Supplement 1/18 memo https://​doi.org/​10.1007/​s12254-​018-​0401-5 © Springer-Verlag GmbH Austria, part of Springer Nature 2018

Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology Frühjahrstagung 2018 der Österreichischen Gesellschaft für Hämatologie und Medizinische Onkologie und der AHOP – Arbeitsgemeinschaft hämatologischer und onkologischer Pflegepersonen in Österreich Villach, 19.–21. April 2018

Tagungspräsident: Prim. Univ.-Prof. Dr. Wolfgang Eisterer Tagungssekretariat: DDr. Manfred Kanatschnig Dr. Ursula Pluschnig Abteilung für Hämatologie und Internistische Onkologie Landeskrankenanstalten – Betriebsgesellschaft Klinikum Klagenfurt am Wörthersee

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Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology

 

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Poster Hämatologie

P01 Quantification of iron overload in Myelodysplastic Syndromes by Magnetic Resonance Imaging Marie-Theres Astl*1, Reinhard Stauder1, Benjamin Henninger2, Heinz Zoller3, Michaela Plaikner2, Karin Koinig1, Bojana Borjan1 Department of Internal Medicine V (Haematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria 3 Department of Internal Medicine I (Gastroenterology, Hepatology and Endocrinology), Medical University of Innsbruck, Innsbruck, Austria 1

Background:  Iron overload represents an adverse prognosticator in Myelodysplastic Syndromes (MDS). Aim of this study was to implement Magnetic Resonance Imaging (MRI) in MDS to assess iron burden. Methods:  We included in total 14 patients: MDS (11), AML (2) and CMML (1); male/female: ten/four; median age 70 years (range: 55–79 yrs). An MRI (1.5 T, Siemens AvantoFit, Siemens Healthineers, Erlangen, Germany) using a multi-echo gradient echo sequence with fat-saturation was applied. R2*/T2* parameter maps were analyzed using manually placed regions of interest. Results:  Raised R2*values (as defined >70 1/s in liver and >45 1/s in pancreas/spleen), were detected in the liver in nine, in the spleen in seven and in the pancreas in three out of 14 patients. According to the EASL International Consensus Conference on Haemochromatosis, iron overload in liver was defined as minimal in five, modest in two and severe in two, whereas no iron overload was found in five patients. In contrast, altered T2*(< 20 ms) values in the heart were not observed in six patients analyzed. A relevant proportion of patients were characterized by a high transfusion need (range 3–78 RBCs in the year before analysis), whereas seven patients had not received RBCs at all. Even in this “never-transfused” group two had elevated liver R2*values, one showed elevated pancreas R2* and two had elevated R2* spleen values. Conclusions: MRI is feasible in MDS and detects iron overload mainly in liver and spleen in a relevant proportion of patients. Iron overload in MDS represents a challenge, even in non-transfused patients.

P02 MiR199a and miR497 in diffuse large B-cell lymphoma (DLBCL) Timna Bergmann*1, Beata Pursche1, Alexander Deutsch1, Peter Neumeister1, Katharina Prochazka1 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Background: High miR199a and miR497 expression are associated with better overall survival of DLBCL patients. The Die mit Sternchen (*) markierten Autoren sind die korrespondierenden Autoren.

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knowledge of their targets is limited. Therefore, we performed gene expression analysis of miR199a or miR497 transfected lymphoma-cells and identified 33 genes to be down-regulated by miR199a and/or miR497 over-expression and possess a potential binding site. The aim of this study was to validate the identified down-regulation of these genes in lymphoma-cells overexpressing miR199a or miR497. Methods: RT-qPCR analysis of these 33 genes was performed on samples of 2 lymphoma-cell-lines (U2932 and Karpas422) transfected with miR199a or miR497 mimics and nontargeting siRNA controls at different time points. Results: The overexpression of miR199a correlated negatively to the expression levels of 13 genes (LAPTM5, RNF207, ZNF284, ZNF329, ZNF440, ZNF831, RHOBTB3, SGCB, PACSIN1, SMPD3, CCL3, CCL4 and TNF) and led to a significant downregulation of 7 genes (GANC, ZNF284, RAP1GAP2, TNFRSF21, PACSIN1, KLF10 and RGS1). Among those, 5 genes (CCL3, CCL4, TNF, KLF10 and RGS1) were identified as genes of the Nf-κB pathway. In miR497 transfected samples, 9 genes (ZNF329, ZNF594, ZNF284, RAP1GAP2, NABP1, PRNP, PLXNA1, RGS1 and SMPD3) showed negative correlations between target gene and miRNA expression levels, and two genes (ZNF440 and PACSIN1) were significantly downregulated. Conclusions:  Our results indicate that miR199a functions as a negative regulator of Nf-κB in aggressive B cell lymphomas. Furthermore, PACSIN1, downregulated in miR199a transfected samples, might be implicated in the observed better overall survival of DLBCL patients, reconsidering its function as positive upstream regulator of the PI3K/AKT/mTOR pathway.

P03 Hairy cell leukemia – retrospective update on epidemiology and clinical outcome in Innsbruck, Austria Jan-Paul Bohn*1, David Wanner1, Günther Gastl1, Michael Steurer1 Department of Internal Medicine V (Haematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria

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Background:  Hairy cell leukemia (HCL) is a rare, but distinct indolent hematologic malignancy. Here, we present an update on the epidemiology and clinical outcome of all HCLpatients treated in Innsbruck from 1990 to 2018. Methods:  91 patients were identified and their outcome was evaluated retrospectively. Results:  82.4% were males and the median age was 56 years (range: 25–84). 83 patients (91.2%) received first-line therapy with cladribine being the agent of choice in 49/83 (59.0%) cases. Detailed assessment of response was available in 43/49 (87.8%) patients (OR 100%, CR 81.4%, PR 18.6%). With a median followup of 103 months (range: 0–312 months), median PFS has not been reached and relapse rate was 18.4%. All nine relapsing patients received another course of cladribine after a median treatment-free survival of 56 months (range: 2–144 months). Detailed assessment of response was available in 8/9 (88.9%) patients (OR 100%, CR 87.5%, PR 12.5%). With a median followup of 42.5 months (range: 17–294 months), second-line median PFS has not been reached as well. Other first-line options included interferon-α (31.3%) with a median PFS of 30 months (n = 19) and splenectomy (8.4%), both of which were chosen before 1993. With a median follow-up of 143 months (range:

Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology

Supplement 1/18 0–498 months), median overall-survival of the whole cohort has not been reached. Conclusions: Cladribine achieves high CR rates in both treatment-naive and pretreated patients. However, relapse is common and duration of response declines with each successive retreatment. Nevertheless, overall-survival in this unselected HCL-cohort is excellent.

P04 Preclinical evaluation of the first-in-class BMI1 inhibitor PTC028 in multiple myeloma Arnold Bolomsky*1, Roy Heusschen2, Kathrin Stangelberger1, Josèphine Muller2, Niklas Zojer1, Wolfgang Hilbe1, Jo Caers2, Heinz Ludwig1 Wilhelminen Cancer Research Institute, Department of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria 2 Laboratory of Hematology, University of Liege, Liege, Belgium 1

Background:  The polycomb group protein BMI1 represents a prominent intrinsic driver of multiple myeloma (MM) without a suitable clinical grade inhibitor. Here, we explored the antimyeloma efficacy of the first-in-class BMI1 protein inhibitor PTC028. Methods:  The anti-MM efficacy of PTC028 (kindly provided by PTC Therapeutics Inc.) was studied in vitro using human MM cell lines (HMCLs). Mechanistic studies were performed using quantitative-PCR, Western Blot and flow cytometry. Confirmatory studies used lentiviral transduction of BMI1 overexpression/knockout plasmids. Results: PTC028 induced a time-dependent reduction of BMI1 protein levels and demonstrated potent activity in all HMCLs tested (median IC50: 39 nM, range: 11–102 nM). This activity persisted in the presence of BMSCs and in proteasomeinhibitor resistant HMCLs. We also observed a significant correlation between IC50 values and the reduction of BMI1 protein levels in HMCLs (R = 0.86, P = 0.01). Mechanistically, PTC028 elicited an accumulation of cells in the G2/M phase of the cell cycle and induction of apoptosis (verified by the presence of cleaved-PARP and depolarization of the mitochondrial membrane). PTC028 induced rapid upregulation of mitosis-associated genes (CCNB1,AURKA,BIRC5) indicating mitotic arrest which was accompanied by MCL1 downregulation. Intriguingly, PTC028 treatment also impaired protein expression of the high-risk genes FOXM1 and MYC in concert with reduced AKT and MYC signaling activity. Conclusions:  We observed potent preclinical activity of the first-in-class BMI1 inhibitor PTC028. Moreover, our data point to significant impact on a currently not targetable high-risk network consisting of BMI1, MYC and FOXM1. These results strongly support further evaluation of PTC028 in the clinical setting.

P05 Distinct expression profiles of chemokine receptors in follicular lymphoma Alexander Deutsch*1, Stefanie Winkler1, Julia Unterluggauer2, Karoline Fechter1, Christine Beham-Schmid2, Katharina Prochazka1, Peter Neumeister1 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background: Chemokine receptors (CRs) mediate migration and activation of lymphocytes through binding of their ligands. Recent studies revealed important contributions of CRs to the development, progression, and dissemination of lymphoid malignancies. Because the knowledge on the CR expression profile in follicular lymphoma (FL) is limited, we aimed to comprehensively study the expression pattern of CRs in FLs. Methods:  Therefore, we performed an expression analysis of 17 well characterized CRs (CCR1-CCR10, CXCR1-CXCR5, XCR1 and CX3CR1) on mRNA level by using real-time RT-PCR on human tissue of FLs (n = 71) and non-neoplastic tonsils (n = 5) as controls. Results:  The chemokine receptor expression profile of FL differed substantially from those of non-neoplastic tonsils, with a higher expression of CCR2 (70 fold, p = 0.005), CCR4 (10 fold, p = 0.005), CCR9 (23 fold, p = 0.044), CXCR3 (113 fold, p = 0.043) and XCR1 (67 fold, p = 0.028) in FL. In contrast, expression of CCR5, CCR8 and CXCR2 were only detected in the minority of FL (n < 10) and control specimens (n < 2). By comparing the CR pattern to clinical data of FL patients, we detected that high expression of CCR7 and CXCR4 were associated with worse cancer specific survival (p < 0.001 for CCR7 and p = 0.054 for CXCR4) whereas high CCR4, CXCR1 and CX3CR1 expression were associated with a better clinical course. Conclusions:  Overall, our results indicate that a distinct CR expression pattern is implicated in the development of FL and that several receptors might serve as useful clinical prognostic marker and/represent a potential novel therapeutic target for lymphoma therapy.

P06 Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1 Leo Edlinger*1, Angelika Berger-Becvar1, Ingeborg Menzl1, Gregor Hörmann2, Georg Greiner2, Eva Grundschober1, Zsuzsanna Bago-Horvath3, Wael Al-Zoughbi4, Gerald Höfler4, Christine Brostjan5, Lars Gille1, Richard Moriggl6, Andreas Spittler5, Veronika Sexl1, Andrea Hoelbl-Kovacic1 Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria 2 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 3 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 1

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Supplement 1/18 Institute of Pathology, Medical University of Graz, Graz, Austria 5 Department of Surgery, Medical University of Vienna, Vienna, Austria 6 Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria 4

Background: The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways. Their activity is increased in many human cancers and associated with poor prognosis. In solid tumours PAK1 and PAK4 are the main isoforms deregulated. Here we show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1+ haematopoietic malignancy. Methods: Knockdown of PAK1 and PAK2 was performed in human BCR/ABL1+ cells, and cell cycle differences were assessed. Medium conditioned by shPAK1- or shPAK2-expressing leukaemic cells was transferred onto HUVEC cells to perform scratch assays. Furthermore, isolated exosomes were added onto HUVEC cells for scratch assays. We evaluated the numbers of formed colonies of shPAK1- or shPAK2-expressing leukaemic cells grown in methylcellulose. Finally, we injected the cells subcutaneoulsy into immunocompromised mice to monitor tumour growth. Results:  In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2- but not shPAK1-expressing leukaemic cells interferes with endothelial cell growth. Leukaemic cells produce exosomes containing PAK2, and transfer of isolated exosomes supports endothelial cell proliferation. Moreover, leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2-deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. Conclusions: PAK2 might be the critical isoform in leukaemic cells by controlling tumour growth via vascularization mediated by exosomes transferred to endothelial cells and remodelling of the extracellular matrix. This finding suggests that PAK2 represents a promising target for the treatment of haematological diseases.

P07 Myc-driven lymphomagenesis together with loss of Nr4a1 causes increased dissemination potential and impacts the composition of immune cells in the tumor microenvironment Karoline Fechter*1, Katrin Pansy1, Katharina Prochazka1, Hildegard Greinix1, Christine Beham-Schmid2, Peter Neumeister1, Alexander Deutsch1 Division of Hematology, Department of Internal Medicine, Medical University Graz, Graz, Austria 2 Department of Hematopathology, Institute of Pathology, Medical University Graz, Graz, Austria 1

Background: Low expression of the transcription factor NR4A1 is associated with poor cancer specific survival in aggressive lymphomas. In this study we aimed to better dissect the role of Nr4a1 loss in lymphoma development by using a Myc-driven mouse model of lymphomagenesis. Methods:  Survival and tumor formation of EµMycNr4a1+/+ and EµMycNr4a1-/- was monitored. Tumors were subjected to RNASeq and results validated by RQ-PCR. Moreover, apoptosis and B cell development in EµMyc and wt mice with and

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without Nr4a1 loss were determined at the premalignant stage. Last, tumors derived from both mouse cohorts were injected i. v. into wt recipients. Survival as well as dissemination potential, immune cell composition and gene expression of the derived tumors were determined and compared to the original cohort. Results:  EµMyc Nr4a1-/- mice showed decreased survival and accelerated tumor development together with reduced apoptosis at the premalignant stage. RNASeq and RQ-PCR revealed an upregulation of immunoregulatory genes in EµMyc Nr4a1-/- derived tumors. Furthermore, these tumors engrafted faster, showed more dissemination potential into bone marrow and spleen and despite more T-cell infiltrates a higher expression of PD-1 and TIM3 on RNA and protein level comparable to the transplanted tumors. Conclusions:  Our results underpin the influence of Nr4a1 loss on tumor formation and survival in a Myc-driven model of lymphomagenesis. Importantly, Nr4a1 impacts cell death even ahead of malignant transformation. Additionally, Nr4a1 loss leads to an altered tumor microenvironment, thereby facilitating tumor growth. Collectively, these data demonstrate the tumor suppressive function of Nr4a1 in aggressive lymphomas.

