Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie, Hamburg, 10.-14. Oktober 2014: Abstracts

Band 37, Supplement 5, Oktober 2014

Offizielles Organ von DGHO – Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie OeGHO – Österreichische Gesellschaft für Hämatologie & Medizinische Onkologie DFaG – Deutsche Fatigue Gesellschaft AIO – Arbeitsgemeinschaft Internistische Onkologie in der Deutschen Krebsgesellschaft e.V. SGH-SSH – Schweizerische Gesellschaft für Hämatologie Mitglied der Deutschen Krebsgesellschaft e.V.

Editors Editor-in-Chief

Associate Editors

M. Hallek, Köln

S. Al-Batran, Frankfurt/M. C. Berking, München C. Bokemeyer, Hamburg M. Borner, Bern T. Cerny, St. Gallen H. T. Eich, Münster A. Engert, Köln M. Fassnacht, Würzburg B. Groner, Frankfurt/M. V. Heinemann, München M. Hentrich, München R. D. Issels, München

W. Janni, Ulm U. R. Kleeberg, Hamburg H. Lang, Mainz M. Moehler, Mainz M. Schuler, Essen R. Stupp, Zürich M. Theobald, Mainz R. Thomas, Köln U. Wedding, Jena J. A. Werner, Marburg O. Zivanovic, New York

A. Heidenreich, Aachen U. Herrlinger, Bonn A. Hochhaus, Jena R.-D. Hofheinz, Mannheim F. Honecker, St. Gallen V. Jacobs, Salzburg K. Jordan, Halle U. Keilholz, Berlin J. P. Klussmann, Gießen H. Kölbl, Wien W. Kuhn, Bonn H.-J. Lenz, Los Angeles P. Mallmann, Köln

H. Moch, Zürich K. Possinger, Berlin P. Reichardt, Bad Saarow S. Reske, Ulm I. Runnebaum, Jena P. Schöffski, Leuven C. Spitzweg, München I. Strohscheer, St. Peter-Ording S. Ugurel, Graz R. Voltz, Köln M. Weller, Zürich

Editorial Board P. Albers, Düsseldorf C. Bausewein, München L. Bergmann, Frankfurt/M. J. Boos, Münster P. Brossart, Bonn W. Budach, Düsseldorf R. Büttner, Bonn J. Debus, Heidelberg E. Dippel, Ludwigshafen A. Du Bois, Essen T. Fehm, Düsseldorf F. Geiser, Bonn N. Harbeck, München

S. Karger GmbH Attn. Dr. Steffi Hentzelt P.O. Box D-79095 Freiburg E-mail [email protected]

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Editorial Office

Tagungspräsident

Prof. Dr. Carsten Bokemeyer, Hamburg Prof. Dr. Norbert Schmitz, Hamburg

Wissenschaftliches Sekretariat PD Dr. Mascha Binder Prof. Dr. Bertram Glaß Abstractgutachter Bernd Alt-Epping, Reinhard Andreesen, Elisabeth Andritsch, Anne Angelillo-Scherrer, Dirk Arnold, Renate Arnold, Ulrike Bacher, Stefan Balabanov, Marija Balic, Mario Bargetzi, Hannsjörg Baum, Walter Baumann, Dietrich W. Beelen, Lothar Bergmann, Jörg Beyer, Mascha Binder, Carsten Bokemeyer, Peter Borchmann, Martin Bornhäuser, Thomas Brodowicz, Peter Brossart, Tim Brümmendorf, Christian Buske, Richard Cathomas, Maximilian Christopeit, Maria De Santis, Maike De Wit, Christine Dierks, Uta Dirksen, Johannes Drach, Martin Dreyling, Ulrich Dührsen, Justus Duyster, Alexander Egle, Hermann Einsele, Wolfgang Eisterer, Jutta Engel, Monika Engelhardt, Andreas Engert, Jonas Walter Feilchenfeldt, Walter Fiedler, Thomas Fischer, Michael Fridrik, Martin Früh, Reinhard Gager, Simon Gampenrieder, Arnold Ganser, Günther Gastl, Armin Gerger, Ulrich Germing, Michael Girschikofsky, Heinz Gisslinger, Hartmut Goldschmidt, Hildegard Greinix, Viktor Grünwald, Cornelie Haag, Rainer Haas, Torsten Haferlach, Michael Herold, Viviane Hess, Pia Heußner, Wolfgang Hiddemann, Andreas Hochhaus, Friedemann Honecker, Yvonne Hummel, Dirk Jäger, Karin Jordan, Christian Junghanß, Ursula Kapp, Felix Keil, Gerd Klein, Michael Kneba, Dieter Köberle, Gabriela Kornek, Thomas Kühr, Ralf Küppers, Alois Lang, Florian Langer, Philipp le Coutre, Werner Linkesch, Andreas Lohri, Anja Lorch, Florian Lordick, Heinz Ludwig, Diana Lüftner, Andreas Mackensen, Robert Mader, Christine Mannhalter, Markus Manz, Christine Marosi, Anja Mehnert, Thomas Melchardt, Johannes Meran, Olaf Merkel, Brigitte Mlineritsch, Carsten Müller-Tidow, Andreas Neubauer, Dietger Niederwieser, Karin Oechsle, Aurelius Omlin, Oliver Ottmann, Friedrich Overkamp, Ingrid Pabinger, Jens Panse, Jakob Passweg, Christian Peschel, Bernhard-C. Pestalozzi, Christina Peters, Petro E. Petrides, Andreas Petzer, Holger Pfaff, Michael Pfeilstöcker, Robert Pirker, Ferdinand Ploner, Markus Raderer, Oliver Rick, Hanno Riess, Thomas Ruhstaller, Renate Schaberl-Moser, Brigitte Schallmoser, Werner Scheithauer, Richard F. Schlenk, Ingo Schmidt-Wolf, Clemens A. Schmitt, Norbert Schmitz, Jochen Schütte, Marco Siano, Michael Stahl, Reinhard Stauder, Jens Stäudle, Günther Steger, Alexander Stein, Michael Steurer, Stephan Stilgenbauer, Florian Strasser, Imke Strohscheer, Roger Stupp, Josef Thaler, Matthias Theobald, Christian Thiede, Eckhard Thiel, Nils Thoennissen, Peter Thuss-Patience, André Tichelli, Marlene Troch, Christof von Kalle, Herbert Watzke, Rudolf Weide, Ansgar Weltermann, Clemens-Martin Wendtner, Martin Wilhelm, Hansjochen Wilke, Daniel Winter, Mathias Witzens-Harig, Dominik Wolf, Bernhard J. Wörmann, Patrick Wuchter, Gerald Wulf, August Zabernigg, Robert Zeiser, Christoph Zielinski, Katja Zirlik

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The editors declare no conflict of interest.

