr Saliza Abdul Aziz (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia) explore the idea of factors affecting the productivity of field tax auditors in the Inland Revenue Board of Malaysia (IRBM). This study is significant because IRBM has not yet implemented a systematic method of deploying officers to the field tax audit unit throughout Malaysia. The factors identified could be used as a reference in designing future human development programme in IRBM with particular emphasis on field tax auditors. Several variables have been defined, which broadly classified into individual characteristics and external factors. Data for the analysis are sourced from IRBM’s internal database, unpublished records and direct questionnaire of all respondents engaged in the field audit in Klang Valley. The proposed idea would analyse the relationship between auditors’ productivity and various variables based on the initial assumption that all variables are influencing the productivity through direct impact. This is, however, merely an initial expectation and subject to further data analysis once the data collection is implemented and completed. In the third paper with the title “Knowledge sharing and barriers in Organisations: A conceptual paper on Knowledge-Management Strategy”, Mr Saravanan Nadason (School of Business Management, Universiti Utara Malaysia), Associate Prof Dr Ram Al-Jaffri Saad (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia) and Dr Aidi Ahmi (Tunku Puteri Intan Safinaz School of Accountancy, Universiti Utara Malaysia) investigates the barriers that give impact towards the knowledge sharing among individuals in organisations. Knowledge sharing becomes the significant part of many organisations’ knowledge-management strategy. Even though the knowledge sharing is signifying practice for organisations’ competitiveness directly and market performance indirectly, several barriers make it difficult for knowledge management to achieve the goals and deliver a positive return on investment (ROI). The barriers were identified through literature reviews. The findings of previous studies revealed that several factors affect the knowledge sharing in organisations. This paper provides the analysis of significant factors that influence knowledge sharing in organisations, which comprise the individuals, culture, technology and organisation. In the fourth paper entitled “Ownership Structure and Earnings Management of listed Conglomerates in Nigeria”, Dr Musa Adeiza Farouk (Department of Accounting, Ahmadu Bello University) and Dr Nafiu Muhammad Bashir (Department of Business Administration, Ahmadu Bello University) examine the effect of ownership structure on earnings management of listed conglomerates in Nigeria. Ownership structure is represented with managerial ownership, institutional ownership, block ownership and foreign ownership, while earnings management is measured using modified Jones model by Dechow, Sloan and Sweeney (1995). Data were obtained from the six listed conglomerates on the Nigerian Stock Exchange covering the period 2008-2014 through their annual reports and accounts. The findings show that managerial ownership and ownership concentration have a significant and adverse effect on earnings management of listed conglomerates in Nigeria, while foreign ownership recorded positive and significant impact on earnings management of firms, institutional ownership was however reported to have an insignificant but negative influence on earnings management. The study, therefore, recommends that management should be encouraged to have more interest through shares in the organisation as it enables them to have more sense of belonging, which in turn will help mitigate their opportunistic tendencies. Also, the institutional ownership should be improved upon through allotment of more shares as these categories of investors are well informed and could be more vigilant over their stake in the organisation thereby performing monitoring role to mitigate earnings management. In the fifth paper with the title “Corporate Governance Structure and Firm Performance: A Case Study of Malaysian University Holdings Companies”, Prof Dr Wan Nordin Wan Hussina (Othman Yeop Abdullah Graduate, College of Business, Universiti Utara Malaysia), Dr. Norfaiezah Sawandi (Tunku Puteri Intan Safinaz School of Accountancy, College of Business, Universiti Utara Malaysia), and Dr Hasnah Shaari (Tunku Puteri Intan Safinaz School of Accountancy, College of Business, Universiti Utara Malaysia) analyse the corporate governance structure and performance of Malaysian public university holding companies from 2010 to 2014. The sample comprises eight public university holding companies. Data were obtained by using three methods, namely: survey, semi-structured interview, and documentation review. The board structure and board sub-committees practices of these case organisations were evaluated against the best practice recommendation of (i) the Malaysian Code on Corporate Governance (MCCG) 2012, (ii) the Green Book 2006, and (iii) other relevant acts. The firm performance is measured using four indicators which are sales, profit before tax, net profit margin and return on equity. Overall, their study finds that the practice and structure of corporate governance of the holding companies are excellent. However, their study reveals non-compliance by companies about certain aspects of the recommendations of Malaysian Code on Corporate Governance 2012 (MCCG) and the Green Book. The study also observed that the practice of governance between the university companies is not uniform. The findings provide an insight into the competence of the ministry of higher education as the shareholder to improve the monitoring of the public university holding companies. As you read through this Vol. 1 Issue 4 of IPJAF, I would like to reiterate that the success of the journal depends on your active participation and those of your colleagues and friends through submission of high-quality articles within the journal scope for review and publication. I acknowledge your support as we endeavour to make IPJAF the most authoritative journal on accounting and finance for the community of academic, professional, industry, society and government.

Mesoblast Limited Key Bone Repair Patent Granted In The United States. Lilly to Acquire Global License to AXIRON Testosterone Solution from Acrux Tools. China Cord Blood Corporation Acquires Stake in Shandong Cord Blood Bank. AutekBio to Build Largest Biologic CMO in Asia. 3SBio, Ascentage Pharma to Jointly Develop Cancer Therapeutics. SIRO Clinpharm Forms Alliance with Korean CRO DreamCIS. Ceragenix Enters into Agreement with Korea's BexPharm. SRL Launches Sports Gene Test for the First Time in India. Fortis Acquires Stake in Singapore's Parkway Holdings. Sony Enters the Flow Cytometry Business in Life Science Field by Acquiring iCyt. AMPAC Fine Chemicals Partners With Inabata & Co., Ltd. of Japan. Astellas Entered into Global Partnership with Basilea for an Azole Antifungal Agent Isavuconazole. Medicago, NITT to Develop Vaccine in Japan. Millipore Launches New Water Purification System for Ion Chromatography.

Abstract Objective To identify the implications of health legislations on the direction of health technology assessment (HTA) institutionalization in the Philippines. Methods We reviewed 15 health laws and extracted information using a preset data extraction tool. The collected data was then subjected to the KJ (Kawakita Jiro) method to group similar provisions, taking into account their respective implications to the HTA direction. Once grouped, a core concept was identified that captured the underlying provisions within the group. After which, the core concepts were tabulated and matched with the core components of HTA institutionalization to identify specific policy implication to HTA. Results Three major paradigms emerged that are considered important in the institutionalization of HTA. First, common among the health laws are the need for the provision or expansion of benefit packages through the Philippine Health Insurance Corporation. Aside from the benefit packages, the reviewed laws also require delivery of new health services that entail the use of specific health technologies. Lastly, as a consequence of the need for new health services, equity concerns became evident in relation to the identified health services specifically in terms of socioeconomic divide, geographical location and disease status. Discussion and Conclusions The three paradigms identified from the review of health laws indicate synergism and antagonism to the HTA-related policy content of the Philippines' UHC Law. Some identify the need for HTA before being funded by the government while others do not explicitly state this. Despite the health laws requiring expansion or creation of benefit packages and delivery of new health services, there is still a need to undergo HTA in order to ensure efficient use of resources. The presence of these laws should not be tantamount to exception of undergoing HTA process but rather should be taken as a guide for priority-setting of topics for assessment. Key messages In the process of institutionalizing HTA, existing legislations on health can help map out areas of priority for assessment. Many health policies preceded the signing of the Universal Health Care Law, thus it is important to review them to determine provisions that are synergistic or antagonistic to the content of UHC Law.

Objective. The study evaluates the clinical profile of patients who underwent coronary artery bypass graft surgery (CABG) under the Philippine Health Insurance Corporation (Philhealth) Z Benefit Package (PZBP), as well as time intervals between PZBP screening, approval, and timing of surgery. Methods. A review of medical records was done to collect data on time intervals between the screening process and Philhealth approval in CABG patients under PZBP. The clinical profile and surgical outcomes of patients were also evaluated. Results. Sixty-three patients were included from March 2017 to December 2018. Most patients were under 61-70 years old. Hypertension was the most commonly observed comorbidity. Time intervals were analyzed including identification for surgery to eligibility screening (2–217 days, median 25 days), Philhealth approval (8–266 days, median 20 days), and surgery (9-403 days, median 33 days). Postoperative atrial fibrillation was seen in 22.58%. The most commonly observed complication prolonging hospitalization was pneumonia. Conclusion. This is the first local study which evaluated the timelines of PZBP. Results may be use as basis of follow up study in the future for identification of an acceptable timeline intervals. Several modifiable factors affecting time intervals were identified for further improvement of healthcare services. The leading cause of increase length in hospitalization were HAP and AF.