P08 Intensive multidisciplinary treatment including allogenic stem cell transplantation: a road to cure in mast cell sarcoma? Karoline Gleixner*1, Werner Rabitsch2, Harald Herrmann3, Walter Klepetko4, Gregor Hörmann5, Christoph Kornauth6, Peter Valent1,7, Wolfgang Sperr1 Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria 2 Department of Medicine I, Medical University of Vienna, Vienna, Austria 3 Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria 4 Department of Surgery, Medical University of Vienna, Vienna, Austria 5 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 6 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 7 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria 1

Mast cell sarcoma (MCS) is as a rare, life-threatening mast cell (MC) neoplasm: to the best of our knowledge, less than 25 cases were reported in the literature. Early stages of MCS are characterized by destructive organ infiltration by immature MC. In most cases, progression to MC-leukemia has been reported. So far, no standard treatment is available. Reported treatmentattempts include surgery, radiotherapy, and cytoreductive therapy. However, all these approaches failed to induce durable responses, resulting in a very poor outcome. Multidisciplinary treatment approaches including allogenic stem cell transplantation (alloSCT) may represent a more promising option. We report on a 30-year old Caucasian woman with a highly aggressive MCS of the mediastinum infiltrating in the lung. After surgical de-bulking, PET-CT revealed a residual tumor mass. To achieve complete remission (CR), two cycles of chemotherapy with cladribine and ARA-C were administered, followed by extended field irradiation (total dose: 30 Gy). This therapy resulted in CR as evidenced by PET-CT. Prior to alloSCT, a bridging

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Supplement 1/18 treatment with the multikinase-inhibitor midostaurin was applied. Six months after diagnosis, alloSCT was performed with CD34+ cells obtained from a sibling donor. From day 130 after alloSCT, midostaurin (50 mg/day) was administered as maintenance-therapy. After a follow-up period of two years, the patient still is in CR, without signs of GvHD. Together, this is the first MCS-patient who could be debulked and underwent alloSCT successfully. Whether our multidisciplinary intensive treatment approach can lead to cure in our patient and/or other MCS-patients remains to be determined in forthcoming studies.

P09 Case report: Pancytopenia and hepatosplenomegaly in a 31-year old male Philipp Hockl*1, Kristina Dax1, Avida Hayat-Khayyati1, Rosemarie Greul1 Kepler Universitätsklinikum, Linz, Austria

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Wilson’s disease is an autosomal recessive inherited disease, resulting in copper deposition in all organs and affecting primarily the liver and the brain. Clinical presentation of patients can be ambiguous and initial misdiagnosis is not unusual. This case report describes a 31-year old male patient who was transferred to our haemato-oncological department with pancytopenia and suspected malignant liver disease. Further anamnesis revealed a history of progressive muscle weakness, ataxia and gait disturbance over the past 4 years. These findings had been interpreted before as dissociative movement disorder and adaptive disorder and psychiatric medication had been started. Consecutive diagnostic investigations showed no evidence of an underlying hematologic disease, despite of a proven pancytopenia and hepatosplenomegaly. Elevated liver enzymes and the history of progressive neuropsychiatric symptoms raised our awareness for further diagnostic beyond hematologic malignancies. Finally an ophthalmological slit-lamp exploration revealed a Kayser-Fleischer ring which led to the suspected diagnosis of Wilson’s disease, which was later confirmed by liver biopsy. Chelating therapy with D-penicillamine was started and over the next months the majority of his symptoms resolved.

P10 Characterization of myeloid-derived suppressor cells (MDSCs) in TKI-treated CML Benedikt Hofer*1, Sieghart Sopper1, Günther Gastl1, Dominik Wolf2, Satu Mustjoki3, Kimmo Porkka3, Jeroen Janssen4, Gert Ossenkoppele4 Department of Internal Medicine V (Haematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Medical Clinic III for Oncology, Hematology, Immunoncology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany 3 Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland 4 Vrije Universiteit Medical Center Amsterdam, Amsterdam, Netherlands 1

Background:  Evidence accumulates that immune mechanisms influence treatment response in CML patients during TKI

therapy. Myeloid populations such as Myeloid-derived suppressor cells (MDSCs) are important mediators of immunity but their role in CML has not been investigated. Therefore, we comprehensively characterized these population in 52 chronic phase CML patients. Methods:  Whole blood from before, and at months 6 and 12 of therapy with nilotinib was phenotyped by 9-color flow cytometry. Soluble factors in plasma were measured by immunoassays. Results:  The proportion of monocytes was lower (p < 0.0001) but the absolute number was higher (p < 0.0001) before compared to after initiation of therapy. Both, the CD16+CD14hi “intermediate” monocytes (p < 0.01) and the CD56+ monocytes (p < 0.0001) were higher at baseline. Granulocytic (p < 0.0001) and early stage MDSC (p < 0.0001), defined according to recent protocols were strongly increased before therapy but, after more detailed flow cytometric analysis, turned out to be identical with neutrophils and basophils, respectively. Definition of monocytic MDSC is based on low HLA-DR expression of CD14+ cells. We therefore quantified HLA-DR expression levels, which increased (p < 0.05) after initiation of therapy. Interestingly, HLA-DR expression before therapy negatively correlated with BCR-ABLIS levels throughout therapy (p < 0.05). Cumulative response rates for MMR were higher in patients with high HLA-DR expression (p < 0.001). HLA-DR expression negatively correlated with plasma levels of sCD62L, a predictive marker we had recently defined, but not with Arginase, reportedly a key enzyme for MDSC function. Conclusions: Our study demonstrates that myeloid cell populations are altered in CML patients and that these cells may influence the individual response to TKI therapy.

P11 Diffus großzellige B-Zell-Lymphome bei alten Patientinnen Karl Jochen Krenosz1, David Kiesl*1, Michael Fridrik1 1

Kepler Universitätsklinikum, Linz, Österreich

Grundlagen: Es gibt nur wenig Information über die Behandlungsstrategie von älteren Patienten mit Diffus großzelligem B-Zell Lymphom (DLBCL). Es ist derzeit nicht klar, ob eine CHOP-basierte Chemo-/Immuntherapie einen Vorteil gegenüber der weniger toxischen Bendamustin-basierten Therapie bringt. Methodik:  Wir führten eine retrospektive Analyse von Patienten über 70  Jahre mit neu diagnostiziertem DLBCL im Behandlungszeitraum vom Jänner 2002 bis Juli 2017 in unserer Klinik durch. Wir berechneten Mediane, 95 %-Konfidenzintervalle und Standardabweichungen für skalierte Variablen. Unterschiede zwischen den Gruppen wurden mit den chiQuadrat-Test, ANOVA und log-rank-Test (Überlebenszeiten) berechnet. Signifikanz wurde bei p < 0,05 angenommen. Ergebnisse: Eingeschlossen wurden insgesamt 39 PatientInnen mit einem medianen Alter von 77 Jahren. Alle Patienten erhielten Rituximab. Eine CHOP-basierte Chemotherapie erhielten 34 PatientInnen (88 %), Bendamustin 5 PatientInnen (12 %). Bei den unter 80-Jährigen war dies bei 92 % vs. 8 %, bei den über 80-Jährigen bei 79 % vs. 21 %. Die Ansprechrate lag bei 84 % bei den unter 80-Jährigen, 85 % bei den über 80-Jährigen. Eine komplette Remission erzielten 64 % der unter 80-Jährigen und 50 % der über 80-Jährigen. Das mediane progressionsfreie Überleben war 15 Monate (95 % CI, 4–25). Das mediane Gesamtüberleben bei 79 (95 % CI,

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Supplement 1/18 32–125). PatientInnen, die eine CHOP-basierte Chemotherapie erhalten hatten, hatten einen signifikanten Vorteil gegenüber jenen, die mit Bendamustin behandelt worden waren (97,8 vs. 9,0 Monate, p = 0,013). Alter (97,7 vs. 69,4 Monate, p = 0,984) und Geschlecht (39,0 vs. 31,8 Monate, p = 0,540). waren keine Einflussfaktoren. Schlussfolgerungen: Eine CHOP-basierte Chemotherapie ist auch bis in hohe Alter eine sehr gute Behandlungsmöglichkeit. Eine Reduktion auf eine Bendamustin-basierte Therapie ist nicht zu empfehlen.

P12 Pomalidomide and dexamethasone in relapsed/ refractory multiple myeloma: Real-world data from an ongoing, multi-center non-interventional study in Austria Daniel Lechner*1, Richard Greil2, Bernd Hartmann3, Heinz Gisslinger4, Leopold Öhler5, Johannes Andel6, Hildegard Greinix7, Siegfried Sormann7, Hermine Agis8 Department of Hematology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria 2 IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Private Medical University, Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria 3 Department of Internal Medicine, Landeskrankenhaus Feldkirch, Austria 4 Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 5 Internal Medicine I, Department of Oncology, St. Josef Hospital, Vienna, Austria 6 Department of Internal Medicine II, Landeskrankenhaus Steyr, Austria 7 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 8 Division of Oncology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria 1

Background: Pomalidomide, in combination with dexamethasone, is approved for the treatment of relapsed/refractory multiple myeloma (rrMM). This ongoing national, multi-center, non-interventional study was initiated to characterize the practical clinical use of pomalidomide in Austria, with strong emphasis on tolerability and efficacy of this immunomodulating agent. Methods:  Patients with confirmed rrMM meeting the eligibility criteria for the treatment with pomalidomide and dexamethasone according to the summary of product characteristics were enrolled. Patients were followed until progression or intolerability. Clinical endpoints were: overall response rate (ORR), progression-free-survival (PFS), duration of response, and incidence of adverse events. Fifty-eight patients from 8 centers in Austria were included from 09/2014. An interim analysis of the uncleaned data documented until 11/2017 will be shown. Results:  The median age of patients enrolled was 70 years [range: 45–90]; the average number of treatments received prior to pomalidomide was 4. Twenty-two patients (37.9%) were still under treatment at data cut-off. Median PFS was 12.03 months. The overall response rate (partial response or better) to pomalidomide treatment was 45%.

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Safety information is available for 40 out of 58 patients (69%), in total 172 adverse events were documented. Of those, 29 events (16.9%) required hospitalization, three events were fatal (1.7%, not drug related). Remaining adverse events were nonserious (n = 138, 80.2%). Conclusions:  These real word data collected in Austria confirm results seen in clinical trials and endorse the use of pomalidomide as a therapeutic option for the treatment of rrMM.

P13 Loss of Nr4a1 causes up-regulation of Nr4a3 and partially over-expression of p53 in Myc-driven lymphomagenesis Katrin Pansy*1, Karoline Fechter1, Hildegard Greinix1, Katharina Prochazka1, Peter Neumeister1, Peter Neumeister1, Alexander Deutsch1 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Background:  NR4A1, as well as NR4A3 are down-regulated in aggressive B cell lymphomas. In the EµMyc mouse-model, loss of Nr4a1 resulted in a decreased survival and accelerated tumor development. For malignant transformation the EµMyc mouse model needs a disruption of the p19Arf-Mdm2-p53 pathway and/or over-expression of Bcl-2, Mcl-1 or Bcl-xL as a second hit. The aim of this study was to investigate the function of Nr4a1 in Myc-driven lymphomagenesis. In detail, we investigated Nr4a1 and Nr4a3 expression in normal B-cell development in comparison to tumors derived from EµMycNr4a1-/and EµMycNr4a1+/+-mice and performed second hit analysis. Methods:  We determined Nr4a1 and Nr4a3 expression levels in premalignant und malignant EµMyc mice and in non-neoplastic mice with and without Nr4a1 loss by using RQ PCR. Further, second hit analysis was investigated by means of Western blot and results compared between EµMycNr4a1-/- and EµMycNr4a1+/+. Results:  Nr4a1 expression was down-regulated in premalignant EµMyc mice and in tumors derived from EµMyc mice. Loss of Nr4a1 resulted in upregulation of Nr4a3 in premalignant and malignant B cells of premalignant and malignant EµMyc mice. Additionally, we found that p53 is less frequently over-expressed in EµMycNr4a1-/- tumors compared to EµMycNr4a1+/+ tumors. Conclusions: Our results indicate that over-expression of c-Myc results in a down-regulation of Nr4a1 and that loss of Nr4a1 causes Nr4a3 over-expression suggesting a compensational function. Furthermore, our second analysis demonstrated that disruption of the p53 pathway might be less important for malignant transformation in EµMycNr4a1-/- mice indicating the tumor suppressive properties of Nr4a1.

P14 Daratumumab beim multiplen Myelom – die initiale Patientenserie am Wilhelminenspital Wien Branka Petricevic1, Ercan Müldür1, Sabine Burger1, Wolfgang Hilbe1, Heinz Ludwig1, Niklas Zojer*1 1

Wilhelminenspital, Wien, Österreich

Grundlagen: Daratumumab ist ein humaner monoklonaler IgG1k Antikörper, der an das CD38 Protein bindet und bei

Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology

Supplement 1/18 rezidiviertem oder refraktärem multiplem Myelom angewandt wird. Methodik:  Hier präsentieren wir unsere initiale Erfahrungen mit Daratumumab. Seit dem Jahr 2016 wurden am Wilhelminenspital Wien vierzehn Patienten mit relapsiertem/ Therapie refraktärem multiplem Myelom mit Daratumumab behandelt. Das Durchschnittsalter der Patienten lag bei 62 Jahren, bei 50 % der Patienten war eine „high risk“ Zytogenetik evident. Daratumumab wurde im Durchschnitt nach 5 Therapielinien angewandt (2 bis 8 Linien), in 57 % (n = 8) der Patienten als Monotherapie. Bei den anderen 43 % (n = 6) der Patienten erfolgte eine Kombination mit Pomalidomid (3), Carfilzomib (1), Pomalidomid/Cyclophosphamid/Dexamethason (1) oder Bendamustin (1). Ergebnisse:  Die Ansprechrate (alle Patienten) lag bei 50 % (PR, VGPR), die Rate des klinischen Benefits bei 64 % (SD, PR, VGPR). Drei Patienten hatten eine VGPR, vier Patienten eine partielle Remission und zwei eine stabile Erkrankung. Daratumumab wurde im Durchschnitt über 5,3 Monate appliziert. Die Dauer des Ansprechens lag zwischen 3 und 17 Monaten. Primäre Refraktärität auf Therapie wurde bei einem Patienten mit Plasmazell-Leukämie, zwei Patienten nach sieben Therapielinien und einem Patienten mit extramedullärer Erkrankung verzeichnet. Die Therapie musste bei einer Patientin aufgrund einer schweren Infusionsreaktion Grad IV dauerhaft beendet werden, sonst waren die Infusionsreaktionen mäßiger Ausprägung und mit entsprechender Begleittherapie gut beherrschbar. Schlussfolgerungen: Unsere initialen Erfahrungen mit Daratumumab liegen im aus der Literatur entwickelten Erwartungshorizont. Bis dato wurden an unserem Zentrum vor allem stärker vorbehandelte Patienten mit Daratumumab behandelt und davon ein relativ hoher Anteil in einer „off label“ Kombinationstherapie.