Jahrestagung der D eutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie Hamburg, 10.– 14. Oktober 2014

ABSTRACTS Herausgeber

Carsten Bokemeyer, Hamburg Norbert Schmitz, Hamburg

Die DGHO, OeGHO, SGMO und SGH übernehmen keine Gewähr für die Richtigkeit der Angaben in den Abstracts. Beiträge und Anzeigen geben nicht notwendigerweise die Auffassung der Vorstände wieder.

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Band 37, Supplement 5, Oktober 2014

Contents ∙ Inhalt ∙ (chronologisch)

Abstract-No. Page-No.

Komplementärmedizin in der Onkologie Nierenzellkarzinom Freier Vortrag Urogenitale Tumore Lungenkrebs I Wissenschaftliches Symposium Moderne Onkologie und alte Patienten. Ein interdisziplinäres Symposium zu medizinischen und ethischen Aspekten Molekulare Analytik als Grundlage moderner, gezielter Arzneimitteltherapie: Unwirtschaftliche Diagnostik oder kosteneffiziente Behandlung? Freier Vortrag Lymphome – sonstiges Plenarsitzung NHL Aggressiv Fortbildung Mammakarzinom MPN Hämostaseologie I Keimzelltumore – Zwischen Toxizitätsminimierung in frühen Stadien und Therapieinnovationen bei Hochrisikopatienten Freier Vortrag Multiples Myelom – klinisch Wissenschaftliches Symposium AML Karzinome der Schilddrüse, Speicheldrüse und des Nasopharynx – selten, aber wichtig! Freier Vortrag Sonstige Hämatologie Fortbildung Multiples Myelom – Update 2014 Kopf-Hals-Tumore – Update zur interdisziplinären Therapie Neurologische Nebenwirkungen von Zytostatika Ärztliches Selbstverständnis und Ökonomisierung in der Onkologie Freier Vortrag AML – klinisch Wissenschaftliches Symposium Stammzellbiologie MDS – Fortschritte beim MDS Expertenseminar Molekulare Diagnostik in der Hämatologie – was ist sinnvoll? Freier Vortrag Aggressive B-NHL – klinisch Wissenschaftliches Symposium Flächendeckende Versorgung von Krebspatienten in der Zukunft Fortbildung Update Infektionen in der Hämatologie und Onkologie CML Hepatische und Gallenwegstumore Multiples Myelom – spezielle Aspekte Freier Vortrag Allogene Transplantation – klinisch I Wissenschaftliches Symposium Immuntherapie – adoptiver T-Zell Transfer Freier Vortrag MDS – experimentell Wissenschaftliches Symposium Palliativmedizin Posterdiskussion Akute Leukämien I CLL CML/MPN Lungenkrebs Lymphome I Sonstige Hämatologie Tumore des Gastrointestinalen Traktes I Urogenitale Tumore (inkl. Prostata und Niere) Wissenschaftliches Symposium Therapie des Rektumkarzinoms Fortbildung Intensivmedizin Freier Vortrag Supportive Therapie – Infektion und Prophylaxe Fortbildung Optimaler Einsatz neuer Therapien beim Melanom: was und wann Therapiekonzepte bei Weichteilsarkomen

V18–V20 V22 V24–V29 V30–V35

1 2 2 5

V38

9

Fortbildung



V39–V41 V45–V50 V52 V54–V55 V57–V58 V61–V63

9 10 12 14 14 15

V65–V67 V68–V73 V74–V76

16 18 20

V78–V80 V83–V88 V94–V97 V98–V100 V103

21 22 26 27 28

V106 V108–V113 V116 V118 V120 V122–V127

28 28 32 32 32 33

V131 V134–V136 V138–V139 V143 V144 V147–V152 V158 V160–V165 V166 P169–P185 P186–P197 P198–P216 P217–P231 P232–P246 P247–P263 P264–P274 P275–P288 V291 V295–V297 V298–V303

35 36 37 37 38 38 41 41 44 44 50 56 64 69 75 81 86 91 92 93

V304–V306 V308

95 96

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Oncol Res Treat 2014;37(suppl 5)

Contents ∙ Inhalt ∙ (chronologisch) Oncol Res Treat 2014;37(suppl 5)


ITP MDS Fortbildung CLL Lymphom, Myelom, MPN: Neue Medikamente versus Transplantation Palliativmedizin I ALL des Erwachsenen Freier Vortrag Kolorektales Karzinom I Wissenschaftliches Symposium Aplastische Syndrome Expertenseminar Mammakarzinom Fortbildung Systemtherapie des Prostatakarzinoms Magenkarzinom Zerebrale Lymphome Klinische Standards beim Follikulären Lymphom Freier Vortrag Kolorektales Karzinom II Wissenschaftliches Symposium Karriere von Frauen in der Onkologie und Hämatologie Freier Vortrag Allogene Transplantation – experimentell Mammakarzinom – klinisch Immuntherapie I Fortbildung Kolorektales Karzinom Hodgkin Lymphom Wissenschaftliches Symposium Ovar/Uterus – Ovarialkarzinom Fortbildung Aktuelle Supportive Therapie Leitlinien compact Freier Vortrag Kopf/Hals, Schilddrüse und ZNS Tumore Fortbildung Palliativmedizin II Freier Vortrag Hepatische Tumore/Magenkarzinom/Pankreaskarzinome Posterdiskussion Akute Leukämien II Allogene Transplantationen Ethik/Palliativmedizin/Psychoonkologie Lymphome II Multiples Myelom I Sonstige Onkologie I Supportive Therapie Tumore des Gastrointestinalen Traktes II Versorgungsforschung I Wissenschaftliches Symposium CML Niere, Harnleiter und Blase – Forschung beim Urothelkarzinom 2014 Freier Vortrag Prostatakarzinome ALL Fortbildung Teamorientierung in der onkologischen Versorgung Freier Vortrag CLL – klinisch Fortbildung Maligne Gliome Freier Vortrag Mammakarzinom – experimentell Langzeitüberlebende und AYA Multiples Myelom – experimentell I Plenarsitzung Best Abstracts Fortbildung Lungenkrebs Wissenschaftliches Symposium Studienzentren B-Zell Rezeptor Signalübertragung in der CLL Freier Vortrag MPN Fortbildung MDS Freier Vortrag Multiples Myelom – experimentell II Hämatopoetische Stammzellen

V310 V311 V314



96 96 97

V317 V320 V324–V325 V327–V332 V334 V337 V339 V342–V344 V347 V349 V351–V356 V360 V363–V368 V369–V374 V375–V380 V381–V384 V385–V386 V389–V390 V392–V394 V395–V400 V402 V408–V413 P414–P430 P431–P448 P449–P458 P459–P471 P472–P483 P484–P497 P498–P515 P516–P527 P528–P542 V543–P545