Engagement in any capacity with mainstream media since mid-2001 has meant immersion in the cross-platform, multimedia phenomenon of Harry Potter: Muggle outcast; boy wizard; corporate franchise. Consumers even casually perusing contemporary popular culture could be forgiven for suspecting they have entered a MÃbius loop in which Harry Potter-related media products and merchandise are ubiquitous: books; magazine cover stories; newspaper articles; websites; television specials; hastily assembled author biographies; advertisements on broadcast and pay television; children's merchandising; and theme park attractions. Each of these media commodities has been anchored in and cross-promoted by America Online-Time Warner's (AOL-TW) first instalment in a projected seven-film sequence—Harry Potter and the Philosopher's Stone.1 The marketing campaign has gradually escalated in the three years elapsing between AOL-TW subsidiary Warner Bros' purchase from J.K. Rowling of the film and merchandising rights to the first two Harry Potter books, and the November 2001 world premiere of the film (Sherber 55). As current AOL-TW CEO Richard Parsons accurately forecast, "You're not going to be able to go anywhere without knowing about it. This could be a bigger franchise than Star Wars" (Auletta 50). Yet, AOL-TW's promotional strategy did not limit itself to creating mere awareness of the film's release. Rather, its tactic was to create an all-encompassing environment structured around the immense value of the Harry Potter brand—a "brand cocoon" which consumers do not so much enter and exit as choose to exist within (Klein 2002). In twenty-first-century mass marketing, the art is to target affluent consumers willing to direct their informational, entertainment, and consumption practices increasingly within the "walled garden" of a single conglomerate's content offerings (Auletta 55). Such an idealised modern consumer avidly samples the diversified product range of the parent conglomerate, but does so specifically by consuming multiple products derived from essentially the same content reservoir. Provided a match between consumer desire and brand can be achieved with sufficient accuracy and demographic breadth, the commercial returns are obvious: branded consumers pay multiple times for only marginally differentiated products. The Brand-Conglomerate Nexus Recyclable content has always been embraced by media industries, as cultural commodities such as early films of stage variety acts, Hollywood studio-era literary adaptations, and movie soundtrack LPs attest. For much of the twentieth century, the governing dynamic of content recycling was sequential, in that a content package (be it a novel, stage production or film) would succeed in its home medium and then, depending upon its success and potential for translation across formats, could be repackaged in a subsequent medium. Successful content repackaging may re-energise demand for earlier formatting of the same content (as film adaptations of literary bestsellers reliably increase sales of the originating novel). Yet the cultural industries providing risk capital to back content repackaging formerly required solid evidence that content had achieved immense success in its first medium before contemplating reformulations into new media. The cultural industries radically restructured in the last decades of the twentieth century to produce the multi-format phenomenon of which Harry Potter is the current apotheosis: multiple product lines in numerous corporate divisions are promoted simultaneously, the synchronicity of product release being crucial to the success of the franchise as a whole. The release of individual products may be staggered, but the goal is for products to be available simultaneously so that they work in aggregate to drive consumer awareness of the umbrella brand. Such streaming of content across parallel media formats is in many ways the logical culmination of broader late-twentieth-century developments. Digital technology has functionally integrated what were once discrete media operating platforms, and major media conglomerates have acquired subsidiaries in virtually all media formats on a global scale. Nevertheless, it remains true that the commercial risks inherent in producing, distributing and promoting a cross-format media phenomenon are vastly greater than the formerly dominant sequential approach, massively escalating financial losses should the elusive consumer-brand fit fail to materialise. A key to media corporations' seemingly quixotic willingness to expose themselves to such risk is perhaps best provided by Michael Harkavy, Warner Bros' vice-president of worldwide licensing, in his comments on Warner Music Group's soundtrack for the first Harry Potter film: It will be music for the child in us all, something we hope to take around the world that will take us to the next level of synergy between consumer products, the [AOL-TW cable channel] Cartoon Network, our music, film, and home video groups—building a longtime franchise for Harry as a team effort. (Traiman 51) The relationship between AOL-TW and the superbrand Harry Potter is essentially symbiotic. AOL-TW, as the world's largest media conglomerate, has the resources to exploit fully economies of scale in production and distribution of products in the vast Harry Potter franchise. Similarly, AOL-TW is pre-eminently placed to exploit the economies of scope afforded by its substantial holdings in every form of content delivery, allowing cross-subsidisation of the various divisions and, crucially, cross-promotion of the Harry Potter brand in an endless web of corporate self-referentiality. Yet it is less frequently acknowledged that AOL-TW needs the Harry Potter brand as much as the global commercialisation of Harry Potter requires AOL-TW. The conglomerate seeks a commercially protean megabrand capable of streaming across all its media formats to drive operating synergies between what have historically been distinct commercial divisions ("Welcome"; Pulley; Auletta 55). In light of AOL-TW's record US$54.2b losses in the first quarter of 2002, the long-term viability of the Harry Potter franchise is, if anything, still more crucial to the conglomerate's health than was envisaged at the time of its dot.com-fuelled January 2000 merger (Goldberg 23; "AOL" 35). AOL-TW's Richard Parsons conceptualises Harry Potter specifically as an asset "driving synergy both ways", neatly encapsulating the symbiotic interdependence between AOL-TW and its star franchise: "we use the different platforms to drive the movie, and the movie to drive business across the platforms" ("Harry Potter" 61). Characteristics of the Harry Potter Brand AOL-TW's enthusiasm to mesh its corporate identity with the Harry Potter brand stems in the first instance from demonstrated consumer loyalty to the Harry Potter character: J.K. Rowling's four books have sold in excess of 100m copies in 47 countries and have been translated into 47 languages.2 In addition, the brand has shown a promising tendency towards demographic bracket-creep, attracting loyal adult readers in sufficient numbers to prompt UK publisher Bloomsbury to diversify into adult-targeted editions. As alluring for AOL-TW as this synchronic brand growth is, the real goldmine inheres in the brand's potential for diachronic growth. From her first outlines of the concept, Rowling conceived of the Potter story as a seven-part series, which from a marketing perspective ensures the broadscale re-promotion of the Harry Potter brand on an almost annual basis throughout the current decade. This moreover assists re-release of the first film on an approximately five-year basis to new audiences previously too young to fall within its demographic catchment—the exact strategy of "classic" rebranding which has underwritten rival studio Disney's fortunes.3 Complementing this brand extension is the potential to grow child consumers through the brand as Harry Potter sequels are produced. Harry Potter and the Philosopher's Stone director Chris Columbus spruiks enthusiastically that "the beauty of making these books into films is that with each one, Harry is a year older, so [child actor] Daniel [Radcliffe] can remain Harry as long as we keep making them" (Manelis 111). Such comments suggest the benefits of luring child consumers through the brand as they mature, harnessing their intense loyalty to the child cast and, through the cast, to the brand itself. The over-riding need to be everything to everyone—exciting to new consumers entering the brand for the first time, comfortingly familiar to already seasoned consumers returning for a repeat hit—helps explain the retro-futuristic feel of the first film's production design. Part 1950s suburban Hitchcock, Part Dickensian London, part Cluny-tapestry medievalism, part public school high-Victorianism, Harry Potter and the Philosopher's Stone strives for a commercially serviceable timelessness, in so doing reinforcing just how very twenty-first-century its conception actually is. In franchise terms, this conscious drive towards retro-futurism fuels Harry Potter's "toyetic potential" (Siegel, "Toys" 19). The ease with which the books' complex plots and mise-en-scene lend themselves to subsidiary rights sales and licensed merchandising in part explains Harry Potter's appeal to commercial media. AOL-TW executives in their public comments have consistently stayed on-message in emphasising "magic" as the brand's key aspirational characteristic, and certainly scenes such as the arrival at Hogwarts, the Quidditch match, the hatching of Hagrid's dragon and the final hunt through the school's dungeons serve as brilliant advertisements for AOL-TW's visual effects divisions. Yet the film exploits many of these "magic" scenes to introduce key tropes of its merchandising programme—Bertie Bott's Every Flavour Beans, chocolate frogs, Hogwarts house colours, the