Supplement 2/17 memo (2017) 10 [2]:S19–S48 DOI 10.1007/s12254-017-0322-8 Online publiziert: 22 March 2017 © Springer-Verlag Wien 2017

Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology Frühjahrstagung 2017 der Österreichischen Gesellschaft für Hämatologie und Medizinische Onkologie und der AHOP – Arbeitsgemeinschaft hamatologischer und onkologischer Pflegepersonen in Österreich Bregenz, 06.–08. April 2017

Congress President: Priv.-Doz. OA Dr. Alois Lang Secretary: OA Dr. Bernd Hartmann OÄ Dr. Margit Sandholzer OA Dr. Klaus Gasser Abteilung für Innere Medizin Hämatologie & Onkologie Landeskrankenhaus Feldkirch

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Poster Hämatologie

P01 RAF kinase inhibitor protein is involved in the development of chronic myelomonocytic leukemia Veronica Caraffini1*, Olivia Geiger1, Angelika Rosenberger1, Stefan Hatzl1, Bianca Perfler1, Johannes Lorenz Berg1, Clarice Lim2, Herbert Strobl2, Karl Kashofer3, Gerald Hoefler3, Klaus Geissler4, Walter Kolch5, Karen Blyth6, Dimitris Athineos6, Albert Wölfler1, Heinz Sill1, Armin Zebisch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria 3 Institute of Pathology, Medical University of Graz, Graz, Austria 4 Medical Department with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria 5 Systems Biology Ireland & Conway Institute, University College Dublin, Dublin, Ireland 6 Cancer Research UK Beatson Institute, Glasgow, United Kingdom 1

Background:  Chronic myelomonocytic leukemia (CMML) is characterized by increased myelomonocytic differentiation and proliferation of hematopoietic stem cells (HSC). Somatic RAS mutations are frequently detected in CMML and induce a CMML-like disorder in mice via causing hypersensitivity to GMCSF. RAF kinase inhibitor protein (RKIP), a negative regulator of RAS-signalling, is frequently lost in acute myelomonocytic/ monocytic leukemia and has recently been shown to inhibit the proliferation of hematopoietic cells. Therefore, we asked for a role of RKIP in CMML. Methods:  RKIP mRNA/protein expression analysis as well as sequencing of 40 CMML-related genes was performed in 23 CMML patient specimens by immunoblotting, qPCR and IonTorrent next-generation-sequencing. Effects of RKIP on GMCSF induced myelomonocytic differentiation were studied in human CD34+ HSC following lentiviral shRNA-knockdown of RKIP, as well as in a genetic mouse model for RKIP deletion (RKIP-/-). To study the role of RKIP in CMML development, we initially employed the same RKIP-/- mice. Additionally, they were crossed with animals carrying a somatically inducible NRAS mutation (RKIP-/-Mx1-Cre-NRASG12D). Results:  A somatic loss of RKIP was observed in 6/23(26%) CMML patient specimens and associated with mutations affecting the RAS-signalling pathway. In addition to the previously demonstrated induction of proliferation, knockdown of RKIP increased the GM-CSF induced myelomonocytic differentiation of HSC in-vitro and in-vivo. Although RKIP was insufficient to cause CMML as a single event in mice, it aggravated its development in animals carrying an additional mutation in NRAS. Conclusions:  RKIP loss is involved in myelomonocytic differentiation and acts as contributing factor to the development of CMML.

NR4A3-mediated apoptosis suppresses lymphomagenesis in a xenograft mouse model and is associated with a favorable cancer-specific survival in DLBCL patients Alexander Deutsch1*, Beate Rinner2, Katrin Pansy1, Karoline Fechter1, Kathrina Prochazka1, Hildegard T Greinix1, Christine Beham-Schmid3, Peter Neumeister1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Core Facility Alternative Biomodels & Preclinical Imaging, Graz, Austria 3 Institut of Pathology, Medical University of Graz, Graz, Austria 1

Background:  The NR4A family of nuclear orphan receptors (NR4A1, NR4A2 and NR4A3) has pleiotropic functions regulating diverse aspects of cell biology. Recently, we described an essential role of NR4A1 as tumor suppressor in aggressive lymphomas. Since the role of NR4A3 in aggressive lymphomas is unknown, we aimed to investigate its etiopathogenetic function in these tumors. Methods: NR4A3 expression levels were determined by qRQ PCR. For functional characterization, NR4A3 was overexpressed in the SuDHL4 lymphoma cell line by using an inducible lentiviral construct followed by various apoptotic assays. Results:  Low expression of NR4A3 was associated with poor survival in aggressive lymphoma patients. Experimentally, induction of NR4A3 expression by inducible ectopic expression or pharmacological activation in lymphoma cell lines led to a significantly higher proportion of apoptotic cells as demonstrated by DNA cleavage, Annexin V staining and increased caspase 3/7 activity. To test the tumor suppressor functions of NR4A3 in vivo, the stably transduced SuDHL4-lymphoma cell line was xenografted in the NOD-SCID-gamma (NSG) mouse model. In this system NR4A3 expression abrogated tumor growth in the NSG mice, whereas vector control and uninduced cells formed massive lymphoid tumors. Furthermore, NR4A3 and NR4A1 were separately over-expressed in four different aggressive lymphoma cell lines resulting in induction of BAK, Puma, BIK, BIM, BID and Trail in the same degree and induction of apoptosis. Conclusions:  Our data suggest that NR4A3 has a pro-apoptotic function in aggressive lymphomas and define that NR4A3 together with NR4A1 function as novel tumor suppressors involved in aggressive lymphoma development.

Die mit Sternchen (*) markierten Autoren sind die korrespondierenden Autoren.

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P03 Treatment of lymphoma cell lines with CXCR4 antagonists inhibits cell growth in vitro Barbara Ehall1*, Beata Pursche1, Hildegard T. Greinix1, Katharina Prochazka1, Miriam Sedej3, Manuel Zoidl2, Tanja Wrodnigg2, Peter Neumeister1, Alexander Deutsch1, Karoline Fechter1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Organic Chemistry, University of Technology, Graz, Austria 3 Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria 1

Background:  CXCR4 together with its ligand CXCL12 play a pivotal role in tumorigenesis of solid and haematological neoplasms. Our comprehensive study on the CXCR4 expression in aggressive lymphoma demonstrated that CXCR4 and its CXCL12 is implicated in the bone marrow infiltration process and is associated with poor clinical course of aggressive lymphoma patients. Therefore, we aim to determine the in vitro effects of CXCR4 antagonists (AMD3100 and AMD070 and WK1-nicotine acid derivatives of AM070) to identify the CXCR4 CXCL12 axis as therapeutic target. Methods:  We treated aggressive lymphoma cell lines (U2932 and RI-1 as ABC-DLBCL and BL2 and Raji as Burkitt lymphoma lines) with AMD3100, AMD070 and WK1 in range from 50 µM to 5 µM and determined cell growth by using the EZ4U assay and for AMD070 and WK1 trans-well migration was used to estimate migration indices. Results:  The cell growth of BL2 and RI-1-exhibiting strong and moderated CXCR4 expression- was significantly inhibited by AMD070 and WK1. Whereas the cell growth of U2932 -exhibiting a weak CXCR4 expression- was just affected by WK1. AMD3100 did not show any effects on the cell growth. The migration index was reduced by AMD070 and WK1 treatment, however, the inhibitory effects of WK1 were lower compared to AMD070. Conclusions: Our results indicate that treatment of lymphoma cells with CXCR4 antagonists might be a promising new therapeutic intervention to eliminate lymphoma cells.

P04 Loss of Nr4a1 accelerates Myc-driven lymphomagenesis Karoline Fechter1*, Katharina Prochazka1, Katrin Pansy1, Beata Pursche1, Hildegard T. Greinix1, Christine Beham-Schmid2, Peter Neumeister1, Alexander Deutsch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institut of Pathology, Department of Hematopathology, Medical University of Graz, Graz, Austria 1

Background:  Low expression of the nuclear orphan receptor NR4A1 was shown to be associated with poor cancer specific survival in aggressive lymphomas patients. In order to better dissect the role of Nra41, we monitored survival and tumor formation in a mouse model of Myc-driven lymphomagenesis.

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Moreover, we investigated the driver effect of Nr4a1, performed apoptotic assays at the premalignant stage and compared data between the different mice cohorts. Methods:  Kaplan Meier analysis was performed for survival and tumor formation in EµMyc Nr4a1+/+, EµMyc Nr4a1-/- and EµMyc Nr4a1+/–, respectively. For the premalignant stage mice aged 4 weeks (n = 4 per genotype) were sacrificed and AnnexinV staining and cleaved-caspase3 assay were performed on cells isolated from the spleen and bone marrow. Data were compared between wt and EµMyc mice with and without Nr4a1 loss. Results:  EµMyc Nr4a1-/- mice showed decreased survival (92 vs. 123 days) and increased tumor formation (45 vs. 107 days) compared to EµMyc Nr4a1+/+ mice, whereby heterozygous mice showed intermediate values. Furthermore, EµMyc NR4A1 (+/+) exhibited induction of apoptosis in all investigated B cell subpopulations at the premalignant stage, whereas apoptosis was significantly diminished in EµMyc Nr4a1 (-/-) mice. Conclusions:  Our results clearly demonstrate the influence of Nr4a1 loss on tumor formation and thus survival in Mycdriven lymphomagenesis. Importantly, Nr4a1 seems to impact cell death early in B cell development, even ahead of lymphoma formation. Collectively, these data underpin the tumor suppressive role of Nr4a1 and make it a new target for risk stratification and therapy.

P05 Effectiveness and toxicity of the EPOCH-R treatment on high-risk DLBCL patients between 01. 01. 2014–31. 01. 2016 at the Medical University Vienna Lisa Frühwald1*, Renate Heinz1, Ulrich Jäger1 Department of Haematology and Haemostaseology, Medical University of Vienna, Vienna, Austria

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Background:  Treatment for high-risk Diffuse Large B-Cell Lymphoma patients is still challenging. Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) is a salvage regimen approach, which shows long lasting success in different trials in the last years. We investigated feasibility, toxicity and efficacy of EPOCH-R in untreated high-risk CD20 – positive B-cell non-Hodgkin Lymphoma. Furthermore we estimated molecular markers, which may be targets for future personalized therapies in this patient population. Methods:  In our retrospective and descriptive investigation we included patients treated with at least one cycle of ­EPOCH-R. Primary objective included adverse events, relationships between molecular markers and feasibility/toxicity. Secondary objective included Remission data and survival analysis also linked to molecular features. Results: Median age of our 20 patients was 63 years. 16 patients had international prognostic index 3 or higher. From 20 patients screened with immunohistochemistry 12 BCL2+ and MYC+ double expressor lymphoma were found. Regarding molecular features 11 MYC translocations, 9 BCL2 recombinations and 4 TP53 deletion/mutation could be detected. Dosereduction, delay of treatment repetition (median 28 days) and mostly haematologic side effects underline the considerable toxicity in our cases. Eight of ten patients with DLBCL WHO diagnose received Complete Remission, two had Partial Remission. Two of the Complete Remissions suffered from a recurrence, one patient died in this stated timeframe.

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Supplement 2/17 Conclusions: As shown from newest randomized trials EPOCH-R has no benefit compared to R-CHOP. This makes our analysis another argument, that aggressive chemotherapy has come to its limits and research groups should investigate in molecular marker targeted therapy.

P06 Effects of ponatinib on endothelial cells may explain the occurrence of vascular adverse events in ponatinib-treated patients with CML Emir Hadzijusufovic1,2,3*, Rudolf Kirchmair4, Nikolaus Krall5, Kilian Huber6, Markus Theurl4, Susanne Gamperl1, Daniela Lener4, Clemens Gutmann4, Ursula Stanzl4, Andrijana Kirsch7, Sasa Frank7, Giulio Superti-Furga5, Peter Valent1,2 Department of Medicine I, Medical University of Vienna, Vienna, Austria 2 Ludwig Boltzmann Cluster Oncology, Vienna, Austria 3 Department for Companion Animals and Horses, University of Veterinary Medicine, Vienna, Austria 4 Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria 5 Research Center for Molecular Medicine (CeMM), Vienna, Austria 6 University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom 7 Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria 1

Ponatinib, a BCR/ABL1-targeting drug, is used for the treatment of drug-resistant chronic myeloid leukemia (CML). However, an accumulation of vascular adverse events (VAE) has been described in ponatinib-treated patients. To discover mechanisms responsible for these VAE, we have analyzed effects of ponatinib on endothelial cells using various in vitro methods. In addition, we examined the effects of ponatinib on angiogenesis in vivo. In chemical proteomics studies, ponatinib recognized several kinase targets relevant for angiogenesis and/or vessel repair, including TEK, MAPKAPK2, PDGFRB, EPHA2, and JAK1 in the human microvascular endothelial cell line HMEC-1 and in human umbilical vein endothelial cells (HUVEC). Furthermore, ponatinib (50–250 nM) induced apoptosis in human coronary artery endothelial cells (HCAEC) and inhibited the proliferation of HUVEC and HMEC-1. We also found that ponatinib increases the expression of adhesion-related molecules on HUVEC and the adhesiveness of HUVEC to a plastic-surface compared to DMSO-control. In C57BL/6 mice, ponatinib (5 mg/ kg/day, 35 days) decreased perfusion recovery after vessel ligation. The perfusion ratios (ischemic/non-ischemic limb) on day 35 were: 0.67 ± 0.07 (control) versus 0.56 ± 0.1 (ponatinib). In phospho-receptor tyrosine kinase profiler experiments with HCAEC, we found that ponatinib inhibits phosphorylation of KDR, MER, and insulin receptors, which play a role in angiogenesis and vessel protection. In summary, ponatinib affects human endothelial cell growth and adhesiveness in vitro as well as perfusion recovery in a mouse model of hind limb ischemia. This may explain the occurrence of VAE in ponatinib-treated patients and help develop strategies for prevention and treatment of ponatinib-induced VAE.

P07 Response and resistance of relapsed/refractory BCR-ABL1 T315I+ ALL to ponatinib Alexander Hauswirth1*, Konstantin Byrgazov3, Sandra Preuner3, Susanne Herndlhofer1, Gabriele Stefanzl1, Daniela Berger1, Gregor Hoermann4, Ulrich Jäger1, Thomas Lion3, Peter Valent1,2, Wolfgang Sperr1 Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 2 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria 3 Children’s Cancer Research Institute, Vienna, Austria 4 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 1

Background:  Drug-resistant Ph+ acute lymphoblastic leukemia (ALL) is associated with a poor prognosis. Although BCR-ABL1-targeting tyrosine-kinase inhibitors (TKIs) have significantly improved the outcome in these patients, clonal evolution in TKI-resistant sub-clones is often found, and triggered by BCR-ABL1 mutations, including T315I. Methods:  We report on three patients (c1: male, 78 years, coronary artery disease; c2: female, 70 years; c3: male, 55 years) with Ph+ ALL in whom leukemic cells expressed BCR-ABL1 T315I in 1st relapse after standard chemotherapy. Results:  All three patients received ponatinib and showed a clinically significant response (c1 & 2: complete remission; c3: complete remission with incomplete peripheral recovery). Moreover, a decrease in the BCR-ABL1 allele burden was found in three patients (c1: 4-fold; c2 & c3: 3-fold). During treatment (c1: 5 months; c2: 4 months; c3: 3 months) no vascular events were observed. In case 2, thrombocytopenia occurred. However, in all three patients in whom a molecular response was seen, BCR-ABL1 increased again after a few months which was followed by a hematologic relapse associated with BCRABL1 T315I and BCR-ABL1 E255K, in 2 cases molecular studies revealed the presence of a compound mutation. Conclusions: In conclusion, treatment with ponatinib seems to be an effective approach in patients with relapsed or refractory Ph+ ALL. However, the duration of response is often limited as in many cases, clonal evolution is associated with the outgrowth of sub-clones exhibiting ponatinib-resistant compound mutations. Combinations with other drugs may be required to overcome this form of resistance in relapsed ALL.

P08 Health-related quality of life in elderly patients with haematological malignancies – high prevalence of fatigue and pronounced impact on survival Florian Hofer1*, Karin Koinig1, Laurenz Nagl1, Reinhard Stauder1 Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria

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Background: Haematological malignancies are frequently observed in elderly patients and are supposed to deteriorate

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Supplement 2/17 quality of life (QoL). Therefore the analysis of impact of blood cancer on assessment status and on QoL in advanced age is crucial. However, relevant data are so far rare. Methods:  149 consecutive patients 70+ years with different haematological malignancies at initial diagnosis underwent a multidimensional geriatric assessment (MGA) including QoLscores. Here we focus on the EORTC-QLQ-C30 questionnaire with particular interest on the prevalence and impact of fatigue on assessment status and clinical outcome. Results:  Fatigue was the most prevalent (84%) and limiting symptom. Additionally our patients frequently suffered from insomnia (48%), dyspnoea (47%), loss of appetite (43%) and pain (40%). Physical functioning (89%) and role functioning (75%) were the most frequently impaired domains. Prevalence of fatigue and role functioning did not show any significant differences between distinct entities, gender or age. Increased fatigue was significantly associated with impaired role and physical functioning as well as reduced WHO- and Karnofskyperformance status and affected depression scale (p < 0.001). Importantly, survival was significantly shorter in the patient cohort suffering from moderate to severe fatigue compared to the group experiencing no fatigue (median 7.0 vs. 33.1 months; p < 0.001). Conclusions: Fatigue and impairments in functional domains were frequently observed in blood cancer patients within different disease, age and gender categories. The strong impact of fatigue on clinical performance and overall survival emphasizes the relevance of patient reported outcomes in clinical assessment and decision making in elderly cancer patients.