97 98 98 99 102 102 103 103 104 104 104 107 107 110 112 115 115 116 117 118 120 121 124 131 138 142 147 152 158 165 169 175

V549 V552–V557 V558–V563 V566–V567 V568–V573 V574–V576 V579–V584 V585–V588 V590–V595 V596–V601 V604 V607–V609 V610 V613–V618 V620–V622 V623–V628 V629–V634

176 177 179 182 183 186 186 189 191 193 196 196 197 197 199 200 202

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Expertenseminar

Contents ∙ Inhalt ∙ (chronologisch) Oncol Res Treat 2014;37(suppl 5)


Transplantation V635–V637 204 Freier Vortrag AML – molekular I V640–V645 205 Immuntherapie III V646–V651 208 Wissenschaftliches Symposium Young Investigators' Awards V652–V657 210 NHL Aggressiv – DLBCL: genetische Heterogenität und personalisierte Therapie V661 213 Prostatakarzinom V663 213 Microenviroment/Angiogenesis V665–V666 213 Freier Vortrag Gerinnung/ Thrombozyte V668–V673 214 CML/MPN V676–V681 218 CLL – molekular I V682–V687 220 Wissenschaftliches Symposium Kontroversen in der Behandlung des Multiplen Myelom V688–V689 222 Expertenseminar CML V691 223 Freier Vortrag AML – molekular II V692–V697 224 Lungenkrebs II V698–V703 226 Allogene Transplantation – klinisch II V704–V709 228 Wissenschaftliches Symposium Fortschritte bei der Prognose und Therapie der AL Amyloidose V710 230 Myeloische Epigenetik – Von präklinischen Forschungsergebnissen in der Epigenetik zur erfolgreichen klinischen Anwendung V713–V716 231 Adjuvante Therapie des Kolonkarzinoms V718 232 Freier Vortrag MDS – klinisch V720–V725 233 CLL – molekular II V731–V736 236 Fortbildung Psychoonkologie V737–V738 238 Freier Vortrag Immuntherapie II V740–V745 239 Versorgungsforschung V746–V751 241 Nichtmaligne Hämatologie V752–V757 243 Posterdiskussion Hämatopoetische Stammzellen und MDS P758–P771 247 Immuntherapie P772–P786 252 Lymphome III P787–P796 258 Mammakarzinom und gynäkologische Tumore P797–P810 261 Sonstige Onkologie II P811–P826 267 Sonstige Onkologie III P827–P840 273 Tumorbiologie P841–P859 279 Multiples Myelom II P860–P871 286 Versorgungsforschung II P872–P886 291 Wissenschaftliches Symposium Antikörpertherapie 2014 V888 297 Fortbildung Neuroendokrine Tumoren V897–V898 297 Freier Vortrag Tumorbiologie V899–V903 298 CML – klinisch V904–V909 300 Fortbildung Survivorship V910 303 Freier Vortrag Hämatopoetische Stammzellen und Niche V913–V918 303 Fortbildung Kompetenznetzwerk Leukämien V922–V926 305 Wissenschaftliches Symposium Tumorkachexie & Mangelernährung – Grundlagen und neueste therapeutische Möglichkeiten V928–V929 306 Freier Vortrag CML – experimentell V930–V935 307 Fortbildung Aggressive B-Zell Non-Hodgkin Lymphome V937–V938 309 Freier Vortrag Immuntherapie IV V939–V944 310 Plenarsitzung Presidential Symposium – Immune checkpoint targeting V945–V946 312 Author Index 314 Imprint 332



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Wissenschaftliches Symposium

Contents ∙ Inhalt ∙ (nach Sitzung)


NHL Aggressiv Best Abstracts Presidential Symposium – Immune checkpoint targeting Wissenschaftliche Symposien Adjuvante Therapie des Kolonkarzinoms AML Antikörpertherapie 2014 Aplastische Syndrome B-Zell Rezeptor Signalübertragung in der CLL CML Flächendeckende Versorgung von Krebspatienten in der Zukunft Fortschritte bei der Prognose und Therapie der AL Amyloidose Immuntherapie – adoptiver T-Zell Transfer Karriere von Frauen in der Onkologie und Hämatologie Karzinome der Schilddrüse, Speicheldrüse und des Nasopharynx – selten, aber wichtig! Kontroversen in der Behandlung des Multiplen Myelom MDS – Fortschritte beim MDS Microenviroment/Angiogenesis Moderne Onkologie und alte Patienten. Ein interdisziplinäres Symposium zu medizinischen und ethischen Aspekten Molekulare Analytik als Grundlage moderner, gezielter Arzneimitteltherapie: Unwirtschaftliche Diagnostik oder kosteneffiziente Behandlung? Myeloische Epigenetik – Von präklinischen Forschungsergebnissen in der Epigenetik zur erfolgreichen klinischen Anwendung NHL Aggressiv – DLBCL: genetische Heterogenität und personalisierte Therapie Niere, Harnleiter und Blase – Forschung beim Urothelkarzinom 2014 Ovar/Uterus – Ovarialkarzinom Palliativmedizin Prostatakarzinom Stammzellbiologie Studienzentren Therapie des Rektumkarzinoms Transplantation Tumorkachexie & Mangelernährung – Grundlagen und neueste therapeutische Möglichkeiten Young Investigators' Awards Fortbildungen Aggressive B-Zell Non-Hodgkin Lymphome Aktuelle Supportive Therapie Leitlinien compact ALL des Erwachsenen Ärztliches Selbstverständnis und Ökonomisierung in der Onkologie CLL CML Hämostaseologie I Hepatische und Gallenwegstumore Hodgkin Lymphom Intensivmedizin Keimzelltumore – Zwischen Toxizitätsminimierung in frühen Stadien und Therapieinnovationen bei Hochrisikopatienten Klinische Standards beim Follikulären Lymphom Kolorektales Karzinom Kompetenznetzwerk Leukämien Komplementärmedizin in der Onkologie Kopf-Hals-Tumore – Update zur interdisziplinären Therapie

V52 V596–V601 V945–V946 V718 V74–V76 V888 V334 V610 V543–P545

12 193 312 232 20 297 102 197 175

V131 V710 V158 V360

35 230 41 107

V78–V80 V688–V689 V118 V665–V666

21 222 32 213

Plenarsitzungen



V38

9

V39–V41

9

V713–V716

231

V661

213

V549 V389–V390 V166 V663 V116 V607–V609 V291 V635–V637

176 116 44 213 32 196 91 204

V928–V929 V652–V657 V937–V938 V392–V394 V324–V325

306 210 309 117 98

V106 V314 V138–V139 V61–V63 V143 V385–V386 V295–V297

28 97 37 15 37 115 92

V65–V67 V349 V381–V384 V922–V926 V18–V20 V98–V100

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Contents ∙ Inhalt ∙ (nach Sitzung)