sorting hat, Scabbers the rat, Hedwig, the Remembrall—such that it resembles a series of home shopping advertisements with unusually high production values. It is this railroading of the film's narrative into opportunities for consumerist display which leads film critic Cynthia Fuchs to dub the Diagon Alley shopping scene "the film's cagiest moment, at once a familiar activity for school kid viewers and an apt metaphor for what this movie is all about—consumption, of everything in sight." More telling than the normalising of shopping as filmic activity in Harry Potter and the Philosopher's Stone is the eclipse of the book's checks on commodity fetishism: its very British sensitivity to class snubs for the large and impecunious Weasley family; the puzzled contempt Hogwarts initiates display for Muggle money; the gentle ribbing at children's obsession with branded sports goods. The casual browser in the Warner Bros store confronted with a plastic, light-up version of the Nimbus 2000 Quidditch broomstick understands that even the most avid authorial commitment to delimiting spin-off merchandise can try the media conglomerate's hand only so far. Constructing the Harry Potter Franchise The film Harry Potter and the Philosopher's Stone constitutes the indispensable brand anchor for AOL-TW's intricate publicity and sales strategy around Harry Potter. Because content recycling within global media conglomerates is increasingly lead by film studio divisions, the opening weekend box office taking for a brand-anchoring film is crucial to the success of the broader franchise and, by extension, to the corporation as a whole. Critic Thomas Schatz's observation that the film's opening serves as "the "launch site" for its franchise development, establishing its value in all other media markets" (83) highlights the precariousness of such multi-party financial investment all hinging upon first weekend takings. The fact that Harry Potter and the Philosopher's Stone broke (then standing) box office records with its 16 November 2001 three-day weekend openings in the US and the UK, garnering US$93.2m and GBP16m respectively, constituted the crucial first stage in AOL-TW's brand strategy (Collins 9; Fierman and Jensen 26). But it formed only an initial phase, as subsequent content recycling and cross-promotion was then structured to radiate outwards from this commercial epicentre. Three categories of recycled AOL-TW Harry Potter content are discernible, although they are frequently overlapping and not necessarily sequential. The first category, most closely tied to the film itself, are instances of reused digital content, specifically in the advance publicity trailer viewable on the official website, and downloads of movie clips, film stills and music samples from the film and its soundtrack.4 Secondly, at one remove from the film itself, is AOL-TW's licensing of film "characters, names and related indicia" to secondary manufacturers, creating tie-in merchandise designed to cross-promote the Harry Potter brand and stoke consumer investment (both emotional and financial) in the phenomenon.5 This campaign phase was itself tactically designed with two waves of merchandising release: a September 2000 launch of book-related merchandise (with no use of film-related Harry Potter indicia permitted); and a second, better selling February 2001 release of ancillary products sporting Harry Potter film logos and visual branding which coincided with and reinforced the marketing push specifically around the film's forthcoming release (Sherber 55; Siegel, "From Hype" 24; Lyman and Barnes C1; Martin 5). Finally, and most crucial to the long-term strategy of the parent conglomerate, Harry Potter branding was used to drive consumer take up of AOL-TW products not generally associated with the Harry Potter brand, as a means of luring consumers out of their established technological or informational comfort zones. Hence, the official Harry Potter website is laced with far from accidental offers to trial Internet service provider AOL; TimeWarner magazines Entertainment Weekly, People, and Time ran extensive taster stories about the film and its loyal fan culture (Jensen 56-57; Fierman and Jensen 26-28; "Magic Kingdom" 132-36; Corliss 136; Dickinson 115); AOL-TW's Moviefone bookings service advertised pre-release Harry Potter tickets on its website; and Warner Bros Movie World theme park on the Gold Coast in Australia heavily promoted its Harry Potter Movie Magic Experience. Investment in a content brand on the scale of AOL-TW's outlay of US$1.4m for Harry Potter must not only drive substantial business across every platform of the converged media conglomerate by providing premium content (Grover 66). It must, crucially for the long run, also drive take up and on-going subscriptions to the delivery services owned by the parent corporation. Energising such all-encompassing strategising is the corporate nirvana of seamless synergy: between content and distribution; between the Harry Potter and AOL-TW brands; between conglomerate and consumer. Notes 1. The film, like the first of J.K. Rowling's books, is titled Harry Potter and the Sorcerer's Stone in the "metaphysics-averse" US ("Harry Potter" 61). 2. Publishing statistics sourced from Horn and Jones (59), Manelis (110) and Bloomsbury Publishing's Harry Potter website: http://www.bloomsburymagazine.com/harryp.... 3. Interestingly, Disney tangentially acknowledged the extent to which AOL-TW has appropriated Disney's own content recycling strategies. In a film trailer for the Pixar/Disney animated collaboration Monsters, Inc. which screened in Australia and the US before Harry Potter sessions, two monsters play a game of charades to which the answer is transparently "Harry Potter." In the way of such homages from one media giant to another, it nevertheless subtly directs the audience to the Disney product screening in an adjacent cinema. 4. The official Harry Potter film website is http://harrypotter.warnerbros.com. The official site for the soundtrack to Harry Potter and the Philosopher's/Sorcerer's Stone is: http://www.harrypottersoundtrack.com. 5. J.K. Rowling." A page and a half of non-negotiable "Harry Potter Terms of Use" further spells out prohibitions on use or modification of site content without the explicit (and unlikely) consent of AOL-TW (refer: http://harrypotter.warnerbros.com/cmp/te...). References "AOL losses 'sort of a deep disappointment'." Weekend Australian 18-19 May 2002: 35. Auletta, Ken. "Leviathan." New Yorker 29 Oct. 2001: 50-56, 58-61. Collins, Luke. "Harry Potter's Magical $178m Opening." Australian Financial Review 20 Nov. 2001: 9. Corliss, Richard. "Wizardry without Magic." Time 19 Nov. 2001: 136. Dickinson, Amy. "Why Movies make Readers." Time 10 Dec. 2001: 115. Fierman, Daniel, and Jeff Jensen. "Potter of Gold: J.K. Rowling's Beloved Wiz Kid hits Screensand Breaks Records." Entertainment Weekly 30 Nov. 2001: 26-28. Fuchs, Cynthia. "The Harry Hype." PopPolitics.com 19 Nov. 2001: n.pag. Online. Internet. 8 Mar. 2002. Available <http://www.poppolitics.com/articles/2001-11-19-harry.shtml>. Goldberg, Andy. "Time Will Tell." Sydney Morning Herald 27-28 Apr. 2002: 23. Grover, Ronald. "Harry Potter and the Marketer's Millstone." Business Week 15 Oct. 2001: 66. Harry Potter and the Philosopher's Stone. Dir. Chris Columbus. Screenplay by Steve Kloves. Warner Bros, 2001. "Harry Potter and the Synergy Test." Economist 10 Nov. 2001: 61-62. Herman, Edward S., and Robert W. McChesney. The Global Media: The New Missionaries of Corporate Capitalism. London: Cassell, 1997. Horn, John, and Malcolm Jones. "The Bubble with Harry." The Bulletin/Newsweek 13 Nov. 2001: 58-59. Jensen, Jeff. "Holiday Movie Preview: Potter's Field." Entertainment Weekly 16 Nov. 2001: 56-57. Klein, Naomi. "Naomi KleinNo Logo." The Media Report. ABC Radio National webtranscript. Broadcast in Sydney, 17 Jan. 2002. Online. Internet. 19 Feb. 2002. Available <http://www.abc.net.au/rn/talks/8:30/mediarpt/stories/s445871.htm>. Lyman, Rick, and Julian E. Barnes. "The Toy War for Holiday Movies is a Battle Among 3 Heavyweights." New York Times 12 Nov. 2001: C1. "Magic Kingdom." People Weekly 14 Jan. 2002: 132-36. Manelis, Michele. "Potter Gold." Bulletin 27 Nov. 2001: 110-11. Martin, Peter. "Rowling Stock." Weekend Australian 24-25 Nov. 2001: Review, 1, 4-5. Pulley, Brett. "Morning After." Forbes 7 Feb. 2000: 54-56. Rowling, J.K. Harry Potter and the Philosopher's Stone. London: Bloomsbury, 1997. Schatz, Thomas. "The Return of the Hollywood Studio System." Conglomerates and the Media. Erik Barnouw et al. New York: New Press, 1997. 73-106. Sherber, Anne. "Licensing 2000 Showcases Harry Potter, Rudolph for Kids." Billboard 8 Jul. 2000: 55. Siegel, Seth M. "Toys & Movies: Always? Never? Sometimes!" Brandweek 12 Feb. 2001: 19. ---. "From Hype to Hope." Brandweek 11 Jun. 2001: 24. Traiman, Steve. "Harry Potter, Powerpuff Girls on A-list at Licensing 2000." Billboard 1 Jul. 2000: 51, 53. "Welcome to the 21st Century." Business Week 24 Jan. 2000: 32-34, 36-38. Links http://www.bloomsburymagazine.com/harrypotter/muggles http://www.harrypottersoundtrack.com http://harrypotter.warnerbros.com http://www.poppolitics.com/articles/2001-11-19-harry.shtml http://www.abc.net.au/rn/talks/8:30/mediarpt/stories/s445871.htm http://harrypotter.warnerbros.com/cmp/terms.html Citation reference for this article MLA Style Murray, Simone. "Harry Potter, Inc." M/C: A Journal of Media and Culture 5.4 (2002). [your date of access] < http://www.media-culture.org.au/mc/0208/recycling.php>. Chicago Style Murray, Simone, "Harry Potter, Inc." M/C: A Journal of Media and Culture 5, no. 4 (2002), < http://www.media-culture.org.au/mc/0208/recycling.php> ([your date of access]). APA Style Murray, Simone. (2002) Harry Potter, Inc.. M/C: A Journal of Media and Culture 5(4). < http://www.media-culture.org.au/mc/0208/recycling.php> ([your date of access]).