P15 NETosis in myeloproliferative neoplasms (MPNs) Stefan Schmidt*1, David Wanner1, Walpurga Weyrer1, Günther Gastl1, Clemens Feistritzer1 Department of Internal Medicine V (Haematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria

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Background: NETosis was first identified as an innate immunity mechanism by which neutrophil granulocytes are activated and produce extracelluar net-like structures (Neutrophil Extracellular Traps, NET) which are composed of DNA which function as scaffolds coated with citrullinated histones, proteases and cytosolic proteins (e. g. MPO). Beyond its implication into immunity NETs facilitate thrombogenesis and and have been demonstrated to be involved in deep vein thrombosis, thrombotic material from myocardial vessel in infarction and atherosclerosis and to be increased in cancer-associated thrombosis. Thrombosis is causing an increased burden of morbidity and resulting a decreased overall survival of patients with Philadelphia-negative myeloproliferative diseases (polycythemia vera, essential thrombocythemia and myelofibrosis). Methods:  In this study we quantify the ex-vivo NET production of neutrophils isolated from healthy donors and patients with myeloproliferative diseases. Neutrophils were separated by density gradient centrifugation and cell concentration and purity were determined by immunophenotyping using side scatter vs. CD45 plot. A total of 100.000 isolated neutrophils were incubated for 4 h at 37° with 4uM ionomycine and NET

production was quantified by an ELISA directed against DNA and histones. Immunoflourescence. In addition NET production was verified by immunoflourescence microcopy using antibodies against MPO and citrullinated histones H3 and a DNA counterstain. Results:  MPN patients (n = 19) show a higher rate of NET production than healthy donors (n = 9). Data collection is continued and results will be updated at the OeGHO meeting. However, only neutrophils incubated at higher levels of human serum showed dose dependent NETosis. Conclusions: Netosis might be a relevant player in MPN associated thrombosis.

P16 Revival of hydroxyurea (HU) in CML: demonstration that HU kills BCR-ABL1-T315I+ CML cells and synergizes with ponatinib and ABL001 to produce anti-CML effects Mathias Schneeweiss*1,2, Konstantin Byrgazov3, Chantal Blanche Lucini3, Susanne Herndlhofer1,2, Sandra Preuner3, Gregor Hörmann4, Georg Greiner4, Thomas Lion3, Wolfgang Sperr1,2, Michael Deininger5, Peter Valent1,2, Karoline Gleixner1,2 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 (CCRI), Vienna, Austria 4 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 5 Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, USA 1

Although CML can be controlled with tyrosine kinase inhibitors (TKI) in most cases, the occurrence of BCR-ABL1 T315I or complex BCR-ABL1-mutations still represent a clinical challenge. Currently, ponatinib is the only available TKI suppressing BCR-ABL1-T315I-mutated cells. However, due to side effects and ponatinib-resistant BCR-ABL1 compound-mutations, ponatinib is not an optimal drug for all patients. Hydroxyurea (HU) has been used for palliative cytoreduction in CML since decades. However, the effects of HU on survival of mutated sub-clones have not been analyzed in detail so far. Clinical observations in our department have revealed, that HU-treatment resulted in suppression of the BCR-ABL1-T315I+ subclone in four heavily pretreated CML-patients. This prompted us to investigate the effects of HU on TKI-resistant Ph+ cells in vitro. HU was found to be more effective in inhibiting proliferation of cells harboring BCR-ABL1-T315I or T315I-including compound-mutations compared to cells expressing wildtype BCR-ABL1. Moreover, HU was found to synergize with ponatinib and ABL001, a novel drug blocking BCR-ABL1-T315I, in producing growth-arrest in CML cells. Furthermore, HU induced cell cycle arrest and decreased the expression of CDK4/6 in CML-cells. Palbociclib, a more specific CDK4/6-inihibitor, was also found to synergize with ponatinib in producing growtharrest in BCR-ABL1-T315I+ cells, suggesting that inhibition of CDK4/6 may be a promising concept to overcome BCRABL1-T315I-associated TKI resistance. Together, our data show that HU can be applied to suppress growth of CML sub-clones exhibiting BCR-ABL1-T315I or complex BCR-ABL1-mutations

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Supplement 1/18 involving T315I. Clinical studies are now warranted to define the exact value of ‚ponatinib+HU‘ or ‚ponatinib+palbociclib‘ in advanced CML.

P17 Plasma metabolic profile in multiple myeloma patients

P18 Hypereosinophilia – Do the classifications support treatment decisions? Christoph Tinchon*1, Angelika Pichler1, Daniel Mayer1, Suzana Babic1, Ursula Olynetz2, Ingeborg Stelzer3, Raimund Kristoferitsch3 Department for Hematology and Oncology LKH Hochsteiermark-Leoben, Austria 2 Department for Gastroenterology, LKH HochsteiermarkLeoben, Austria 3 Institute of Laboratory Medcine, LKH HochsteiermarkLeoben, Austria 1

Normann Steiner*1, Udo Müller2, Roman Hajek3, Sabina Sevcikova4, Bojana Borjan1, Karin Jöhrer5, Georg Göbel6, Andreas Pircher1, Eberhard Gunsilius1 Laboratory for Tumor Biology and Angiogenesis, Department of Internal Medicine V (Hematology and Medical Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Biocrates Life Sciences AG, Innsbruck Austria 3 Department of Hematology-Oncology, University Hospital Ostrava, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic 4 Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic 5 Tyrolean Cancer Research Institute, Innsbruck, Austria 6 Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria 1

Background:  Multiple myeloma (MM) is still an incurable disease. Thus, the identification of novel therapeutic targets is urgently needed. Therefore this study aims to evaluate the potential of metabolomics to provide information on metabolic profiles that could be useful in the management of MM. Methods:  Peripheral blood plasma levels of 188 endogenous metabolites, including amino acids, biogenic amines, acylcarnitines, glycerophospholipids, sphingomyelins, and hexoses were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 15), patients with newly diagnosed MM (NDMM, n = 32), patients with relapsed/refractory MM (RRMM, n = 19) and 25 healthy controls by mass spectrometry. Results: For 8 metabolites significantly different plasma levels between the NDMM and MGUS group were measured: free carnitine, acetylcarnitine, glutamate, asymmetric dimethylarginine (ADMA) and four phosphatidylcholine (PC) species. Also, 8 metabolite-levels (C18, ADMA and 6 PCs) were significantly different between RRMM and MGUS patients. 13 different concentrations of metabolites were found between RRMM and NDMM patients (free carnitine, acetylcarnitine, creatinine, five LysoPCs and PCs. Conclusions:  We identified different metabolic profiles in MGUS und MM patients in comparison to healthy controls. These findings, which will be presented in detail at the meeting, might have the potential to serve as a tool for treatment decisions, assessment of treatment efficacy and identification of novel therapeutic targets in the future.

Background:  There are two classifications for hypereosinophilia (HE): the WHO and the ICON classification. We analyzed 16 patients that presented to our hematologic department for exploration of HE since 2008 to see if classifying is feasible and relevant. Furthermore we analyzed all 151 patients with eosinophilia (>1500 µl) in the year of 2017 to see if the definitions separate benign reactive eosinophilia from eosinophilia accompanying severe diseases. Methods:  Retrospective analysis of 16 patients from our registry of HE. Retrospective analysis of 151 patients with eosinophils >1500/µl in at least one hemogram found in the laboratory information system (LIS) of our hospital. Descriptive statistics. Results:  12 of 16 patients presenting for exploration of HE had some signs of infectious or rheumatic diseases, but a clear diagnosis was difficult to make. 11 patients were mainly treated with steroids, 2 patients were observed. 12 of 151 patients with eosinophils > 1500/µl had this eosinophilia for more than 1 month. 11 patients had malignancies, 1 had Crohn’s colitis. All of these patients were treated for their main diagnoses and their eosinophilia was not seen as a separate problem. Conclusions:  HE is most often a symptom that accompanies known malignant diseases. In patients presenting for exploration of HE, there are often many signs—but no proof—of infectious or rheumatic diseases. Finding a diagnostic label is difficult and often not very helpful for treatment decisions.

P19 Efficacy and safety of Voriconazole as first-line IFI-prophylaxis in patients with acute myeloid leukemia – A single centre experience Thomas Vockenhuber*1, Ansgar Weltermann1, Michaela Binder1, Sigrid Machherndl-Spandl1, Michael Girschikofsky1 Department of Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria

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Background:  Sufficient prevention of invasive fungal infection (IFI) strongly influences the outcome of AML-patients. Beside the less tolerable drug Itraconazole, Voriconazole was the first available oral mould-active azole in Austria. Methods: Since 2002 AML-patients (≥ 18 a) received offlabel 2 × 200 mg Voriconazole orally as IFI-prophylaxis during the neutropenic phase of induction chemotherapy (< 500 neutrophils/µl) at our institution. Proven, probable, or possible

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Supplement 1/18 fungal infections are classified in accordance with published criteria from the 2008 version of the EORTC/MSG. This retrospective cohort study reports 166 patients and a total of 306 induction therapies (first line, as well as relapse therapy; AML M3 excluded). Results:  During an evaluable observation period from 2006 to 2017 a total of 4 proven IFIs were detected, reflecting a rate of 1.3%, based on all chemotherapy cycles administered. Additionally, we observed 18 possible cases. 85% of patients received Voriconazole-prophylaxis until the end of neutropenia. Reasons for early abortion were adverse reactions (6%), suspected IFI (5.5%), persistent fever (1.6%), insufficiently low drug levels (0.3%) and others (1.6%). No IFI-related deaths occurred during the first 100 days of observation after induction chemotherapy. Possible drug related adverse reactions were detected in 21 cases (6.9%) during all induction therapies. Most commonly observed as an increase of cholestasis parameters/transaminases (6.2%), followed by optical hallucination and neuropathy (each 0.3%). Conclusions:  With respect to the retrospective manner of our single centre analysis efficacy and safety of Voriconazole as first-line IFI-prophylaxis seems to be comparable to Posaconazole, licensed and recommended for prophylaxis of IFI during AML induction therapy.

P20 B cell malignancy as the first clinical manifestation of primary antibody deficiency Hermann M. Wolf*1, Christoph B. Geier1, Kai M. T. Sauerwein1, Alexander Piller1, Martha M. Eibl1 Immunology Outpatient Clinic; and Biomedizinische Forschungs GmbH, Vienna, Austria

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Defective antibody formation is the main phenotypic feature in the majority of primary immunodeficiency diseases, with common variable immunodeficiency (CVID) as the most common clinically severe form of primary immunodeficiency. The number of patients with secondary antibody deficiency is increasing due to the use of new immunosuppressive therapies, in particular those targeting B cells. Not all patients with hypogammaglobulinemia present with infectious complications, and a clinically relevant antibody deficiency e. g. specific polysaccharide antibody deficiency can lead to significant susceptibility to infections even if serum immunoglobulin levels are normal. The assessment of antibody responses to vaccination and/or naturally encountered microbial antigens enables the decision on immunoglobulin replacement therapy (IGRT). In addition to susceptibility to infections CVID patients show an increased risk of cancer, especially B cell lymphoma. In the current study we present the clinical and immunological characteristics of eight out of 64 consecutive CVID patients in whom B cell malignancy such as B-NHL was the first clinical manifestation. The mean delay between the diagnosis of a lymphoid malignancy and the diagnosis of CVID was 5.4 years (range 0.5 to 19 years). Upon diagnosis of CVID all patients presented with undue susceptibility to infections which normalized upon initiation of IGRT. Our findings indicate that immunological examination of patients with hematological malignancy, in particular B cell tumors, should be mandatory in order to achieve early diagnosis of clinically relevant antibody deficiency.

Poster Onkologie

P21 Lymphopenia predicts response to anti-VEGFRtargeted 1st-line therapy in patients with metastatic renal cell carcinoma Florian Fillafer*1, Jasmin Terzic1, Florian Posch1, Maximilian Seles2, Georg Hutterer2, Martin Pichler1, Herbert Stöger1, Thomas Bauernhofer1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Department of Urology, Medical University of Graz, Graz, Austria 1

Background: Lymphopenia is associated with poor systemic host immunity, possibly facilitating tumor initiation and progression. Recent reports implicate lymphopenia with adverse outcomes in patients with metastatic clear-cell renal cell carcinoma (mccRCC). The aim of this study was to quantify the impact of lymphopenia on response to anti-VEGFR-targeted therapy in mccRCC. Methods:  In this cohort study, we retrospectively included 63 patients with mccRCC who underwent 1st-line therapy with sunitinib (n = 31) or pazopanib (n = 32) between Jan, 1st, 2007 and Dec, 31st, 2017 at a single academic center (median age: 68 years, ECOG > 0: n = 28 (44%), IMDC favorable/intermediate risk: n = 46 (73%)). The association between the pre-treatment absolute lymphocyte count (ALC) and the objective response rate (ORR) during 1st-line treatment according to RECIST 1.1 criteria was estimated with generalized linear models (GLM). Results: Median ALC was 1.6 G/L [25th-75th percentile: 1.2–2.0, range: 0.5–4.5]. The ORR was 39% (95%CI: 27–52; n = 0 complete and n = 25 partial responses). Pre-treatment lymphopenia predicted for a lower ORR. In detail, the ORR was 22% in patients with an ALC ≤ the 25th percentile of its distribution, and 44% in patients above this cut-off, respectively. In univariable GLM, a doubling of the ALC was associated with a 16% higher ORR (95%CI: 0–33, p = 0.057), and this prevailed after adjusting for ECOG status and IMDC risk category (increase in ORR per doubling of ALC = 18%, 95%CI: 5–31, p = 0.007). Conclusions:  Lymphopenia predicts poor response to 1stline therapy in mccRCC. These data highlight a critical link between exhausted adaptive immunity and impaired efficacy of anti-VEGF-targeted treatments in mccRCC.