P09 Geriatrisches Assessment in der Hämatologie Benedikt Hofer1*, Laurenz Nagl1, Florian Hofer1, Reinhard Stauder1 Universitätsklinik für Innere Medizin V, Hämatologie und Onkologie, Medizinische Universität Innsbruck, Innsbruck, Österreich

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Grundlagen: Hämatologische Neoplasien sind typische Alterserkrankungen. Der zunehmende Anteil an älteren Menschen in der Bevölkerung führt daher zu einer signifikanten Zunahme von älteren Patienten mit hämatologischen Erkrankungen. Diese Entwicklung hat mehrere wichtige Folgen für die Medizin. So nimmt der Bedarf an Instrumenten, mit denen man den funktionellen und globalen Status von älteren Patienten evaluieren kann, zu. Diese Scores erlauben dem Hämatologen die Patienten besser zu selektieren, Therapiemöglichkeiten besser abzustimmen, supportive Maßnahmen und Interventionen nach Bedarf des Patienten zu implementieren um Toxizitäten zu minimieren und letztlich den Behandlungsplan individualisiert auf den Patienten zuzuschneiden. Methodik:  In diesem Review werden wir verschiedene Instrumente des Geriatrischen Assessment (GA) und deren Relevanz im Praxisalltag und in klinischen Studien detailliert darstellen. Ergebnisse:  Die Relevanz des GA in der Erfassung von Defizienzen bei älteren KrebspatientInnen wird dargestellt. Die Bedeutung des GA in der Prognose und Prädiktion von Toxizitäten von Chemotherapien wird dargestellt. Insbesondere wird auf Screening Scores wie den VES-13 (Vulnerable Elders Survey), GFI (Groningen Frailty Indicator), G8-Instrument (geriatric 8), und das aCGA (abbreviated comprehensive geriatric assessment) eingegangen werden.

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Auf neuere Anwendungen wie die Integration in der HSCT (Stammzelltransplantation) wird eingegangen werden. Zudem wird das mögliche therapeutische Potential von geriatrischen Interventionen erläutert und diskutiert werden. Schlussfolgerungen: Bei älteren Patienten sollte zur Verbesserung der individualisierten Therapieplanung das CGA durchgeführt werden. Es empfiehlt sich eine interdisziplinäre Zusammenarbeit um ältere Patienten bestmöglich zu versorgen.

P10 Towards preventing overestimation of resistance to tyrosine kinase inhibitors conferred by mutant BCR-ABL1 subclones Konstantin Byrgazov1, Chantal Lucini1, Thomas Lion1* St. Anna Kinderkrebsforschung (CCRI – Children’s Cancer Research Institute), Vienna, Austria

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Background:  Point mutations in the ABL1 kinase domain are an important mechanism of resistance to tyrosine kinase inhibitors (TKIs) in BCR-ABL1-positive leukemias. Published heat maps indicating the responsiveness of single and compound mutations to various TKIs are generally based on sensitivity testing in vitro using the Ba/F3 cell line lentivirally transduced with mutant BCR-ABL1 constructs. However, this approach is prone to mediating multiple BCR-ABL1 insertions into the genome resulting in elevated IC50 levels for individual TKIs, and consequently, in overestimating the actual resistance of mutant subclones. Methods: We have established a transposon-based technique offering several advantages over lentiviral transduction including the absence of biosafety issues, faster generation of transgenic cell lines, and greater efficacy in introducing large gene constructs. To provide an appropriate basis for TKI-sensitivity testing in vitro, we have established flow-sorting-based fractionation of BCR-ABL1-transformed Ba/F3 cells for efficient enrichment of cells carrying single-site insertions, as confirmed by FISH-analysis. Results: Ba/F3 cells with documented insertion of the respective mutant constructs at single sites in the genome revealed BCR-ABL1 expression levels corresponding to clinical specimens of patients in chronic phase CML. By contrast, unselected Ba/F3 cells revealed variable and significantly higher BCR-ABL1 expression levels as well as considerably higher IC50 values often indicating resistance to the TKIs tested. Conclusions:  Our data demonstrate that targeted flow-sorting of BCR-ABL1-transformed Ba/F3 cells facilitates enrichment of virtually pure cell fractions carrying single insertions of individual gene constructs. Employment of appropriate cell selection is important for unbiased in vitro testing of drug resistance.

P11 Comorbidities at initial diagnosis significantly impact functional capacities and clinical outcome in elderly patients with haematological neoplasms Laurenz Nagl1*, Karin Koinig1, Florian Hofer1, Reinhard  Stauder1 1

Medical University of Innsbruck, Innsbruck, Austria

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Supplement 2/17 Background: Comorbidities essentially influence clinical course and therapy planning in cancer patients. This study focuses on prevalence of comorbidity as assessed by different scores, and their impact on other domains of the geriatric assessment and on overall survival (OS). Methods:  209 elderly blood cancer patients were enrolled prospectively for multidimensional geriatric assessment (MGA) at initial diagnosis. Comorbidities were assessed by Charlson Comorbidity Index (CCI), Cumulative Illness Rating Scale – Geriatric (CIRS-G) and Haematopoietic Cell Transplantation – Comorbidity Index (HCT-CI). We analysed OS (Kaplan-Meier plots) and performed Spearman-Rank correlations across the MGA. Results:  Coexisting diseases were frequent in our patients with at least one comorbidity present in 62.2% of patients rated by CCI, 93.8% by CIRS-G and 68.5% by HCT-CI; severe comorbidities (CIRS-G grade 3 + 4) were present in 57.9%. The mean number of affected organ systems was 3.61 (CIRS-G categories). The different scores neither differed in age nor in gender, whereas advanced comorbidities significantly correlated with impaired performance status, functional capacities, emotional situation and mobility. Elevated scores in CCI and CIRS-G, a HCT-CI greater than 4, or high-grade comorbidities (CIRS-G grade 3 + 4) resulted in a significantly shortened OS (p < 0.05). Conclusions: Comorbidities reveal a high prevalence in elderly blood cancer patients. Moreover, comorbidities negatively impact clinical outcome and different domains of the MGA. Thus, comorbidities should be assessed and integrated in therapy planning. In this cohort CCI proved to be simple and useful, while CIRS-G was characterised by pronounced sensitivity through additionally rating severity of comorbidity.

P12 NR4A1 is implicated in gene regulation in non-malignant lymphoid tissue in a context specific manner Katrin Pansy1*, Karoline Fechter1, Hildegard T Greinix1, Katharina Prochazka1, Peter Neumeister1, Alexander Deutsch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Background:  NR4A1 functions as transcription factor and is known to be a potent tumor suppressor of acute myeloid leukemia (AML) and, as previously reported by our group, of aggressive lymphomas. The aim of this project is to investigate the function of NR4A1 in gene regulation as transcription factor under non-malignant conditions in NR4A1 −/− and NR4A1 +/+ mice. Methods:  Therefore, using qPCR, we performed expression analyses of 22 genes, which negatively correlated in a publically available gene expression dataset of DLBCL patients to NR4A1 expression and which were significantly higher expressed in tumors derived from EµMyc NR4A1−/− mice in comparison to EµMyc NR4A1+/+ tumors. Therefore, RNA from different tissues (thymus, spleen and splenic B- and T-cells) was extracted. Results:  We observed that in the thymus 7 of the 22 investigated genes were significantly lower expressed in the NR4A1−/− mice compared to NR4A1+/+ mice. In the spleens of NR4A1−/− mice 10 of the 22 investigated genes were also significantly lower expressed. In splenic B cells no difference was observed. In stark contrast, 9 of the 22 investigated genes were significantly higher expressed in the splenic T cells of NR4A1−/− mice com-

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pared to NR4A1+/+. Remarkably, it was observed that NR4A1 loss caused a deregulation of NF-κB-target genes in the different tissue types and cell types under non-malignant condition. Conclusions:  Our data indicate that NR4A1 is involved in gene regulation in a context specific manner and that its regulatory function might be influenced by interaction with other transcription factors.

P13 CXCR4 and CXCL12 are implicated in the bone marrow infiltration process of aggressive B cell lymphomas Beata Pursche1*, Karoline Fechter1, Elisabeth Steinbauer2, Hildegard Greinix1, Katharina Prochazka1, Helmut Schaider3, Christine Beham-Schmid2, Peter Neumeister1, Alexander Deutsch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Department of Hematopathology, Medical University of Graz, Graz, Austria 3 Dermatology, University of Queensland Diamantina Institute, Faculty of Medicine, Brisbane, Australia 1

Background: The chemokine receptor CXCR4 with its prime ligand CXCL12 were recently identified to be involved in multiple key processes in tumour cells including proliferation, survival, migration, invasion and metastasis in more than 20 different types of cancer, providing evidence for the importance of this chemokine signalling pathway in cancer. Based on our preliminary study demonstrating that higher expression of CXCR4 was associated with a worse clinical outcome in aggressive lymphomas, we aimed to comprehensively study the implication of the CXCR4 – CXCL12 axis in bone marrow infiltration process of aggressive lymphoma. Methods:  We performed gene expression analysis on bone marrow biopsies of our diffuse large B-cell lymphoma patient cohort. Therefore, we used 63 bone marrow specimens, whereby 52 bone marrow biopsies were taken at time of diagnosis. Results:  By correlating CXCL12 expression levels of 16 infiltrated bone marrow biopsies, consisting of 12 specimens at time of diagnosis and 4 relapsed specimens, we observed a significant positive correlation between CXCL12 expression and the percentage of infiltration levels (Spearman-Rho = 0.764; p = 0.001). Further we analyzed 7 previously infiltrated bone marrows losing their infiltration following chemotherapy (under remission) and compared CXCR4 expression to the untreated paired biopsies. Remission of the bone marrow infiltration caused a reduction of CXCR4 expression (p = 0.075). Conclusions: These data strongly support our hypothesis whereupon CXCR4 and its ligand CXCL12 might be a good prognostic marker of diffuse large B-cell lymphomas and represent a potential target for therapy of aggressive lymphomas.

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P14 Analysis of criteria for tyrosine kinase inhibitor discontinuation in CML patients in a real-life setting Veronika Schmidt1*, Armin Zebisch1, Sybille Hofer1, Dagmar Steinwender1, Gerald Höfler2, Christine Beham-Schmid2, Heinz Sill1, Albert Wölfler1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background:  Several studies have demonstrated that tyrosine kinase inhibitors (TKI) can be safely discontinued in distinct CML patients and minimal criteria for therapy cessation have been established from these trials. These criteria include duration of TKI therapy for more than three years and a stable deep molecular response at the level of MR4 for at least one year. However, it is not known how many CML patients fulfill these criteria in a real-life setting. Methods:  In this retrospective study all our patients who had been diagnosed with BCR-ABL positive CML in chronic phase between 2001 and 2016 were analyzed for their molecular treatment response and other criteria needed for TKI cessation. Results: Out of 107 patients diagnosed with CML within this period eleven were excluded from this analysis, because they either had died (9) or moved to another place. Among the remaining 96 patients, 35 patients (37%) were not in deep molecular response (less than MR4) and two patients (2%) had MR4 duration of less than a year. Six patients (6%) had TKI treatment duration of less than three years and five patients (5%) had been switched to another TKI due to failure of first-line TKI therapy. Thus, 48 patients (50%) fulfilled all criteria for therapy cessation. Conclusions:  In this real-life setting 50% of CML patients who are currently in outpatient medical care at our department fulfill the minimal criteria for TKI cessation. Management of TKI discontinuation will be a common challenge in clinical care of CML patients.

P15 FLT3-L in bone marrow of patients with advanced myeloma: a potential target for future therapy strategies? Normann Steiner1,2*, Roman Hajek5,6, Georg Göbel4, Karin Jöhrer3, Eberhard Gunsilius1,2, Bojana Borjan2,3, Gerold Untergasser1,3 Department of Internal Medicine V (Hematology and Medical Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Laboratory for Tumor Biology & Angiogenesis, Medical University of Innsbruck, Innsbruck, Austria 3 Tyrolean Cancer Research Institute, Innsbruck, Austria 4 Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria 5 Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic 6 Department of Hemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic 1

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Background:  Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting response to treatment and/or progression is urgently needed. Here, we evaluated the cytokine FLT3ligand (FLT3-L) in bone marrow of MM patients (pts.) for its prognostic significance. Methods:  Bone marrow plasma levels of FLT3-L were determined in pts. with monoclonal gammopathy of undetermined significance (MGUS, n = 14), pts. with newly diagnosed MM (NDMM, n = 42) and pts. with relapsed/refractory MM (RRMM, n = 27) by sandwich ELISA. Results:  Median FLT3-L expression increased from MGUS (58.77 pg/ml) to NDMM (63.15 pg/ml) and was maximal in RRMM (122 pg/ml; NDMM vs. RRMM p < 0.001). A cut-off value of FLT3-L (> 92 pg/ml) was associated with relapse or refractoriness in MM pts. Pts. with FLT3-L levels > 92 pg/ml had a probability to be relapsed or refractory to treatment of 61% (positive predictive value), whereas pts. with FLT3-L levels ≤ 92 pg/ml had a probability for a non-relapsed or non-refractory setting in 79% (negative predictive value). Conclusions: High levels of FLT3-L (threshold FLT3L > 92 pg/ml) in bone marrow of MM pts. identify pts. with progressive disease and are associated with relapse or refractoriness in MM pts. FLT3-L could be useful as marker to identify RRMM pts. and may be evaluated as potential target for future therapy strategies.

P16 Follicular lymphoma grade 3a: prognosis and analysis of treatment with R-bendamustine versus R-CHOP Christoph Tinchon1*, Angelika Pichler1, Daniel M. Mayer1, Markus Lammer1, Suzana Babic1, Alexander C. Reisinger1 Department of Hemato-Oncology, LKH HochsteiermarkStandort Leoben, Leoben, Austria

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Background: Treatment of patients with follicular lymphoma grade 3a (FL3a) is controversial, the ESMO guidelines recommend rituximab-CHOP (R-CHOP) or rituximab-bendamustine (BR) in follicular lymphoma except in grade 3b, but there are no randomized data for FL3a patients. We analyzed our patients to 1) compare prognosis of FL3a versus FL grade 3b (FL3b) versus FL grade 1/2 (FL1/2), 2) see if treatment with BR performs as well as R-CHOP in FL3a patients. Methods:  We retrospectively analyzed all our patients with follicular lymphoma diagnosed from 01. 01. 2004 to 01. 12. 2016 receiving chemo-immunotherapy. Remission and relapse rates were calculated. PFS and OS of patients with FL grades 1/2 (FL1/2) versus FL3a versus FL3b were compared by KaplanMeier analysis and log-rank test. Results:  There were 88 FL patients with chemo-immunotherapy (84 in first line, 4 in second line), median follow up was 5.6 years. Survival curves for FL3a (n = 29) versus FL3b (n = 11) were different with a p-value of 0.07 for PFS (HR = 4.93) and 0.004 (HR 12.62) for OS respectively. PFS curves for FL1/2 versus FL3a were similar with a p-value of 0.96 (HR 1.06). Treatment of FL3a: R-CHOP (n = 21): median follow up 4.2 years, 4 relapses; BR (n = 8): median follow up 1.6 years, 100% remission, no relapse. Conclusions:  Survival curves are different for FL3a versus FL3b patients but similar for FL3a versus FL1/2 patients. Our early data seem to confirm that treatment of FL3a with BR is effective.

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Supplement 2/17 Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria 5 Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany 4

P17 CCR7 expression is associated to favourable cancer-specific survival of patients with aggressive lymphoma Barbara Uhl1*, Wenzl Kerstin1, Karoline Fechter1, Prochazka Katharina1, Christine Beham-Schmid2, Hildegard Theresia Greinix1, Peter Neumeister1, Alexander Deutsch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background:  The chemokine receptor CCR7 was identified to be involved in multiple key processes of lymphomagenesis like lymph node infiltration, survival and homing of lymphoma cells to the T cell zone of lymphoid tissue. The knowledge on CCR7 expression in aggressive B-cell lymphomas is limited; therefore we comprehensively studied the CCR7 expression pattern in DLBCL and FLIII in comparison to non-malignant controls (germinal centre B cells) on mRNA levels. Additionally, we investigated whether CCR7 is implicated in suppression of tumor infiltrating T cells mediated by PDL1- and PDL2-interaction with PD1. Methods:  We investigated CCR7 expression by semiquantitative real-time PCR of tumor tissue of aggressive lymphoma patients (n = 46) and set it in relation to clinical data, PD1 expression of tumor-infiltrating T-cells and tumour cells and PDL1- and PDL2-expression of tumor cells. Results: Compared to germinal center B cells we found an 8-fold higher expression of CCR7 in aggressive B cell lymphoma. Our survival analysis revealed that lymphoma patients with a high CCR7 expression were associated with poor cancerspecific overall survival. Furthermore, the expression of CCR7 in our cohort showed no correlation to PD1-, PDL2- and PDL1 expression. Conclusions: Our data suggests that CCR7 substantially contributes to the pathogenesis of aggressive B cell lymphomas and thus, could serve as a new therapeutic target for anti-lymphoma therapy. However, based on the fact that CCR7 expression does not correlate with PD1-, PDL2- and PDL1- expression it seems that CCR7 is not implicated in immune escape of aggressive B cell lymphomas.