Introduction While Free Software Foundation founder Richard Stallman argues that Free Software is not Open Source, he is only half right—or only speaking about the question of motivation (the half that matters to him). The definition of Open Source, as enshrined in the Open Source Definition (OSD) is a nearly verbatim copy of the Debian Free Software Guidelines (DFSG). Both the OSD and DFSG are practical articulations of Stallman’s Free Software Definition (FSD). Open Source, with a different political and philosophical basis, can only exist because the FSD is broad enough to allow for its translation into other terms yet defined enough to allow for a directed and robust social movement. As much as Stallman might want to deemphasize Open Source, he would never change the broadly defined definition of freedom that made its existence possible. This level of translatability within the domain of Free and Opens Source Software (FOSS) is echoed in the accessibly of its philosophies and technologies to groups from across the political spectrum. Recalibrating the broad meaning of freedom outlined in the FSD to align with their own philosophies and politics, these groups perceive FOSS as a model of openness and collaboration particularly well suited to meet their own goals. In this process of re-adoption and translation, FOSS has become the corporate poster child for capitalist technology giants like IBM, the technological and philosophical weapon of anti-corporate activists, and a practical template for a nascent movement to create an intellectual “Commons” to balance the power of capital. In these cases and others, FOSS’s broadly defined philosophy—given legal form in licenses—has acted as a pivotal point of inspiration for a diverse (and contradictory) set of alternative intellectual property instruments now available for other forms of creative work. Iconic Tactics As a site of technological practice, FOSS is not unique in its ability to take multiple lives and meanings. For example, Gyan Prakash (1999) in Another Reason_ _describes the way that many of the principles and practices of early twentieth century techno-science were translated, in ways similar to FOSS, during India’s colonial era. British colonizers who built bridges, trains, and hospitals pointed to their technological prowess as both a symbol of a superior scientific rationality and justification for their undemocratic presence in the subcontinent. Prakash describes the way that a cadre of Indian nationalists re-visioned the practice and philosophical approach to techno-science to justify and direct their anti-colonial national liberation movement. Techno-science, which was an instrument for colonialism and an icon for idea of progress, was nonetheless re-valued and redirected toward “another reason,” thus acting as a “tactic” productive of other social and political practices. We call this dynamic iconic tactic. FOSS has been deployed as an iconic tactic in a wide range of projects. FOSS philosophy simply states that it is the right of every user to use, modify, and distribute computer software for any purpose. The right to use, distribute, modify and redistribute derivative versions, the so called “four freedoms,” are based in and representative of an extreme form of anti-discrimination resistant to categorization into the typical “left, center and right” tripartite political schema. This element of non-discrimination, coupled with the broad nature of FOSS’s philosophical foundation, enables the easy adoption of FOSS technologies and facilitates its translatability. FOSS’s broadly defined freedom acts as an important starting point and one conceptual hinge useful in understanding the promiscuous circulation of FOSS as a set of technologies, signs, methodologies and philosophies. Also helpful is an analysis of the way in which this philosophical and legal form is animated and redirected in historically particular, and at times divergent, ways through the use of FOSS technologies and licensing schemes. It is to three contrasting examples of such transmutations that we now turn to. Translation in FOSS With over USD 81 billion in yearly revenue deriving in no small part from the companies vast patent and copyright holdings, IBM is an example of global capitalism whose bedrock is intellectual property. With a development methodology that IBM recognizes as more agile and profitable than proprietary models in many situations, IBM was quick to embrace FOSS. Hiring a cadre of FOSS developers to work in-house on FOSS software, IBM launched the first nationwide advertising campaign promoting the FOSS operating system GNU/Linux. In their first campaign, they highlighted the ideas of openness and freedom in ways that, unsurprisingly, reinforced their corporate goals. Featuring the recognizable Linux mascot Tux the penguin and a message of “Peace, Love, and Linux,” IBM connected using and buying FOSS-based enterprise solutions with 1960’s counter-cultural ideals of sharing, empowerment, and openness. IBM’s engagement with FOSS is representative of a much larger corporate movement to translate FOSS principles into a neoliberal language of market agility, consumer choice, and an “improved bottom line.” While their position, as the recent SCO and IBM court cases over Linux have demonstrated, is not uniformly shared in the corporate world, IBM is a highly visible example of a larger corporate push toward Free Software as the basis of a service-based business model. While the money behind IBM’s advertising machine makes their take on FOSS particularly visible, they hold no monopoly on the interpretation of FOSS’s meaning and importance. This is evidenced by the extensive use of FOSS as an iconic tactic by leftist activists around the world. Also bearing a three letter acronym, the Independent Media Centers (IMC) are a socio-political project whose mission and spirit are completely contrary to the goals of a large corporation like IBM. Indymedia is a worldwide collective of loosely affiliated grassroots online media websites and non-virtual spaces that allow activists to directly make, move, and “become” the media. IMCs are an important and integrated part of the anti-corporate and counter-globalization movement. In their work, IMC activists have aligned FOSS philosophy with their goals and visions for openness, media-reform, and large-scale socio-political justice. Like IBM, IMCs use existing FOSS software and create their own tools. IMC software, is, by charter, FOSS. As a volunteer organization with limited economic resources, FOSS has been crucial in its technology-heavy operations. Beyond use for pragmatic reasons, there is widespread support and admiration for FOSS, which is often identified as a revolutionary example of mutual aid, structural openness and the power of collaboration. The following quotes from the IMC’s online-meeting where the decision to formally adopt FOSS was made exemplify activist’s understandings of how FOSS can be used as a tool to further their political aspirations. xxxx: I assume it is safe to say that we are making this choice in order to try to choose the thing which has the least chance of benefiting any corporation, or any other form of hoarding in any way xxxx: There is a wonderful pool of very well-developed free software out there. Earlier, someone said that IMC is a revolutionary project, and free software is a revolutionary tool for it. I stan[d] very firmly behind using free software first These activists—and others in the IMC and anti-corporate, anti-capitalist, and counter-globalization movements—find inspiration in FOSS as proof of the possibility of successful alternatives to capitalist forms of production. In recent years, a political position—with a centrist political philosophy distinct from both capitalists like IBM and anti-capitalists like the IMC—has emerged with FOSS as its primary point of philosophical justification. This group is constituted by a growing number of North American and European scholars who have employed the metaphor of a “Commons” to argue for legally protected resources and knowledge for common use by all. The commons endeavor is one example of a larger “liberal” critique of the neoliberal face of “socially destructive unfettered capitalism” which is seen as a threat to democracy (Soros 2001). The information commons movement, largely spearheaded by Lawrence Lessig (1999; 2001; Creative Commons) and David Bollier (2002; Public Knowledge), explicitly points to FOSS as its inspiration. Within the Commons movement, FOSS has been tactically held up as proof that Commons are achievable and as a model of the process through which they can be created; the Creative Commons organization, a key institution within the Commons movement, has adopted FOSS-style licensing to foster and protect other other kinds of non-technical knowledge. Conclusion These three cases, which don’t exhaust the examples of translation, demonstrate how FOSS functions as an iconic tactic for a range of projects, which is not the simple result of the lexical ambiguity of the words free or open. The ability of FOSS to act as an “engine of translation” is one of the most compelling political aspects of FOSS and an important starting point in the assessment of the variable ways in which FOSS has been used as a set of technologies and an icon for openness—one we feel is often overlooked or obscured in popular and scholarly accounts on the broader implications of FOSS. The terms openness and freedom are often the key categories by which advocates, activists, journalists, and scholars approach the social and political implications of FOSS. While some accounts attribute a type of radical political intention to the domain of FOSS, others critique FOSS as indicative of late-capitalism’s drive to create and exploit free labor (Terranova 2000). Some problematically collapse the efforts of Lessig and Creative Commons with those of FOSS (Boyton 2004) obscuring some of the important differences between the goals and licenses of the groups. Certainly, the way in which FOSS is translated also shifts the ways that FOSS developers understand their own actions and motivations. However, commentators often interpret isolated cases of this process of inspiration, adoption, and re-valuation as indicative of the whole. In this early stage of research into FOSS, it behooves us to be wary of wholesale pronouncements on the social, political, and economic nature of FOSS. We should instead remain mindful of the range of socio-historical processes by which FOSS has enabled a diversity of ideas and practices of opennesses. We should be open to the idea that an analysis of the interplay between FOSS philosophy and practices as it travels through multiple social, economic and political terrains may reveal more than (first) meets the eye. About the Authors Biella Coleman is a cultural anthropologist from the University of Chicago currently writing her dissertation on the ethical dynamics and political implications of the Free and Open Source movement. She spent nearly three years doing research on