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Safety and efficacy of nab-paclitaxel plus gemcitabine in the clinical routine treatment of metastatic pancreatic cancer patients: First interim-analysis of an Austrian multicenter noninterventional study Armin Gerger*1, Leopold Öhler2, Werner Scheithauer3, Brigitte Mlineritsch4, Thamer Sliwa5, Klaus Wilthoner6, Andreas Petzer7, Petra Pichler8, Eva Hubmann9, Thomas Winder10, Sonja Burgstaller11, Markus Korger12, Johannes Andel13, Ewald Wöll14, Hans-Jörg Neumann15, Martin Pecherstorfer16, Kathrin Philipp-Abbrederis17, Herbert Stöger1, Gerald Prager3, Wolfgang Eisterer18 Medical University Graz, Graz, Austria 2 Sankt Josef Krankenhaus, Vienna, Austria 3 Medizinische Universität Wien Medical University Vienna, Vienna, Austria 4 Landeskrankenhaus Salzburg, Salzburg, Austria 5 Hanuschkrankenhaus, Vienna, Austria 6 Landeskrankenhaus Vöcklabruck, Vöcklabruck, Austria 7 Krankenhaus der Barmherzigen Schwestern, Linz, Austria 8 Universitätsklinikum St. Pölten, St. Pölten, Austria 9 Krankenhaus der Barmherzigen Brüder, Graz, Austria 10 Landeskrankenhaus Feldkirch, Feldkirch, Austria 11 Klinikum Wels-Grieskirchen, Wels, Austria 12 Krankenhaus der Barmherzigen Brüder, Eisenstadt, Austria 13 Landeskrankenhaus Steyr, Steyr, Austria 14 Krankenhaus Zams, Zams, Austria 15 Krankenhaus der Elisabethinen, Klagenfurt, Austria 16 Landesklinikum Krems, Krems, Austria 17 Medizinische Universität Innsbruck, Innsbruck, Austria 18 Klinikum Klagenfurt, Klagenfurt, Austria 1

Background: Nab-paclitaxel (Abraxane®, Celgene) plus gemcitabine (G) has proven efficacy and safety as first-line treatment for metastatic pancreatic cancer (mPC) in the MPACT randomized phase III trial.[1] Here we report on prospective, non-interventional real-world data regarding the use of nabpaclitaxel in mPC patients (pts) in the Austrian clinical routine. Methods:  Pts with confirmed mPC were treated with nabpaclitaxel plus G and prospectively observed until disease progression or unacceptable toxicity. Results:  Between 5/2015 and 7/2017, 179 pts (median age: 68 years, range 44–89; 86 (48%) > 70) were included across 18 sites. At baseline, 66/168 pts (39%) had ≥ 2 metastatic lesions, 118/163 (72%) had elevated CA19-9 (> 37 U/ml) and 51/113 pts (45%) had grade 3 disease. At the beginning of treatment 96% had ECOG 0/1, median treatment duration was 4 cycles (range 1–16). At time of data analysis ORR of 103 evaluable pts was 41% (PR), 41% of pts achieved SD. Nab-paclitaxel plus G was generally well tolerated with most adverse drug reactions being mild (52%) or moderate (39%) in severity. The most common reason for treatment discontinuation was tumor progression or death in 77/121 pts (64%); 5/121 pts (4%) discontinued treatment due to toxicity. No new safety signals were identified. Conclusions: This real-world data confirm the results of randomized studies. Nab-paclitaxel plus G was well tolerated and effective in an elderly cohort of mPC patients.

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A high AST/ALT (De Ritis)-ratio represents a poor prognostic factor in a large cohort of patients with pancreatic cancer Eva Valentina Klocker*1, Michael Stotz1, Florian Posch1, Tatjana Stojakovic2, Herbert Stoeger1, Peter Kornprat3, Armin Gerger1, Martin Pichler1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Clinical 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 1

Background: Aminotransaminases, which are strongly involved in cellular metabolism and cancer cell turnover, represent easily measureable, potential blood-based biomarkers. We evaluated the prognostic relevance of the AST/ALT (De Ritis)ratio on cancer-specific survival in a large Austrian cohort of patients with pancreatic adenocarcinoma. Methods: We retrospectively evaluated clinicopathological data on 638 patients with adenocarcinoma of the pancreas treated between 2005 and 2017 at a single tertiary academic center. The potential prognostic value of the AST/ALT ratio was analyzed using the Kaplan-Meier method, and univariate and multivariate Cox proportional regression models. Results:  An increased AST/ALT ratio at the date of diagnosis was statistically significantly associated with poor survival in univariate analysis (hazard ratio: 1.17, 95%CI: 1.09–1.26, p < 0.001, used as a continuous variable). The prognostic value prevails even after adjustment for gender, grade and tumor stage (hazard ratio: 1.13, 95%CI: 1.05–1.23, p = 0.01, used as a continuous variable). Conclusions:  In our study cohort with pancreatic cancer, the AST/ALT ratio represented an independent prognostic factor in this dismal disease.

P24 Effect of renin-angiotensin-aldosterone system inhibitors on the survival of patients with advanced non-small-cell lung cancer (NSCLC) – influence on the collagen network Florian Kocher*1, Arno Amann1, Michael Fiegl2, Edith Lorenz3, Eberhard Gunsilius1, Wolfgang Hilbe4, Andreas Pircher1 Department of Internal Medicine V (Hematology and Oncology), Medical University Innsbruck, Innsbruck, Austria 2 Department of Internal Medicine, Privatklinik Hochrum, Rum, Austria 3 Tyrolean Cancer Research Institute, Innsbruck, Austria 4 Department of Internal Medicine I, Center for Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria 1

Background:  The tumor microenvironment is an interesting therapeutic target in non-small-cell lung cancer (NSCLC). Evidence exists that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) reduce extra-

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Supplement 1/18 cellular fibrosis. Studies have shown that intake of ACE-I and ARB are associated with improved outcome in cancer patients (e. g. pancreatic, brain). We hypothesize that ARB/ACE-I reduce collagen synthesis by blocking key-enzymes involved in proline (most important component of collagen) metabolism and lead to reduction of desmoplastic tumor reactions. Methods:  A cohort of 444 NSCLC patients receiving first line platinum-based therapy was retrospectively analyzed. A focus was set on the prognostic role of ACE-I/ARB intake. Publicly available datasets of NSCLC patients (using the SynTarget tool) were used to evaluate crucial genes involved in collagen synthesis. Results:  Concomitant ACE-I/ARB intake was documented in 100 patients (22.5%). Baseline characteristics were comparable between the groups. The overall-response rate (ORR) and overall survival (OS) were significantly better in the ACE-I/ARB group (ORR 34.4% vs. 23.1%, p = 0.033; OS 20.4 vs. 12.1 months, p = 0.049). An exploratory analysis of crucial genes involved in proline metabolism, using the TCGA database, showed that high expression of the most important enzymes in collagen production as ALDH18A, PYCR1/2 and P4HA1/2 are associated with reduced survival in NSCLC. Conclusions:  The positive impact of ACE-I/ARB in NSCLC patients might be explained by degradation of collagen in the microenvironment consequently leading to higher intratumoral drug levels. Further experiments with 3-D stromal co-cultures currently conducted in our laboratory might add further evidence to our hypothesis.

P25 Analyse des Österreichischen Registers für Gastrointestinale Stromatumore Thomas Kühr*1, Herbert Stöger2, Richard Greil3, Andreas Petzer4, Michael Girschikofsky5, Jörg Tschmelitsch6, Michael Fridrik7, David Fuchs7, Klaus Wilthoner8, Günter Gastl9, Alois Lang10, Matthias Zitt11, Johannes Andel12, Friedrich C. Lang13, Martina Baur14, Michael Pötscher15, Daniela Zauner15 Abteilung für Innere Medizin IV, Klinikum Wels-Grieskirchen, Wels, Österreich 2 Klinische Abteilung für Onkologie, Medizinische Universität Graz, Graz, Österreich 3 Universitätsklinik für Innere Medizin III, Paracelsus Medizinische Privatuniversität, Salzburg, Österreich 4 Interne Abteilung, Ordensklinikum Linz Barmherzige Schwestern, Linz, Österreich 5 I. Interne Abteilung, Ordensklinikum Linz Elisabethinen, Linz, Österreich 6 Abteilung für Chirurgie, Krankenhaus der Barmherzigen Brüder, St. Veit, Österreich 7 Klinik für Hämatologie und Onkologie, Med Campus III, Kepler Universitätsklinikum, Linz, Österreich 8 Salzkammergut-Klinikum Vöcklabruck, Vöcklabruck, Österreich 9 Universitätsklinik für Innere Medizin V (Hämatologie und Onkologie), Medizinische Universität Innsbruck, Innsbruck, Österreich 10 Abteilung Interne E, Landeskrankenhaus Feldkirch, Feldkirch, Österreich 11 Krankenhaus Dornbirn, Dornbirn, Österreich 12 Abteilung Innere Medizin II, Landeskrankenhaus Steyr, Steyr, Österreich

Abteilung für Chirurgie, Landesklinikum Neunkirchen, Neunkirchen, Österreich 14 3. Medizinische Abteilung, Kaiser-Franz-Josef-Spital, Wien, Österreich 15 Clinical Trial Unit Wels, Wels, Österreich 13

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 404 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 5760 Tage. Ergebnisse: Bei ausgeglichener Geschlechts- und Altersverteilung fand sich bei der Mehrzahl der PatientInnen histologisch ein spindelzelliger GIST (64 %), gefolgt von Mischtypen (19 %) und epitheloidzelligem GIST (8 %). 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 175 aller im Register aufgenommenen Patienten erfolgte ausschließlich eine chirurgische Intervention. Primär palliative Patienten 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.

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P26 Large platelet size is associated with poor out­ come in patients with metastatic pancreatic cancer Anna Lena Lembeck*1, Florian Posch1, Joanna Szkandera1, Konstantin Schlick2, Tatjana Stojakovic3, Peter Kornprat4, Karoline Lackner5, Armin Gerger1, Herbert Stöger1, Michael Stotz1, Martin Pichler1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Private Medical University, Salzburg, Austria 3 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria 4 Division of General Surgery, Department of Surgery, Medical University of Graz, Graz, Austria 5 Institute of Pathology, Medical University of Graz, Graz, Austria 1

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Supplement 1/18 Background: Platelets are a major cellular component of blood and their interaction with cancer cells is well-establihsed to influence cancer progression and metastases. The physical size of platelets may have critical impact on the interaction with cancer cells. In this study, we explored the potential prognostic role of platelet size measured by determination of the mean platetlet volume (MPV) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods:  Data from 527 patients with PDAC diagnosed and treated between 2004 to 2015 at a single center were evaluated retrospectively. Associations between MPV and baseline covariates were assessed with Wilcoxon’s rank-sum tests, χ2-tests, and Fisher’s exact tests. Median follow-up was estimated with a reverse Kaplan-Meier estimator according to Schemper & Smith. Analysis of time-to-death was performed with KaplanMeier estimators, log-rank tests, and uni- and multivariable Cox proportional hazards models. Results:  The median MPV was 10.5 femto litre (fL) [9.8–11.3], ranged from 5.9 to 17.7 fL. A large platelet volume was associated with high-grade G3/4 tumors (p = 0.004) and worse overall survival (OS) in patients with metastatic disease in univariable analysis (Hazard ratio [HR] per fL increase in MPV = 1.13 [95%CI: 1.04–1.23, p = 0.005]). In multivariable analysis of metatatic PDAC patients, the adverse association between large platelets and a higher risk-of-death prevailed (adjusted HR per doubling of MPV = 2.00; 95%CI: 1.10–3.62, p = 0.02). Conclusions:  Large platelets represent a negative prognostic factor and add an independent prognostic information to well-established factors in PDAC patients. MPV should be considered for future individual risk assessment in patients with stage IV PDAC.

P27 MicroRNAs are helpful biomarkers in discriminating elevated alpha-fetoprotein levels in a patient with testicular germ-cell tumor and pre-existing liver disease undergoing curative polychemotherapy Anna Lembeck*1, Angelika Terbuch1, Philip Puchas1, Florian Posch1, Jan Basri Adiprasito1, Herbert Stöger1, Thomas Bauernhofer1, Martin Pichler1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Background:  Testicular germ cell tumors (TGCTs) are the most commonly diagnosed malignancies in younger men. The monitoring and early detection of recurrence is supported by tumor markers including a-fetoprotein (AFP). AFP, physiologically synthesized in the liver, can be detected at increased levels under certain circumstances, including liver diseases. A cluster of stem cell-associated microRNAs (miR-371, miR367) has been reported to outperform traditional tumor markers in terms of sensitivity and specificity in TGCTs. Case Summary:  A patient with chronic hepatitis B and normal liver function tests presented with a surgically removed primary TGCT of the right testicle. Clinical staging IIA revealed a retroperitoneal metastatic lymph node involvement. During curative treatment with PEB regime, significantly rising AFP levels (>300 U/l) despite antiviral treatment and no change of lymph node involvement, led to the assumption of a chemoresistant disease. Consequently, salvage polychemotherapy with TIP regime was initiated. During TIP, the AFP levels did

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not substantially change and only a no change of lymph node involvement was achieved. To rule out chemotherapy-associated liver toxicity, the treatment was stopped and a liver biopsy was performed revealing advanced fibrosis and steatohepatitis. Three months of treatment-free follow-up led to a significantly decrease of AFP levels, confirming chemotherapy-associate liver toxicity as cause of AFP level elevation. In retrospective analysis of serum harvested at the time of rising AFP levels, we could not detect stem cell-associated microRNAs. These novel biomarkers carry the potential to discriminate between tumor-induced elevated AFP levels and toxicity induced elevation in patients with preexisting liver disease.

P28 Pembrolizumab plus brentuximab-vedotin in a patient with pretreated metastatic germ cell tumor Karl Mayrhofer*1, Wolfgang Hilbe1, Kathrin StrasserWeippl1, Dora Niedersüß-Beke1 Department of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria

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Background:  We report the outcome of combined immunotherapy with brentuximab-vedotin and pembrolizumab in a patient with a heavily pretreated metastatic extragonadal embryonal carcinoma. Case Report:  In April 2015 a 31 year-old patient was diagnosed with advanced embryonal carcinoma metastasized to the liver and abdominal lymph nodes. After multiple lines of therapy including high-dose chemotherapy with autologous stem cell support in December 2015, he received combined splenectomy, retroperitoneal lymph node dissection, segmental resection of the duodenum and segmental liver resection in September 2016. Recurrent disease was evident in March 2017 with hepatic lesions and paraaortal lymphadenopathy. Based on the tumor’s expression of CD30 we initiated treatment with brentuximabvedotin and after three courses added pembrolizumab because of immune-cell-infiltration with 15% PD-L1 positivity, resulting in a very good partial remission. After four cycles of pembrolizumab, the patient developed grade 3 immune-mediated hepatitis requiring corticosteroids. During prednisolone tapering he subsequently developed grade 2 pneumonitis, which regressed after re-elevating the dosage of prednisolone. Monotherapy with brentuximab-vedotin was continued. Restaging in November 2017 showed a partial remission. Pembrolizumab was added to brentuximab-vedotin again in December 2017 and the combination is ongoing and well-tolerated. Conclusions:  Previous case series have described brentuximab-vedotin as effective salvage therapy in patients with CD30+ relapsed germ cell tumors. PD1-blockade has also shown biomarker independent antitumor activity in various case reports in this entity. To our knowledge, this is the first case report of combined immunotherapy with brentuximab-vedotin and pembrolizumab resulting in a notable response in a patient with pretreated metastatic germ cell tumor.