Background:  Eukaryotic translation Initiation Factors (eIFs) are crucial for the first steps of the translation process helping to load the messenger RNA (mRNA) onto the ribosome and start protein synthesis. Today it is known that they are implicated in tumorigenesis. However, data on the role of eIFs in aggressive lymphomas is limited. Therefore we aimed to investigate whether eIFs can serve as biomarkers and/or therapeutic targets to support diagnostic precision and planning of individualized treatment strategies in patients affected by aggressive lymphomas. Methods:  We correlated eIF expression to cancer specific survival in a public available gene expression data set of an aggressive lymphoma patient cohort to test possible prognostic implications. Furthermore, we investigated eIF expression in 6 diffuse large B-cell lymphoma (DLBCL) and 2 Burkitt lymphoma (BL) cell lines in comparison to an immortalized B-cell line by Western blot analysis (16 eIFs analyzed) and eIF expression in primary DLBCL tissue samples by immunohistochemical analysis (n = 20, 4 eIFs analyzed). Results:  The survival analysis revealed that 8 out of 56 analyzed eIFs significantly correlate with worse cancer specific survival (p < 0.05). Increased expression for certain eIFs was observed in DLBCL- and BL-cell lines. Our immunohistochemical analysis indicated higher eIF expression for the more aggressive nonGCB-subtype compared to the GCB-subtype of DLBCL. Conclusions: Our results highlight, as also previously shown for other cancer entities, eIFs as important players in malignant lymphomas and indicate that they should be further evaluated as potential biomarkers and/or therapeutic targets.

P19 Prognostic value of early WT1 response in AML patients undergoing intensive chemotherapy Thomas Vockenhuber1*, Sigrid Machherndl-Spandl1, Otto Zach1, Mathilde Födermayr1, Michael Girschikofsky1, Michaela Binder1, Ansgar Weltermann1 1

P18 Expression analysis indicates implication of translation initiation factors in development of aggressive B-cell lymphomas Julia Unterluggauer1*, Christine Beham-Schmid1, Heinz Sill2, Peter Valentin Tomazic3, Karoline Fechter2, Rudolf Schicho4, Peter Neumeister2, Alexander Deutsch2, Johannes Haybaeck1,5 Institute of Pathology, Medical University of Graz, Graz, Austria 2 Division for Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 3 Department of Otorhinolaryngology, Medical University of Graz, Graz, Austria 1

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Ordensklinikum Linz Elisabethinen, Linz, Austria

Purpose: To evaluate the relevance of Wilms-Tumour 1 (WT1) expression for the prognosis of patients with acute myeloid leukaemia (AML). Methods: Bone marrow samples from 174 adult AML patients (18–85 years, median 61) were used for WT1 mRNA quantification. We retrospectively followed 129 patients with WT1 overexpression at diagnosis who achieved a haematological remission after the first cycle of induction chemotherapy. APL patients were excluded. Results: The extent of WT1 expression at diagnosis had no prognostic relevance. In contrast, achievement of low WT1 levels after induction chemotherapy was associated with a significant better overall (OS) and disease free survival (DFS) as compared to persistent high WT1 expression at hCR1: 5 years OS 54% vs. 0% (p < 0.001); DFS 44% vs. 0% (p < 0.001). Additionally, compared with patients with a low WT1 reduction (< 5 log) at hCR1, the relative risk of death was 0.32 (95% CI 0.1–0.7) in patients with intermediate WT1 reduction (5–8 log) and 0.15

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Supplement 2/17 (95% CI 0–0.05) in patients with high WT1 reduction (> 8 log), after adjustment for age, ELN-risk group, and stem cell transplantation in CR1. The corresponding 5-years OS for patients with low, intermediate and high WT1 reduction were 10%, 42% and 71% (p < 0.001), respectively. Conclusions: Persisting high WT1 expression in AML patients achieving a CR1 after induction chemotherapy is a strong, independent predictor for DFS and OS in patients with AML. This marker may be widely applicable for early risk reevaluation and corresponding therapy adaption.

P20 Characterisation of lymphoma patients treated at the Universtity Hospital Krems (UHK) in the years 2012–2014 Ulrike Wittig1*, Adina-Ecaterina Peyravesh-Ilyes2, Gudrun Kreye2, Ullrich Jäger1, Martin Pecherstorfer2, Karoline Gleixner1 Medical University of Vienna, Vienna, Austria Department of Internal Medicine I, University Hospital Krems, and Karl Landsteiner Private University of Health Sciences, Krems, Austria

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Lymphoma-patients are usually managed at a specialised regional hospital like the hospital Krems (UHK) or at a tertiary referral center like the Medical University of Vienna (MUW). In this study, patients with Hodgkin’s lymphoma (HL, n = 6), follicular lymphoma (FL, n = 15), or diffuse large B-cell-lymphoma (DLBCL, n = 27) treated from 2012 to 2014 at the UHK were compared to MUW-patients (HL: n = 71; FL: n = 46; DLBCL: n = 89). UHK-patients were significantly older at diagnosis (64,6 y vs. 51,1 y), more likely to suffer from comorbidities, and – in case of HL and FL – belonged to higher risk categories than MUW-patients. The percentage of HLpatients was significantly lower at the UHK (12.5 % vs. 34.5 % at MUW). Further, 6 patients suffering from post-transplant lymphoma (PTLD) were identified at MUW, whereas no PTLD were treated at UHK. Despite these differences, the histologic and radiologic work-up, the time to diagnosis and the first-line therapies administered were comparable in all three entities. Refractory/relapsed patients receiving an autologous or allogenic stem cell transplantation were more frequently in the MUW-cohort (9 % vs. 2.1 % at UHK). By contrast, the palliative care unit was significantly more often involved at UHK (14.6 % vs. 1.5 % at MUW). The percentage of patients reaching a complete remission and the one-year survival were comparable. In summary, despite differences in the patient-cohorts, the diagnostic work-up, the first-line treatment and the short-term outcome were comparable between UHK and MUW. Potential differences in terms of long-term outcome, outcome of select patient-cohorts, and quality of life need to be determined in upcoming studies.

P21 Genetic aberrations of myeloid sarcomas Karl Kashofer1, Max Gornicec2, Veronica Caraffini2, Karin Lind2, Silvia Schauer1, Christine Beham-Schmid1, Albert Wölfler2, Gerald Hoefler1, Heinz Sill2, Armin Zebisch2* Institute of Pathology, Medical University of Graz, Graz, Austria 2 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 1

Background:  Myeloid sarcoma (MS) is an extramedullary manifestation of acute myeloid leukemia (AML), which may occur even without concomitant leukemic bone marrow (cLBM) involvement. Although cytogenetic and molecular risk stratification has evolved as clinical standard in the management of AML, it is currently not established in MS specimens. We asked, whether genetic analysis is possible in MS biopsies and whether this would add information to risk profiles obtained from simultaneously analyzed cLBM. Methods:  DNA/RNA was extracted from 18 formalin-fixed, paraffin-embedded (FFPE) specimens of MS and corresponding cLBM in cases where MS coincided with systemic disease (n = 12). Ion Torrent based next-generation-sequencing (NGS) analysis was performed to detect mutations in 40 AML-related genes and 38 translocation events including RUNX1-RUNX1T1, CBFB-MYH11, PML-RARA and MLL. Results: Sixteen out of 18 (89%) MS specimens exhibited at least one somatic mutation with a median of three genetic variations per sample (range, 1–5). The most frequently affected genes were NPM1, DNMT3A and NRAS, each of them showing mutation(s) in 5/18 (28%) cases. Translocation analysis revealed existence of the favorable risk marker CBFB-MYH11 in 3/18 (17%) of cases. Extended analysis of the twelve patients with accompanying systemic disease revealed no differences in the molecular makeup between MS and cLBM specimens. Conclusions: NGS profiling as well as the detection of selected chromosomal translocations is possible in FFPE MS and enables the detection of favorable and adverse risk markers. In case MS accompanies systemic AML, its genetic analysis adds no further information to risk stratification obtained from cLBM.

Poster Onkologie

P22 A 3D angiogenesis model to study tumour – endothelial cell interactions and the effects of anti-angiogenic drugs Arno Amann1*, Marit Zwierzina2, Gabriele Gamerith1, Stefan Koeck1, Florian Kocher1, Andreas Seeber1, Edith Lorenz3, Heinz Zwierzina1, Johann Kern1 Department of Internal Medicine V (Hematology and Medical Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Innsbruck, Austria 3 Tyrolean Cancer Research Institute, Innsbruck, Austria 1

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Supplement 2/17 Background:  We are experiencing a transition from disease to target-oriented therapy. One major hurdle for the development of these targeted therapeutic regimens, however, is the limited availability of predictive in vitro models. Based on our 3D co-culture system, we describe the development of to a novel tri-culture model including beside cancer cells and fibroblasts also endothelial cells. Methods:  96-well hanging drop microtiter plates (InSphero AG, Zürich, Switzerland) were applied for the production of 3D microtissues, including the human lung cancer cell lines A549 or Colo699 alone or in combination with a human lung fibroblast cell line (SV-80) and either the human umbilical vein endothelial cell line (HUVEC) or the human lung microvascular endothelial cell line (HMVEC-L). Tumour fibroblast spheroid aggregation was displayed immunohistochemically (IHC) by protein expression of E-cadherin, vimentin, Ki-67, CD31, alpha smooth muscle actin (ASMA) and von Willebrand factor (vWF). Viability and secretion of angiogenic factors was determined either by Flow cytometry of by a multiplex assay. In addition, inhibition of endothelial cell invasion with anti angiogenic drugs (bevacizumab and nindetanib) was performed. Results:  Endothelial cells aggregated either in small colonies or as single cells adhered in tube like structures mainly in the stromal compartments. Expression of angiogenic associated growth factors and cytokines were measured in supernatants. Inhibition of these pro- angiogenic factors (VEGF, FGF and PDGF) by either bevacizumab or nindetanib led to a significant decrease in migration of endothelial cells into microtissues. Conclusions: We demonstrate a functional multicellular model that allows the investigation of anti-angiogenic drugs.

Mean eGFR changes were calculated for 90-day periods. The classification margin for rise or fall was defined as 3 ml/min. Results: In 243 analyzed patients, a mean overall eGFR increase of 2.81 ± 8.97 ml/min was observed during the first 90-day period. Over the whole observation period (up to 1,800 days), we observed a slight overall decline (mean change -0.19 ± 6.57 ml/min per period), effecting an eGFR decrease of 3.6 ml/min. Male patients showed a tendency towards stronger eGFR fluctuation than women within the first year both with regard to the initial rise and the subsequent fall, yet without statistical significance. Factors determinable at diagnosis (type of immunoglobulin, light chain, hemoglobin, bone marrow infiltration, total serum protein) did not predict RI course. Conclusions: Renal function follows a non-linear course in MM patients. After an initial amelioration, possibly due to hematological treatment installation after diagnosis, a slight decline of eGFR should be expected.

P24 Elevated amylase in peripheral blood represents an adverse prognostic marker in patients with metatastatic pancreatic cancer Eva Asamer1*, Michael Stotz1,5, Paul Gibiser1, Joanna Szkandera1, Tatjana Stojakovic2, Peter Kornprat3, Herbert Stöger1, Armin Gerger1,5, Martin Pichler1,6 Division of Oncology, Department of Medicine, Medical University of Graz, Graz, Austria 2 Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria 3 Division of General Surgery, Department of Surgery, Medical University of Graz, Graz, Austria 4 Institute of Pathology, Medical University of Graz, Graz, Austria 5 Research Unit Genetic Epidemiology and Pharmacogenetics, Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria 6 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer, Houston, USA 1

P23 Longitudinal evaluation of renal disease trajectories in multiple myeloma Marlies Antlanger1*, Eleonore Pablik2, Thomas Reiter1, Susanne Rasoul-Rockenschaub3, Heinz Gisslinger4, Hermine Agis5, Maria-Theresa Krauth4 Division of Nephrology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria 2 Institute of Medical Statistics, Medical University of Vienna, Vienna, Austria 3 Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria 4 Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 5 Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 1

Background:  Renal impairment (RI) is frequent in patients with Multiple Myeloma (MM). To date, no substantial data on the long-term course of RI exist. Further, it remains unknown whether factors determinable at diagnosis might predict the course. Methods:  601 patients with a new MM diagnosis between 1985 and 2015 were eligible for analysis. Renal function was determined by estimated glomerular filtration rate (eGFR). In 479 patients at least 3 measurements were available allowing a disease trajectory creation. Patients with incomplete data, without eGFR measurement within the first 30 days and/or an observation period of less than 180 days were excluded (n = 236).

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Background:  Laboratory parameters such as amylase and lipase are among other values frequently determined at the time of diagnosis in patients with pancreatic cancer. These two laboratory values are often used as follow-up assessment in case of acute pancreatitis but are only rarely considered to be significant with regard to cancer patients. The aim of this study is to investigate the prognostic relevance of these two parameters concerning the overall survival rate of patients suffering from metastatic pancreatic cancer. Methods: This retrospective study includes 351 patients with metastatic pancreatic cancer, who were treated between the years 2004 and 2015 at the Division of Oncology, Medical University of Graz, Austria. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. To further evaluate the prognostic significance of lipase and amylase, univariate and multivariate Cox regression models were calculated. Results:  In our study cohort, we found significant correlation between the two values amylase and lipase (R = 0.821, p < 0.001). In univariate analysis, we observed that increased amylase level was a significant factor for lower CSS in PC patients (HR = 1,258; 95%CI = 1,011–1,566; p = 0.039). In multivariate analysis we con-

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Supplement 2/17 firmed increased amylase levels as an independent prognostic factor for CSS (HR = 1,373; 95%CI = 1,004–1,878; p = 0.047). Conclusions:  In conclusion, we identified increased plasma Amylase levels at diagnosis as an independent prognostic factor in PC patients. Our results indicate that amylase might represent a novel and useful marker for patient stratification in PC management.

P25 Risikofaktoren für das Auftreten einer febrilen Neutropenie unter Cisplatin-hältiger Chemotherapie bei Hodenkrebspatienten Angelika Bezan1*, Florian Posch1, Thomas Bauernhofer1, Martin Pichler1, Joanna Szkandera1, Georg C. Hutterer2, Karl Pummer2, Richard Partl3, Brigitte Zurl3, Karin S. Kapp3, Herbert Stöger1, Armin Gerger1, Michael Stotz1 Klinische Abteilung für Onkologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Graz, Österreich 2 Universitätsklinik für Urologie, Medizinische Universität Graz, Graz, Österreich 3 Universitätsklinik für Strahlentherapie, Medizinische Universität Graz, Graz, Österreich 1

Grundlagen: Das Auftreten einer febrilen Neutropenie (FN) ist eine schwerwiegende und potentiell lebensbedrohliche Nebenwirkung einer myelosuppressiven Chemotherapie. FN Raten unter adjuvanter oder kurativer PEB Chemotherapie liegen zwischen 10–20 %. Die primäre GCSF Gabe wird in der Routine nicht empfohlen. Unser Ziel war es, Risikofaktoren für das Auftreten einer febrilen Neutropenie zu identifizieren. Methodik: 413 Hodenkrebspatienten, welche zwischen Jänner 1994 und September 2013 an der Medizinischen Universität Graz eine adjuvante oder kurative Cisplatin-hältige Chemotherapie erhielten, wurden retrospektiv evaluiert. Es wurden sowohl relapsierte als auch neu diagnostizierte Patienten in die Analyse eingeschlossen. Ergebnisse: Bei 70 (16,9 %) von insgesamt 413 Patienten kam es zum Auftreten eines neutropenischen Fiebers. In der univariaten Analyse waren ein höheres Patientenalter, ein reduzierter Karnofsky Index, eine nicht-seminomatöse Histologie, eine höhere IGCCCG Risikoklassifikation, eine vorangegangene Chemotherapie oder Strahlentherapiebehandlung mit dem Auftreten einer febrilen Neutropenie assoziiert. In der multivariaten Analyse zeigten sich ein reduzierter Karnofsky Index (RR 2,5, 95 %CI 1,17–5,18, p 0,018) sowie eine vorangegangene Strahlentherapiebehandlung (RR 6,9 95 %CI 1,51–31,57, p 0,013) als signifikante Risikofaktoren für das Auftreten einer febrilen Neutropenie. Schlussfolgerungen: Hodenkrebspatienten mit reduziertem Karnofsky Index oder vorangegangener Strahlentherapiebehandlung haben ein erhöhtes Risiko für das Auftreten einer febrilen Neutropenie unter Cisplatin-hältiger Chemotherapie. Eine primäre GCSF Gabe sollte bei diesen Patienten in Erwägung gezogen werden.

P26 Malnutrition in elderly patients with hematological malignancies – high prevalence and impact on status in geriatric assessment and overall survival Bojana Borjan1*, Julia Augschoell1, Georg Kemmler2, Marije Hamaker3, Reinhard Stauder1 Department of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Biological Psychiatry, Medical University of Innsbruck, Innsbruck, Austria 3 Department of Geriatric Medicine, Diakonessenhuis, Utrecht, Netherlands 1

Background:  The prevalence of malnutrition increases with age and cancer development. The present study aimed to evaluate prospectively the effects of nutritional status on clinical performance and outcome in elderly patients with hematological cancer. Methods:  Nutritional parameters, comprising loss of appetite, recent weight loss, Mini Nutritional Assessment (MNA), body mass index (BMI), serum albumin and the inflammation marker C-reactive protein (CRP), were correlated with components of multidimensional geriatric assessment (GA) and with overall survival (OS) in 124 newly diagnosed blood cancer patients ≥ 67 years. Results:  Loss of appetite, classified as severe or moderate was observed in 17 or 25%, respectively. However, only 2% of patients displayed BMI of ≤ 18 kg/m². The frequency of recent weight loss of 1–3 kg was 15% of patients, while 31% lost > 3 kg. MNA-evaluation revealed a risk of malnutrition in 40% and 13% of patients were malnourished. Decreased serum albumin was detected in 48% and elevated CRP in 56% patients. Impaired MNA and low serum albumin significantly correlated with restrictions in distinct dimensions of GA. Recent weight loss and low serum albumin remained significant predictors of OS in multivariate Cox regression analysis. Conclusions: This study demonstrates prognostic significance of nutritional deficiencies observed in a high proportion of elderly patients with hematological malignancies at initial diagnosis. Malnutrition negatively affects status in geriatric evaluation and OS. Therefore, nutrition support is required and results of nutritional assessment should be implemented in intervention planning.