Lungenkrebs Lymphom, Myelom, MPN: Neue Medikamente versus Transplantation Magenkarzinom Maligne Gliome Mammakarzinom MDS MPN Multiples Myelom – spezielle Aspekte Multiples Myelom – Update 2014 Neuroendokrine Tumoren Neurologische Nebenwirkungen von Zytostatika Nierenzellkarzinom Optimaler Einsatz neuer Therapien beim Melanom: was und wann Palliativmedizin I Palliativmedizin II Psychoonkologie Survivorship Systemtherapie des Prostatakarzinoms Teamorientierung in der onkologischen Versorgung Therapiekonzepte bei Weichteilsarkomen Update Infektionen in der Hämatologie und Onkologie Zerebrale Lymphome Expertenseminare CML ITP Mammakarzinom MDS Molekulare Diagnostik in der Hämatologie – was ist sinnvoll? Freie Vorträge Aggressive B-NHL – klinisch ALL Allogene Transplantation – experimentell Allogene Transplantation – klinisch I Allogene Transplantation – klinisch II AML – klinisch AML – molekular I AML – molekular II CLL – klinisch CLL – molekular I CLL – molekular II CML – experimentell CML – klinisch CML/MPN Gerinnung/ Thrombozyte Hämatopoetische Stammzellen Hämatopoetische Stammzellen und Niche Hepatische Tumore/Magenkarzinom/Pankreaskarzinome Immuntherapie I Immuntherapie II Immuntherapie III Immuntherapie IV Kolorektales Karzinom I Kolorektales Karzinom II Kopf/Hals, Schilddrüse und ZNS Tumore Langzeitüberlebende und AYA Lungenkrebs I Lungenkrebs II Lymphome – sonstiges Mammakarzinom – experimentell

V604

196

V317 V342–V344 V574–V576 V54–V55 V620–V622 V57–V58 V144 V94–V97 V897–V898 V103 V22

97 103 186 14 199 14 38 26 297 28 2

V304–V306 V320 V402 V737–V738 V910 V339 V566–V567 V308 V134–V136 V347 V691 V310 V337 V311 V120 V122–V127 V558–V563 V363–V368 V147–V152 V704–V709 V108–V113 V640–V645 V692–V697 V568–V573 V682–V687 V731–V736 V930–V935 V904–V909 V676–V681 V668–V673 V629–V634 V913–V918 V408–V413 V375–V380 V740–V745 V646–V651 V939–V944 V327–V332 V351–V356 V395–V400 V585–V588 V30–V35 V698–V703 V45–V50 V579–V584

95 98 120 238 303 103 182 96 36 104 223 96 102 96 32 33 179 107 38 228 28 205 224 183 220 236 307 300 218 214 202 303 121 112 239 208 310 99 104 118 189 5 226 10 186



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Contents ∙ Inhalt ∙ (nach Sitzung) Oncol Res Treat 2014;37(suppl 5)

Mammakarzinom – klinisch MDS – experimentell MDS – klinisch MPN Multiples Myelom – experimentell I Multiples Myelom – experimentell II Multiples Myelom – klinisch Nichtmaligne Hämatologie Prostatakarzinome Sonstige Hämatologie Supportive Therapie – Infektion und Prophylaxe Tumorbiologie Urogenitale Tumore Versorgungsforschung Akute Leukämien I Akute Leukämien II Allogene Transplantationen CLL CML/MPN Ethik/Palliativmedizin/Psychoonkologie Hämatopoetische Stammzellen und MDS Immuntherapie Lungenkrebs Lymphome I Lymphome II Lymphome III Mammakarzinom und gynäkologische Tumore Multiples Myelom I Multiples Myelom II Sonstige Hämatologie Sonstige Onkologie I Sonstige Onkologie II Sonstige Onkologie III Supportive Therapie Tumorbiologie Tumore des Gastrointestinalen Traktes I Tumore des Gastrointestinalen Traktes II Urogenitale Tumore (inkl. Prostata und Niere) Versorgungsforschung I Versorgungsforschung II

Posterdiskussionen


V369–V374 V160–V165 V720–V725 V613–V618 V590–V595 V623–V628 V68–V73 V752–V757 V552–V557 V83–V88 V298–V303 V899–V903 V24–V29 V746–V751 P169–P185 P414–P430 P431–P448 P186–P197 P198–P216 P449–P458 P758–P771 P772–P786 P217–P231 P232–P246 P459–P471 P787–P796 P797–P810 P472–P483 P860–P871 P247–P263 P484–P497 P811–P826 P827–P840 P498–P515 P841–P859 P264–P274 P516–P527 P275–P288 P528–P542 P872–P886

110 41 233 197 191 200 18 243 177 22 93 298 2 241 44 124 131 50 56 138 247 252 64 69 142 258 261 147 286 75 152 267 273 158 279 81 165 86 169 291



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Author Index 314 Imprint 332

Abstracts Oncol Res Treat 2014;37(suppl 5):1–313

Komplementärmedizin in der Onkologie V18

Herbal drugs in oncology – indications and state of evidence Rostock M. Universitätsklinikum Hamburg-Eppendorf, Hubertus Wald Tumorzentrum Universitäres Cancer Center, Hamburg, Germany

There are different intentions why patients with tumor-diseases use herbal extracts. The use of herbs as supportive therapy is often based on a century-old experience and in the last years this use is increasingly examined and evaluated. In the following we show actual examples with positive outcomes. Under intake of 2000 mg root extract of Wisconsin Ginseng (Panax quinquefolius) in an RCT with n = 364 patients with cancer-related fatigue a statistical significant effect on the general subscale of the MFSI-SF was shown ( Barton D et al., 2013). Another RCT with breast cancer patients suffering from cancer-related fatigue succesfully proved the therapeutic effect of 50 mg Guarana extract twice daily vs. placebo (de Oliveira Campos MP et al., 2011). After all Mistletoe is one of the most controversially discussed herbal drugs in oncology. According to the Cochrane review from 2008 a positive effect on quality of life in breast cancer patients during chemotherapy was shown (Horneber M et al.). A study from 2013 on mistletoe extract in patients with locally advanced or metastatic pancreatic cancer (n = 220) injected s.c. thrice weekly showed a significant effect on overall survival compared to best supportiv care (Tröger W et al., 2013). Interesting results on herbal drugs have been shown on PSA progression in men with prostate cancer. A study of Paller et al. (2013) confirmed the positive effects of pomegranate juice in men with slow rising PSA following primary curative intended therapy of the first study from Pantuck et al. (2006). A similar effect was found by Thomas et al. (2013) in a combination of pomegranate-, green tea-, broccoli-, and turmeric-extract in a double-blind RCT (n = 199): the median rise in PSA in the verum group was 14.7% (95% CI 3.4–36.7%) compared to 78.5% (95% CI 48.1–115.5%) in the placebo control. Especially in the last years specific research on combinations of several herbal extracts with different targets demonstrated in preclinical studies (in this case effects on inflammation, angiogenesis, metastasis, adhesion, and apoptosis) is rising. In general the active components of phytotherapeutic drugs are pleiotropic multi-ingredient compounds with multi-target properties. Their therapeutic potential in oncology has to be evaluated further in well planned clinical trials. Disclosure: No conflict of interest disclosed. V19