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P29 Expression patterns and epigenetic regulation of immune-related genes in renal cell carcinoma Jennifer Moritz*1, Verena Tiran1, Johannes Foßelteder1, Herbert Stöger1, Martin Pichler1, Nadia Dandachi1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Background: Tumor-infiltrating lymphocytes have been proposed as a prognostic histological hallmark in cancer. Our study aims to determine epigenetic regulation of immunerelated gene expression patterns in renal cell carcinoma (RCC) and prognostic relevance of immune-related gene expression in RCC patients. Methods:  The clear cell RCC cell lines RCC-FG1 and RCCMF were treated with 5 µM and 10 µM of the demethylating agent 5-azacytidine for 72 hours. Real-time quantitative PCR was performed to compare the expression of the immune-related genes CD3G, CD3D, CXCR1, CCRL2, LAX1, Sit1 and ICOS between 5-AZA-treated and untreated cells. In addition, data from the Cancer Genome Atlas (TCGA) was used to compare methylation and expression patterns of these genes between RCC cancerous tissue and matched pairs of normal renal tissue. Results:  Both RCC-FG1 and RCC-MF showed significantly increased expression of CD3G, CD3D and CCRL2 after 5-AZA treatment. Using TCGA profiles from RCC patients, we found the promoter region of these immune-related genes to be higher methylated in normal tissue compared to tumor tissue as well as a higher gene expression in tumor tissue. Finally, analysis of the TCGA dataset also revealed a significant better overall survival for RCC patients with high expression of CCRL2. Conclusions:  The increased expression of CD3G, CD3D and CCRL2 indicated to some extent a methylation-dependent regulation of these genes in cancer cells. The higher gene expression of immune genes in tumor tissue could be explained by tumor infiltration with lymphocytes and may be linked to better overall survival in RCC patients.

P30 Real-life efficacy and toxicity of checkpoint inhibitors in solid tumors: A single-center experience Dora Niedersüß-Beke*1, Michael Schwarz1, CarinaVanessa Gindl1, Wolfgang Hilbe1, Kathrin StrasserWeippl1 Department of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria

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Background:  Several checkpoint inhibitors have been evaluated in the treatment of solid tumors as well as for lymphomas. Real life data in approved and non-approved indications are lacking. Methods:  We retrospectively analyzed patients treated with immune-oncological therapies (I-Os) outside of clinical trials between November 2015 and December 2017 at our center. We assessed progression-free (PFS) and overall survival (OS), with stage, histology, treatment line, PD-L1 and MSI status as covariables. Data on toxicity were collected as well.

Results: Of the 50 patients (35 male, 15 female) with a median age of 64.3 years, 25 (50%) were treated with nivolumab, 22 (44%) with pembrolizumab and 3 (6%) with atezolizumab. The most common approved indications for therapy were non small-cell lung cancer (36%), urothelial carcinoma (26%) and renal cell cancer (12%). Based on tumor biology, 2 patients with germ cell tumors (4%), 2 with anal cancer (4%), and one patient each with colorectal, pancreatic and gastric cancer were treated, as well as one patient with diffuse large B-cell lymphoma. Patients had received a median of 2 (1–6) prior treatment lines with a median of 4 (1–33) cycles. Median PFS was 2.6 months, median OS was 4.5 months. Grade 3–4 immune-related toxicities were rare (n = 3; 6%). However, one patient developed fatal I-O associated encephalitis. Conclusions:  Our report provides real-life data of I-O usage. Although the observed toxicities were mostly moderate, the fact that one patient died from I-O therapy shows the necessity to carefully collect real-life clinical data of I-O usage.

P31 Robo4 – the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature Andreas Pircher*1, Andrea Eigentler2, Renate Pirchler2, Martin Puhr2, Eberhard Steiner2, Georg Schäfer3, Eberhard Gunsilius1, Helmut Klocker2, Isabel Heidegger2 Department of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria 3 Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria 1

Background:  The magic roundabout receptor 4 (Robo4) is a tumor endothelial marker expressed in various tumor entities. However, the role of Robo4 in prostate cancer (PCa) has not been described yet. Thus, the present study investigates the impact of Robo4 on PCa aggressiveness both in vitro as well as in the clinical setting. Methods:  Robo 4 was overexpressed or downregulated in metastatic PCa cell lines (PC3, DU145, LNCaP) and we assessed cell proliferation and cell viability. Moreover, we analyzed 95 patients diagnosed with PCa who underwent a radical prostatectomy (RPE) for the analysis of Robo4 and its ligand Slit 2 using immunohistochemistry. Results:  In contrast to the as yet described role of Robo 4 as tumor endothelial cell marker we observed that Robo4 is expressed in PC3 PCa tumor cells. Overexpression of Robo4 in PC3 as well as in Robo4 negative DU145 and LNCaP PCa cells was associated with a significant decrease in cell-proliferation and cell-viability. Furthermore we found a significantly elevated Robo4 and ligand Slit2 protein expression in cancerous compared to benign tissue. Moreover, increased Robo4 expression was associated with higher Gleason score and pT stage. In a small patient collective (n = 39) we observed a trend towards reduced Robo4 expression in patients with a biochemical recurrence after RPE. Conclusions:  We observed a dual effect of Robo4 in PCa as it is associated with more aggressive cancers in the localized disease setting as well as a trend towards a protective effect of Robo4 regarding tumor recurrence after RPE.

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P32 Usage of bevacizumab in Austria from 2012–2016 Matthias Ranftler*1, Martin Zuba2, Wolfgang Hilbe1, Herwig Ostermann2, Kathrin Strasser-Weippl1 Department of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria 2 Gesundheit Österreich GmbH, Vienna, Austria 1

Background:  Bevacizumab, a monoclonal anti-VEGF antibody is used for the treatment of a variety of tumors at different dose levels and with various chemotherapy backbones. Methods: In the Austrian LKF-system, bevacizumab is recorded by entering the code for a dose of 2.5 mg/kg of bevacizumab multiplied by a number from 1–6 to code the dose actually given. The approved doses of bevacizumab in oncology are 5, 7.5, 10 and 15 mg/kg, whereas 2.5 and 12.5 mg/kg are not approved. We evaluated the patterns of bevacizumab use in Austria in 2012–2016 by tumor entity, chemotherapy backbone and individual hospital. Results:  Treatment with bevacizumab was recorded 95,405 times between Jan 1, 2012 and December 31, 2016 at an average dose of 8.53 mg/kg. A substantial number of administrations were recorded at non-approved doses, namely 2.5 mg/ kg (11.5%) and 12.5 mg/kg (1.6%). Bevacizumab was most commonly used in gastrointestinal tumors (34.2%) followed by ovarian (22.4%) and breast (11.5%) tumors. The most frequently used chemotherapy backbones where FOLFOX and FOLFIRI. We found a high dosage variation of bevacizumab in combination with some chemotherapy backbones. Also, a significant number of patients (410 or 20.3% in 2015 and 2016) received bevacizumab only once. Conclusions:  The recorded usage of bevacizumab in Austria is often not adherent to approved doses and indications. The high extent of non-approved use and the high number of one-time treatments may be partly, but not fully explained by erroneous LKF-coding. Our findings suggest a need for standardization and possibly education.

P33 MUG-Mel2, a novel highly pigmented and well characterized NRAS mutated human melanoma cell line Beate Rinner1 Division of Biomedical Research, Medical University of Graz, Graz, Austria

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Background: NRAS mutation in melanoma has been associated with aggressive tumor biology and poor prognosis. Although targeted therapy has been tested for NRAS mutated melanoma, response rates still appear much weaker, than in BRAF mutated melanoma. While plenty of cell lines exist, however, only few melanogenic cell lines retain their in vivo characteristics. In this work we present an intensively pigmented and well-characterized cell line derived from a highly aggressive NRAS mutated cutaneous melanoma, named MUG-Mel2. Methods:  Various detection techniques were used: 3D culture, targeted exome sequencing, copy number profiling, western blot analyses, proliferation assays, cell forming units assays, tumorigenicity assays and ex ovo CAM Assay.

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Results:  We present the clinical course, unique morphology, angiogenic properties, growth characteristics using in vivo experiments and 3D cell culture, and results of the exome gene sequencing of an intensively pigmented melanogenic cell line MUG-Mel2, derived from a cutaneous metastasis of an aggressive NRAS pQ61K mutated melanoma. Amongst several genetic alterations, mutations in GRIN2A, CREBP, PIK3C2G, ATM, and ATR were present. These mutations, known to reinforce DNA repair problems in melanoma, might serve as potential treatment targets. In vitro and in vivo imaging achieved an enormous contribution to the detailed characterization of the new established cell line MUG-Mel2. Conclusions:  The aggressive and fast growing behavior in animal models and the obtained phenotype in 3D culture reveal a perfect model for research in the field of NRAS mutated melanoma.

P34 Die perioperative Chemotherapie mit FLOT bei PatientInnen mit Adenokarzinomen des ösophagogastralen Übergangs und Magens – Ergebnisse der onkologischen Zentren der Vinzenz Gruppe Wien Sophie Roider-Schur*1, Eva Autzinger1, Verena Gartner1, Alice Kafka1, Ursula Maria Vogl2, Lauren Vormittag1, Thomas Winkler1, Günther Michael Wimberger3, Alexander Klaus4, Johannes Zacherl5, Leopold Öhler1 1. Abteilung für Innere Medizin/Onkologie, Sankt Josef Krankenhaus, Wien, Österreich 2 2. Medizinische Abteilung/Onkologie, Barmherzige Schwestern Krankenhaus Wien, Wien, Österreich 3 Abteilung für Chirurgie, Krankenhaus Göttlicher Heiland Wien, Wien, Österreich 4 Abteilung für Chirurgie, Barmherzige Schwestern Krankenhaus Wien, Wien, Österreich 5 Abteilung für Chirurgie, Sankt Josef Krankenhaus Wien, Wien, Österreich 1

Grundlagen: Magen- und Adeno-Karzinome des ösophagogastralen Übergangs (AEGs) gehören zu den häufigsten malignen Erkrankungen. Ab dem Stadium IB sollten alle operablen PatientInnen eine perioperative Chemotherapie (CHT) erhalten. Seit 2017 ist FLOT (5-FU+Leucovorin/Oxaliplatin/Docetaxel, q14d, 4 Zyklen prä-und postoperativ) in dieser Indikation etablierter Behandlungsstandard. Fragestellung:  Ziel dieser Arbeit war es die Durchführbarkeit und die Wirkung der perioperativen CHT mit FLOT in der klinischen Routine zu evaluieren. Methodik:  Eine retrospektiven Untersuchung umfasste alle PatientInnen, welche eine perioperative CHT mit FLOT an den Onkologien des SJK und BHS erhalten hatten. Ergebnisse:  Im Zeitraum von Juli 2015 bis Dezember 2017 erhielten 49 PatientInnen eine perioperative CHT mit FLOT. 47 % (n = 23) der PatientInnen hatten ein Magen-Karzinom, 53 % (n = 26) ein AEG, 61 % (n = 30) waren männlich, 39 % (n = 19) weiblich. Das mediane Alter betrug 64  Jahren (29–75a). 47 % (n = 23) aller PatientInnen erhielten 8 Zyklen der perioperativen Therapie. Bei 18 Patienten war im Verlauf der CHT eine Dosisreduktion notwendig. Der häufigste Grunde für eine Dosis-Adaptierung war Neutropenie. Bis zum Zeitpunkt der Analyse lag bei 67 % (n = 33) der PatientInnen der Regressionsgrad im Opera-

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Supplement 1/18 tionspräparat nach Verabreichung der präoperativen Therapie vor. Ein Regressionsgrad > 90 % zeigte sich bei 8 PatientInnen, 50–90 % bei 9 PatientInnen und ein Regressionsgrad von < 50 % bei 16 PatientInnen. Zum Zeitpunkt der Einreichung standen 7 PatientInnen unter laufender Therapie mit FLOT. Schlussfolgerungen:  Die perioperative CHT mit FLOT stellt für PatientInnen mit operablen AEG und Magenkarzinomen im Vergleich zu anderen Protokollen eine effektive Therapiestrategie dar. Die erhöhte Rate an Toxizitäten erfordert engmaschige Kontrollen und supportive Maßnahmen.

P36 Untersuchung von 22 Genen auf das progressionsfreie Überleben von Patienten mit metastasiertem Kolorektalen Karzinom Maria Anna Smolle*1, Jakob Michael Riedl2, Michael Stotz2, Martin Pichler2, Karl Kashofer3, Armin Gerger2 Universitätsklinik für Orthopädie und Unfallchirurgie, Medizinische Universität Graz, Graz, Österreich 2 Klinische Abteilung für Onkologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Graz, Österreich 3 Institut für Pathologie, Medizinische Universität Graz, Graz, Österreich 1

P35 High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma Andreas Seeber*1, Kai-Christian Zimmer1, Gerald Klingelmair2, Wolfgang Horninger2, Günther Gastl1, Bettina Zelger3, Andrea Brunner3, Renate Pichler2 Department of Internal Medicine V (Haematology and Oncology), Medical University of Innsbruck, Innsbruck, Austria 2 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria 3 Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria 1

Background: Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 as predictive biomarker is still under critical evaluation. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues. Methods:  IDO-1 and other immune inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3, CD4, CD8) were measured on formalin-fixed, paraffin-embedded sections of 15 RCC patients by immunohistochemistry. Results: IDO-1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO-1 overexpression (> 10%) could be detected more frequently in responders (100%, n = 6/6) compared to nonresponders (33.3%, n = 3/9; p = 0.028), resulting in a better progression-free survival during immunotherapy (IDO-1 ≤ 10% vs. > 10%, median: 3.5 vs. NE months, p = 0.01 by log-rank test). In addition, IDO-1 was positively correlated with CD8+ T cell expression (rs = 0.691, p = 0.006). PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs. non-responders: 83.3% vs. 88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating immune cells (PD-L1 < 1% in 66.7% of both responders and non-responders). Conclusions: In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC.