P27 Identification of a novel breast tumor-promoting fibroblast population Maximilian Bösch1*, Mario Novkovic1, Hung-Wei Cheng1, Lucas Onder1, Michael Knauer2, Thomas Ruhstaller2, Burkhard Ludewig1 Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland 2 Breast Center St. Gallen, Kantonsspital St. Gallen, St. Gallen, Switzerland 1

Background:  Fibroblastic stromal cells are a major component of the solid tumor stroma. In the breast tumor microenvi-

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Supplement 2/17 ronment (TME), fibroblastic stromal cells are particularly abundant but have different effects on malignant growth, depending on context and cellular identity. Here, we set out to molecularly characterize a genetically-defined population of breast cancerassociated fibroblasts (CAFs). Methods:  We used a syngeneic orthotopic model of breast cancer in conjunction with cre/lox-based reporter mouse strains to track specific populations of CAFs in vivo. Harnessing CAF-specific expression of iDTR (inducible diphtheria toxin receptor), CAFs were selectively ablated and tumor growth was monitored. To disclose novel microenvironmental regulators of breast tumor growth, CAFs were flow-purified and subjected to global expression profiling. Results:  CAFs that express the hematopoietic growth and survival factor interleukin-7 (IL-7) were abundantly present in the breast TME, showed an activated phenotype, and located mainly to perivascular niches in the tumor margin. Concomitant labelling of tumor cells revealed immediate spatial association with IL-7-producing fibroblasts, enabling both paracrine and juxtacrine exchange. Importantly, DT-mediated ablation of IL-7-expressing CAFs significantly reduced tumor growth. Transcriptomic profiling uncovered a distinct oncogenic signature of IL-7-positive cells with high expression of several growth factors, stem cell ligands, and immune modulators. Conclusions:  We here describe a novel population of breast cancer-promoting fibroblasts molecularly characterized by IL-7 expression which produce various oncogenic factors. Functional assays in conjunction with conditional knockout technology will uncover the mechanism(s) underlying the observed phenotype. Tumor stemness regulation by IL-7-producing CAFs is conceivable and subject to further investigations.

P28 BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib Konstantin Byrgazov1*, Chantal Lucini1, Peter Valent2, Oliver Hantschel3, Thomas Lion1 Children’s Cancer Research Institute, Vienna, Austria Medical University of Vienna, Vienna, Austria 3 École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland 1 2

Background:  The third-generation tyrosine kinase inhibitor (TKI) ponatinib exerts strong anti-neoplastic effects even in advanced CML stages and Ph+ ALL. Nevertheless, resistance to ponatinib can evolve in sub-clones carrying BCR-ABL1 variants with two or more mutations on the same allele, the so-called compound mutations (CMs). Resistant mutations display IC50 values exceeding the maximum achievable effective plasma concentration (efCave). Identification of the responsiveness to ponatinib is of paramount importance for the subsequent clinical management. Methods:  We have established a BCR-ABL1 protein model facilitating assessment of the presumptive impact of 27 different CMs. We transferred BCR-ABL1 CM-constructs into Ba/F3 cells using a transposon-mediated approach, and determined the IC50 values for ponatinib. Results: CMs revealing elevated ponatinib-IC50 almost invariably included T315I or F317L mutations. While most CMs involving T315I revealed very high ponatinib-IC50, some of the predicted compound mutations containing F317L displayed a ponatinib-IC50 in the range of efCave achievable only with a daily dose of 45 mg. These observations are supported by clinical

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findings in the PACE trial which revealed impaired responses of patients with CMs involving F317L who had received ponatinib at doses < 45 mg/​d. Conclusions: Current strategies aiming at decreasing the dose of ponatinib to prevent severe side effects should carefully consider the presence and type of mutations in the BCR-ABL1 TKD to enable effective treatment. It would be highly desirable, therefore, to implement testing of the effective plasma drug concentrations and monitoring the kinetics of single- and compound-mutant sub-clones in the routine diagnostic surveillance.

P29 Loss of RAF kinase inhibitor protein in myeloid sarcoma Veronica Caraffini1*, Silvia Schauer2, Karl Kashofer2, Albert Wölfler1, Gerald Hoefler2, Heinz Sill1, Armin Zebisch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background:  Myeloid sarcoma (MS) is a subgroup of acute myeloid leukemia (AML), where myeloid blasts invade extrahematopoietic tissues and form solid tumor masses. Loss of RAF kinase inhibitor protein (RKIP), a negative regulator of RAS signalling, is frequently observed in AML and functionally involved in leukemogenesis. Since RKIP is a well-known metastasis-suppressor in solid cancers, we aimed at delineating the role of RKIP in MS and tissue infiltration of leukemic cells. Methods: RKIP immunohistochemistry was performed in 14 primary MS patient samples and 14 leukemic BM specimens of AML patients without any evidence of MS (BM-AML). Ion-Torrent next-generation-sequencing was carried out on 40 genes showing recurrent mutations in AML. The functional role of RKIP in tissue infiltration of myeloid blasts was tested in migration and invasion assays employing the RAS-mutated THP-1 AML cell line following lentiviral knockdown and overexpression of RKIP, respectively. Results:  The frequency of specimens demonstrating a loss of RKIP expression was significantly increased in MS as compared to BM-AML (7/14, vs. 1/14; P = 0.0329). Interestingly, five out of six (83%) MS patients exhibiting RKIP loss additionally carried mutation(s) affecting the RAS signalling pathway, thereby suggesting a functional synergism between these genetic events. In functional in-vitro assays employing RAS-mutated AML cells, RKIP knockdown induced a significant increase of both migration (P = 0.0097) and invasion (P = 0.0197), whereas its overexpression caused the opposite effects (P = 0.0036 and P = 0.0037, respectively). Conclusions: RKIP loss is a frequent event in MS and is functionally involved in tissue infiltration of leukemic cells.

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P30 Eribulin – eine retrospektive Datenanalyse eines österreichischen Brustgesundheitszentrum Christine Deutschmann1*, Christian F. Singer1 Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien – AKH Wien, Wien, Österreich

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Grundlagen:  Eribulin (Halaven) ist ein nicht-Taxan basiertes Mikrotubuli-destabilisierendes Zytostatikum. Es ist zugelassen für die Therapie des lokal fortgeschrittenen oder metastasierten Mammakarzinoms nach vorangegangener Anwendung von mindestens einem – ein Taxan und ein Anthrazyklin-beinhaltendes – Chemotherapieschema für das fortgeschrittene Krankheitsstadium. Methodik: Die vorliegende Studie ist eine retrospektive Datenanalyse von Patientinnen, die von 01/2015 bis 12/2016 mit Eribulin an einem österreichischen Brustgesundheitszentrum behandelt wurden. Ergebnisse:  Insgesamt wurden 5 Patientinnen mit folgenden Tumorbiologie-Merkmalen eingeschlossen: Patientin 1 (invasiv-duktal, G3, Östrogenrezeptor-Status:+, Progesteronrezeptor-Status: negativ, Her2-Status: negativ, MIB: 60 %, T2/N0/Mx), Patientin 2: (invasiv duktal, triple-negativ, p53: negativ, MIB: 90 %, T4b/Nx/Mx), Patientin 3 (invasiv duktal, G3, triple-negativ, p53: 80 %, MIB: 30 %, T2/N1a/Mx), Patientin 4 (invasiv duktal, G3, triple-negativ, p53: < 10 %, MIB: 90 %, T1c/N1/Mx), Patientin 5 (invasiv duktal, G2, Östrogenrezeptor-Status:+++, Progesteronrezeptor-Status:++, Her2-Status: negativ (+), p53: 10 %, MIB: 40 %, T1c/N1a/Mx). Die Krankheitslast beinhaltete im Mittel drei Lokalisationen metastatischer Absiedelungen, wobei diese am häufigsten in Lymphknoten, der Lunge und Knochen auftraten. Der Median an vorangegangenen Chemotherapieschemata für das fortgeschrittene Krankheitsstadium betrug 3 (1–3). Zwei Patientinnen erhielten Eribulin als Zweit- beziehungsweise Drittlinientherapie für das fortgeschrittene Krankheitsstadium. In drei Fällen wurde Eribulin als Viertlinientherapie angewandt. Durchschnittlich wurden 9 Zyklen (3–21) verabreicht. In keinem der untersuchten Fälle traten unerwünschte Arzneimittelreaktionen auf. Alle 5 Patientinnen zeigten jedoch unter Eribulin einen Befundprogress, der zu einem Therapiewechsel führte, wobei die mittlere Progressions-freie-Überlebensrate (PFR) 5.8 Monate (SD = 1,828) betrug. Die Gesamtüberlebensrate (OS) betrug im Mittel 14 Monate (SD = 3,757). Schlussfolgerungen: Die vorliegende Studie konnte eine gute Verträglichkeit von Eribulin sowie eine mit aktuellen Studien vergleichbare PFR zeigen.

P31 Establishment of a clinical registry for soft tissue sarcoma: patient characteristics & outcome Andreas Seeber1, Miriam Dirler1*, Kathryin Philipp-Abbrederis1, Arno Amann1, Günther Gastl1, Florian Kocher1 Department of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria

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Background:  Soft tissue sarcomas (STS) are rare malignancies deriving from the mesenchymal tissue. Due to the histo-

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logical and molecular heterogeneity of STS and their variablity of localization and stages at diagnosis a multidisciplinary therapy approach is often necessary to achieve the best outcome in patients suffering from either localized or metastatic STS. We established a STS registry to evaluate clinical characteristics and outcome of patients diagnosed and treated at the Innsbruck Medical University. Methods:  Medical files of STS patients diagnosed between 1997 and 2014 were retrospectively analyzed. In this first work the focus was set on clinical characteristics and survival data. Results: In total, 147 STS patients were diagnosed at the Innsbruck Medical University. Median age at diagnosis was 56.8 years (19–90) and 90 patients (61.2%) were male. The most common histology was liposarcoma (n = 32, 21.8%) followed by leiomyosarcoma (n = 25, 17.0%) and synovial sarcoma (n = 15, 10.2%). At the time of diagnosis, 24 patients (16.3%) presented with metastatic disease compared to 83.7% (123 patients) in a localized stage. Five-year overall survival for patients in a primary palliative setting, in a secondary palliative setting after initially curative treatment intention, and in a curative setting were 33.5%, 56.0%, and 83.7%, respectively. Conclusions:  These retrospective data analysis of our newly established hospital-based STS registry provide first insights on the clinical presentation and outcome of patients treated at Innsbruck Medical University.

P32 A liquid biopsy approach to detect Androgen Receptor Variant 7 in prostate cancer Amin El-Heliebi1*, Christoph Haudum1,2, Erkan Ercan1, Maria Smolle2, Shukun Chen1, Thomas Kroneis1, Annika Ahlford3, Tomasz Krzywkowski3, Jessica Svedlund3, Navya Laxman3, Evangelia Darai3, Inge Dekruijff4, Martin Pichler5, Christopher Rossmann5, Stephan W Jahn6, Peter Sedlmayr1, Mats Nilsson3, Thomas Bauernhofer5,6 Institute of Cell Biology, Histology & Embryology; Medical University of Graz, Graz, Austria 2 Center for Biomarker Research in Medicine (CBmed), Graz, Austria 3 Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden 4 Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, Netherlands 5 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 6 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background: Prostate cancer (PCa) remains the most common cancer in men. Treatment of PCa involves targeting the androgen receptor (AR)-signaling pathways by hormonal therapy, but patients develop a high rate of resistance to the AR-targeting drugs. This resistance can be attributed to alternative AR-splicing generating AR-variants (e. g.: AR-V7). Therefore, methods to detect AR-V7 in circulating tumor cells (CTCs) are of high clinical relevance. Methods:  We applied a novel in vivo CTC isolation device (CellCollector) which can be combined with in situ padlock probe technology. Combination of both techniques allows for highly specific detection and visualization of transcripts on

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Supplement 2/17 a cellular level. We applied padlock probes for AR-V7, AR-full length (AR-FL) and prostate specific antigen (PSA) on CTCs from prostate cancer patients. Results: We assessed the CTCs status of 10 patients by applying in situ padlock probe technology on cells attached to the CellCollector. In total 50% (5/10) of patients were positive for CTCs. In situ analysis revealed that 40% (4/10) of patient CTCs had detectable AR-V7 mRNA expression. AR-FL positive CTCs were detectable in 30% (3/10) of patients and one CTC was positive for PSA Conclusions: Padlock Probe technology allows visualization of AR-V7, AR-FL and PSA transcripts directly in CTCs from prostate cancer patients. This technology may be a suitable diagnostic tool to identify AR-V7 positive patients.

P33 Eribulin in patients with advanced/ metastatic liposarcoma – a case series by the Medical University of Vienna Rainer Hamacher1, Benjamin Schmid1, Bernadette Gad1*, Lukas Fuchs1, Jirka Levin Kupitz1, Sophie Roider-Schur1,2, Thomas Brodowicz1,2 Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 2 Sarcoma Platform Austria, Vienna, Austria 1

Background:  Data of a randomised-phase 3 trial led to the recent approval for Eribulin (ERI), a microtubule-dynamicsinhibitor isolated from the marine sponge halichondrin B, in the treatment of pretreated, advanced liposarcoma (LPS). The aim of this study was to evaluate the efficacy of ERI in pts. with advanced/metastatic LPS in the routine clinical setting. Methods:  The current retrospective analysis includes data from 13 consecutive LPS pts. treated with ERI 1.23 mg/m2, d1,8, q21d between October 2015 and December 2016. Results:  Nine pts. were male (69%), 4 female (31%). Median age was 61 yrs. (range 34–74 yrs.). Histology included 10 pts. with dedifferentiated LPS, 2 myxoid round cell LPS and one well differentiated LPS. LPS localisation was: abdomen 9, pelvis 2, extremities 2 pts. Extent of disease at initial diagnosis was localized in 11 (85%) and advanced/metastatic in 2 (15%) pts. In total, 61 cycles of ERI were administered (median 3 per pt., range 1–9 cycles). In 5 pts. ERI treatment was ongoing at the time of data cut-off, twelve pts. were alive, one pt. died. The median number of previous lines of systemic treatment before ERI was 2 (range 0–4 lines). The median progression-free survival was 6 months (95% CI 1.6–10.4). The extent and severity of ERI-induced toxicity was low and manageable. Conclusions: Our findings support the use of ERI as an active therapeutic option among advanced/metastatic LPS pts. in the daily clinical routine setting.

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P34 Early-stage NSCLC displays significant alterations of the innate immune system and B-cell compartment Gabriele Gamerith1*, Florian Augustin2, Edith Lorenz3, Elisabeth Hoflehner3, Herbert Maier2, Arno Amann1, Stefan Köck1, Johann Kern3, Claudia Manzl4, Bettina Zelger4, Patrizia Moser4, Georg Schäfer4, Dietmar Öfner2, Heinz Zwierzina1, Sieghart Sopper1 Department of Internal Medicine V (Hematology and Medical Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria 3 Tyrolean Cancer Research Institute, Innsbruck, Austria 4 Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria 1

Background: The recent revolution in cancer therapies highlighted the crucial role of the immune cell subtypes, their functions and cross-talks. For the plethora of immunomodulatory agents selection criteria and a profound knowledge of tumor-associated alterations are warranted. Therefore, we investigated prospectivley the immunome of early-stage nonsmall-cell-lung cancers. Methods: Regional ethic boards approval and ICs were given. Via mechanical disruption and enzymatic digestion single-cell suspensions of tumor and normal tissues, besides whole blood of 40 early-stage NSCLCs were obtained. Flow-cytometry analyses using FlowJo-software were performed for six antibody panels aimed at immune cell subtypes, their differentiation and activation. Significance (p < 0.05) was determined by Friedman tests with Dunn’s multiple comparison analyses. Results:  B-cells were more frequent in tumors with higher levels of chemokine receptor CD183 (CXCR3) than in blood or lung tissue, indicating its involvement in regulating migration to the tumor site. NK-cells were less frequent in tumors compared to normal tissue and blood, accompanied by a lower CD158b (KIR2D) expression. In contrast, the inhibitory receptor CD159a (NKG2A) was higher expressed in tumors. Regarding T-cells, their proportions and subsets (CD4, CD8 and γδTCR) were comparable in all compartments. Only central-memory CD4 T-cells were enriched in tumors, whereas effector-memory were in healthy tissues. This work highlights early changes in the immunome of lung cancers with NK- and B-cells as keyplayers and potential druggable targets besides T-cells. Conclusions:  We demonstrate both, B- and NK-cell subsets to play a role in early stage NSCLCs. Further investigations concerning their functional, prognostic and therapeutic impact are needed.