the Debian project and studying hacker and technology activism in the Bay Area. Her next project draws from this research to investigate the use of expressive and human rights among psychiatric survivors as a political vector to make claims against forced treatment and to halt the global exportation of an American model of psychiatry. email: egcolema@uchicago.edu and biella@healthhacker.org Benjamin "Mako" Hill is a Free and Open Source Software developer and advocate. He is a director of Software in the Public Interest and a member of the Debian project—by most accounts the single largest Free Software project. In addition to volunteer and professional Free Software work, Hill writes and speaks extensively on issues of free software, intellectual property, collaboration, and technology. email: mako@bork.hampshire.edu Works Cited Boynton, Robert. ”The Tyranny of Copyright.”New York Times Magazine http://www.nytimes.com/2004/01/25/magazine/25COPYRIGHT.html Bollier, David. Silent Theft: the Private Plunder of our Common Wealth. New York: Routledge, 2002. Lessig, Lawrence. Code and Other Laws of Cyberspace. New York: Basic Books, 1999. .The Future of ideas. New York: Random House, 2001. Prakash, Gyan. Another Reason: Science and the Imagination of Modern India. Princeton, NJ: Princeton University Press, 1999. Soros, George. Open Society: Reforming Global Capitalism. New York: Public Affairs, 2000. Terranova, Tiziana. “Free Labor: Producing Culture for the Global Economy.” Social Text. (18): 2: 33-57, 2000. Warner, Michael. Publics and Counterpublics. New York: Zone Books, 2002. Weblinks: http://www.gnu.org/philosophy/free-sw.html http://www.debian.org/social_contract.html#guidelines, http://www.opensource.org/docs/definition.php http://www.slweekly.com/editorial/2004/feat_2004-01-22.cfm http://www.indymedia.org http://creativecommons.org/ http://www.publicknowledge.org/ Citation reference for this article MLA Style Coleman, Biella & Hill, Mako. "How Free Became Open and Everything Else Under the Sun" M/C: A Journal of Media and Culture <http://www.media-culture.org.au/0406/02_Coleman-Hill.php>. APA Style Coleman, B. & Hill, M. (2004, Jul1). How Free Became Open and Everything Else Under the Sun. M/C: A Journal of Media and Culture, 7, <http://www.media-culture.org.au/0406/02_Coleman-Hill.php>

Data becomes something of a mirror in which people see themselves reflected. (Sorapure 270)In a 2014 essay for The New Yorker, the humourist David Sedaris recounts an obsession spurred by the purchase of a Fitbit, a wearable activity-tracker that sends a celebratory “tingle” to his wrist every 10, 000 steps. He starts “stepping out” modestly but is soon working hard, steadily improving on the manufacturer’s recommended baseline. “But why?” asks Sedaris’ partner Hugh: “Why isn’t twelve thousand enough?” “Because,” I told him, “my Fitbit thinks I can do better” (n.p.).The record of daily, incidental activity that the Fitbit collects and visualises is important to Sedaris as a record of his (increasing) bodily fitness but it is also evidence in another way, a testament to virtue and a correlate of self-improvement: “The tingle feels so good,” Sedaris says, “not just as a sensation but also as a mark of accomplishment” (n.p.). Improvement is presented as both traceable and quantifiable; data and self are inextricably, though also ironically, linked. With his Fitbit, Sedaris accesses new and precise degrees of bodily information and he connects himself to a visible community of wearers. At first, Sedaris is smug and optimistic; by the time he begins “rambling” compulsively, however, and achieving his “first sixty-thousand-step day,” he has also had an epiphany: “I staggered home with my flashlight knowing that I’d advance to sixty-five thousand, and that there will be no end to it until my feet snap off at the ankles. Then it’ll just be my jagged bones stabbing into the soft ground” (n.p.). When the device finally “dies,” Sedaris experiences an immediate feeling of freedom; within five hours he has “ordered a replacement, express delivery” (n.p.).In their book Self-Tracking, Gina Neff and Dawn Nafus note that both digital technology and a turn to biomedicalisation in the broader culture have amplified the capacity and reach of quantification practices in everyday life. Wearable activity trackers, of which the Fitbit is arguably the most iconic, offer individuals the ability to track minute or previously imperceptible permutations of bodily sensation within an everyday and non-medical context. It is a technological capacity, however, thoroughly embedded in a mobilising rhetoric of “health,” a term which itself has “become a loaded word, not merely a description of a bodily state but also a euphemism for what the speaker believes is desirable” (Neff and Nafus 19). The Fitbit measures movement, but it also signals something about the wearer’s identity that is framed, in the device’s marketing at least, in positive and desirable terms as an indication of character, as a highly desirable aspect of self.In a recent discussion of new forms of online life writing, Madeline Sorapure argues that acts of interpretation and representation in relation to biometric data are “something very similar to autobiographical practice. As in autobiography, subject and object, measurer and measured, are collapsed” (270). In its capacity to track and document over time and its affective role in forming a particular experience of self, the Fitbit bears a formal resemblance to autobiographical practice and specifically to modes of serial self-representation like diaries, journals, or almanacs. The discursive context is crucial here too. Early self-trackers use the pre-formatted almanac diary or calendar to better organise their time and to account for expenditure or gain. The pocket calendar was an innovation that had mass-market appeal and its rapid circulation in the early twentieth century directly shaped diary and account-keeping habits amongst historical populations, and to this day (McCarthy). Such forms are not simply passive repositories but bear cultural ideology. As popular templates for practices of accounting, self-documentation, and affecting, pocket calendars shape what content an individual across their individual day or week is coaxed to attend to or record, and effects what might then be relegated “marginal” or less consequential in relation.How do the technological affordances of the Fitbit similarly coax and shape self-knowledge or ideas of value and worth in relation to personal experience? What kinds of formal and discursive and resonance might there be drawn between wearable personal devices like the Fitbit and historical forms of tracking self-experience, like the diary? Is a Fitbit a diary? In this discussion, I consider pre-formatted diaries, like the almanac or pocket calendar, as discursive and technological precursors or adjuncts to wearable personal trackers like the Fitbit and I explore some assertions around the kinds of subject that digital forms and modes of self-tracking and personal data might then seem to coax or imagine.Tracking SelvesSelf-tracking is a human activity, one far more interesting than the gadgets that have made it easier and far more widespread. (Neff and Nafus 2)In 1726, at the age of 20, the inventor and polymath Benjamin Franklin recorded in his journal the inception of a plan to improve his character. In a chart created to track goals of virtue and progress in character, “black marks” are literal and symbolic, denoting when he has failed to live up to his expectations—two black marks represent a particularly bad effort (Rettberg 438). At age 79, Franklin was still tracking his progress when he wrote about the project in his Autobiography:It was about this time I conceived the bold and arduous project of arriving at moral perfection. I wished to live without committing any fault at any time; I would conquer all that either natural inclination, custom, or company might lead me into. (89)Franklin’s desire to document and chronicle the self-conscious development of his character drives his interest in the form. He was as an almanac devotee and an innovative publisher of the form, which gained immense popularity at this time. Franklin added blank pages to the almanacs he helped produce in the mid eighteenth century and this addition expanded the possibilities for the kinds of data that might be recorded, particularly personal and anecdotal material. The innovation also earned the publishers a good deal more money (McCarthy 49). The mass production of printed almanacs thus had a profound effect on how individuals engaged in various kinds of daily and temporal and social regulation and documentation, including of the self:At the same time as it kept readers aware of the outside world, the almanac could also direct them to the state of their own being. Almanacs were all about regulation, inside and out. Almanacs displayed a regulated universe governed by the laws of planetary motion, by the church calendar, by the zodiac. It seemed natural, then, that some readers might turn to an almanac to regulate themselves. What better way to do that than in a text that already possessed its own system? All one had to do was insert one’s own data in that printed form, like connecting the dots. (McCarthy 53)Mass-market forms that engender habits of accounting are also cultural templates: pre-formatted journals are systems for private documentation that reflect broader cultural and social ideologies. Rebecca Connor observes that historical gender assumptions in relation to time “well-spent” are frequently visible in eighteenth-century mass-market journals explicitly aimed at women, which tended to allocate more space for “social” engagements versus, for example, financial accounting (18).In the twenty-first century, technologies like the Fitbit promise access to data in relation to personal experience but they also reveal dominant cultural and social attitudes to bodies and selves. Deborah Lupton argues that self-tracking as a phenomenon is essentially connected to specific ideological imperatives: “Underlying many accounts of self-tracking is a barely hidden discourse of morality, which takes the form of championing those who take action to improve themselves” (74). Within these influential discourses, acts of self-tracking, no less than Franklin’s virtue chart, acquire significance as moral activities and as the outward sign of good character.Neither self-tracking nor the ideology of virtue that underwrites it are new phenomena. In their cultural study of weight measurement devices, Kate Crawford, Jessa Lingl, and Tero Karpii have explored how both weight scales and wearable devices “emphasize self-knowledge and control through external measurements” (479). Similarly, Lupton has noted that, the “metrics” generated by personal self-tracking devices are “invested with significance” because “data visualisation” is “viewed as more credible and accurate by participants than the ‘subjective’ assessments of their bodily sensations” ("Personal Data" 345).In various