Grundlagen: Verschiedene prognostische und prädiktive Marker wurden in den vergangenen Jahren für das Kolorektale Karzinom (CRC) entdeckt, wie hochgradige MikrosatellitenInstabilität, ein RAS Wildtyp und die Lokalisation (links- vs. rechtsseitiger Tumor). In der vorliegenden Studie haben wir uns die Frage gestellt, 1) ob genetische Marker zwischen rechtsund linksseitigem CRC unterschiedlich exprimiert werden und 2) ob diese Gene einen prognostischen Einfluss haben. Methodik: 87 Patienten mit metastasiertem CRC wurden retrospektiv eingeschlossen, die zwischen 2010 und 2017 an unserer Abteilung behandelt wurden. Bei allen Patienten wurden Mutationsanalysen mit dem Ion AmpliSeq Colon and Lung Cancer Research Panel V2 (ThermoFisher Scientific), welches 22 Gene beinhaltet, durchgeführt. Chi-Quadrattests, KaplanMeier-Überlebensanalysen und Cox-Regressions-Analysen wurden angewandt. Ergebnisse: Das mediane Follow-up ab Start der palliativen Chemotherapie lag bei 8 Monaten (Interquartilbereich: 3,5–12,5 Monate). Sechzig Patienten hatten bei Diagnosezeitpunkt Metastasen (69,0 %). Vierundzwanzig Tumoren waren rechtsseitig lokalisiert (27,6 %) und 63 linksseitig (72,4 %, 31 Rektumkarzinome inkludiert). Mutationen in den Genen BRAF (p = 0,026) und DDR2 (p = 0,020) fanden sich signifikant häufiger bei rechtsseitig gelegenen Tumoren, während andere Gene keinen Unterschied zeigten. In der univariaten Analyse zeigten NRAS und BRAF Mutationen einen negativen Einfluss auf das progressionsfreie Überleben. In der multivariaten Analyse allerdings blieb einzig die Tumorlokalisation (links vs. rechts) als unabhängiger prognostischer Faktor bestehen, unabhängig von der Art der Chemotherapie, NRAS und BRAF Mutationen (HR: 0,400, 95 %CI: 0,166–0,969, p = 0,042). Schlussfolgerungen:  Die Untersuchung von 22 relevanten Genen brachte in dieser Studie keinen neuen prognostischer/ prädiktiver Marker für das CRC hervor. Die Tumorlokalisation bleibt ein signifikanter prognostischer Faktor.

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P37 Elucidation of cytotoxic effects of β-βdimethylacrylshikonin in melanoma cells Alexander Stallinger*1, Nadine Kretschmer2, Katharina Meditz1, Marie-Therese Frisch1, Heike Kaltenegger3, Birgit Lohberger3, Alexander Deutsch4, Rudolf Bauer2, Beate Rinner1 Core Facility Alternative Biomodels & Preclinical Imaging, Biomedical Research, Medical University Graz, Graz, Austria 2 Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria 3 Department of Orthopedics and Orthopedic Surgery, Medical University Graz, Graz, Austria 4 CBmed Center for Biomarker Research in Medicine, Division of Hematology, Medical University Graz, Graz, Austria 1

Background:  Melanomas account for about 1% of skin cancers, but are responsible for 79% of skin cancer deaths. Preliminary data has shown that β-β-dimethylacrylshikonin (DMAS) kills melanoma cells in cell culture. Therefore the aim of this project is the elucidation of cytotoxic effects of DMAS on melanoma in-vitro and in-vivo. DMAS effects on melanoma cell lines with different mutational profiles should be investigated and the suitability of DMAS as a possible anti-cancer drug determined. Methods:  DMAS effects on cell viability of five melanoma cell lines with different mutational profiles were examined with the EZ4U viability assay, potentially induced apoptosis with Annexin-V/SYTOX staining and caspase 3/9 assays. To show potential cell cycle arrests, cell cycle analysis were performed. Potentially affected apoptosis genes were investigated with RT-qPCR and western blots, new target genes determined with mRNA sequencing. Furthermore, mouse tumour xenograft models were used to show DMAS effects in-vivo. Results: DMAS induced apoptosis in melanoma cells invitro, thereby killing different cell lines at different drug concentrations. Additionally, melanoma cell lines faced a G2 cell cycle arrest. NOXA and PUMA were overexpressed under DMAS treatment. Furthermore, DMAS treatment had a significant effect on mouse tumour xenografts, resulting in tumour necrosis, while no effect was observed in surrounding tissues. Conclusions:  DMAS is a promising new anti-cancer drug which induces apoptosis of melanoma in-vitro and necrosis invivo. Further research is needed to examine the exact molecular targets of DMAS.

P38 Palliative Care und Sexualität bei onkologischen Patientinnen und Patienten Petra Sumnitsch*1, Margit Sandholzer1, Julia Mähr1, Daniela Zanolin2 Landeskrankenhaus Feldkirch, Feldkirch, Österreich VIVIT Feldkirch, Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Österreich

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Grundlagen:  Als ein Tabuthema im onkologischen Bereich ist derzeit immer noch der Umgang mit der Sexualität in dieser schweren Zeit. Ziel dieser Arbeit ist, das Bewusstmachen und Sensibilisieren von Sexualität bei onkologischen Patientinnen und Patienten in der palliativen Situation im stationären Alltag.

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Methodik:  Im Rahmen eines kleinen Projektes wurde ein Fragebogen entwickelt mit fünf Fragen zum Thema persönlicher Umgang mit Sexualität, welche Informationen haben sie erhalten und mit welcher Vertrauensperson möchten sie darüber sprechen. Befragt wurden Krebserkrankte mit Metastasierung und in palliativer Situation. Ergebnisse: Insgesamt wurden 20 Fragebogen eingesetzt und 18 Krebserkrankte im Alter zwischen 27 und 57  Jahren, davon zwölf Frauen und sechs Männer (zwei Drittel leben in einer Partnerschaft) in einem persönlichen Einzelgespräch interviewt. Die Betroffenen äußerten, dass das Thema Sexualität wenig bis kaum angesprochen wird und entsprechende Informationen fehlen. Für die Befragten ist das aktive Ansprechen von Sexualität trotz Krankheit ein Bedürfnis. Informations- und Aufklärungsbedarf besteht vor allem in den Bereichen, wie gehe ich im Alltag mit dem Thema Sexualität um, welche Hilfen und Unterstützungsmöglichkeiten gibt es, wie sage ich es meinem Partner. Als Vertrauensperson für diese Thematik wurden Pflegende, Arzt oder Psychoonkologin genannt. Schlussfolgerungen: Die Ergebnisse dieser Arbeit bestätigen, dass das Thema Sexualität ein sehr wichtiges Thema im palliativen Setting ist. Und auch der Wunsch, mutig zu sein, Thema Sexualität immer wieder anzusprechen.

P39 MiR-371a-3p as a diagnostic biomarker for detection of recurrence in testicular germ cell tumours Angelika Terbuch*1, Verena Stiegelbauer1, Jan B. Adiprasito1, Maximilian Seles1, Georg P. Pichler1, Margit Resel1, Florian Posch1, Anna L. Lembeck1, Joanna Szkandera1, Herbert Stoeger1, Karl Pummer1, Thomas Bauernhofer1, Armin Gerger1, Georg C. Hutterer1, Michael Stotz1, Martin Pichler1 1

Medical University of Graz, Graz, Austria

Background: Blood-based tumour markers (β-HCG, AFP and LDH) are commonly used for diagnosis and prognosis in testicular germ cell tumour (TGCT) patients although their sensitivity is only < 20% (seminoma) to 60% (overall) in TGCT patients. TGCT are enriched of embryonic stem cell-associated microRNAs (miR-371a-3p and miR-302/367 cluster). Cumulating evidence propose that blood levels of these miRNAs are potentially useful in diagnosis and treatment-monitoring of newly diagnosed TGCT patients. The aim of this study was to investigate whether these miRNAs are also useful for detection of disease recurrence in TGCT patients. Methods:  We retrospectively determined the levels of the two most promising candidates (miR-371a-3p and miR-367) in 52 serum samples of ten TGCT patients at the time of disease relapse and during salvage chemotherapy treatment. Results:  Both miRNAs were detectable in serum samples up to 17 years of storage. MiR-371a-3p levels in serum samples of untreated patients with proven disease recurrence were 13.65 fold higher than serum levels from the same patients with no evidence of disease (p = 0.014). In contrast, miR-367 did not show a significant difference in these patients groups (p = 0.985). Regarding serum samples from seminoma patients only (n = 24), we found significantly increased levels of miR-371a-3p (10.2 fold, p = 0.031) in serum from patients with proven disease recurrence compared to no evidence of disease samples.

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Supplement 1/18 Conclusions:  We demonstrated that miR-371a-3p is a sensitive and potentially new biomarker for detecting relapse in TGCT patients. This promising biomarker should be investigated in further large prospective trials, particularly in relapsing seminoma patients.

P40 Langzeitüberleben eines 49-jährigen mNCC-Patienten durch interdisziplinäres Therapiemanagement Jasmin Terzic*1, Christoph Tinchon2, Martin Uggowitzer2, Hans Rabl2 Onkologische Abteilung, Landeskrankhaus Graz, Graz, Österreich 2 Abteilung für Chirurgie, LKH Hochsteiermark, Leoben, Österreich 1

Grundlagen:  Die Einführung von zielgerichteten Therapien vor mehr als 10 Jahren hat die Behandlung des metastasierten Nierenzellkarzinoms revolutioniert. Der Stellenwert der zytoreduktiven Nephrektomie und die in diesem Case Report durchgeführte Adrenalektomie bei solitärer Nebennierenmetastase ist ein weiterer Eckpfeiler im interdisziplinären Therapiemanagement des mNCC (metastasiertes Nierenzellkarzinom) und ist mit verlängertem OS (overall survial) verbunden. Fallbericht:  Der Patient wird im Stadium IV – initial intermediäres Risiko nach IMDC score – 5  Jahre mit lokal chirurgischen sowie interventionell radiologischen Verfahren (Wedge-Resektionen, Radiofrequenzablationen) bei zeitlich diskonkordantem Auftreten pulmonaler Filiae behandelt. Bei Auftreten einer primär inoperablen Schilddrüsenmetastase links wird als tumorspezifische Therapie Pazopanib als Induktionstherapie nach selektiver Embolisation des Truncus thyreocervicalis und der A. thyreoidea superior links eingeleitet. Innerhalb von 10 Monaten kommt zur sehr guten partiellen Remission nach RECIST 1.1. Eine bereits terminisierte Operation zur kompletten Entfernung des Resttumors in der Schilddrüse und somit das Erzielen einer Tumorfreiheit im Stadium eines oligometastasierten NCC war aufgrund eines akut auftretenden analen Fournier-Gangrän nicht möglich. Nach Pausieren von Pazopanib trat eine rasche Tumorprogredienz ein. In weiterer Folge kam es zum Einsatz sequentieller Therapielinien bis zur Viertlinientherapie (Sorafenib, Everolimus, Axitinib) und somit zur Hemmung des VGEFR und mTOR-pathways bei gleichzeitiger Unterbindung der Vaskularisierung der Therapie induzierten Nekrose mittels erneuter Embolisation, Elektrovaporisation und Hochfrequenzablation bei weiterhin solitärer Schilddrüsenmetastase. Die konsekutive onkologische Weiterbehandlung bei progredienter Filialisierung (Lunge, Leber, Lymphknoten) war die Einleitung einer CheckpointInhibitor-Therapie. Schlussfolgerungen:  Durch das interdisziplinäre Therapiemanagement und den multimodalen Therapieansatz wurde bei einem primär metastasierten Nierenzellkarzinom mit einem durchschnittlichen medianen Überleben von 22,5 Monaten – in der TKI-Ära nach IMDC-Score – erreicht.

P41 Enzalutamide resistance in basal prostate cancer organoids Simon Udovica*1, Erwin Tomasich1, Maria König1, Helga Schachner3, Andreas Spittler2, Reinhard Horvat3, Michael Krainer1, Maximilian Marhold1 Division of Oncology, Department for Internal Medicine I, Medical University of Vienna, Vienna, Austria 2 Department of Surgery, Medical University of Vienna, Vienna, Austria 3 Institute for Pathology, Medical University of Vienna, Vienna, Austria 1

Background:  Second generation antiandrogens like Enzalutamide have the ability to overcome androgen independence in castration resistance prostate cancer (CRPC). However, treating CRPC with Enzalutamide is not curative, and the underlying mechanisms of resistance towards Enzalutamide treatment are poorly understood. Several studies have proposed that the progression to neuroendocrine prostate cancer as well as the persistent activation of the androgen receptor could facilitate Enzalutamide-resistance. Whether these processes occur predominantly in cells with a luminal or basal phenotype is still under debate. Aim:  To compare the effects of Enzalutamide on organoids derived from basal cells with organoids derived from luminal cells. Methods: We isolated both cell types from tumors of a murine transgenic cancer model. This model mimics both aggressive variants of prostate cancer as well as neuroendocrine differentiation (TRAMP mice). Results: Enzalutamide successfully inhibited growth of organoids originating from luminal tumor cells (68% ± 0.07% reduction in organoid size [p < 0.001]), whilst it had no effect on growth of organoids derived from basal cells. Mean organoid size of organoids derived from basal cells did not differ significantly between treatment groups (290.7 ± 20.12 µm vs. 334.9 ± 31.95 µm; p = 0.247). Real-time PCR analyses revealed significant upregulations of the androgen receptor and markers for neuroendocrine differentiation in basal cell-derived organoids treated with Enzalutamide. Conclusions:  We provide persuasive evidence for primary basal tumor cell resistance to Enzalutamide treatment in a transgenic mouse model of prostate cancer. Our findings could promote the identification of novel biomarkers of resistance development and therapeutic targets in Enzalutamide-resistant CRPC.

P42 Nab-Paclitaxel and Gemcitabine or FOLFIRINOX as first-line treatment in patients with unresectable pancreatic cancer. Does sequence matter? Ursula Vogl*1, Haleh Andalibi1, Laurenz Vormittag2, Alice Kafka2, Thomas Winkler2, Wolfgang Schima3, Alexander Klaus4, Leopold Öhler2 Department of Medicine 2/Oncology, Barmherzige Schwestern Krankenhaus Wien, Vienna, Austria

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Supplement 1/18 Department of Medicine 1/Oncology, St. Joseph Hospital, Vienna, Vienna, Austria 3 Department of Radiology, Barmherzige Schwestern Krankenhaus Wien, Vienna, Austria 4 Department of Surgery, Barmherzige Schwestern Krankenhaus Wien, Vienna, Austria 2

Background: Locally advanced or metastatic pancreatic cancer remains a disease with short overall survival (OS). We present the data of 84 patients treated with FOLFIRINOX, nabPGem or both at our center. Methods: Eighty-four patients with locally advanced or metastatic adenocarcinoma of the pancreas were treated at our center between 2011 and 2017. We analysed outcome of our patients for OS and progression-free survival (pfs) in terms of chemotherapy protocol and sequence. Forty-four patients received both chemotherapies in either first-or second-line treatment. Results:  The majority of patients had a good performance status (ECOG 0) with a median age of 68 years. Forty-six percent received FOLFIRINOX as first-line therapy, the remaining patients nabPGem. OS was 14 months (95% CI: 12.6–15.3), resulting in a 1-year survival rate of 60%. Patients received a median of three treatment lines (range 1–6). Forty-four patients received FOLFIRINOX followed by nabPGem or vice versa. There was no significant difference in OS or pfs for either of the two treatment sequences. The OS for FOLFIRINOX followed by nabPGem or nabPGem followed by FOLFIRINOX was 15.5 months (95% CI: 13.4–17.6) and 15.6 months (95%CI:4.3–27), respectively. Toxicity of FOLFIRIOX was higher and resulted in a significant dose reduction in 88.5% of the administered treatments. Conclusions: FOLFIRINOX followed by nabPGem or vice versa did not show significant differences in terms of OS in patients with inoperable or metastatic pancreatic cancer. Patients who received more treatment lines (> 3) had the greatest OS benefit.