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P35 5-FU based chemotherapy with Bevacizumab in synchronous metastatic colorectal cancer patients with bleeding primary tumor Birgit Grünberger1*, Patrick Starlinger2, Elisabeth Messinger3, Sabine Weibrecht4, Philipp Jonas5, Barbara Weitmayr6, Thomas Grünberger5 Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria 3 Apotheke, Krankenhaus der Barmherzigen Brüder, Vienna, Austria 4 Department of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Vienna, Austria 5 Department of Surgery I, Krankenanstalt Rudolfstiftung, Vienna, Austria 6 Institute of Pathology, Krankenanstalt Rudolfstiftung, Vienna, Austria 1 2

Background:  The benefit of systemic chemotherapy (5-FU based) in combination with Bevacizumab in patients with mCRC is well proven. Nevertheless, anti-VEGF therapy for patients with an intact primary is still controversial. As bleeding is a well-known side effect during treatment with anti-VEGF therapy Bevacizumab is not recommended in patients with active bleeding. The primary aim of this analysis is to evaluate the safety and efficacy of Bev in patients with clinical bleeding colorectal primary. Methods: mCRC patients enrolled from January 2010 to December 2015 were identified from a prospective multi-site Austrian registry. Patients with an intact primary tumor and synchronous metastases who were treated with first line chemotherapy (5-FU based) with Bev were studied. Results:  Out of 207 patients with synchronous mCRC 89 had the primary tumor in situ. 67 of these pts received a 5-FU based chemotherapy with Bev. 41 presented at first visit with an iron deficiency anemia with clinical bleeding signs. 57% described stool abnormality. A minority of pts presented with a subileus, one required a gastric tube for decompression. In all patients bleeding stopped after the first treatment cycle, and bowel habits improved within a month. 40% underwent surgery of metastases and primary during follow-up. Two patients had to undergo emergency surgery due to perforation at a diverticulum, no perforation at the primary was recorded. Conclusions:  In routine clinical practice Bev seems safe in patients with clinical bleeding primary. These study findings indicate that VEGF blockade has a direct and rapid antivascular effect on primary CRC.

P36 The effect of bevacizumab on the duration of intervals between chemotherapy cycles Elmir Ljubuncic1*, Temeida Alendar1, Klaus Geissler1 5th Medical Department with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria

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Background:  The hematopoietic niche surrounding a stem cell largely governs its fate by regulating molecular programs

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including quiescence, self renewal, survival and differentiation. An adequate stem cell function is critical for the regeneration of hematopoiesis after chemotherapy. Among several niche aberrations a low expression of vascular endothelial growth factor (VEGF) has been shown to compromise HSC function in preclinical models. The VEGF blocking antibody bevacizumab is widely used in the management of cancer patients. In some randomized trials the addition of bevacizumab to chemotherapy was associated with more myelosuppression as compared to patients without bevacizumab. The effect of bevacizumab on hematopoiesis recovering from chemotherapy and its consequence for treatment delay has not been investigated in a real life setting. Methods: We calculated from a retrospective database the mean intervals between chemotherapy cycles (n = 315) in colorectal cancer patients (n = 39) receiving repetitive chemotherapy cycles with (n = 134) or without (n = 181) bevacizumab. Treatment intervals with definitely non hematological delay of chemotherapy were excluded. Results: There was a statistically significant difference in the duration of the intervals between chemotherapy cycles in patients receiving bevacizumab or not (mean + SD duration 17.9 + 7.0 vs 15.8 + 3.8 days; p = 0.0017). Conclusions:  Our data show that in a real life setting the addition of bevacizumab to chemotherapy in patients with colorectal cancer is associated with a prolongation of the intervals between chemotherapy cycles. Compromised reconstitution of hematopoiesis following chemotherapy by bevacizumab may be the cause for delay of subsequent chemotherapy.

P37 Targeting Cbl-b in human NK cells increases IL-2 induced proliferative responses Christina Lutz-Nicoladoni1,2*, Stephanie Aschauer-Wallner1,2, Elisabeth Hoflehner1,2, Franziska Spoeck1,2, Günther Gastl1,2, Sieghart Sopper1,2 Department of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Tyrolean Cancer Research Institute, Innsbruck, Austria 1

Background: The E3 ligase Cbl-b negatively regulates T and NK cell activation by interacting with TCR and costimulatory pathways in T cells and ubiquitylating TAM receptors in NK cells. Cbl-b deficient CD8+ T cells, anergy resistent and insensitive to TGF-β mediated inhibition, induce potent anti-tumor immunity in mouse models. Anti-metastatic NK cell activity is mediated by NK cells treated with a TAM kinase inhibitor. Here we investigate, whether downregulation of Cbl-b in human NK cells increases NK cell activity and TGF-β sensitivity. Methods:  Human NK cells were enriched by MACS. LAK cells were differentiated with high dose IL-2. Both celltypes were electroporated with CBLB-siRNA, pretreated with TGF-β and stimulated with cytokines. Proliferation, cytokine production, surface-marker expression and cytotoxic activity were analyzed. Results: Cbl-b is efficiently downregulated in huNK and huLAK cells. Silencing Cbl-b in NK cells increases IL-2 induced proliferation and IFN-γ production. In contrast to T cells, Cbl-b silenced huNK cells are not resistant to inhibitory effects of TGFβ. In huLAK cells, cultivated with high IL-2 concentrations prior

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Supplement 2/17 to nucleofection, CBLB silencing seems to not further increase proliferative capacities and cytotoxic activity. Conclusions:  Targeting Cbl-b via siRNA in PBMCs, as currently tested in a Phase I trial, synergistically enhances innate and adaptive immune responses. Cbl-b silenced effector T cells more efficiently infiltrate the tumor and increase local IL-2 levels, which further stimulate Cbl-b silenced NK cells. Since Cbl-b silenced human NK cells are sensitive to inhibition by TGF-β it might further improve anti-tumor responses to combine this approach with inhibition of TGF-β signalling.

P39 MicroRNA-1200s inhibits cellular growth of breast cancer through downregulation of PI3K signaling

P38 Benefit of second-line chemotherapy in patients with advanced biliary tract cancer: A propensity score analysis Florian Moik *, Jakob Riedl , Thomas Winder , Angelika Bezan1, Christopher Rossmann1, Joanna Szkandera1, Anne-Katrin Kasparek1, Renate Schaberl-Moser1, Martin Pichler1,3, Herbert Stöger1, Michael Stotz1, Armin Gerger1,4, Florian Posch1 1

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Division of Oncology, Department of Medicine, Medical University of Graz, Graz, Austria 2 Department of Oncology, University Hospital Zurich, Zurich, Switzerland 3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Center for Biomarkers in Medicine (CB-MED), Medical University of Graz, Graz, Austria 1

Background:  Second-line-chemotherapy (2LCTX) is increasingly applied in advanced-biliary-tract-cancer (aBTC), although no randomized trial has so far demonstrated any benefit of this intervention. In the absence of randomized data, we conducted a propensity-score-weighted comparative-effectiveness-analysis of survival-outcomes in aBTC-patients treated with BSC ± 2LCTX. Methods: This single-center observational cohort-study includes 80 patients with aBTC (metastatic, recurrent, inoperable), who completed 1st-line-CTX at our department (overall: 185 BTC-patients 2003–2016). Thirty-eight (48%) received 2LCTX + BSC (Fluoropyrimidine-mono: n = 26 (68%), Fluoropyrimidine-based-combination-CTX: n = 9 (24%), others: n = 3 (8%)). Primary endpoint was 18-month overall-survival (OS). An inverse-probability-of-treatment-weighted analysis (IPTW) was conducted to account for imbalances in prognostic variables between the groups. Results:  During a median follow-up of 14.2 months (25th– 75th percentile: 5.0–17.6), we observed 50 deaths. Median OS was 12.0 vs. 2.7 months in BSC ± 2LCTX-patients. Corresponding 6-/8-/12-month-OS-estimates were 77%/53%/19% in BSC + 2LCTX-patients, and 31%/23%/17% in the BSC-group (univariable hazard-ratio (HR) for OS: 0.40 (95%CI: 0.23–0.72, p = 0.002)). However, patients receiving 2LCTX + BSC had a significantly higher prevalence of favorable prognostic variables (higher Karnofsky-Index (p = 0.05), poly- rather than mono-CTX in 1st-line (p = 0.03), higher serum-albumin (p = 0.04)). After carefully adjusting these imbalances using IPTW, 2LCTX + BSC was associated with a smaller relative benefit (Adjusted HR = 0.51, 95%CI: 0.24–1.08, p = 0.076). The OS-benefit was highly timedependent (adjusted HRs: 0.20 (p = 0.005), 0.42 (p = 0.06), 1.26

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(p = 0.74) after 1/3/6 months). In IPTW-analysis, 1-year-OS was 34% for BSC + 2LCTX-patients and 27% in the BSC-group. Conclusions: Within the limitations of an observational cohort-study, our data suggest, that 2LCTX is associated with an OS-benefit. However, this benefit is of short-term nature, with no OS-difference between the groups after 1 year.

Martin Pichler1*, Daniela Schwarzenbacher1, Verena Stiegelbauer1, Gabriel Rinnerthaler2, Thomas Bauernhofer1, Gerald Höfler3, Herbert Stöger1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Private Medical University, Salzburg, Austria 3 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background:  MicroRNAs are master regulators of cancerrelated gene expression and influence several hallmarks of cancer. MicroRNAs offer great potential as therapeutic targets and prognostic biomarkers. Methods:  In this study, we performed a microarray-based profiling approach to identify several novel breast cancer associated microRNAs. The most promising candidates were further characterized with regard to their biological role, molecular mode of action and potential for drug combinatorial therapeutic approaches. Results: We identified a novel breast-cancer associated microRNA (miR-1200s) that is down-regulated in breast cancer stem cells and cancerous tissue. In four cohorts of more than 1000 breast cancer patients, low levels of miR-1200s represent an adverse prognostic factor. Gain and loss of function experiments showed a growth inhibitory role of miR-1200s in breast cancer cells and mouse xenografts. Whole transcriptome analysis identifies members of the PI3Kinase pathway as direct targets of miR-1200s. Combining miR-1200s with different chemical compounds (PI3Kinase inhibitors) increase synergistically the growth inhibitory effects. Conclusions:  Our data suggest that miR-1200s function as a tumor-suppressor in breast cancer and that this microRNA might be useful in combining microRNA therapeutics and PI3Kinase inhibitors.

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P40 REGO-ACT Assessment of physical activity during therapy with regorafenib for metastatic colorectal cancer Gudrun Piringer1*, Laurenz Vormittag2, Leopold Öhler2, Birgit Grünberger3,4, Johannes Meran3, Marlies Moshammer5, Johannes Andel6, Wolfgang Eisterer7, Vera Trommet1, Josef Thaler1 Klinikum Wels-Grieskirchen, Wels, Austria St. Josef Krankenhaus, Vienna, Austria 3 Barmherzige Brüder Wien, Vienna, Austria 4 Landesklinikum Wiener Neustadt, Wiener Neustadt, Austria 5 Bayer Austria, Vienna, Austria 6 Landeskrankenhaus Steyr, Steyr, Austria 7 University Hospital Innsbruck, Innsbruck, Austria 1 2

Background: Fatigue is the most common drug-related adverse event during regorafenib therapy. Enhanced physical activity is a promising treatment strategy for improvement of fatigue that still has to be fully investigated. This study evaluated the average amount of physical activity during regorafenib therapy quantitatively. Methods:  This prospective, non-interventional, multi-center, single arm pilot study included heavily pretreated patients with metastatic colorectal cancer, who participated in the NIS CORRELATE and who were treated with regorafenib. Physical activity was measured by a pedometer and an international physical activity questionnaire within the first 84 days of regorafenib therapy. Results: Twenty-five patients with a median age of 62 years (range 43-88) were evaluated. Nine (36.0%) and sixteen (64.0%) out of these patients were women and men, respectively. Patients wore their pedometer for a mean of 41.8 days (range 6-100). The mean level of steps per day was 3.021 (range 10-14.931). Early end of study was documented in 8 patients. Final data of the international physical activity questionnaire, fatigue and duration of regorafenib therapy as well as progression free survival will be presented. Conclusions:  This is the first study to determine the amount of physical activity in patients treated with regorafenib. The average amount of daily steps per day varies considerably in these patients. This reference serves however as a basis to enable the development of a reasonable and tailored training program for potential interventional and randomized studies, assessing the impact of physical activity on fatigue occurrence and its proactive treatment during regorafenib therapy.

P41 Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic adenocarcinoma Alexander Christian Reisinger1*, Angelika Pichler1, Hans Rabl2, Daniel Mayer1, Markus Lammer1, Reinhold Stering3, Christoph Tinchon1 Department of Hemato-Oncology, General Hospital Leoben, Leoben, Austria 2 Department of Surgery, General Hospital Leoben, Leoben, Austria 3 Department of Pathology, General Hospital Leoben, Leoben, Austria 1

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Background:  Currently surgery is the only potentially curative option for pancreatic adenocarcinoma. However, upfront surgery in borderline resectable disease results in a high rate of R1-resections. The FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan and oxaliplatin) chemotherapeutic regimen showed a high remission rate in the palliative setting. Therefore it is reasonable to use this effective therapy also in the neoadjuvant setting in patients with borderline resectable adenocarcinoma. Methods: Between October 2010 and February 2014 all consecutive patients with borderline resectable pancreatic adenocarcinoma, defined by AHPBA (Americas Hepato-Pancreato-Biliary Association) criteria and good performance status underwent neoadjuvant chemotherapy with FOLFIRINOX for two to four months. Response was assessed by imaging studies and reviewed in a multi-disciplinary team conference. Patients without progression underwent surgery. Results: Twenty-two consecutive patients were included. Twenty of these patients (91%) underwent surgery. Two patients had progressive disease. Pathological remission status was obtained. R0-resection was achieved in 19 of 20 patients (95%). Toxicity of chemotherapy was generally manageable – only one patient had grade 4 toxicity with bilateral pulmonary embolism. Median PFS in patients with pathological response was > 3.89 years (not mature) versus 1.16 years in patients without (p = 0.04, hazard ratio 4.7). Conclusions:  FOLFIRINOX as a neoadjuvant chemotherapeutic regimen was safe and feasible in patients with borderline resectable pancreatic carcinoma. A high rate of patients underwent surgery (91%) and had R0 resection (95%). PFS was significantly longer in patients with pathological response.

P42 Patterns of venous thromboembolism risk in patients with localized colorectal cancer undergoing adjuvant chemotherapy or active surveillance Jakob Michael Riedl1*, Florian Posch1, Angelika Bezan1, Joanna Szkandera1, Maria Anna Smolle1, Thomas Winder2, Christopher H. Rossmann1, Renate Schaberl-Moser1, Martin Pichler1,3, Michael Stotz1, Herbert Stöger1, Armin Gerger1,4 Division of Oncology; Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz; Graz, Austria 2 Clinical Division of Medical Oncology, University Hospital Zurich, Zurich, Switzerland 3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer, Houston, USA 4 Research Unit Genetic Epidemiology and Pharmacogenetics, Division of Clinical Oncology, Medical University of Graz, Graz, Austria 1

Background:  The risk of cancer-associated venous thromboembolism (VTE) is highly elevated in patients with metastatic colorectal cancer (mCRC), and particularly during antineoplastic therapy. However, patterns of VTE risk in localized CRC are ill-defined. Here, we estimate the risk of VTE in CRC after curative surgery, and its association with baseline risk factors, adjuvant chemotherapy (adjCTX) and disease recurrence. Methods:  In this single-center retrospective cohort study, 516 patients with CRC (median age = 65.1 years, stage II and III:

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Supplement 2/17 n = 151 (29.5%), n = 361 (70.5%); adjCTX: n = 339 (65.7%)) were included at the time of surgery and followed up until the onset of VTE, disease recurrence, or death. Results: During a median follow-up of 2.7 years, we observed 15 VTEs (2.7%), 116 recurrences (22.5%), and 46 patients (8.9%) died. The 6-month, 1-year, and 5-year risk of VTE was 1.6%, 2.0% and 3.2%, respectively. In time-to-VTE regression, adjCTX was not associated with an increased risk of VTE (Subdistribution hazard ratio = 0.98, 95%CI:0.33–2.88, p = 0.97). In multi-state modeling, the occurrence of disease recurrence strongly increased the risk of VTE (Transition hazard ratio (THR) = 13.03, 95%CI:4.39–38.74, p < 0.0001)). Conversely, the onset of VTE did not predict for recurrence (THR = 1.95, 95%CI:0.62–6.16, p = 0.25). Conclusions:  In localized CRC, the risk of VTE is very low and does not appear to be increased by adjuvant chemotherapy. Therefore, primary thromboprophylaxis is unlikely to result in clinical benefit. The strongest determinant of VTE risk appears to be disease recurrence.

was significant in the first two chemotherapy lines and in case of BSC. Conclusions: Our data suggests that inflammatory biomarkers are important and independent indicators of response to antineoplastic chemotherapy, relevant not only in first, but also in later treatment lines.