historical cultures, objectivity about one’s self is seen as a desire (if not a fact) in relation to conscious self-examination; externalisation, through written or oral confession, is both a virtue and a discipline. While diary writing is, particularly in popular culture, often derided as an overly subjective and narcissistic mode, the diary is also framed within contexts of therapy, or spiritual development, as a possible methodology for self-improvement. For Puritans, though, the act was also understood to entail risks; recording one’s thoughts into a written journal could enable the individual to see patterns or faults in everyday behaviour, and so to identify and rectify habits of mind holding back personal spiritual development. In the twentieth century, “how-to write a diary” self-help guidebooks remediate the discourse of self-knowledge as self-improvement, and promised to refine the method, advising adherents on the kinds of writing practices that might best circumvent problems of individual bias or subjectivity (a claim of an ever-more objective methodology that reverberates to the current moment). Invariably, the more “unconscious” the diary writing practice, the greater the assumed potential for “objective” knowledge (Cardell 34).Contemporary practices of self-tracking extend the prioritisation of external, objective measurement in relation to documenting personal experience. Crawford, Lingel, and Karppi observe that “the discourse around wearable devices gives the impression of radical new technology offering precise and unambiguous physical assessment: devices that reflect back the ‘real’ state of the body” (480). The technology, of course, is not new but it is “improved.” The ideal of a better, more accurate (because externalised and so auditable by the community) self-knowledge sought by Puritans in their journals, or by Benjamin Franklin in his charts and almanacs, resurfaces in the contemporary context, in which wearables like the Fitbit assume powerful discursive status in relation to ideals of truth and objectivity and where the individual is decentred from the position of as “the most authoritative source of data about themselves” (Crawford, Lingel, and Karppi 479).Data SelvesWhat kind of selves do people develop in relation to the technology they use to record or visualise their experience? “There is no doubt,” writes Jill Walker Rettberg, in Seeing Our Selves through Technology, “that people develop ‘affective ties’ to the data they track, just as diaries, blogs, photo albums and other material archives are meaningful to those who keep them” (87). That the data is numerical, or digital, does not lessen this connection:Apps which allow us to see our data allow us to see ourselves. We look at our data doubles as we gazed into the mirror as teenagers wondering who we were and who we might be. We look at our data in much the same way as you might flick through your selfies to find the one that shows you the way you want to be seen. (Rettberg 87)Crucially, Rettberg sees data as both affective and agential and she observes that data can also be edited and shaped by the individual. Some of this practice is deliberate, taking the form of an engagement with narrative as a “story” of self that underpins the practice of writing autobiography, for example. However, the representation of self can also be more oblique. “The first writing” says Rettberg, “was developed not to record words and sentences but to keep accounts. Arguably, recording quantities of grain or other valuables can be a form of self-representation, or at least representation of what belongs to the self” (10).Like log-books or field notebooks, like calendars or almanacs—prosaic forms of daily sequential recording that are understood to prioritise information capture over self-reflection—the Fitbit is usually presented as a method for accruing and representing personal data. In contemporary digital culture, “data” is a complex and fraught term and recent debates around “big data,” which describes the capacity of machines to make connections and perform calculations that a human might not necessarily notice or be able to perform, has crystallised this. What Melissa Gregg calls the power and “spectacle” of data is an ideological pivot in digital cultures of the twenty-first century, one that turns in conjunction to discourses of evidence and authority that emerge in relation to the visual: “sharing the same root as ‘evidence,’ vision is the word that aligns truth and knowledge in different historical moments” (3).For autobiography scholars exploring how formal modes of capture might also be genres, or how a Fitbit might coax a narrative of self, these questions are formative. Sorapure says: Information graphics that visually represent personal data; collaboratively constructed and template-based self-representations in social media and networking sites; the non-narrative nature of aggregated life writing: in these and other new practices we see selves emerging and being represented through interactions with technologies. (271)In the twenty-first century, self-quantification and tracking technologies like the Fitbit are ever more present in individual spheres of everyday activity. These devices prompt behaviour, affect self-knowledge, and signal identity: I am a fit person, or trying to be, or was. A Fitbit cannot record how it feels to spend 34 minutes in the “peak zone,” but it can prompt recollection, it is a mnemonic, and it provides an account of time spent, how, and by whom. Is a Fitbit a diary? The diary in the twenty-first century is already vastly different to many of its formal historical counterparts, yet there are discursive resonances. The Fitbit is a diary if we think of a diary as a chronological record of data, which it can be. However, contemporary uses of the diary, just like their historical antecedents, are also far more diverse and complex than this.Crucially, the Fitbit, like the diary, signals identity in relation to experience and so it reflects various and shifting cultural values or anxieties over what is worth measuring or documenting, and conversely, over what is not. “The private diary,” as Lejeune asserts, is a way of life: “the text itself is a mere by-product, a residue” (31). Historical diary keeping practices unfold from and emerge within cultures that position self-expression and its documentation of this as a means to self-improvement. Seeing the Fitbit within this tradition draws attention to the discursive ideology behind self-tracking as a personal practice that nonetheless positions itself in relation to cultural norms and to ideals (such as health, or fitness, or conscientiousness, or goodness).ConclusionWhat kind of self-representation is produced by practices of self-quantification, where personal data is amassed continuously and contiguously to individual experience? The legacy of centuries of historical diary-practice has been evident to various scholars exploring the cultures of self-tracking that are evolving in response to wearable technologies like the Fitbit. In her book length study of self-tracking cultures, The Quantified Self, Lupton observes that “self-tracking tools” are inevitably “biographical and personal” and that “contemporary self-tracking tools and records are the latter-day versions of the paper diary or journal, photo album, keepsake and memento box or personal dossier” (73). While, in Self-Tracking, Neff and Nafus argue that new technologies “intersect with the way that people have self-tracked for centuries like keeping diaries or logs. The growth of these digital traces raises new questions about this old practice” (2).What does it mean to think of wearable technology like Fitbits in relation to diaries, and what are the implications of such a conception? Privacy settings allow the Fitbit to comply with popular stereotypes of diaries that exist in popular culture; that is, as a locked or secret record. However, in the case of wearable technology the content is in the form of data. While data often poses as neutral and objective information, seeing this instead as diaristic can draw valuable attention to dominant cultural ideals that shape value in relation to self and technology in the twenty-first century. Crucially, “while self-knowledge may be the rhetoric of wearable device advertising, it is just as much a technology of being known by others” (Crawford, Lingel, and Karppi 493-494).Is my Fitbit a diary? It tracks my body’s movements and gestures and reports them to the conscious self. It stores chronologically accumulated data over time. It enables self-reflection and the visualisation of a set of daily habits, and it may produce or coax new behaviour. Diaries have long performed this function: tracking, recording and, documenting for making sense of later, on reflection, or after enough time has passed. Contemporary advances in technology related to self-tracking and personal data collection make possible a new range of previously unimaginable information in relation to individual experience. However, the diary’s cultural status as a “confessional” form intersects with exigencies around “health” and “self-improvement” that corporations producing devices like Fitbit promote to their customers in ways that will demand further attention.ReferencesCardell, Kylie. Dear World: Contemporary Uses of the Diary. Wisconsin UP, 2014.Connor, Rebecca Elisabeth. Women, Accounting and Narrative: Keeping Books in Eighteenth-Century England. London: Routledge, 2011.Crawford, Kate, Jessa Lingel, and Tero Karppi. “Our Metrics, Ourselves: A Hundred Years of Self-Tracking From the Weight Scale to the Wrist Wearable Device.” European Journal of Cultural Studies 18.4-5 (2015): 470-96.Franklin, Benjamin. The Autobiography of Benjamin Franklin: The Complete Illustrated History. Minneapolis: MN Voyageur Press, 2016.Gregg, Melissa. “Inside the Data Spectacle.” Television & New Media 16.1 (2014): 1-15.Lejeune, Philippe. On Diary. Eds. Jeremy D. Popkin and Julie Rak. Trans. Katherine Durnin. Honolulu: U of Hawai’i P, 2009.Lupton, Deborah. “Personal Data Practices in the Age of Lively Data.” Digital Sociologies. Eds. Jessie Daniels, Tressie McMillan Cottom, and Karen Gregory. Bristol: Policy P, 2016. 339-54.———. The Quantified Self. Cambridge: Polity, 2016.McCarthy, Molly A. The Accidental Diarist: A History of the Daily Planner in America. Chicago: U of Chicago P, 2013.Neff, Gina, and Dawn Nafus. Self-Tracking. Cambridge: The MIT P, 2016.Rettberg, Jill Walker. Seeing Our Selves through Technology: How We Use Selfies, Blogs and Wearable Technology to Shape Ourselves. Basingstoke: Palgrave Macmillan, 2014.———. “Self-Representation in Social Media.” The Sage Handbook of Social Media, Eds. Jean Burgess, Alice E. Marwick, and Thomas Poell. London: Sage, 2017. 429-43.Sedaris, David. “Stepping Out.” The New Yorker 30 Jun. 2014. 18 Apr. 2018 <https://www.newyorker.com/magazine/2014/06/30/stepping-out-3>.Sorapure, Madeleine. “Autobiography Scholarship 2.0?: Understanding New Forms of Online Life Writing.” Biography 38.2 (2015): 267-72.

