Targeted Therapy With the Mutant IDH2 Inhibitor Enasidenib for High-Risk IDH2-Mutant Myelodysplastic Syndrome

The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ∼5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%). Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% of patients (8%; grades 3 and 4), and IDH-inhibitor-associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: complete remission [CR] + marrow CR [mCR] + partial remission) was 74%, including 70% composite CR (CRc: CR + mCR). Median time to best response was 1 month (range, 1-4), and a median of 4 cycles was received (1-32). The median overall survival (OS) was 26 months (range, 14 to not reached). In the enasidenib monotherapy cohort after HMA failure, ORR and CRc were both 35% (n = 8), with 22% CR (n = 5). Median time to first response was 27 days, and time to best response was 4.6 months (2.7-7.6 months). A median of 7 cycles was received (range, 1-29), and the median OS was 20 months (range, 11 to not reached). Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as #NCT03383575

The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis

Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKI) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); with a median age of 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12 of 15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients five could re-escalate the TKI dose and nine improved their response. None of the six patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1,000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted (clinicaltrials gov. Identifier: NCT01428635)

Clinical Outcomes Associated With NPM1 Mutations in Patients With Relapsed or Refractory AML

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P \u3c .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML

Quasi-Density of Sets, Quasi-Statistical Convergence and the Matrix Summability Method

In this paper, we define the quasi-density of subsets of the set of natural numbers and show several of the properties of this density. The quasi-density dp(A) of the set A⊆N is dependent on the sequence p=(pn). Different sequences (pn), for the same set A, will yield new and distinct densities. If the sequence (pn) does not differ from the sequence (n) in its order of magnitude, i.e., limn→∞pnn=1, then the resulting quasi-density is very close to the asymptotic density. The results for sequences that do not satisfy this condition are more interesting. In the next part, we deal with the necessary and sufficient conditions so that the quasi-statistical convergence will be equivalent to the matrix summability method for a special class of triangular matrices with real coefficients

Ein Vergleich der Darstellung der „Flüchtlingskrise“ und Repräsentationen von Flüchtlingen in tschechischen und österreichischen Online-Zeitungen im Frühling/Sommer 2016

Im Rahmen der vorliegenden Arbeit wurde die mediale Berichterstattung der österreichischen und tschechischen Online-Zeitungen DiePresse.com und iDnes.cz über die „Flüchtlingskrise und Flüchtlinge“ im Frühling und Sommer 2016 analysiert. Es wurde untersucht, welche Diskursstränge in der Berichterstattung in dem untersuchten Zeitraum prägend sind und wie die „Flüchtlingskrise“ mit Islam, Islamismus und MuslimInnen in Verbindung gebracht wurde, beziehungsweise in welchen Kontexten die Zeitungen über Islam und MuslimInnen berichtet haben. Um die Repräsentationsbilder von Flüchtlingen untersuchen zu können, wurden drei Hauptrahmen (Bedrohung, Opfer und aktiv handelndes Subjekt) herangezogen. Somit wurde untersucht, welches Bild von Flüchtlingen die Online-Zeitungen am häufigsten ihrer Leserschaft präsentieren. Das Material wurde anhand korpusanalytischer, strukturanalytischer und diskursanalytischer Methoden analysiert. Zur Vervollständigung des Gesamtbildes der Darstellung der „Flüchtlingskrise“ und Repräsentationen von Flüchtlingen wurden zwei ausgewählte Artikel einer kritischen Diskursanalyse nach Siegfried Jäger unterzogen.The topic of this thesis is the media coverage of the Austrian and Czech online newspapers DiePresse.com and iDnes.cz on the “Refugee Crisis and Refugees” in spring and summer of 2016. It was examined which discourse strands were characteristic in the reporting period and how the “refugee crisis” has been linked to Islam, Islamism and Muslims, or in what contexts the newspapers have reported about Islam and Muslims. To investigate the representative images of refugees, three main frames (threat, victim and active agents) were used to show which image of refugees most often spread by the online newspapers to their readership. The material was analysed by means of corpus analytical tools, structural analysis and discursive analysis. To complete the overall picture of the “refugee crisis” and representations of refugees, two selected articles were subjected to a critical discourse analysis according to Siegfried Jäger

Terminologie der Asyl- und Flüchtlingspolitik des UNHCR in den Sprachen Deutsch und Englisch

Die vorliegende Masterarbeit setzt sich mit den Grundlagen der Terminologiewissenschaft sowie den Grundlagen des terminologiewissenschaftlichen Arbeitens auseinander und unterstreicht dabei die Bedeutung der Terminologiarbeit für die Fachkommunikation. Im Speziellen fokussiert sich diese Arbeit auf die Asyl- und Flüchtlingspolitik des UNHCR, einer der bedeutendsten Akteure aus diesem Bereich. Weiter wird die Problematik der Abgrenzung der Begriffe „Flüchtling“ und „Migrant“ behandelt. Der Schwerpunkt liegt dabei auf dem europäischen Raum, im Besonderen wird auf die „Flüchtlingskrise“ 2015-2016 in Europa im Allgemeinen sowie in Österreich und Großbritannien im Speziellen eingegangen. Die Themen Asyl, Flucht und Migration werden im theoretischen Teil näher ausgeführt. Im praktischen Teil dieser Masterarbeit werden Schlüsselbegriffe der Asyl- und Flüchtlingspolitik des UNHCR im Rahmen einer detaillierten terminologiewissenschaftlichen Untersuchung unterzogen. Mithilfe des korpusanalytischen Programms AntConc wurden insgesamt 50 Begriffe mit pro Sprache jeweils 77 Benennungen in einem terminologischen Fachwortglossar zusammengestellt, welches neben dem Terminus selbst weitere Angaben zu dessen Quelle, Fachgebiet, Definition, Synonymen und deren Quellen sowie Anmerkungen enthält.This master thesis deals with the basics of terminology and the basics of the terminological working while emphasizing the importance of terminological work in professional communication. Specifically, this work focuses on the asylum and refugee policy of UNHCR, one of the major players in this field. Subsequently, the focus of this lies on the distinction of the two terms "refugee" and "migrant". Special attention is given to the European region in the context of the "refugee crisis" 2015-2016 in Europe in general and in Austria and the UK in particular. The issues of asylum, refugees and migration are discussed in the theoretical part. In the practical part of this thesis key concepts of asylum and refugee policy of the UNHCR are subject to a detailed terminological analysis. With the aid of the corpus analytical program AntConc, a terminological glossary with 50 terms in each language has been compiled