P44 CART cells targeting erbB2/HER2neu demonstrate an efficient anti tumor response in a 3D cellular model Jakob Rudzki1,2*, Guenther Gastl1,2, Lydia Kapferer1, Franziska Spöck1, Elisabeth Hoflehner1,2, Sieghart Sopper1,2, Arno Amann1,2 Tyrolean Cancer Research Institute and Internal Medicine V (Hematology and Oncology – Tumorinteraction/ Microinvironment and Immunology), Medical University of Innsbruck, Innsbruck, Austria 2 UKIM V – Tirol Kliniken, Landeskrankenhaus Innsbruck, Innsbruck, Austria 1

P43 Inflammatory biomarkers are independent predictive markers in metastatic colon cancer patients over several treatment lines Jakob Riedl1*, Florian Posch1, Angelika Bezan1, Florian Moik1, Maria Anna Smolle1, Joanna Szkandera1, Martin Pichler1,3, Herbert Stöger1, Michael Stotz1, Armin Gerger1,2 Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria 2 Research Unit Genetic Epidemiology and Pharmacogenetics, Division of Oncology, Medical University of Graz, Graz, Austria 3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer, Houston, USA 1

Background:  The aim of this study is to quantify the value of inflammatory biomarkers including the neutrophil/lymphocyte ratio (NLR), the lymphocyte/monocyte ratio (LMR), the platelet/lymphocyte ratio (PLR), the C-reactive protein (CRP) level and the advanced lung cancer inflammation index (ALI) as predictive and prognostic markers for therapy response over the first three chemotherapy lines in metastatic colorectal cancer (mCRC) patients. Methods: Two-hundred-fifty-eight patients with mCRC undergoing palliative chemo(immuno-)therapy were included in this retrospective study. The primary endpoints were 6-month progression free survival (PFS) and overall response rate (ORR) during 1st-line, 2nd-line, and 3rd-line treatment, and 6-month OS during best supporting care. Results: In multivariable analysis adjusting for polychemotherapy, 1 standard deviation (SD) increase in NLR was associated with a 8.5% absolute lower ORR in first line (11-7, p < 0.0001), 3% lower ORR in second line (4-2, p < 0.0001), and 3% lower ORR in third line (8–2, p = 0.24), respectively. The other inflammatory markers were not significantly associated with ORR. Regarding PFS, an increase in the NLR was significantly associated with rising hazard ratios (HR) over all treatment lines (HR 1.30, p = 0.021 first line); (HR 1.37, p < 0.0001 second line); (HR 1.44, p = 0.042 third line). The PLR was associated with 6 month PFS over all lines. For CRP, the prognostic association

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Background:  Adoptive cell therapies have become a fascinating method to fight efficiently against cancer by generating engineered autologous immune cells (CARtg – Chimeric antigen receptor transgenic cells) acting in a MHC-I independent manner bypassing tumor escape due to MHC-molecules down-regulation. In addition, the fact that CARtg immune cells are clinically less potent as expected illustrates the need for devising innovative concepts that break tumor tolerance. The primary goal of this project is to overcome this hurdle by establishing complex immunotherapeutic strategies in cellularbased models. Methods: The CAR comprises a scFV-domain (erbB2/ HER2neu) linked to co-stimulatory elements (hu-CD28, huCD3zeta) in a gateway-compatible lentiviral vector system. Subsequently selected primary human T cells (CD4+:74.7%; CD8+:80.4%) were lentivirally transduced, enriched by MACS selection or cell sorting. Anti tumor response was established by adopting a cellular based 2D & 3D model (hanging drop technique). Efficacy of cell lysis by CARtg cells was assessed by a CRA- (chromium release assays) and a LDH cytotoxicity assay. Results: CARtg immune cells induced a specific lysis of approximately 63% (E:T = 20:1; n:13; CRA of 2D cell culture) of HER2-expressing mamma carcinoma cells (MCF7-HER2) and in comparable way in subsequent 3D cell culture experiments underlining these results. Conclusions:  Adopting 3D cell models like “hanging drops” assembled by HER2 positive target cells demonstrate immunerelated tumor shrinkage due to CARtg CD4+ Tcells in augmenting antitumor response together with CARtg CD8+ Tcells. This supports to generate more information about interaction of immune- and target cells by mimicing the microtumorenvironment in a three-dimensional cellular based way.

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P45 MicroRNA-196 blocks colorectal cancer cell migration and metastases formation through regulation of HOXB and GalNT Verena Stiegelbauer1*, Anna-Maria Pehserl1, Alexander Deutsch2, Jan Basri Adiprasito1, Herbert Stöger1, Johannes Haybaeck3, Michael Stotz1, Gerald Höfler3, Armin Gerger1, Martin Pichler1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 3 Institute of Pathology, Medical University of Graz, Graz, Austria 1

MicroRNA-196 has been previously implicated in malignant transformation, however its role in colorectal cancer (CRC) has not been fully explored yet. In the current study, we examined the clinical and biological relevance of miR-196, and the molecular pathways regulated by miR-196 in CRC.MiR-196 expression was quantitated by qRT-PCR in two independent cohorts comprised of 292 CRC patients in total, to explore its biomarker potential. Transient and stable gain and loss of function experiments were conducted in a panel of CRC cell lines, to evaluate the impact of miR-196 on proliferation, chemo-sensitivity, migration/invasion and metastases formation in vitro and in vivo. The molecular pathways influenced by miR-196 were characterized using whole transcriptome profiling, in-silico target prediction tools, luciferase-interaction assays, and pheno-copy gene knock-down experiments. Low miR-196 expression was significantly associated with metastatic status and poor outcomes in both independent CRC patient cohorts (p < 0.05, logrank test). MiR-196 suppression led to increased CRC cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196 and HOXB and GalNT, which in turn regulates CRC cell migration. Our findings provide new insights into the role of miR-196 in CRC metastases formation through regulation of proteins involved in CRC progression.

P46 Patient-derived lung adenocarcinoma cells challenge the association of cancer stem cells with epithelial to mesenchymal transition Verena Tiran1*, Joerg Lindenmann2, Stefanie Stanzer1, Luka Brcic3, Ellen Heitzer4, Helmut Popper3, Nadia Dandachi1, Marija Balic1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, Graz, Austria 3 Institute of Pathology, Medical University of Graz, Graz, Austria 4 Institute of Human Genetics, Medical University of Graz, Graz, Austria 1

ciated and used to describe both the formation of metastasis and therapy resistance. Information about EMT only results from cell lines and mice experiments, which are not able to capture this transient mechanism sufficiently. Methods:  Out of a single resected primary lung adenocarcinoma tumor we could establish two cell populations. Both were characterized with qRT-PCR, flow cytometry and immunofluorescence and functional analysis such as in vitro assays and in vivo chorioallantoic membrane model assay were performed. Results: One clone initiated and sustained in spheroid culture (LT22s) whereas the other clone was only capable of growth and proliferation under adherent conditions (LT22a). In contrast to our expectations, LT22s were strongly associated with the epithelial phenotype, and expressed additionally CSC markers ALDH1 and CD133, whereas the LT22a was characterized as mesenchymal but lack of CSC markers. Grown on a chorioallantoic membrane the invasive LT22s cells mimicked gland formation. Moreover, in drug treatment assay LT22s were more resistant to higher doses of Cisplatin than LT22a cells. Conclusions:  The patient-derived tumor cells with putative CSC (LT22s) characteristics demonstrated aggressive behavior and retained an epithelial phenotype during invasion. Subpopulation with mesenchymal phenotype expressed no CSC marker and had a better response to conventional therapy. Therefore, the association of CSC with EMT stated in literature could not be confirmed. We showed for the first time the independence of CSC markers and EMT features in a patient derived primary cells.

Klinische Studien

K47 AGMT_CML-1 Phase 1 study to evaluate feasibility and efficacy of addition of P1101 (PEG-Proline-Interferon alpha-2b) to imatinib treatment in patients with chronic phase chronic myeloid leukaemia not achieving complete molecular response (MR 4 or 4.5) Josef Thaler1, Sonja Burgstaller1* Division of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria

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Start of Study:  July 2013 End of recruitment:  Q1 2018 Design: This is a phase 1, open label pilot study of adding P1101 to treatment with imatinib in patients with CML in chronic phase. Patients are eligible, if a molecular remission 4.5 or below has not been achieved with imatinib therapy alone after at least 18 months of therapy. Only patients achieving a CHR and a CCyR at study entry will be included. P1101 will be added in a dose of 50 µg subcutaneously every 14 days. In the absence of a dose limiting toxicity (DLT) after 12 weeks of therapy, P1101 will be increased to 100 µg subcutaneously every 14 days. In the absence of a DLT after another 12 weeks of therapy, treatment will be continued with the same dose level for further 12 months. A dose of 100 µg every 14 days is considered as maximum dose. Imatinib will be continued at the same dose level as before study entry.

Background:  The cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) models have been closely asso-

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Supplement 2/17 Primary objective:  to determine the safety and tolerability of the addition of P1101 to the currently established dose of imatinib A total of 12 patients with BCR-ABL positive CML in chronic phase will be included. Patients must be on imatinib treatment for at least 18 months.

K48 AGMT_GLIOMA1 Ascending-dose-study with liposomal curcumin in combination with bevacizumab + irinotecan in patients with recurrent glioblastoma multiforme following standard therapy with temozolamide + ionizing radiation Richard Greil1* 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Start of study:  Q2 2017 End of recruitment:  Q1 2019 Design: This is an open-label phase IIa study. The study will be conducted with male and female patients >18 years with a histologically confirmed diagnosis of glioblastoma whose tumors have progressed following treatment with surgery, radiation, and a standard of care treatment with temozolamide. The starting dose level of liposomal curcumin 300 mg/m² in this study is based on the results in the phase 1b study. If no DLT occurs during the first week on study the patient can continue at a dose of 345 mg/m2 (15% increment) for a succeeding week. Dose levels for each patient in additional weeks will be increased by 15% (max. 460 mg/m2) until an MTD is reached. The total number of patients for this Phase IIa trial is expected to be 20. Primary safety endpoint:  Safety and tolerability of ascending doses of liposomal curcumin in combination with bevacizumab and irinotecan Primary efficacy endpoint: Response rate (CR, PR, SD) according to RANO criteria

K49 AGMT_MBC_Reg: PATIENT REGISTRY Metastatic breast cancer in Austria

Indication:  Histological evidence of breast cancer Histological and/or radiological evidence of metastases Metastasis within 10 years of registry initiation Primary objective: Epidemiological evaluations (general characteristics of metastatic stage patients in Austria, assessment of metastatic stage breast cancer subtypes in Austria, assessment of the specific characteristics and frequency of metastatic breast cancer, data on survival of female patients with metastatic breast cancer in Austria) and therapy-specific evaluations Recruitment:  1000–3000 patients

K50 LYSARC_Ro-CHOP: phase3 multi-center randomized study to compare efficacy + safety of Romidepsin-CHOP (Ro-CHOP) versus CHOP in patients with previously untreated-peripheral t-cell-lymphoma Richard Greil1*, Lukas Weiss1 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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EudraCT: 2012-001580-68 Start of study:  Q3 2016 End of recruitment:  Q2 2018 Design: This is a randomized multi-center open-labelphase-III-study, to compare efficacy and safety of Ro-CHOP with standard CHOP regimen in patients with previously untreated, histologically proven PTCL. Patients are randomized 1:1 to receive either (Arm A) CHOP administered in 3-weekcycles for 6 cycles or (Arm B) romidepsin CHOP (Ro-CHOP) administered in 3-week-cycles for 6 cycles. In the Ro-CHOP arm, romidepsin will be administered at a dose of 12 mg/​m² IV on D1 and D8 every 3 weeks. In this study, patients will advance through three phases of the study: screening phase, treatment phase and follow-up phase. Patients will receive study drug(s) for up to 6 cycles, or until unacceptable toxicity will develop or progression or voluntary withdrawal. Patients will be followed for survival until the earliest of either 80% of patients have died or 3 years from the last patient randomized. Primary objective:  of the study is to compare the efficacy of romidepsin when administered with CHOP versus CHOP alone in subjects with previously untreated PTCL in terms of PFS assessed according to Response criteria for malignant lymphoma 1999 by Response Adjudication Committee (RAC). Patients:  A total of 10 patients will be included in Austria.

Richard Greil1*, Simon Gampenrieder1, Gabriel Rinnerthaler1 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Design: This registry is a prospective and retrospective, multicenter collection of data on patients with metastatic breast cancer in Austria. All tumor characteristics, medical histories and also treatment sequences are documented in anonymized form. For documentation in the registry, no further diagnostic or therapeutic measures are required than those already necessary in general. Participation in the registry must not interfere with treatment routines. A written consent must be obtained prior to the input of data. No informed consent is required from deceased patients.

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HD21 Treatment optimization trial in the first-linetreatment of advanced-stage Hodgkin lymphoma; comparison of 6cycles of escalated BEACOPP with 6cycles of BrECADD Richard Greil1*, Thomas Melchardt1 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Supplement 2/17 Start of study:  Q1 2017 (Austria) End of recruitment:  June 2020 Design: In this prospective, multicenter, randomized and open-label trial, patients in the standard group are treated with 6 cycles of escalated BEACOPP. Patients in the experimental group receive 6 cycles of the BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, adriamycin, dacarbazine, dexamethasone) chemotherapy regimen. In both groups patients with PET positive residual tumor masses ≥ 2.5 cm are subjected to local irradiation with 30 Gy. It is planned to enter 1500 patients into this trial during a recruitment period of approximately 4 years. About 250 centers in Germany and other countries will participate in the trial. Primary objective of the trial is to demonstrate non-inferior efficacy of six cycles of BrECADD compared to six cycles of escalated BEACOPP, each followed by radiotherapy to PET-positive residual lesions ≥2.5 cm, in terms of progression free survival (efficacy objective). Primary endpoint is progression-free suvival.

K52 AGMT_HMA in Myeloid Neoplasms: PATIENT REGISTRY Registry on hypomethylating agents in myeloid neoplasms, including myelodysplastic syndrome (MDS), CMML and AML Richard Greil1*, Lisa Pleyer1 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Design: The VIDAZA® Patient Registry is set up to collect real-world experience in the management of patients with MDS, CMML or elderly patients with AML ineligible for high dose chemotherapy, treated with VIDAZA® (azacitidine) in Austria. This registry will collect data in a retrospective as well as in a prospective manner at various sites in Austria. The aim is to gain valuable insights on both efficacy and toxicity of this drug in a routine clinical setting in patients with various comorbidities. No pre-defined visits, medical tests, laboratory tests, procedures, or interventions are required. Physicians who have already treated patients with VIDAZA® or are planning to initiate VIDAZA® treatment can include patient data in this registry. To help maintain patient confidentiality, each patient will be assigned a unique patient identifying number upon enrollment. Additionally from some patients with ALL, AMS or CMML, blood or tissue samples will be stored for further analyses. These samples will also be obtained from patients, who are not treated with Vidaza®, to comprise a control. Recently, EMA granted DACOGEN® (decitabine) approval for the treatment of Acute Myeloid Leukemia, irrespective of bone marrow blast count. Patients treated with DACOGEN® have been already enrolled in this registry. Inclusion: Begin with or already have received treatment with a hypomethylating agent. Objectives:  Number of cycles and dosage of VIDAZA® therapy, response evaluation, toxicities, severe adverse reactions, overall survival

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K53 AGMT_MBC-10: Ixazomib (MLN9708) in combination with carboplatin in pretreated women with advanced triple negative breast cancer Richard Greil1*, Gabriel Rinnerthaler1, Simon Gampenrieder1 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Study duration:  Q2 2016 – Q2 2019 Design: This is an open-label phase I/II study. Subjects meeting all inclusion criteria will be enrolled receiving ixazomib on day 1,8 and 15 in combination with carboplatin on day 1 and 15. Cycles will be repeated every four weeks and safety measurements and analysis will be performed at each visit. Phase I: The phase I part of this study uses an alternate dose escalation accelerated titration design. In the accelerated dose-escalation phase a single-patient cohort per dose level will be enrolled, until one dose limiting toxicity (DLT) or 2 moderate toxicities are observed during cycle 1, or until dose level 4 is reached. At this dose level the cohort is expanded to three patients and dose escalation reverts to a conventional 3 + 3 escalation design. Phase II:  After establishing MTD in phase I, accrual continues to evaluate the efficacy and safety of the combination. A total of 35 patients including patients enrolled in the phase I part within the conventional dose escalation phase at the dose level considered as the MTD will be included. Primary Endpoint: Phase I Determination of maximum tolerated dose (MTD) and doselimiting toxicities (DLTs) Phase II Overall response rate (ORR) Patients: Phase I: 9 to 24 patients Phase II: (6 patients of phase I) + 29 patients

K54 AGMT_NGS_Reg: PATIENT REGISTRY The use of genomic testing and the resulting medical decisions according to target identification Richard Greil1* 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Design:  This registry is designed as multicenter non-interventional (observational) cohort of oncology patients who received or plan to receive comprehensive genomic testing anytime on or after January 1, 2016. Patient medical, testing and treatment information will be obtained through extraction of data from existing patient medical charts. Longitudinal followup data, including survival and tumor progression, will also be extracted from patient medical charts. This patient follow-up data will be obtained until patient death or loss to follow-up.

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Supplement 2/17 For documentation in the registry, no further diagnostic or therapeutic measures are required than those already necessary in general. Participation in the registry must not interfere with treatment routines. Only routine data, which has already been recorded in the patient’s medical chart, is transferred to the electronic Case Report Forms. To maintain patient confidentiality, each patient will be assigned a unique patient identifying number upon enrolment; this number will accompany the patient’s medical and other registry information throughout the lifetime of the registry. The goal of this registry is to landscape the clinical practice of molecular profiling in Austrian cancer patients with focus on identification of methods used, evaluation when the tests are performed in the course of the disease, and definition of the impact of the test result on the subsequent treatment decision. It is expected, that the main data-bulk will be obtained from approximately 15 sites. Recruitment:  approx. 500 patients

K55 AGMT_PTCL-Reg: PATIENT REGISTRY Austrian registry and biobank of peripheral T-cell lymphomas Richard Greil1*, Lukas Weiss1 3rd Medical Department, University Hospital of the Paracelsus Medical University (PMU), Salzburg, Austria

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Design:  This Registry is a prospective as well as retrospective, observational, multi-center research initiative. Data will be collected from all sites in Austria willing to participate. Data and material of patients, that are enrolled prospectively, will be considered for inclusion into the international “T-cell project” (NCT01142674). The clinical data should provide more accurate information on the epidemiology of this rare disease in Austria, supplemented by information on type of therapy and response. Correlation of the clinical course with clinical variables or parameters assessed in primary tumor tissue samples will provide a deepened understanding of PTCL biology, as well as identify potential prognostic and predictive factors. The integration of imaging studies into this registry will allow retrospective, centralized, independent, blinded response evaluation in certain patient subgroups, thereby achieving a quality of data comparable to current randomized phase 3 clinical trials. Given the low incidence of PTCL, only the establishment of a substantial biobank can lay the foundations for scientifically meaningful and internationally competitive translational research. The incorporation of a biobank into a well characterized clinical registry will build the heart of this project, with the ultimate goal to enable research for the benefit of PTCL patients in Austria and around the world. Within the registry biomaterial should be collected in the AGMT biobank, managed by the Medical University of Vienna and the Salzburg Cancer Research Institute.