Introduction The recent AOL/Time-Warner merger invites us to re-think the relationships amongst content producers, distributors, and audiences. Worth an estimated $300 billion (US), the largest Internet transaction of all time, the deal is 45 times larger than the AOL/Netscape merger of November 1998 (Ledbetter). Additionally, the Time Warner/EMI merger, which followed hard on the heels of the AOL/Time-Warner deal and is itself worth $28 billion (US), created the largest content rights organisation in the music industry. The joining of the Internet giant (AOL) with what was already the world's largest media corporation (Time-Warner-EMI) has inspired some exuberant reactions. An Infoworld column proclaimed: The AOL/Time-Warner merger signals the demise of traditional media companies and the ascendancy of 'new economy' media companies that will force any industry hesitant to adopt a complete electronic-commerce strategy to rethink and put itself on Internet time. (Saap & Schwarrtz) This comment identifies the distribution channel as the dominant component of the "new economy" media. But this might not really be much of an innovation. Indeed, the assumption of all industry observers is that Time-Warner will provide broadband distribution (through its extensive cable holdings) as well as proprietary content for AOL. It is also expected that Time-Warner will adopt AOL's strategy of seeking sponsorship for development projects as well as for content. However, both of these phenomena -- merger and sponsorship -- are at least as old as radio. It seems that the Internet is merely repeating an old industrial strategy. Nonetheless, one important difference distinguishes the Internet from earlier media: its characterisation of the audience. Internet companies such as AOL and Microsoft tend towards a simple and simplistic media- centred view of the audience as market. I will show, however, that as the Internet assumes more of the traditional mass media functions, it will be forced to adopt a more sophisticated notion of the mass audience. Indeed, the Internet is currently the site in which audience definitions borrowed from broadcasting are encountering and merging with definitions borrowed from marketing. The Internet apparently lends itself to both models. As a result, definitions of what the Internet does or is, and of how we should understand the audience, are suitably confused and opaque. And the behaviour of big Internet players, such as AOL and MSN, perfectly reflects this confusion as they seem to careen between a view of the Internet as the new television and a contrasting view of the Internet as the new shopping mall. Meanwhile, Internet users move in ways that most observers fail to capture. For example, Baran and Davis characterise mass communication as a process involving (1) an organized sender, (2) engaged in the distribution of messages, (3) directed toward a large audience. They argue that broadcasting fits this model whereas a LISTSERV does not because, even though the LISTSERV may have very many subscribers, its content is filtered through a single person or Webmaster. But why is the Webmaster suddenly more determining than a network programmer or magazine editor? The distinction seems to grow out of the Internet's technological characteristics: it is an interactive pipeline, therefore its use necessarily excludes the possibility of "broadcasting" which in turn causes us to reject "traditional" notions of the audience. However, if a media organisation were to establish an AOL discussion group in order to promote Warner TV shows, for example, would not the resulting communication suddenly fall under the definition as set out by Baran and Davis? It was precisely the confusion around such definitions that caused the CRTC (Canada's broadcasting and telecommunications regulator) to hold hearings in 1999 to determine what kind of medium the Internet is. Unlike traditional broadcasting, Internet communication does indeed include the possibility of interactivity and niche communities. In this sense, it is closer to narrowcasting than to broadcasting even while maintaining the possibility of broadcasting. Hence, the nature of the audience using the Internet quickly becomes muddy. While such muddiness might have led us to sharpen our definitions of the audience, it seems instead to have led many to focus on the medium itself. For example, Morris & Ogan define the Internet as a mass medium because it addresses a mass audience mediated through technology (Morris & Ogan 39). They divide producers and audiences on the Internet into four groups: One-to-one asynchronous communication (e-mail); Many-to-many asynchronous communication (Usenet and News Groups); One-to-one, one-to-few, and one-to-many synchronous communication (topic groups, construction of an object, role-playing games, IRC chats, chat rooms); Asynchronous communication (searches, many-to-one, one-to-one, one to- many, source-receiver relations (Morris & Ogan 42-3) Thus, some Internet communication qualifies as mass communication while some does not. However, the focus remains firmly anchored on either the sender or the medium because the receiver --the audience -- is apparently too slippery to define. When definitions do address the content distributed over the Net, they make a distinction between passive reception and interactive participation. As the World Wide Web makes pre-packaged content the norm, the Internet increasingly resembles a traditional mass medium. Timothy Roscoe argues that the main focus of the World Wide Web is not the production of content (and, hence, the fulfilment of the Internet's democratic potential) but rather the presentation of already produced material: "the dominant activity in relation to the Web is not producing your own content but surfing for content" (Rosco 680). He concludes that if the emphasis is on viewing material, the Internet will become a medium similar to television. Within media studies, several models of the audience compete for dominance in the "new media" economy. Denis McQuail recalls how historically, the electronic media furthered the view of the audience as a "public". The audience was an aggregate of common interests. With broadcasting, the electronic audience was delocalised and socially decomposed (McQuail, Mass 212). According to McQuail, it was not a great step to move from understanding the audience as a dispersed "public" to thinking about the audience as itself a market, both for products and as a commodity to be sold to advertisers. McQuail defines this conception of the audience as an "aggregate of potential customers with a known social- economic profile at which a medium or message is directed" (McQuail, Mass 221). Oddly though, in light of the emancipatory claims made for the Internet, this is precisely the dominant view of the audience in the "new media economy". Media Audience as Market How does the marketing model characterise the relationship between audience and producer? According to McQuail, the marketing model links sender and receiver in a cash transaction between producer and consumer rather than in a communicative relationship between equal interlocutors. Such a model ignores the relationships amongst consumers. Indeed, neither the effectiveness of the communication nor the quality of the communicative experience matters. This model, explicitly calculating and implicitly manipulative, is characteristically a "view from the media" (McQuail, Audience 9). Some scholars, when discussing new media, no longer even refer to audiences. They speak of users or consumers (Pavick & Dennis). The logic of the marketing model lies in the changing revenue base for media industries. Advertising-supported media revenues have been dropping since the early 1990s while user-supported media such as cable, satellite, online services, and pay-per-view, have been steadily growing (Pavlik & Dennis 19). In the Internet-based media landscape, the audience is a revenue stream and a source of consumer information. As Bill Gates says, it is all about "eyeballs". In keeping with this view, AOL hopes to attract consumers with its "one-stop shopping and billing". And Internet providers such as MSN do not even consider their subscribers as "audiences". Instead, they work from a consumer model derived from the computer software industry: individuals make purchases without the seller providing content or thematising the likely use of the software. The analogy extends well beyond the transactional moment. The common practice of prototyping products and beta-testing software requires the participation of potential customers in the product development cycle not as a potential audience sharing meanings but as recalcitrant individuals able to uncover bugs. Hence, media companies like MTV now use the Internet as a source of sophisticated demographic research. Recently, MTV Asia established a Website as a marketing tool to collect preferences and audience profiles (Slater 50). The MTV audience is now part of the product development cycle. Another method for getting information involves the "cookie" file that automatically provides a Website with information about the user who logs on to a site (Pavick & Dennis). Simultaneously, though, both Microsoft and AOL have consciously shifted from user-subscription revenues to advertising in an effort to make online services more like television (Gomery; Darlin). For example, AOL has long tried to produce content through its own studios to generate sufficiently heavy traffic on its Internet service in order to garner profitable advertising fees (Young). However, AOL and Microsoft have had little success in providing content (Krantz; Manes). In fact, faced with the AOL/Time-Warner merger, Microsoft declared that it was in the software