Acupuncture in oncology – the current evidence Witt C.M. University Hospital Zurich, Institute for Complementary and Integrative Medicine, Zurich, Switzerland

Acupuncture, a non-pharmacological intervention with a positive safety profile, is often provided as adjunct treatment to cancer patients. A recent observational study in routine care included 641 patients receiving acupuncture at the MD Anderson Cancer Center. Those patients suffered mainly from fatigue, nausea, pain, dry mouths, poor sleep, and



numbness and reported improvements for most symptoms as well as wellbeing after treatment (Garcia 2014). However, these results have to be judged with caution, because this type of study design can’t control for confounding, regression to the mean and co-interventions. Focusing on acupuncture point specific effects and taking into account only studies with low risk of bias, a recent systematic review (Garcia 2013) has found acupuncture to be an appropriate adjunct treatment for nausea/vomiting. For other symptoms such as pain, fatigue and numbness some of the RCTs included in this systematic review showed promising results, but either the sample was small or the risk of bias high. For reducing aromatase inhibitor initiated musculoskeletal symptoms two very recent studies (Mao 2014, Bao 2014) with around 25 patients per group found no statistical significant differences between acupuncture and sham acupuncture, however, one of them had a third study arm and observed that acupuncture was superior to usual care (Mao 2014). In both studies due to the small sample size only large group differences would have been statistical significant. Future research in acupuncture for cancer patients should include more high quality trials that are also powered to detect moderate effect sizes. References Garcia K eta al.: Analysis of outpatient acupuncture treatments at a major cancer center. The Journal of Alternative and Complementary Medicine. 2014;20(5):A93. Garcia MK et al.: Systematic review of acupuncture in cancer care: a synthesis of the evidence. Journal of Clinical Oncology. 2013;31(7):952–960. Mao JJ et al.: A randomised trial of electro-acupuncture for arthralgia related to aromatase inhibitor use. European Journal of Cancer. 2014;50:267–276. Bao T et al.: Patient-reported outcomes in women with breast cancer enrolled in a dual-center, double-blind, randomized controlled trial assessing the effect of acupuncture in reducing aromatase inhibitor-induced musculoskeletal symptoms. Cancer. 2014;120(3):381–399. Disclosure: Claudia Witt: Employment or Leadership Position: Director of the Institute for Complementary and Integrative Medicine, UniversityHospital Zurich; Expert Testimony: Research Grant by the Otto Foundation for an Acupuncture Trial in Breast Cancer Patients V20

Risk of herb-drug interactions in oncology – state of evidence Lendeckel A., Ritter C. Ernst-Moritz-Arndt-Universität Greifswald, Institut für Pharmazie, Klinische Pharmazie, Greifswald, Germany

Complementary and alternative medicine (CAM) is an emerging field in oncology and information about efficacy and safety is increasingly demanded by both prescibers and users. Particularly when phytotherapeutics are recommended or asked for, the CAM community has developed some degree of consciousness about potential herb-drug interactions risks. However, evidence is still sparse and difficult to interpret. Thus, systematic approaches to select and grade evidence of herb-drug interaction risks are urgently warranted. Using systematic literature reviews we have collected any evidence for pharmacokinetic herb-drug interactions of five phytotherapeutically applied plants (St. John´s Wort, Milk thistle, Coneflower, Asian Ginseng and Mistletoe). Due to variable existence and consistencies of evidence data we developed an algorithm to extrapolate drug interaction risk categories based on existing knowledge. Of over 1.000 publications, 176 studies were eligible to be included into the herb-drug interactions knowledge database based on drug interaction mechanism, herbal dose, number of drugs tested and activity status of drug metabolizing enzymes. Data extraction resulted in 510 single reDownloaded by: 75.109.202.52 - 5/19/2015 11:03:46 AM

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Disclosure: No conflict of interest disclosed.

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Nierenzellkarzinom V22

ic/lumbar spine is rare and challenging but needs complete resection for curative intent. We report on our single centre experience in the management of such complex cases. Patients and Methods: PCRPLND was performed in 162 pts. with advanced NS and normalized/plateauing tumour markers. A total of 13 patients required adjunctive skeletal and vascular surgery to the lumbar spine and the aorta/inferior vena cava due to tumour involvement in conjunction with a full bilateral radical PC-RPLND. Results: Median patient age was 24.5 (18–52) years. All patients were of intermediate or poor prognosis according to IGCCCG. Median tumour diameter at time of surgery was 18.6 (9.0–35) cm. In 5 patients 1–2 metastatic lumbar vertebral bodies were completely resected, stabilized and replaced by metal cages. In 6 patients the infrahilar aorta/inferior vena cava was replaced by a graft. In 2 patients complete resection of the common iliac arteries and veins with graft replacement was performed. Histological evaluation of the resected specimens revealed teratoma, vital cancer and necrois in 3, 2 and 0 patients with resection of vertebral bodies. However, teratoma and vital cancer was identified in 5 and 3 patients who had undergone vascular surgery. In addition, retrocrural lymph nodes had to be resected in 5 patients and 3 patients required adjunctive nephrectomy. After a median follow-up of 2.5 years 1 patient developed recurrent disease. Conclusions: Few patients with advanced NS need complex surgery in an interdisciplinary setting with good functional and oncological outcome. Even the presence of vertebral metastases should not restrain the surgeon to perform PC-RPLND. Due to the complexity, treatment should be performed at specialized centres.

Immunotherapy: new targets in metastatic renal cell carcinoma?