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K56 AGMT-ALL Reg: PATIENT REGISTRY Registry and biobank for the collection of clinical data and biomaterial from adult ALL patients Ulrich Jäger1, Alexander Hauswirth1* Division of Hematology and Haemostaeology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

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Design:  In Austria approximately 70 patients are diagnosed with adult ALL per year and are treated in up to 17 institutes. Obviously there is a need to collect all data possible in order to harmonize diagnosis and treatment and to make optimal therapy available for every Austrian patient. Therefore information on these patients should be prospectively collected, analysed and used for the generation of treatment protocols by a specialized study group. As a first step a registry with a standardized data set including diagnosis, therapy and outcome should be implemented. In order to achieve a maximum of data harmonisation it is recommended that patients are treated according to a standardized international protocol endorsed by the EWALL. The use of molecular diagnosis in disease monitoring, risk stratification and the use of target orientated therapies are increasingly important in patient management of ALL. These diagnosis tools are currently not implemented in Austria. For that reason there are many open questions in adult ALL and the new prospects leave clinicians with uncertainty about how to optimally manage adult patients with ALL. A centralized and standardized diagnosis program is needed to assure quality. Objectives: Data collection regarding diagnosis, therapy and progression of disease for Austrian ALL patients older than 18 years. Biobank:  Within the ALL registry biomaterial should be collected at diagnosis and once a year for 5 years and at relapse.

K57 AGMT_AIHA_Reg: PATIENT REGISTRY Autoimmune Hemolytic Anemia (AIHA) with corresponding biobank Ulrich Jäger1* Division of Hematology and Haemostaeology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

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Design: This registry is a prospective and retrospective, multicentre collection of data on patients with AIHA in Austria. All disease characteristics, medical histories and also treatment sequences are documented in anonymised form. Additionally patients will be asked to complete the FACIT-Fatigue questionnaire. For documentation in the registry no further diagnostic or therapeutic measures are required than those already necessary in general. Participation in the project must not interfere with treatment routines. Data will be collected from all sites in Austria willing to participate. An estimated 100 patients are expected to be included;

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Supplement 2/17 this number may be revised over time as interest and demand dictates. Within this project biomaterial of patients with AIHA in Austria will be collected in the AGMT biobank. This collection of biomaterial is optional. Primary objective:  The aim of the AIHA registry is to collect data regarding the following objectives of disease for all Austrian AIHA patients older than 18 years. Epidemiological evaluations Assessment of AIHA subtypes in Austria Assessment of specific characteristics and frequency of AIHA Patient care and treatment in Austria Treatments used, sequence of treatments Efficacy and toxicity Establishment of a central biobank to provide a basis for future AIHA related research (optional)

K58 AGMT_ALCL1 A „window-of-opportunity“ trial with brentuximabvedotin and imatinib in patients with relapsed or refractory ALK + anaplastic-large-celllymphoma or patients ineligible for chemotherapy Ulrich Jäger1* Division of Hematology and Haemostaeology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

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Start of study:  Q2 2015 End of recruitment:  Q4 2018 Design:  This is an open label pilot study of combining BV in a licensed indication with imatinib in patients with ALCL. It is intended as a “window-of-opportunity” trial in which the study drugs will be given as an initial substitute for conventional chemotherapy with the intention to achieve a remission enabling the patients to proceed to autologous or allogeneic stemcell-transplantation, if eligible. Imatinib will be given continuously starting from day 1 of the first cycle at an oral dose of 100 mg daily. The dose will be increased to 200 mg daily starting from day 1 of the second cycle if no DLT occurs during the first cycle. BV will be given 3 weekly starting on day 1 at a dose of 1.8 mg/kg body weight. In the absence of a dose limiting toxicity (DLT) after 3 weeks of therapy, and in the presence of a clinical response (CR or PR) after cycle 1, the BV dose will continue every 3 weeks for 48 weeks. Primary endpoint of this study is to determine the safety and tolerability of simultaneous administration of brentuximabvedotin and imatinib mesylate in substitution of conventional chemotherapeutic treatment. Patients: A total of 10 patients will be included. Patients must have received at least one prior line of conventional chemotherapy for ALCL. Patients who are not eligible for conventional chemotherapy can also be included.

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K59 AGMT_NHL-15B Phase-II single-arm „window-of-opportunity“ study of a combination of obinutuzumab (GA-101) and venetoclax (ABT-199) in relapsed or refractory diffuse-large-B-cell-lymphoma (DLBCL) Ulrich Jäger1* Division of Hematology and Haemostaeology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

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Start of study:  Nov 2016 End of recruitment:  Q2 2018 Design: This is an uncontrolled, open-label, single arm phase II pilot study. Obinutuzumab will be given i. v. at a dose of 1000 mg on days 1, 8, 15 in cycle 1 and on day 1 of each following cycles. Venetoclax will be given at 800 mg daily p. o. One cycle is 21 days. This combination treatment will be repeated for up to 3 cycles. Eligible patients will then proceed to stem cell transplantation. A 9 cycles (27 weeks) maintenance phase with obinutuzumab and venetoclax will be given in patients ineligible for transplant. Primary endpoint is to evaluate clinical activity and tolerability of a combination of obinutuzumab plus venetoclax in patients with relapsed/refractory DLBCL. Patients: 21 patients (Phase II Fleming design). A runin phase for the first 6 patients and a futility analysis after 10 patients is planned.

K60 NIVEAU Improvement of outcome in elderly patients or patients not eligible for high dose chemotherapy with aggressive non Hodgkin lymphoma in first relapse or progression by adding nivolumab to gemcitabine, oxaliplatin + rituximab in case of CD20+ Disease Ulrich Jäger1* Division of Hematology and Haemostaeology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

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Niveau: Improvement of Outcome in Elderly Patients or Patients not eligible for high-dose chemotherapy with Aggressive Non-Hodgkin Lymphoma in first Relapse or Progression by adding Nivolumab to Gemcitabine, Oxaliplatin and Rituximab in case of CD20+ Disease Start of study:  Q2 2017 (Austria) End of recruitment:  Q1 2022 Design: It is the aim to demonstrate an improvement in 1-years PFS rate from 27% to 42% (i. e. a hazard ratio of 0.66). The two-sided question will be answered with an error probability of alpha = 5% (two sided) and a power of 80%. Therefore, it will be necessary to analyze 292 B cell lymphoma patients (146 patients in each arm). Approximately 5% of patients are expected to be lost to follow-up. Therefore 310 patients with B-cell lymphoma

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Supplement 2/17 will be randomized. In parallel a maximum of 78 patients with T-cell lymphoma will be included. Primary objective:  Improvement of 1-yr PFS of (R)-GemOx in patients with progressed or relapsed aggressive NHLs not eligible for autologous nor allogeneic stem cell transplantation by nivolumab followed by nivolumab consolidation. Primary endpoint is 1-yrs progression-free suvival.

K61 AGMT_HNO-PN Supplemental parenteral nutrition for patients with locally advanced inoperable tumors of the head + neck, receiving definitive radiotherapy + Cetuximab or Cisplatin Felix Keil1* Third Medical Department, Hanusch Hospital, Vienna, Austria

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EudraCT: 2014-003833-24 Start of study:  Q1 2017 End of recruitment:  Q2 2020 Design: In patients with squamous cell carcinoma of the head and neck (SCCHN) weight loss is a relevant clinical problem during radiotherapy and might result in higher treatment related toxicity and discontinuation of a potential curative treatment. Thus we want to evaluate the efficacy of overnight parenteral nutritional (PN) support in patients with SCCHN treated with curative RTX in combination with Cetuximab or Cisplatin. Patients randomized into Arm A (control group) will -regarding nutrition- receive standard of care with or without parenteral nutrition. Patients in interventional Arm B will receive parenteral overnight nutrition with ZentroOLIMEL 5.7% (with electrolytes) starting with 15 ml/kg body weight/day. Concomitant radio-immunotherapy with Cetuximab: RTX: 70 Gy/5 fractions per week, over 7 weeks; Cetuximab 400 mg/m2 (saturation 1 week prior to RTX), Cetuximab 250 mg/m2 (during radiotherapy; in total 7x). Concomitant radio-chemotherapy with Cisplatin: RTX: 70 Gy/5 fractions per week, over 7 weeks; Cisplatin total dose of > 200 mg administered weekly (40 mg/week) or every three weeks (100 mg every three weeks) according to local standard. Primary endpoint of this study is the loss of body weight by more than 5% at the end of RTX, compared with weight at the beginning of therapy. Patients: A total of 154 patients (77 per arm) will be included.

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K62 Analyse des Österreichischen Registers für Gastrointestinale Stromatumore Michael Pötscher15, Klaus Wilthoner8, Thomas Kühr1*, Johannes Andel12, Michael Fridrik7, David Fuchs7, Friedrich Lang13, Daniela Zauner15, Herbert Stöger2, Andreas Petzer4, Richard Greil3, Günther Gastl9, Matthias Zitt11, Michael Girschikofsky5, Alois Lang10, Martina Baur14, Jörg Tschmelitsch6 Abteilung für Innere Medizin IV, Klinikum Wels-Grieskirchen, Wels, Österreich 2 Klinische Abteilung für Onkologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Graz, Österreich 3 Universitätsklinik für Innere Medizin III, Paracelsus Medizinische Privatuniversität Salzburg, Salzburg, Österreich 4 Interne I, Ordensklinikum Linz Barmherzige Schwestern, Linz, Österreich 5 I. Interne Abteilung, Ordensklinikum Linz Elisabethinen, Linz, Österreich 6 Chirurgie, Krankenhaus der Barmherzigen Brüder St. Veit, St. Veit an der Glan, Österreich 7 Klinik für Hämatologie und Onkologie, Kepler Universitätsklinikum, Med Campus III, Linz, Österreich 8 Salzkammergut-Klinikum Vöcklabruck, Vöcklabruck, Österreich 9 Universitätsklinik für Innere Medizin V (Hämatologie und Onkologie), Medizinische Universität Innsbruck, Innsbruck, Österreich 10 Interne, Landeskrankenhaus Feldkirch, Feldkirch, Österreich 11 Krankenhaus Dornbirn, Dornbirn, Österreich 12 Innere Medizin II, Landeskrankenhaus Steyr, Steyr, Österreich 13 Chirurgie, Landesklinikum Neunkirchen, Neunkirchen, Österreich 14 3. Medizinische Abteilung, Kaiser-Franz-Josef-Spital, Wien, Österreich 15 Clinical Trial Unit Wels, Wels, Österreich 1

Grundlagen: Das Österreichische GIST Register hat sich zum Ziel gesetzt, von verschiedenen Krankenanstaltenabteilungen, die Patienten mit GIST operieren, medikamentöse Therapie verabreichen oder deren Gewebe untersuchen, Daten zu sammeln und in Statistiken aufzuarbeiten. Die medizinische Datenbank soll dazu beitragen, eine epidemiologische Datenbasis zu erstellen und wertvolle Informationen zu sammeln um künftig bessere Behandlungserfolge zu erzielen. Methodik:  Insgesamt wurden Stammdaten von 371 PatientInnen in 15 Zentren erfasst und ausgewertet. Zudem erfolgte eine Nachbeobachtung des Krankheits- und Therapieverlaufs. Der Zeitraum, in dem die aufgenommenen Patienten nachbeobachtet wurden und dem die vorliegende Auswertung zugrunde liegt, beträgt zwischen 2 und 5354 Tage. Ergebnisse:  Bei ausgeglichener Geschlechts- und Altersverteilung fand sich bei der Mehrzahl der PatientInnen histologisch ein spindelzelliger GIST (63 %), gefolgt von Mischtypen (18 %) und epitheloidzelligem GIST (9 %). Gemäß Risikostratifizierung nach Miettinen/Lasota wiesen die Mehrzahl der Fälle ein niedriges bis moderates Rezidivrisiko auf. Dagegen bestand bei einem Viertel der Kollektivs ein hohes Risiko. Bei 158 aller im Register aufgenommenen Patienten erfolgte ausschließlich eine chirurgische Intervention. Primär palliative Patienten

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Supplement 2/17 wurden standardgemäß mit Imatinib behandelt. Obwohl Sunitinib als 2nd-line Therapie nach Imatinibversagen/Intoleranz als Therapie der Wahl angesehen wird, erhielten auch in dieser Therapielinie die Hälfte aller PatientInnen Imatinib, während in weiteren Therapielinien Sunitinib dominierte. Regorafenib war vor allem ab der vierten Linie eine weitere Therapieoption. Schlussfolgerungen: Das österreichische GIST Register stellt ein wertvolles Instrument dar, um Therapieentscheidungen und daraus resultierende Erfolge in der täglichen Praxis abzubilden. Es dient zudem als Basis, um innovative Substanzen im Rahmen von Studienprotokollen zu akquirieren. Eine Aktualisierung der Daten wird präsentiert.

K63 AGMT_ERCC1 Pilot study: biomarker directed treatment in metastatic colorectal cancer Alois Lang1*, Thomas Winder2 Division of Hematology and Medical Oncology, Dept. of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria 2 Department of Oncology, University Hospital Zurich, Zurich, Switzerland 1

EudraCT: 2011-003217-41 Start of study:  Aug. 2012 End of recruitment:  Q3 2017 Design:  This pilot study will investigate ERCC-1 (ExcisionRepair Cross-Complementing) as a predictive marker for treatment with platinum based regimens in mCRC patients. In a Pre-Screening phase the RAS mutation status and ERCC-1 gene expression will be assessed at the CLIA approved laboratory Response genetics in Los Angeles, California, USA. RAS wt patients will then be treated with 6 cycles of one of the following regimens chosen for optimization based on patient characteristics: Patients with ERCC-1 < 1.7 relative gene expression of ERCC-1 over β-actin (ERCC-1 low): mFOLFOX6 in combination with Cetuximab Patients with ERCC-1 gene expression > 1,7 (ERCC-1 high): FOLFIRI in combination with Cetuximab The primary objective is to assess treatment response in patients with previous untreated wt RAS advanced colorectal cancer using mFOLFOX6 or FOLFIRI and cetuximab with therapy chosen using ERCC-1 gene expression assessment.

K64 AGMT_MM1 Ixazomib in combination with thalidomide – dexamethasone in patients with refractory and/or relapsed multiple myeloma Heinz Ludwig1*, Niklas Zojer1 Wilhelminen Cancer Research Institute, c/​o 1st Medical Department, Wilhelminenspital, Vienna, Austria

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EudraCT: 2014-002749-23 Start of study:  Q2 2015 End of recruitment:  Q4 2017

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Design:  This is an open phase II, single-arm, multi-center study to evaluate progression free survival in patients receiving ixazomib in combination with thalidomide and dexamethasone (ITD) followed by an ixazomib maintenance phase of a maximum period of 12 months. The patient population will consist of adult male and female patients with multiple myeloma (MM) with relapsed and/or refractory disease after at least one prior treatment line. Therapy regime: Ixazomib: 4.0 mg on days 1, 8, 15 Thalidomide: 100 mg on days 1 –28 Dexamethasone: 20/40 mg on days 1, 8, 15 Primary endpoint is progression free survival (PFS), defined as the time from day 1 of cycle 1 to the date of first documentation of disease progression based on IMWG criteria or death due to any cause, whichever occurs first. Patients:  A total of 77 patients with at least 2 study cycles completed will be evaluated for statistical analyses in the study. Patients must be in need of therapy with a diagnosis of relapsed or refractory multiple myeloma who had at least one prior line of anti-myeloma therapy.

K65 AGMT_MM2 A randomized phase II study in transplant ineligible patients with newly diagnosed multiple myeloma (NDMM) comparing Carfilzomib + Thalidomide + Dexamethasone(KTd) with Carfilzomib + Lenalidomide + Dexamethasone(KRd) induction therapy followed by Carfilzomib (K) maintenance or control Heinz Ludwig1* Wilhelminen Cancer Research Institute, c/​o 1st Medical Department, Wilhelminenspital, Vienna, Austria

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Start of study:  Q1 2017 End of recruitment:  Q4 2018 Design:  This is a randomized, 2-arm phase-II, multi-centerstudy to evaluate the overall response rates in newly diagnosed, transplant ineligible patients receiving 9 cycles induction therapy with either KTd or KRd followed by randomization to either Carfilzomib maintenance treatment for 12 months or to observation only. Maintenance is given for 12 cycles or progression of disease or intolerance, whatever occurs first. Therapy regime (after Amendment in Q1 2017): Arm A) KTd: K: 56 mg/m2 weekly = day 1, 8, 15 of each cycle; (Note: C1D1 + 2 start with 20 mg/m2 K, D8 + 9 & 15 + 16 of C1: 27 mg/m2; C2D1, 2, 8, 9, 15 + 16: 27 mg/m2); Thalidomide 100 mg/day, day 1–28; dexamethasone: 40 mg/week, day 1, 8, 15, 22) or Arm B) KRd: K: 56 mg/m2 weekly = day 1, 8, 15 of each cycle (Note: C1 and C2 see Arm A); Lenalidomide: 25 mg/day, day 1–21; Dexamethasone: 40 mg/week–day 1, 8, 15, 22) for a maximum of 9 cycles as induction therapy. Each cycle has 28 days. Primary endpoint is to show non-inferiority with respect to response rates between KTd and KRd. Patients:  A total of 140 adult patients (≥ 18 years) with newly diagnosed symptomatic MM will be enrolled in this study. Excluded are patients who are planned for an autologous-stem-

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Supplement 2/17 cell-transplantation following induction, who are intolerable to IMiDs or Carfilzomib, are NYHA-class III/IV, or present with PS > 2, and/or CrCl < 15 ml/min, and/or PN ≥ 2.