Klinische Studien

K43 CARCINOSIS – a prospective phase II clinical trial investigating the histopathological response to FOLFOXIRI + bevacizumab in patients with peritoneal metastasis from colorectal cancer Thomas Bachleitner-Hofmann*1, Gerald Prager2 Department of Surgery, Medical University of Vienna, Vienna, Austria 2 Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 1

Background:  Peritoneal metastasis from colorectal cancer (CRC) has a dismal prognosis. Multimodality treatment using neoadjuvant chemotherapy, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) offers a possibility for cure in selected patients. However, little is known about the histopathological response to neoadjuvant systemic chemotherapy within the peritoneum. Methods: CARCINOSIS (ClinicalTrials.gov: NCT02591667, EUDRACT: 2015-002917-30) is an academic, prospective phase II trial sponsored by the Medical University of Vienna. It is coordinated by the Departments of Surgery and Internal Medicine

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I of the Medical University of Vienna. Primary endpoint is the histopathological response of the peritoneal tumor deposits to 4 cycles of systemic chemotherapy with 5-FU, leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) and bevacizumab administered at 3-weekly intervals. Patients with peritoneal metastasis from CRC, < = 3 resectable liver metastases, an ECOG performance status < = 2 and an adequate bone marrow reserve, renal and liver function are eligible. Exclusion criteria include active extraabdominal disease, recent (< 28 days) major surgery and > 3 liver metastases at presentation. Patients undergo diagnostic laparoscopy at baseline, followed by 4 cycles of FOLFOXIRI + bevacizumab and CRS and HIPEC if complete resection of all peritoneal tumor deposits is possible. It is planned to include 30 patients over a period of 3 years. Results: Recruitment has started in April 2016. So far, 9 patients have been included into the trial. Conclusions:  CARCINOSIS is the first trial to prospectively investigate the histopathological response in the peritoneum to neoadjuvant systemic chemotherapy with FOLFOXIRI and bevacizumab in patients with peritoneal metastasis from CRC.

K44 AGMT_MBC-10: Ixazomib (MLN9708) in combination with carboplatin in pretreated women with advanced triple-negative breast cancer (CARIXA) Richard Greil*1, Gabriel Rinnerthaler1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, Salzburg, Austria

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Study duration:  Dez 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 1,8 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 3 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 41 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 dose-limiting toxicities (DLTs) Phase II:  Overall response rate (ORR) Patients:  Phase I: 9 to 24 patients Phase II:  41 patients (incl. patients phase I)

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K45 AGMT_MBC_Reg: PATIENT REGISTRY Metastatic breast cancer in Austria Richard Greil1

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

IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, 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. 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

K46 AGMT_NGS_Reg: PATIENT REGISTRY The use of genomic testing and the resulting medical decisions according to target identification Richard Greil1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, 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. 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.

K47 AGMT_HMA in Myeloid Neoplasms: PATIENT REGISTRY Registry on hypomethylating agents in myeloid neoplasms, including Myelodysplastic Syndrome (MDS), CMML and AML Richard Greil*1, Lisa Pleyer1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, 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.

K48 AGMT_BV-NIS: Austrian Brentuximab vedotin observational study Richard Greil1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, Salzburg, Austria

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Design: This non-intervenional clinical study (NIS) is a prospective and retrospective, observational, multi-center research initiative.

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Supplement 1/18 Brentuximab vedotin has been shown to offer a high overall response rate, including durable complete responses in both of its indications. This signifies an important advancement in the treatment of adult patients with these rare CD30 positive hematological cancers who are relapsed or refractory and previously had limited options. This Brentuximab vedotin NIS is set up to collect real-world experience in the management of patients with Hodgkin’s disease and PTCL (sub-entity sALCL) (according to the WHO 2008 classification) 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. Indication:  Patients with Hodgkin’s disease and PTCL (subentity sALCL) who are willing to participate and receive or qualify for BV therapy. Primary objective:  The objective of this study is to evaluate the use, efficacy and toxicity of Brentuximab vedotin (BV) in Hodgkin’s disease (HD) and systemic anaplastic large cell lymphoma sALCL according to WHO 2008 in Austria and to identify the duration of therapy in these indications. Further objectives are the evaluation of Progression free and Overall Survival (PFS and OS). Recruitment:  100 patients

K49 AGMT_PTCL-Reg: PATIENT REGISTRY Austrian registry and biobank of peripheral T-cell lymphomas Richard Greil*1, Lukas Weiss1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, 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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K50 HD21: Treatment optimization trial in the first-line treatment of advanced stage Hodgkin lymphoma; comparison of 4–6 cycles of escalated BEACOPP with 4–6 cycles of BrECADD Richard Greil1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, Salzburg, Austria

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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 4–6 cycles of escalated BEACOPP. Patients in the experimental group receive 4–6 cycles of the BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, adriamycin, dacarbazine, dexamethasone) chemotherapy regimen. After a recent amendment based on the results of the HD 18 trial, the GHSG defines 4 cycles of escalated BEACOPP as new standard of care for PET-2 negative patients, whereas PET-2 positive patients receive 6 cycles of escalated BEACOPP. 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, Austria 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.

K51 GHSG_AERN: Abscopal effect of radiotherapy and nivolumab in relapsed Hodgkin lymphoma after anti-PD1 therapy Richard Greil1 IIIrd Medical Department, University Hospital Salzburg, Paracelsus Private Medical University, Salzburg, Austria

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Start of study:  Q2 2018 End of recruitment:  Q4 2019 Design:  The trial is a prospective, international, non-randomized, multicenter phase II investigator-sponsored trial for patients with relapsed or refractory cHL progressing while on treatment with an anti-PD1 antibody. A Simon’s optimal twostage design has been chosen with 9 patients to be evaluated for the primary endpoint in stage 1. If there are 1 or more stage1-patients with an abscopal response to localized RT and 6 applications of nivolumab (ARR-6), 20 additional patients will be recruited into the second stage of the trial for a total of 29 patients to be evaluated for ARR-6. Primary endpoint: Abscopal response rate (ARR-6) with abscopal response centrally confirmed as restaging result after RT to a single lesion and at least four but not more than six nivolumab infusions (RE-6 result)

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Supplement 1/18 The primary objective of the trial is to show efficacy of the experimental treatment strategy. Secondary objectives are to further evaluate efficacy, show safety and feasibility and perform correlative studies. Treatment: Nivolumab 240 mg i. v. at 2-weekly intervals combined with 20 Gy radiotherapy (RT) to a preferably progressive and not pre-irradiated single lesion. Nivolumab will be continued for a maximum of 18 months or until disease progression or unacceptable toxicity.

K52 AGMT_AIHA_Reg: PATIENT REGISTRY Autoimmune Hemolytic Anemia (AIHA) with corresponding biobank

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). After a runin phase of 6 patients a safety analysis was performed. A futility analysis after 10 patients is planned.

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Ulrich Jäger1 Division of Haematology and Haemostaseology, Comprehensive Cancer Centre, Department of Internal Medicine I, Medical University of 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; 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)

K53 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)

AGMT-ALL Reg: PATIENT REGISTRY Registry and biobank for the collection of clinical data and biomaterial from adult ALL patients Ulrich Jäger*1, Alexander Hauswirth1 Division of Haematology and Haemostaseology, Comprehensive Cancer Centre, Department of Internal Medicine I, Medical University of 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 Austian 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.

Ulrich Jäger1 Division of Haematology and Haemostaseology, Comprehensive Cancer Centre, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

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K55 DSHNHL_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 Haematology and Haemostaseology, Comprehensive Cancer Centre, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

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Start of study:  Q3 2018 (Austria) End of recruitment:  Q1 2022 Design: International, multicentre, randomised, openlabel, treatment optimization study, preceded by safety run-in phases conducted for B-cell and T-cell lymphoma separately. 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 twosided 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 will be randomized. In parallel a maximum of 78 patients with T-cell lymphoma will be included. Population: Patients with first relapse or progression of aggressive Non-Hodgkin’s Lymphoma who are not eligible for neither autologous nor allogeneic stem cell transplantation, defined as age >65 years or > 18 years old with HCTCI score >2. Primary objective:  Improvement of 1-yr PFS by nivolumab plus (R)-GemOx followed by nivolumab consolidation instead of (R)-GemOx alone. Primary endpoint is 1-yrs progression-free survival.

K56 AGMT_HNO-PN: Randomized phase-III study: Supplemental parenteral nutrition for patients with locally advanced inoperable tumors of the head and neck, receiving definitive radiotherapy with Cetuximab or Cisplatin Felix Keil1 1

3rd Medical Department, Hanusch Hospital, Vienna, Austria

Start of study:  Q1 2017 End of recruitment:  Q3 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.

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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.

K57 MRD-triggered consolidation therapy with KRd following ASCT in MM: Protocol presentation of an Austrian, multicenter, prospective phase-II trial (EudraCT# 2016-004778-16; National lead ethics protocol# A-181-17) Daniel Lechner*1, Michael Vockenhuber2, Peter Bettelheim1, Alexandra Böhm3, Eberhard Gunsilius4, Hildegard Greinix5, Hermine Agis6, Andreas L. Petzer1, Ansgar Weltermann1 Department of Hematology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria 2 Institute for Medical and Chemical Laboratory Diagnostics, Ordensklinikum Linz Elisabethinen, Linz, Austria 3 Department of Medicine 3, Hematology and Oncology, Hanusch Krankenhaus, Vienna, Austria 4 Department of Medicine V (Hematology and Medical Oncology), Medical University of Innsbruck, Innsbruck, Austria 5 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 6 Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 1

Background:  • Combined induction therapy followed by autologous stem cell transplantation (ASCT) is the standard first line therapy of fit multiple myeloma (MM) patients. • To date, there is no validated model of prognostication allowing therapeutic decision making on the basis of the depth of remission achieved after ASCT (consolidation vs. maintenance vs. observation). • Assessment of minimal residual disease (MRD) is not yet part of clinical routine in myeloma care. Aim: To test whether an MRD-dependent consolidation therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) is a feasible and effective tool to induce and/or re-induce MRD negativity. Methods:  • Starting from spring 2018, 41 patients are enrolled by 5 Austrian transplant centers. Maximum follow-up per patient is 3 years. • Patients receive 3 or 6 cycles of KRd. Thereafter, patients with persistent MRD are observed for disease progression, pati-

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Supplement 1/18 ents with proven MRD negativity are followed by 4-monthly MRD assessments. Patients with recurring MRD receive another set of KRd in an attempt to re-induce MRD-negativity. • MRD-assessments are performed by 8-color multi-parameter flow cytometry (sensitivity: 10–5 to 10–6) according to the most recent EuroFlow protocol. In selected patients, post-hoc MRD-assessment by Next Generation Sequencing will be performed. Concordance of results yielded by the two methods will be analyzed. • The primary endpoint of the study is the rate of MRD-negativity achieved following a first set of KRd. The secondary endpoint is re-achievement of MRD-negativity in MM patients with MRD-recurrence. Tertiary endpoints are explorative and include overall and progression-free survival.

K58 AGMT_MM2: A randomized Phase-II-study in transplant ineligible patients with newly diagnosed multiplemyeloma (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, Wilhelminenspital, Vienna, Austria

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Start of study:  Q1 2017 End of recruitment:  Q1 2020 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 until 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 146 adult patients (≥ 18 years) with newly diagnosed symptomatic MM will be enrolled in this study. Excluded are patients who are planned for an autologous-stemcell-transplantation following induction, who are intolerable to IMiDs or Carfilzomib, are NYHA-class >II, present with PS ≥ 2, CrCl ≤ 30 ml/min, and/or neuropathy grade ≥ 2.

K59 AGMT_MM-3: Denosumab for high-risk SMM and slim-CRABpositive, early myeloma patients – A randomized, placebo-controlled, phase-II-trial „DEFENCE“ (DEnosumab For the rEductioN of the smoldering myeloma transformatioN inCidence ratE) Heinz Ludwig*1, Wolfgang Willenbacher2 Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria 2 Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria 1

Start of study:  Q2 2018 End of recruitment:  Q4 2020 Design:  This is a randomized, placebo controlled, multicenter study of denosumab in patients with high risk SMM (Smoldering Multiple Myeloma) and “ultra-high risk” SMM (= now defined as “SLIM” CRAB defined early MM without symptoms). Eligible patients will be randomized 1:1 in each of the two groups (stratification according to high risk SMM and “ultrahigh risk” SMM): • Arm A: treatment with denosumab 120 mg SC every 4 weeks (Q4 W) for 6 months, then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM • Arm B: treatment with placebo SC every 4 weeks (Q4 W) for 6 months, then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM Primary objective: Time until transformation from highrisk SMM and early ‘slim CRAB’ positive MM to CRAB positive multiple myeloma and/or developing serological progression (as defined by IMWG criteria for MM) Patients: A total of 164 high risk and “ultra-high risk” Smoldering Multiple Myeloma will be included.

K60 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 Josef Thaler1 1

Klinikum Wels-Grieskirchen, Wels, Austria

Start of study:  Q3 2016 End of recruitment:  Q2 2021 Design:  This is a multicenter randomized open label trial in cooperation with SAKK. 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

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Supplement 1/18 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).