Grünwald V., Interdisziplinäre Arbeitsgruppe Nierentumoren (IAG-N)

V25

Medizinische Hochschule Hannover, Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Hannover, Germany

Targeted therapies have advanced the field of metastatic renal cell carcinoma (RCC). Objective response rates (ORR) of 30%, a progression free survival (PFS) of 8–10 months and an overall survival (OS) of approx. 30 months remain the benchmarks for contemporary therapies. In contrary to these agents, historic immunotherapy promised long-term remissions with discontinuous treatment in a minority of patients. With the advent of checkpoint inhibitors – a new era of targeted immunotherapies has arrived in the clinic and raises great expectations. Initial clinical trials assess the role of combinations to further improve clinical outcome. Whether combination therapy may prevail in the future remains an open task and current studies are ongoing. Certainly, targeted immunotherapy has pushed our expectations to the next level in RCC. Disclosure: Viktor Grünwald: Advisory Role: GSK, Pfizer, Novartis, Bayer, Mologen, Astellas; Financing of Scientific Research: GSK, Pfizer, Novartis, Bayer, Astellas

Freier Vortrag

Urogenitale Tumore V24

Surgical management of testicular cancer patients with complex postchemotherapy residual masses: Aachen University experience Heidenreich A., Porres D., Piper C., Thissen A., Pfister D. Uniklinik RWTH Aachen, Aachen, Germany

Background: Postchemotherapy retroperitoneal lymphadenectomy (PC-RPLND) represents the treatment of choice in patients with residual masses following systemic chemotherapy for advanced testicular nonseminomas (NS). Involvement of major retroperitoneal vessels or thorac-

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Oncol Res Treat 2014;37(suppl 5):1–313

Impact of bone metastases at initial diagnosis in male patients with metastatic germ cell tumors: Results from an international database Oing C.1, Oechsle K.1, Necchi A.2, Loriot Y.3, De Giorgi U.4, Fléchon A.5, Daugaard G.6, Fedyanin M.7, Cohn-Cedermark G.8, Sava T.9, Lorch A.10, Winquist E.11, Gietema J.12, Hentrich M.13, Farè E.2, Bokemeyer C.1 Universitätsklinikum Hamburg-Eppendorf, II. Medizinische Klinik, Hamburg, Germany, 2Fondazione IRCCS, Istituto Nazionale dei Tumori, Medical Oncology Unit 2, Milan, Italy, 3Institut Gustave Roussy, University of Paris-Sud, Department of Cancer Medicine, Villejuif, France, 4IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T), Department of Oncology, Meldola, Italy, 5Centre Léon Bérard, Department of Medical Oncology, Lyon, France, 6Copenhagen University Hospital, Department of Oncology, Copenhagen, Denmark, 7N.N. Blokhin Russian Cancer Research Center, Department of Clinical Pharmacology and Chemotherapy, Moscow, Russian Federation, 8Karolinska Institute and University Hospital, Department of Oncology, Stockholm, Sweden, 9 Azienda Ospedaliera Universitaria Integrata Verona, Department of Oncology, Verona, Italy, 10University Medical Center Düsseldorf, Department of Urology, Düsseldorf, Germany, 11London Health Sciences Center, London, Canada, 12University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands, 13Harlaching Hospital and Neuperlach Hospital, Department of Hematology, Oncology and Palliative Care, Munich, Germany 1

Introduction: Bone metastases (BM) are rare in metastatic germ cell tumor (GCT) patients (pts). Systematic data on risk factors, treatment and outcome are limited. Methods: An international database of 140 GCT pts with BM at first diagnosis at a median age of 32 years (range, 15–77) diagnosed between 1983–2013 from 23 centers was retrospectively analyzed. Results: Pts had a primary gonadal / retroperitoneal / mediastinal GCT in 68% / 16% / 16% and histology was nonseminoma / seminoma in 78% / 20% (2% unknown). BM were located in spine (71%), pelvis (24%), ribs (12%), upper extremities (9%), lower extremities (8%), cranium (7%), scapula (2%), and sternum (2%). 40% had a single and 60% multiple BM. Additional sites of metastases were retroperitoneal lymph nodes (69%),

Abstracts

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sult in vitro and in vivo datasets. From these datasets an algorithm was developed that leads to four herb-drug interaction risk categories of: interaction is certain, interaction is possible, interaction is unlikely, prediction is not possible. The algorithm considers clinical trials outcomes, drug metaboism and transport, consistancy of study results, and a risk relevance estimation. Drug interaction risk categories are presented in a pairwise manner of herbs and cytostatic drugs, which is accompanied by information on herb-drug interaction mechanisms, clinical consequences and treatment recommendations. In addition, herb-drug interaction fact sheets were developed for further and more detailed information on the interaction potential of the selected herbal preparations. In conclusion, we have developed a useful information tool on herb-drug interaction risks based on systematically selected and graded evidence which is presented in a comprehensive and clear manner. This will enable prescribers and ultimately users to critically evaluate the use of phytotherapeutical complementary preparations and thereby increase treatment safety in oncology. This work is part of the Competence Network Complementary Medicine in Oncology – KOKON and is funded by the Deutsche Krebshilfe e.V.

Disclosure: No conflict of interest disclosed. V26

Efficacy and safety of gemcitabine and oxaliplatin with or without paclitaxel in cisplatin-refractory germ cell tumours beyond clinical trials – Registry data from clinical practice Seidel C.1, Lorch A.2, Rickmann M.3, Cathomas R.4, de Wit M.5, Bokemeyer C.1, Grünwald V.3, Oechsle K.1 University Medical Center Eppendorf, Department of Oncology, Hematology and BMT, Hamburg, Germany, 2University Hospital Düsseldorf, Genitourinary Medical Oncology, Düsseldorf, Germany, 3 Hannover Medical School, Hematology, Hemostasis, Oncology and Stem cell transplantation, Hannover, Germany, 4Kantonsspital Chur, Medical Oncology, Chur, Switzerland, 5Vivantes Klinikum Neukölln, Hematology and Oncology, Berlin, Germany 1

Introduction: Combination chemotherapy with gemcitabine, oxaliplatin with or without paclitaxel GO(P) has shown efficacy within clinical trials in patients (pts) with multiply relapsed or cisplatin-refractory germ cell tumour. Here we present the efficacy, safety and potential prognostic factors in pts treated with GO(P) in routine care in order to see if the results achieved within trials are reproducible in daily practice. Methods: A national database for pts who received GO(P) treatment was implemented. So far, 44 pts were contributed from of five centers. Pts response to chemotherapy, treatment duration and overall survival (OS) were measured and uni- and multivariate analyses were performed to evaluate the prognostic impact of patient characteristics. Results: Regimen was GOP in 39 pts and GO in 5 pts. Prior to GO(P) a median of 3 treatment lines (range, 1 to 7) were applied. Hereby, high dose chemotherapy was applied in 34 pts. prior GO(P). The median treatment duration lasted 3.2 months. In 38 pts (33 GOP; 5 GO) best response could be defined by radiologic assessment and/or serum marker measurements. A complete remission (CR) was achieved in 4/38 pts (11%) with one patient receiving additive metastatic resection and one patient with non-measurable disease who achieved marker normalization. Partial remissions were achieved in 14/38 pts (37%). Stable disease was detected in 5/38 pts (13%). A total of 15/38 pts (39%) had disease progression at first tumour evaluation. At the time of data collection 15/38 pts (39%) were still alive. Median OS from treatment initiation of was 16.8 months

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(95%CI 12.3–21.3). In 16/44 pts (36%) dose reductions were required and in 3/44 pts (7%) treatment had to be stopped due to intolerable toxicity. Univariate analysis revealed an elevated CRP-level and objective tumour remission to be prognostic factors for OS (p = 0.03 and p 20%) side effects under 1st-line treatment SO vs SU were alopecia (29/4%), diarrhea (43/29%), dysgeusia (8/21%), fatigue (21/34%), HFSR (37/20%), hypertension (24/24%), nausea (18/24%) and rash (22/3%). AEs were generally lower during 2nd-line therapy. Conclusions: There was no significant difference in T-PFS, OS, DCR and 1st-line PFS between the two sequential treatments. Both drugs provided overall benefit regardless of sequence. Side effect profiles differ, but were generally less frequent during 2nd-line therapy. More patients reached 2nd-line in the SO/SU arm.