rather than the content business (Trott). In short, they are caught between a broadcasting model and a consumer model and their behaviour is characteristically erratic. Similarly, media companies such as Time-Warner have failed to establish their own portals. Indeed, Time-Warner even abandoned attempts to create large Websites to compete with other Internet services when it shut down its Pathfinder site (Egan). Instead it refocussed its Websites so as to blur the line between pitching products and covering them (Reid; Lyons). Since one strategy for gaining large audiences is the creation of portals - - large Websites that keep surfers within the confines of a single company's site by providing content -- this is the logic behind the AOL/Time-Warner merger though both companies have clearly been unsuccessful at precisely such attempts. AOL seems to hope that Time- Warner will act as its content specialist, providing the type of compelling material that will make users want to use AOL, whereas Time- Warner seems to hope that AOL will become its privileged pipeline to the hearts and minds of untold millions. Neither has a coherent view of the audience, how it behaves, or should behave. Consequently, their efforts have a distinctly "unmanaged" and slighly inexplicable air to them, as though everyone were simultaneously hopeful and clueless. While one might argue that the stage is set to capitalise on the audience as commodity, there are indications that the success of such an approach is far from guaranteed. First, the AOL/Time-Warner/EMI transaction, merely by existing, has sparked conflicts over proprietary rights. For example, the Recording Industry Association of America, representing Sony, Universal, BMG, Warner and EMI, recently launched a $6.8 billion lawsuit against MP3.com -- an AOL subsidiary -- for alleged copyright violations. Specifically, MP3.com is being sued for selling digitized music over the Internet without paying royalties to the record companies (Anderson). A similar lawsuit has recently been launched over the issue of re- broadcasting television programs over the Internet. The major US networks have joined together against Canadian Internet company iCravetv for the unlawful distribution of content. Both the iCravetv and the MP3.com cases show how dominant media players can marshal their forces to protect proprietary rights in both content and distribution. Since software and media industries have failed to recreate the Internet in the image of traditional broadcasting, the merger of the dominant players in each industry makes sense. However, their simultaneous failure to secure proprietary rights reflects both the competitive nature of the "new media economy" and the weakness of the marketing view of the audience. Media Audience as Public It is often said that communication produces social cohesion. From such cohesion communities emerge on which political or social orders can be constructed. The power of social cohesion and attachment to group symbols can even create a sense of belonging to a "people" or nation (Deutsch). Sociologist Daniel Bell described how the mass media helped create an American culture simply by addressing a large enough audience. He suggested that on the evening of 7 March 1955, when one out of every two Americans could see Mary Martin as Peter Pan on television, a kind of social revolution occurred and a new American public was born. "It was the first time in history that a single individual was seen and heard at the same time by such a broad public" (Bell, quoted in Mattelart 72). One could easily substitute the 1953 World Series or the birth of little Ricky on I Love Lucy. The desire to document such a process recurs with the Internet. Internet communities are based on the assumption that a common experience "creates" group cohesion (Rheingold; Jones). However, as a mass medium, the Internet has yet to find its originary moment, that event to which all could credibly point as the birth of something genuine and meaningful. A recent contender was the appearance of Paul McCartney at the refurbished Cavern Club in Liverpool. On Tuesday, 14 December 1999, McCartney played to a packed club of 300 fans, while another 150,000 watched on an outdoor screen nearby. MSN arranged to broadcast the concert live over the Internet. It advertised an anticipated global audience of 500 million. Unfortunately, there was such heavy Internet traffic that the system was unable to accommodate more than 3 million people. Servers in the United Kingdom were so congested that many could only watch the choppy video stream via an American link. The concert raises a number of questions about "virtual" events. We can draw several conclusions about measuring Internet audiences. While 3 million is a sizeable audience for a 20 minute transmission, by advertising a potential audience of 500 million, MSN showed remarkably poor judgment of its inherent appeal. The Internet is the first medium that allows access to unprocessed material or information about events to be delivered to an audience with neither the time constraints of broadcast media nor the space limitations of the traditional press. This is often cited as one of the characteristics that sets the Internet apart from other media. This feeds the idea of the Internet audience as a participatory, democratic public. For example, it is often claimed that the Internet can foster democratic participation by providing voters with uninterpreted information about candidates and issues (Selnow). However, as James Curran argues, the very process of distributing uninterrupted, unfiltered information, at least in the case of traditional mass media, represents an abdication of a central democratic function -- that of watchdog to power (Curran). In the end, publics are created and maintained through active and continuous participation on the part of communicators and audiences. The Internet holds together potentially conflicting communicative relationships within the same technological medium (Merrill & Ogan). Viewing the audience as co-participant in a communicative relationship makes more sense than simply focussing on the Internet audience as either an aggregate of consumers or a passively constructed symbolic public. Audience as Relationship Many scholars have shifted attention from the producer to the audience as an active participant in the communication process (Ang; McQuail, Audience). Virginia Nightingale goes further to describe the audience as part of a communicative relationship. Nightingale identifies four factors in the relationship between audiences and producers that emphasize their co-dependency. The audience and producer are engaged in a symbiotic relationship in which consumption and use are necessary but not sufficient explanations of audience relations. The notion of the audience invokes, at least potentially, a greater range of activities than simply use or consumption. Further, the audience actively, if not always consciously, enters relationships with content producers and the institutions that govern the creation, distribution and exhibition of content (Nightingale 149-50). Others have demonstrated how this relationship between audiences and producers is no longer the one-sided affair characterised by the marketing model or the model of the audience as public. A global culture is emerging based on critical viewing skills. Kavoori calls this a reflexive mode born of an increasing familiarity with the narrative conventions of news and an awareness of the institutional imperatives of media industries (Kavoori). Given the sophistication of the emergent global audience, a theory that reduces new media audiences to a set of consumer preferences or behaviours will inevitably prove inadequate, just as it has for understanding audience behavior in old media. Similarly, by ignoring those elements of audience behavior that will be easily transported to the Web, we run the risk of idealising the Internet as a medium that will create an illusory, pre-technological public. Conclusion There is an understandable confusion between the two models of the audience that appear in the examples above. The "new economy" will have to come to terms with sophisticated audiences. Contrary to IBM's claim that they want to "get to know all about you", Internet users do not seem particularly interested in becoming a perpetual source of market information. The fragmented, autonomous audience resists attempts to lock it into proprietary relationships. Internet hypesters talk about creating publics and argue that the Internet recreates the intimacy of community as a corrective to the atomisation and alienation characteristic of mass society. This faith in the power of a medium to create social cohesion recalls the view of the television audience as a public constructed by the common experience of watching an important event. However, MSN's McCartney concert indicates that creating a public from spectacle it is not a simple process. In fact, what the Internet media conglomerates seem to want more than anything is to create consumer bases. Audiences exist for pleasure and by the desire to be entertained. 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M/C: A Journal of Media and Culture 3.1 (2000). [your date of access] <http://www.uq.edu.au/mc/0003/mass.php>. Chicago style: Daniel M. Downes, "The Medium Vanishes? The Resurrection of the Mass Audience in the New Media Economy," M/C: A Journal of Media and Culture 3, no. 1 (2000), <http://www.uq.edu.au/mc/0003/mass.php> ([your date of access]). APA style: Daniel M. Downes. (2000) The Medium Vanishes? The Resurrection of the Mass Audience in the New Media Economy. M/C: A Journal of Media and Culture 3(1). <http://www.uq.edu.au/mc/0003/mass.php> ([your date of access]).