K61 AGMT_CML-1: Phase-1 study to evaluate feasibility and efficacy of the addition of P1101 (PEG-Proline-Interferonalpha-2b) to imatinib treatment in patients with chronic-phase-chronic-myeloid leukaemia not achieving complete molecular-response (MR-4 or 4.5)

Start of study:  Q2 2018 (in Austria) End of recruitment:  Q2 2020 Design:  This is an interventional, multicentre, open-label, randomized phase III trial with two parallel arms to compare two different regimens. Quadruple elotuzumab in combination with carfilzomib, lenalidomide, and dexamethasone [E-KRd] versus triple carfilzomib, lenalidomide, and dexamethasone [KRd] is given during induction treatment prior to ASCT and as consolidation treatment after ASCT in patients suffering from newly diagnosed multiple myeloma according to the updated IMWG criteria. Consolidation treatment is followed by maintenance treatment (elotuzumab in combination with lenalidomide versus lenalidomide monotherapy). Patients are randomized in a 1:1 ratio to be administered 6 cycles induction treatment, either E-KRd (Arm A) or KRd (Arm B). Primary objective:  To compare the rate of MRD negativity in patients with VGPR or better response according to IMWG criteria following two different induction regimens (quadruple [E-KRd] vs. triple [KRd]) in newly diagnosed multiple myeloma patients and to determine progression-free survival (PFS) following maintenance treatment. Patients:  576 patients will be randomized into this phase III trial. It is planned that the study will be performed in up to 45 German trial centres and 10 Austrian trial centres.

Josef Thaler*1, Sonja Burgstaller1 1

K63

Klinikum Wels-Grieskirchen, Wels, Austria

Start of Study:  July 2013 End of recruitment:  Q4 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. 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.

K62 DSMM_XVII: Elotuzumab(E) in combination with carfilzomib, lenalidomide and dexamethasone(E-KRd) versus KRd prior to and following autologous stem cell transplant in newly diagnosed multiple myeloma + subsequent maintenance with elotuzumab + lenalidomide versus single agent lenalidomide

AGMT_ERCC1: Pilotstudy: Biomarker directed treatment in metastatic colorectal cancer Thomas Winder1 Department of Internal Medicine II/ Interne E, LKH Feldkirch, Feldkirch, Austria

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Start of study:  Aug. 2012 End of recruitment:  Q3 2018 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.

Wolfgang Willenbacher1 Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria

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K64 AGMT_GASTRIC 5: PATIENT REGISTRY 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, Krankenhaus St. Vinzenz, 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.

Young Investigator Meeting

Y65 GPR56 is a putative marker of leukemic stem cells in CD34-positive acute myeloid leukemia Shruti Daga*1,2, Angelika Rosenberger1,2, Nina Krisper1,2, Andreas Reinisch1, Armin Zebisch1, Heinz Sill1, Albert Wölfler1,2 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 CBmed Center of Biomarker Research, Medical University of Graz, Graz, Austria 1

Background:  Acute myeloid leukemia (AML) arises from a rare pool of leukemic stem cells (LSC). AML LSC have been identified predominantly within the CD34 + 38- leukemic subpopulation, but have also been observed in other compartments. In this study, we aimed at characterization of novel putative LSC markers with a specific focus on their expression in leukemic subpopulations defined by different CD34 and CD38 levels. Methods:  Bone marrow or peripheral blood samples from 150 newly diagnosed AML patients were analyzed for several LSC markers including GPR56 using flow cytometry. Expression

of 17 genes associated with leukemic stemness (Ng et al., Nature 2016;540:433–437) was determined in sorted CD34 + 38-GPR56hi and CD34 + 38-GPR56lo leukemic cells by qPCR. Overall survival (OS) was calculated using the Kaplan-Meier method. Results: In CD34+ AML samples GPR56 expression was highest in the CD34 + 38- LSC-containing subpopulation, lower in CD34 + 38+ cells and lowest in the CD34- compartment (p < 0.001). Analysis of paired diagnostic and relapse samples indicated that GPR56 expression was conserved throughout disease. Expression of LSC-associated genes was higher in CD34 + 38-GPR56hi cells as compared to CD34 + 38-GPR56lo cells. In a cohort of AML patients receiving intensive chemotherapy, high GPR56 expression was associated with lower OS (p = 0.03). Conclusions:  GPR56 was highest expressed in the LSC-containing CD34+CD38- leukemic compartment and its surface levels correlated well with LSC-associated gene expression as well as with inferior OS. Thus, GPR56 might not only serve as a potential prognostic marker, but also as a promising marker for LSC activity in CD34+ AML.

Y66 Increased expression of micro-RNA-23a causes resistance to cytarabine in acute myeloid leukemia Stefan Hatzl*1, Susanne Ebner2, Bianca Perfler1, Franz Quehenberger3, Jakob Troppmair2, Andreas Reinisch1, Albert Wölfler1, Heinz Sill1, Armin Zebisch1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria 3 Institute of Statistics and Bioinformatics, Medical University of Graz, Graz, Austria 1

Background: Development of chemoresistant disease is one of the major problems in acute myeloid leukemia (AML) treatment. Micro-RNA-23a (miR-23a) causes chemoresistance in solid tumors and has recently been shown to be deregulated in AML. Here, we studied its role in AML chemoresistance. Methods:  Stable overexpression/knockdown of miR-23a in HL-60, THP-1 and U937 AML cells was achieved by lentiviral transduction. Chemoresistance to cytarabine and daunorubicin was assessed by MTT-cell viability and soft-agar colony formation assays. miR-23a and topoisomerase-II-beta (TOP2B) expression were analyzed in 24 paired AML patient samples, collected at diagnosis and chemoresistant relapse/refractory disease. miR-23a and TOP2B expression as well as overall survival (OS) were additionally analyzed in 146 cases of the AMLThe Cancer Genome Atlas (TCGA) dataset. This study included only patients treated with 7 + 3 (cytarabine + anthracycline) induction regimens. Results: Overexpression of miR-23a decreased the sensitivity to cytarabine in three different AML cell lines, whereas miR-23a knockdown caused the opposite effects. No effects on anthracycline sensitivity were noted. Mechanistically, we could show that miR-23a targets and downregulates TOP2B, a major player in mediating chemoresistance, both at mRNA and protein level. In agreement with these data, we observed that both, increased expression of miR-23a and decreased expression of

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Supplement 1/18 TOP2B correlated with relapsed/refractory AML disease stages and with inferior OS in AML. Conclusions:  MiR-23a mediates chemoresistance to cytarabine in AML, most likely via downregulation of TOP2B. Increased expression of miR-23a is associated with relapsed/ refractory AML and correlates with inferior survival in 7 + 3 treated patients.

Y67 Impaired monocyte to osteoclast differentiation potential affects the hematopoietic niche and results in myelodysplasia Lukas Kazianka*1, Klaus Schmetterer2, Sinan Gültekin3, Emiel van der Kouwe1, Christoph Kornauth1, Julia Koller1, Daniel G. Tenen4, Christian Bach5, Philipp B. Staber1 Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria 2 Department of Laboratory Medicine; Medical University of Vienna, Vienna, Austria 3 Department of Equine Surgery; University of Veterinary Medicine Vienna, Vienna, Austria 4 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, United States 5 Department of Internal Medicine 5 – Hematology and Oncology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany 1

Background:  CCAAT enhancer binding protein α (C/EBPα) and PU.1 are hematopoietic master regulators required to drive myelopoiesis. Osteoclasts are part of the bone marrow niche and considered to evolve from the myeloid lineage. However, it has remained unclear from which precursor cell osteoclasts evolve and which mechanisms direct their development. Methods:  We created a knock-in mouse model in which C/ EBP family member-induced expression of PU.1 is specifically disrupted. This model serves as an ideal tool to study functional consequences of the interaction of these hematopoietic key players. Results:  Experimental mice (PU.1Ki/Ki) developed neutropenia and, more prominently, thrombopenia detectable at five weeks of age (p = 0.04). Bone marrow (BM) analysis revealed dysplasia in the myeloid lineage. PU.1Ki/Ki animals demonstrated a significant decrease of PU.1 (50%) in the common monocyte progenitor (cMoP; p < 0.0001) population resulting in a shift towards the Ly6C+ monocyte subset (p = 0.005). Osteoclast differentiation capacity of BM monocytes derived from PU.1Ki/Ki mice was remarkably reduced (p = 0.04) and resulted in a defective hematopoietic niche compared to wildtype littermate controls. Ly6C- monocyte subsets were identified as the cell of origin of osteoclast differentiation. Conclusions: These data provide first time evidence that a shift in early monocytic differentiation from Ly6C- to Ly6C+ monocytes perturbs osteoclastogenesis. Selective reduction of osteoclasts significantly impaired the bone marrow niche resulting in an MDS-like phenotype.

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Y68 Efficacy of venetoclax as a single agent and in combination with 5-azacytidine in refractory or relapsed T-prolymphocytic leukaemia Christoph Kornauth*1, Bernd Boidol2, Julia Koller1, Emiel van der Kouwe1, Lukas Kazianka1, Gregor Hörmann3, Ingrid Simonitsch-Klupp4, Ulrich Jäger1, Stefan Kubicek2, Philipp Staber1 Division of Haematology and Haemostaseology, Comprehensive Cancer Centre, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria 2 Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria 3 Clinical Institute of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 4 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 1

T-cell prolymphocytic leukaemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. We applied next-generation functional testing of primary patient-derived leukaemic cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development in order to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT199) demonstrated the strongest T-PLL-specific response when comparing individual ex-vivo drug response in 86 patients with refractory hematologic malignancies. The relapsing course of T-PLL argues for combinatorial therapy to overcome resistance. We addressed this by functional testing with venetoclax in combination with 5-azacytidine, 6-mercaptopurin, alitretinoin, bendamustine, bortezomib and cisplatin on seven patient samples. Bliss’ independence determined synergistic, additive or antagonistic effects. The most promising candidate for combination was the hypomethylating agent 5-azacytidine whereas cisplatin antagonized the effect of venetoclax. Based on the ex-vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in striking clinical responses. Another T-PLL patient presented recently with dyspnea, leukocytosis and reduced clinical condition at third relapse. Co-treatment with venetoclax and 5-azacytidine was started and is ongoing after a failed treatment attempt with alemtuzumab. During short follow-up (one week), the patient showed prompt clinical improvement. Our findings demonstrate first evidence of single-agent activity of venetoclax. Furthermore, they present 5-azacytidine as an effective combination partner both ex vivo and in humans, offering a novel treatment concept in T-PLL.

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Supplement 1/18 Department of Otorhinolaryngology, Medical University of Graz, Graz, Austria 4 Institute for Automation Engineering, Otto von Guericke University Magdeburg, Magdeburg, Germany 5 Department Life Sciences, IMC University of Applied Sciences Krems, Krems, Austria 6 Institute of Computational Biotechnology, University of Technology, Graz, Austria 7 BioTechMed Omics Center, Graz, Austria 8 Biomedical Research, Medical University of Graz, Graz, Austria 9 Department of Internal Medicine, Medical University of Graz, Graz, Austria 10 Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany 11 Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria 12 Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany 3

Y69 Lower expression of distinct chemokine – and nuclear orphan receptors in aggressive follicular lymphoma (progressing within 24 months) Tanja Schukoff*1, Stefanie Winkler1, Karoline Fechter1, Julia Unterluggauer1, Christine Beham-Schmid2, Alexander Deutsch1, Katharina Prochazka1, Peter Neumeister1 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 2 Institute of Pathology, Medical University of Graz, Graz, Austria 1

Background:  Follicular lymphoma (FL) is a heterogeneous disease. Progression of disease within 24 months (POD24) is the most accurate predictor for worse clinical outcome but specific parameters useful for risk stratification before start of therapy are lacking. Since our group clearly demonstrated that nuclear orphan receptors and chemokine receptors (CR) were significantly associated with clinical course of indolent and aggressive lymphomas, we aim to study these receptors in FL with and without POD24. Methods:  Therefore, we performed an expression analysis of NR4A1, NR4A3 and 17 well characterized CRs (CCR1-CCR10, CXCR1- CXCR5, XCR1 and CX3CR1) on mRNA levels by using real-time RT-PCR on human tissue of clinically well documented FLs with POD24 (n = 14) and without POD24 (n = 57) with a median observation time of 7.3 years. Results: In our cohort the cancer specific survival of FL patients with POD24 was significantly reduced compared to FL patient without POD24 (5.3 years vs. 14.9 years, p < 0.01). By comparing the expression levels the 19 investigated receptors between these two subgroups, we detected a lower expression of NR4A3 (2.1 fold, p = 0.035), CCR4 (7.2 fold, p = 0.062), CCR6 (2.9 fold, p = 0.015), CCR10 (4.1 fold, p = 0.025) and CXCR4 (2.7 fold, p = 0.081) in FLs with POD24 compared to FLs without POD24. Conclusions: Overall, our results indicate that a distinct chemokine- and nuclear orphan receptor pattern might be implicated in the early progression of FL. Thus, these receptors might serve as useful clinical prognostic marker for risk stratification and/or as potential novel therapeutic target for lymphoma therapy.

Y70 Specific translation initiation factors influence clinical course of aggressive lymphomas Julia J. Unterluggauer* , Katharina Prochazka , Peter V. Tomazic3, Heinrich J. Huber4, Rita Seeboeck5, Karoline Fechter2, Elisabeth Steinbauer1, Verena Gruber1, Julia Feichtinger6,7, Beate Rinner8, Martin Pichler9, Marc Weniger10, Ralf Kueppers10, Heinz Sill2, Rudolf Schicho11, Peter Neumeister2, Christine Beham-Schmid1, Alexander J. A. Deutsch2, Johannes Haybaeck1,12 1

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Background:  Eukaryotic initiation factors (eIFs) are crucial contributors to the first steps of eukaryotic protein synthesis. Recently, they have been linked to tumorigenesis. However, data on the role of eIFs in aggressive lymphomas are limited and we thus aimed to analyze their expression levels in diffuse large B cell lymphoma (DLBCL). Methods:  We investigated the mRNA expression profile of 16 eIF-subunits in a cohort of 56 DLBCL patients in comparison to five non-neoplastic germinal center B cells as controls by quantitative real-time PCR. Furthermore, we studied eIF expression in DLBCL regarding disease relevant subtypes and patient outcome. Finally, immunohistochemical investigation (IHC) of DLBCL specimens and tonsillar controls was performed to confirm mRNA data of three eIF-subunits. Results:  Expression analysis on mRNA level showed that 12 out of 16 tested eIF-subunits are significantly higher expressed in DLBCL compared to non-neoplastic germinal center B cells (up to 40-fold, p < 0.003). 8 eIF-subunits exhibited furthermore higher mRNA expression in the more aggressive non-germinal center B-cell-like (non-GCB)-subtype compared to the GCBsubtype (p < 0.05). IHC analysis of eIF1A, eIF3d and eIF2B5 confirmed mRNA data (p < 0.05). Most importantly, for eIF2B5, we detected moreover a significant association between very high expression and worse cancer-specific survival (p < 0.007, mRNA and IHC, uni- and multivariate analysis). Conclusions: Our expression analysis indicates eIFs and especially eIF2B5 as important players in aggressive lymphomas, providing thereby a basis for their further investigation in this malignancy.

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Institute of Pathology, Medical University of Graz, Graz, Austria 2 Division for Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 1

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