Background: Cisplatin based chemotherapy is an integral part of the multimodal therapy of patients with testicular cancer. The purpose of this analysis is to evaluate the chemotherapy associated side effects of primary treatment in a modern patient cohort and to correlate them to clinical stage and IGCCCG risk profile. Patients: We retrospectively analyzed charts of patients with testicular cancer in our institution from 01/2003 until today. A total of 88 patients received systemic treatment, among those 74 as a primary treatment with 2 -4 cycles of PEB. Side effects had been categorized according to the Common Terminology Criteria for Adverse Events, CTCAE Version 4. Results: 46 of 74 patients receiving PEB had at least one side effect. The most common side effects were haematotoxic with leucopenia in 34 (45,9%), febrile neutropenia in 10 (13.5%), gastrointestinal in 22 (29,7%) and thromboembolic events in 10 (14.8%) of the patients including 3 therapy associated deaths. Adverse events in clinical stage I are low. Nevertheless there is one therapy associated death due to neutropenic fever. Although there are no differences in haematotoxic AE´s in clinical stage II and III there is a significant trend of developing pulmonary embolism. Patients with clinical stage >IIb and intermediate/poor prognosis have the highest risk of pulmonary embolism (20%). Conclusion: In patients with curative treatment with PEB there are significant AE´s. To reduce therapy associated morbidity and mortality, supportive treatment with granulocyte stimulating factor and therapeutic anticoagulation should be discussed at least in high-risk patients. Disclosure: No conflict of interest disclosed.

Freier Vortrag Lungenkrebs I V30

PD-L1 expression and genotype in Non-Small Cell Lung Cancer (NSCLC) Ansén S.1, Schultheis A.2, Hellmich M.3, Leenders F.4, Zander T.1, Michels S.1, Brockmann M.5, Stoelben E.6, Groen H.7, Timens W.8, Buettner R.2, Thomas R.K.4, Perner S.9, Wolf J.1 Department I of Internal Medicine, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany, 2Institute of Pathology, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany, 3Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany, 4Department of Translational Genomics, Center for Integrated Oncology Köln-Bonn, University of Cologne, Cologne, Germany, 5Department of Pathology, Hospital Merheim, Cologne, Germany, 6Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln gGmbH, Cologne, Germany, 7 University of Groningen and University Medical Center, Department of Pulmonary Diseases, Groningen, Netherlands, 8University of Groningen and University Medical Center Groningen, Department of Pathology, Groningen, Netherlands, 9Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany 1

Disclosure: Ludwig Fischer von Weikersthal: No conflict of interest disclosed. Maurice Michel: Employment or Leadership Position: Klinikdirektor Urol.Universitätsklinik; Advisory Role: Bayer; Expert Testimony: Bayer

Introduction: Tumor cells expressing programmed cell death 1 ligand (PD-L1) are believed to suppress host immune responses through activation of the PD-1/PD-L1 pathway. Current immunotherapeutic strategies blocking the interaction of PD-L1 with its receptor PD-1 have shown encouraging activity in various tumors types, including lung carcinomas. Preliminary data indicate that PD-L1 tumor status might be predictive for responses to PD-1 – and PD-L1 – directed therapies. Methods: PD-L1 expression was evaluated in genomically annotated 256 adenocarcinomas (AD) and 180 squamous cell carcinomas of the lung

Abstracts


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V28

Disclosure: Sascha Ansén: No conflict of interest disclosed. Jürgen Wolf: Advisory Role: Advisory boards & lecture fees: AstraZeneca, BMS, Boehringer-Ingelheim, Clovis, Novartis, Pfizer, Roche.; Financing of Scientific Research: Advisory boards & lecture fees: AstraZeneca, BMS, Boehringer-Ingelheim, Clovis, Novartis, Pfizer, Roche.; Expert Testimony: Research support: Bayer, Boehringer-Ingelheim, Novartis, Pfizer, Roche. V31

Acquired resistance in NSCLC with EGFR mutation treated with TKI´s Lüers A.1,2, Hallas C.3, Henke R.-P.4, Falk M.3, Tiemann M.3, Griesinger F.1,2 Pius-Hospital, Dept. of Hematology and Oncology, Oldenburg, Germany, University Department Internal Medicine Oncology, Oldenburg, Germany, 3 Hematopathology, Hamburg, Germany, 4Institute for Pathology, Oldenburg, Germany 1 2

Introduction: Acquired resistance in NSCLC with activating EGFR mutations has been defined by Jackman et al. The molecular mechanisms have been studied in small series of patients: in about 50% of cases, T790M mutation confers acquired resistance and in 25% c-Met amplification. Other as of yet unknown mechanisms might also play a role. Here we present the acquired resistance mechanisms in a cohort of 16 patients with activating EGFR mutations treated with TKI and identified at our center. Methods: 219 consecutive patients were molecularly studied for EGFR mutations in exons 18–21. EGFR mutation analysis was performed by Sanger Sequencing or by hybridization based COBAS methodology. c-Met IHC was performed automatized by standard procedure (BondMax, Menarini). ALK rearrangement was studied using a break apart FISH-Probe (Abbott). Results: Of 219 patients tested, 45 had an EGFR mutation, of which 6 had primary resistance mutations (T790M 1 case, Exon 20 insertions 5 cases). Of these 39 pts., 21 had acquired resistance on 1st line TKI. 16 were rebiopsied. Of these 16 pts., 8/15 had T790M, 9/13 had overexpression of c-Met (2+,3+) in IHC, 1/11 patients had an acquired ALK translocation. Therapy in the acquired resistance situation was afatinib, chemotherapy, afatinib + cetuximab and crizotinib. Two patients with T790M were rebiopsied when resistance to afatinib occurred, the identical T790M was reconfirmed. Overall survival with 2nd line strategies