K66 Phase III randomized trial of endurance exercise following adjuvant chemotherapy for colorectal cancer “ABCSG C08-II trial” Gudrun Piringer1*, Michael Fridrik2, Alfred Fridrik3, Josef Thaler1 Klinikum Wels-Grieskirchen, Wels, Austria Kepler Universitätsklinikum, Linz, Austria 3 General Practitioner, Sports Physician, Leonding, Austria 1 2

Background: There is consistent evidence from several observational epidemiologic studies that physical activity reduces the risk of developing colon cancer. In recent years several observational studies even showed a reduction in relapse rate, colon cancer-specific mortality and overall mortality by physical activity in patients with colon and breast cancer, but randomized trials are needed to determine a causal relationship between exercise training therapy and reduction of recurrence and improvement of overall survival. Methods:  This is an academic, prospective, two-arm randomized, multi-center phase III study. Approximately 25 sites in Austria will participate. FPI is Q1/2017 and LPO is Q1/2025. Results: 788 patients with newly diagnosed, locally advanced colorectal cancer after adjuvant chemotherapy will be randomized in a 1:1 ratio to an arm invited for a one-year endurance exercise intervention in addition to usual care (arm A) versus a control arm (arm B) receiving usual care while maintaining their habitual physical activity pattern. Primary objective is DFS and secondary objectives include evaluation of RFS, OS, physical activity endpoints, patient-reported outcomes, cost-effectiveness and -utility and safety objectives. Prior to the final analysis an advanced feasibility investigation will be performed based on the first 100 patients. Only if the recruitment and compliance of the patients are sufficient within this feasibility investigation, the study will be expanded as planned. Conclusions: This prospective study investigates whether physical activity has an influence on survival in patients with locally advanced colorectal cancer after adjuvant chemotherapy.

K67 AGMT_SAKK 41/14 ACTIVE-2 Physical activity in patients with metastatic colorectal cancer who receive palliative first line chemotherapy. A randomized controlled phase III trial

Design:  This is a multicenter randomized open label trial. Patient with histologically or cytologically confirmed colorectal carcinoma (CRC) required to start palliative first-line systemic therapy for inoperable or metastatic disease. All patients will undergo standard systemic therapy for metastatic colorectal cancer. Patients in the care-as-usual group are not actively encouraged to change their physical activity level e. g. to start a fitness program during chemotherapy. The physical exercise ACTIVE-program describes a 12-week exercise program consisting of a combination of a bi-weekly aerobic exercise (cycle ergometer) supervised by a physical therapist and a self-paced increase in physical activity during daily life using a pedometer with a daily step goal as a motivational tool. The program will be individually tailored to each patient based on the training protocol and is aimed at increasing physical activity levels and cardiorespiratory fitness. Trial objective(s):  To assess whether a structured physical activity program (PA) during palliative chemotherapy improves progression-free survival (PFS) and/or patient-reported outcomes (ESAS-r) in patients with metastatic colorectal cancer. The co-primary endpoints are PFS and patient-reported symptoms as measured by the ESAS-r (Edmonton Symptom Assessment System revised).

K68 AGMT_GASTRIC 5: Screening for human epidermal growth factor receptor 2 (HER2) positivity in patients with inoperable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer Ewald Wöll1* Department of Internal Medicine, Hospital St. Vinzenz Zams, Zams, Austria

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Design:  This Registry is a prospective, observational, multicenter research initiative. In all eligible patients HER2 testing will be performed by means of IHC and in equivocal cases (Score 2+) in addition by ISH. HER2 positive and HER2 negative samples will be sent to a central pathology where a second HER2 testing will be performed. These test results will not influence the treatment of the individual patient, but will be analyzed retrospectively. All HER2 positive patients will receive further therapy at the discretion of the principal investigator. Kind of therapy and duration will be documented. Indication:  Inoperable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer Primary objective:  Rate of HER2 positive locally advanced or metastatic gastric or GEJ cancer Secondary objectives: Comparison of HER2 results from local and central labs Safety of chemo-immunotherapy in HER2 positive patients PFS and OS after chemo-immunotherapy Recruitment:  200–300 patients

Josef Thaler1* Department of Internal Medicine IV, Klinikum WelsGrieskirchen, Wels, Austria

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EudraCT: 2015-003.733-10 Start of study:  Q3 2016 End of recruitment:  Q2 2021

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Young Investigator Meeting

Y69 TIGIT as a new target for checkpoint inhibition in chronic lymphocytic leukemia Kemal Catakovic *, Franz Gassner , Christoph Rathswohl1,2, Maria Schubert1,2, Richard Greil1,2, Tanja Nicole Hartmann1,2, Roland Geisberger1,2 1,2

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Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical Private University, Salzburg, Austria 2 Salzburg Cancer Research Institute (SCRI) – Laboratory for Immunological and Molecular Cancer Research (LIMCR), Salzburg, Austria 1

Background:  Exhausted T cells initially gain effector function, but become gradually dysfunctional due to persistent antigen stimulation. Characteristic for T cell exhaustion is the upregulation of inhibitory receptors and current therapy strategies (so called checkpoint inhibitors) aim at blocking these receptors to partially reverse T cell exhaustion and to regain anti-cancer immunity. In this study, we investigated the expression and function of the recently identified inhibitory receptor T-cell immunoreceptor with Ig and ITIM domain (TIGIT) in chronic lymphocytic leukemia (CLL) patients. Methods: TIGIT expression of T cells from whole blood CLL patients and healthy controls was cytometrically assessed. Impact of TIGIT blockade on T cell cytokine production and CLL viability was determined upon CLL cell co-culture with activated T cells. Results:  We found increased TIGIT expression on CD4+ T cells in CLL, primarily on effector memory, terminally differentiated effector memory, Th1 and regulatory T cells, and a correlation of TIGIT with PD-1 expression. Additionally, patients with advanced disease and/or under current treatment exhibited significantly higher TIGIT expression than untreated or low stage patients. Finally TIGIT blockade significantly decreased cytokine production by T cells (IL-10, IFNγ, IL-21) upon stimulation and reduced viability of CLL cells co-cultured in vitro with autologous T cells from TIGIThigh (> 50% CD4 + TIGIT + cells) but not from TIGITlow (< 50% CD4 + TIGIT + cells) patients. Conclusions: In summary, we suggest that particularly the TIGIT+ T cell compartment functions as a survival factor for CLL cells, making it an attractive therapeutic target for CLL treatment.

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The spleen microenvironment induces a CD44 variant on murine chronic lymphocytic leukemic cells promoting proliferation and disease progression in vivo Julia Christine Gutjahr1,2*, Eva Szenes1,2, Lisa Tschech1,2, Michaela Schlederer3, Simone Roos3, Tamara Girbl1,2, Richard Greil1,2, Lukas Kenner4, Veronique Orian-Rousseau5, Tanja Nicole Hartmann1,2 Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical Private University, Salzburg, Austria 2 Cancer Cluster Salzburg, Salzburg Cancer Research Institute (SCRI) – Laboratory for Immunological and Molecular Cancer Research (LIMCR), Salzburg, Austria 3 Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria 4 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 5 Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Karlsruhe, Germany 1

Background:  The survival and proliferation of chronic lymphocytic leukemia (CLL) cells depend on interactions with the microenvironment. The adhesion molecule CD44 together with its main ligand hyaluronic acid (HA) orchestrates lymphocyte activation and tissue retention. The CD44-HA binding is thereby tightly regulated in a tissue-dependent manner by alternative splicing of CD44 variants and post-translational modifications. In this study, we addressed the in vivo contribution of CD44 and its high affinity isoform to CLL progression in an organ-specific manner. Methods:  We developed a murine CLL model with a B-cell specific CD44 deficiency by crossing Tcl1 transgenic mice to CD19 Cre and CD44fl/fl mice. Immunohistochemistry of tissue sections was performed at CLL end stage. Homing and proliferation capacity was determined by competitive short-term (3 hours) and engraftment (3 days) experiments, transplanting CD44 wild type and CD44 knockout CLL cells from spleens of diseased mice into C57BL/6 mice. HA binding was determined by flow-cytometry and alterations in CD44 variant exons by reverse transcription PCR. Results: We present that B-cell specific CD44 deficiency leads to delayed CLL onset and decreased leukemic infiltration of spleen but not bone marrow. We show that the spleen microenvironment induces a particular CD44 isoform containing the variant exon 6 capable of binding HA, which favors proliferation of CLL cells within this microenvironment and accelerates disease progression in vivo. Conclusions: Splenic infiltration of CLL is particulary dependent on CD44v6, which enables the tumor cells to proliferate in this microenvironment and thereby represents a potential therapeutic target.

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Maternal Embryonic Leucine Zipper Kinase (MELK) is a key player and attractive novel drug target in proliferation associated high risk myeloma

A phase II study of ofatumumab monotherapy for extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma)

Arnold Bolomsky1, Roy Heusschen2*, Karin Schlangen3, Kathrin Schönfelder1, Joséphine Muller2, Wolfgang Schreiner3, Niklas Zojer1, Wolfgang Hilbe1, Jo Caers2, Heinz Ludwig1

Barbara Kiesewetter1*, Ortrun Neuper1, Marius E. Mayerhoefer2, Werner Dolak3, Julius Lukas4, Ingrid Simonitsch-Klupp5, Markus Raderer1

Wilhelminen Cancer Research Institute, 1st Medical Department, Wilhelminenspital, Vienna, Austria 2 Laboratory of Hematology, GIGA-I3, University of Liège, Liège, Belgium 3 Center for Medical Statistics, Informatics and Bioinformatics, Medical University of Vienna, Vienna, Austria 1

In spite of recent advances in the therapy of multiple myeloma (MM) effective treatment options are still lacking for high-risk patients. Here, we report maternal embryonic leucine zipper kinase (MELK) as a promising target in proliferation (PR)-associated high-risk MM. MELK was significantly overexpressed in the PR-associated high-risk subgroup compared to healthy-donor plasma cells and other MM subgroups (n = 551). This finding translated into poor overall survival in patients with high compared to low MELK expression in the TT2, TT3 and apex trial. Moreover, enrichment analysis confirmed the strong implications of MELK in MM cell proliferation. Targeting of MELK with OTSSP167 downregulated MELK protein levels and dose-dependently reduced MM cell viability. OTSSP167 induced apoptosis and G2/M cell cycle arrest in MM cells along with downregulation of central MM genes (IRF4, MCL-1, CCNB1, AURKA, PLK-1). Importantly, OTSSP167 impaired clonogenic growth of MM cells and maintained its activity in the presence of stromal cells. In vivo, OTSSP167 dosedependently reduced bone marrow infiltration and serum paraprotein levels in the 5TGM.1 murine model of MM. MELK inhibition also prevented bone disease in these mice, as assessed by micro-computed tomography, and direct effects on bone cells have been observed. Finally, we revealed a strong link between MELK and other PR-associated high-risk genes (PLK-1, FOXM1, EZH2, DEPDC1) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature associated with high-risk disease and that targeting of MELK represents an attractive treatment approach for PR-subgroup patients.

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Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 2 Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria 4 Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria 5 Institute of Pathology, Medical University of Vienna, Vienna, Austria 1

Background: Based on data generated in other B-cell malignancies ofatumumab, a second generation anti-CD20 antibody, appears to be an attractive agent for the treatment of MALT lymphoma. Methods:  O-MA1 was a single center phase II study evaluating the capacity and safety of ofatumumab to induce objective responses in patients with advanced MALT lymphoma (in case of gastric MALT lymphoma with demonstrated refractoriness to HP-eradication). Ofatumumab was given at four weekly doses (1000 mg i. v.) followed by four doses at two-month intervals, starting at week 8. These are our final results. Results:  According to protocol a total of 16 patients were recruited (median age 69 years). 31% (5/16) of patients had primary gastric MALT lymphoma while the remaining 69% (11/16) presented with extragastric manifestations. 75% (12/16) had localized lymphoma and four patients disseminated disease. The overall response rate to treatment with ofatumumab was 81% (13/16) with the median time to best response being 5.5 months. In detail, 50% (8/16) achieved a complete remission, 31% (5/16) a partial remission and 19% (3/16) disease stabilization as best response. However, one patient with gastric lymphoma and complete remission at second restaging had a relapse at final assessment but ongoing complete remission during further follow-up. Tolerability was excellent accept low grade infusion reactions occurring in 86% (14/16). At a median follow-up time of 25 months one patient has relapsed, suggesting durable remissions in the majority of patients. Conclusions:  This pilot trial shows clearly that ofatumumab is active and safe for the treatment of MALT lymphoma.

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Y73 A novel long non-coding RNA, SCA-RNA1, is associated with aggressive biological behaviour and poor prognosis in breast cancer patients Martin Pichler1*, Stefanie Cerk1, Daniela Schwarzenbacher1, Armin Gerger1, Jan Basri Adiprasito1, Verena Stiegelbauer1, Gerald Höfler2, Herbert Stöger1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background:  In recent years, long non-coding RNAs (lncRNAs) have gained tremendous attention due to their involvement in fundamental cellular processes. Numerous studies have demonstrated that lncRNAs are likely to play a functional role in breast cancer but data about their involvement in breast cancer stem cells are rare. Methods:  We used a commonly used breast cancer stem cell model (“mammospheres”) to profile the expression of thousands of lncRNAs by microarray in different breast cancer cell lines. Patient cohorts (n > 1000), gene knock-down techniques, lenti-viral-mediated stable overexpression techniques, RNAseq and xenografts were used to further characterize biological and molecular role of the novel identified lncRNA candidates. Results:  In this study, we identified one novel lncRNA as up-regulated in putative breast cancer stem cells (which we accordingly called stem cell-associated RNA 1 (SCA-RNA1). High expression levels of SCA-RNA1 were associated with poor survival (p < 0.05) in two independent patient cohorts. Knockdown experiments of SCA-RNA1 led to significantly reduced cellular proliferation, G1-phase cell cycle arrest, anchorageindependent growth and mammosphere formation in independent breast cancer cell lines and tumour growth in vivo. Gene expression profiling indicates several cancer-associated pathways including cell cycle and stem cell associated genes as influenced by SCA-RNA1 expression. Conclusions: In conclusion, these findings suggest that SCA-RNA1 is involved in breast cancer progression and might serve as a potential prognostic marker in breast cancer patients.

Y74 Benefit of adjuvant radiotherapy for local control, distant metastasis, and survival outcomes in patients with localized soft tissue sarcoma

Department of Orthopedic Surgery, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria 4 Institute of Pathology, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria 5 Research Unit Genetic Epidemiology and Pharmacogenetics, Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 6 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer, Houston, USA 3

Background:  Adjuvant radiotherapy (ARTX) reduces local recurrence (LR) risk in patients with localized soft-tissuesarcoma (STS). However, the magnitude of benefit of ARTX regarding local control, and its impact on non-local treatment outcomes such as distant metastasis (DM) and overall survival (OS) are ill-defined. Here, we quantify the contribution of ARTX to long-term outcomes in STS patients after surgical resection. Methods: We studied 443 STS patients who underwent curative surgery at a single academic center. Two-hundred-sixty (58.7%) patients received ARTX. After median follow-up of 5.5 years, we observed 41 (9.3%) local recurrences, 74 (16.7%) DM, 64 (14.5%) STS-related deaths, and 59 (13.3%) deaths from other causes. An inverse-probability-of-treatment-weighting (IPTW) analysis was implemented to account for imbalances in prognostic variables between adjuvant treatment groups. Results: In naïve analysis, ARTX was not associated with improved recurrence-free survival (Hazard ratio (HR) = 0.99, 95%CI: 0.72–1.36, p = 0.96). However, after IPTW, ARTX was associated with a 43% relative risk reduction (RRR) of recurrence or death (HR = 0.57, 95%CI: 0.37–0.89, p = 0.01). This benefit was driven by a strong reduction in the risk of local recurrence (HR = 0.46, 95%CI: 0.23–0.89, p = 0.02), whereas relative risks of DM (HR = 0.71, 95%CI: 0.43–1.19, p = 0.20) and OS (HR = 0.79, 95%CI: 0.52–1.20, p = 0.27) only non-significantly favored ARTX. In subgroup analyses, patients with G3 tumors undergoing ARTX appeared to have not only a benefit regarding local recurrence, but also regarding OS (HR = 0.54, 95%CI: 0.36–0.83, p = 0.005). Conclusions:  In this large cohort of STS-patients, ARTX was associated with a 54% RRR of LR. In high-grade STS-patients, ARTX may not only improve local control but also confer an OS benefit. No consistent association between ARTX and a lower risk of DM was observed.

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latest news from international oncology congresses see: http://www.springermedizin.at/ memo-inoncology

Jakob Michael Riedl1*, Florian Posch1, Carmen Döller2, Richard Partl2, Lukas Leitner3, Bernadette Liegl-Atzwanger4, Michael Stotz1, Maria Anna Smolle1, Angelika Bezan1, Martin Pichler1,6, Armin Gerger1,5, Herbert Stöger1, Andreas Leithner3, Joanna Szkandera1 Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria 2 Department of Therapeutic Radiology and Oncology, Medical University of Graz, Graz, Austria 1

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