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(chemotherapy, afatinib) were similar in T790M+ and WT patients with a higher DCR in T790Mmt+ vs. WT patients for afatinib, however PFS and OS were not significantly different, most likely due to small number of patients. Conclusion: The understanding of resistance mechanisms in acquired TKI resistance is of academic interest and might be important for subsequent treatment options. Therefore, rebiopsy at progress while on TKI therapy should be discussed with patients. As targeted treatment options are available for c-Met, ALK as well as T790M, resistance mechanisms potentially may guide therapeutic strategies in EGFR mutated patients with acquired resistance. Disclosure: Anne Lüers: Financing of Scientific Research: Pfizer; Other Financial Relationships: Celgene (Reisekosten) Frank Griesinger: Advisory Role: Roche, Pfizer, BMS, Boehringer-Ingelheim, Astra-Zeneca; Financing of Scientific Research: Vortragshonorare Roche, Pfizer, BMS, Boehringer-Ingelheim, Astra-Zeneca V32

RET rearrangement in adenocarcinoma of the lung Michels S.1, Schultheis A.2, Scheffler M.1, Rosner T.1, MerkelbachBruse S.2, Heukamp L.2, Engel-Riedel W.3, Serke M.4, Krüger S.5, Benedikter J.6, Gerigk U.7, Schulte W.8, Draube A.9, Ko Y.D.10, Büttner R.2, Wolf J.1, Lung Cancer Group Cologne Uniklinik Köln, Klinik I für Innere Medizin, Köln, Germany, 2Uniklinik Köln, Institut für Pathologie, Köln, Germany, 3Krankenhaus Merheim, Lungenklinik, Köln, Germany, 4Lungenklinik, Hemer, Germany, 5FlorenceNightingale Krankenhaus, Klinik für Pneumologie, Allergologie, Schlaf- und Beatmungsmedizin, Düsseldorf, Germany, 6Klinikum Bogenhausen – Städtisches Klinikum München GmbH, Pneumologie, München, Germany, 7 Malteser Krankenhaus Bonn, Klinik Thoraxchirurgie, Bonn, Germany, 8 Malteser Krankenhaus Bonn, Klinik für Pneumologie, Allergologie und Kardiologie, Bonn, Germany, 9St. Vinzenz-Hospital, Innere Medizin IV – Onkologie, Köln, Germany, 10Johanniter Krankenhaus Bonn, Internistische Onkologie, Bonn, Germany 1

Purpose: Translocation of rearranged during transfection gene (RET) has recently been described as one of the rare genetic rearrangements driving tumorigenesis of adenocarcinomas of the lung. Only small cohorts of Asian adenocarcinoma patients with RET translocation have been described so far, resulting in uncertainty of the clinicopathologic characteristics of Caucasian patients. Patients and Methods: In this study we have analysed tissue of 700 adenocarcinoma patients by fluorescence in-situ hybridisation (Cyto Vision) for RET translocations and by next generation sequencing (Illumina MiSeq System) for mutations in a subset of 14 oncogenes. Clinical, pathological, and genetic characteristics of these patients are described and compared with a control group of non RET translocated patients. Results: Prevalence of RET rearrangement in our cohort of 700 patients with adenocarcioma was 1.7% (12). 7 patients had a translocation ratio of less than 0.4, whereas only 3 showed a translocation ratio of more than 0.6. The tumor of one patient showed high polysomy of the RET gene. RET translocation was co-occuring with TP53 mutations in 7 patients and with MET mutations (exon 14) in one patient. No further mutations and abberations, notably in EGFR, KRAS, ALK and ROS1 were found. Patients were first diagnosed at a median age of 51 years with a predominance for male patients (75%). Three patients were current and 4 former smokers at time of diagnosis. Conclusion: In this study we describe clinicopathological features in a cohort of RET translocation positive NSCLC. Rearrangements in the RET gene are mutually exclusive to known oncogenic driver mutations and abberations. Median age at diagnosis in this subgroup of patients was notably younger than in the RET translocation wild type cohort. In contrast to data published, our data suggests that RET translocations are not predominantly associated with female gender and never- or light-smoking history. Our data shows that screening of patients for RET translocation should include young patients without other oncogenic mutations, but not exclude patients with a smoking history. Disclosure: No conflict of interest disclosed.

Abstracts

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(SQ) using immunohistochemistry (IHC). Moreover, PD-L1 expression and its correlation with clinical data, histology and genotype were analyzed. Results: PD-L1 expression by immunohistochemistry was assessed for all tumor samples with regard to quantity of PD-L1 positive tumor cells and intensity of PD-L1 expression in tumor cells. Tumors were considered PD-L1 positive if tumor cells showed at least weak membranous staining by IHC. 88 of 256 patients with AD were positive for PD-L1 surface expression (=34,4%). The observed staining intensity was weak, intermediate and strong in 28, 42 and 18 cases respectively. 63 of 180 patients with SQ were PD-L1 positive (=35,0%). The observed staining intensity was weak, intermediate and strong in 23, 31 and 9 cases respectively. For both histological subtypes AD and SQ no significant association between PD-L1 expression and clinical characteristics (gender, age, smoking history, stage) could be found. However, PD-L1 expression in AD is significantly more frequent in samples with KRAS mutation (OR = 2,5; 95%-CI=1,2–5,6; p = 0,018), TP53 mutation (OR = 2,4; 95%-CI=1,1–5,2; p = 0,029) or RB1 deletion (OR = 4,0; 95%CI=1,3–11,7; p = 0,009). On the contrary, PD-L1 expression in AD is significantly less frequent in samples with STK11 mutations (OR = 0,2; 95%-CI=0,0–0,8; p = 0,013). Finally, PD-L1 expression in SQ is significantly more frequent in samples with a mutation in exon 2 of NFE2L2 (OR = 6,9; 95%-CI=1,7–27,9; p = 0,007). Conclusions: PD-L1 expression in the two most common histological NSCLC subtypes is associated with distinct genotypes that might further facilitate identification of patients most suitable for therapeutic anti PD-1 and anti PD-L1 intervention.

Genetic variability and clinical presentation of patients with non-small cell lung cancer (NSCLC) harboring METamplifications Eisert A.1, Scheffler M.2, Michels S.2, Schultheis A.3, König K.3, Merkelbach-Bruse S.3, Serke M.4, Ko Y.-D.5, Gerigk U.6, Heukamp L.C.3, Büttner R.3, Wolf J.2 Uniklinik Köln, Lung Cancer Group Cologne, Köln, Germany, 2Uniklinik Köln, Klinik I für Innere Medizin, Köln, Germany, 3Uniklinik Köln, Institut für Pathologie, Köln, Germany, 4Lungenklinik Hemer, Hemer, Germany, 5 Johanniter Krankenhaus Bonn, Bonn, Germany, 6Malteser Krankenhaus Bonn, Bonn, Germany 1

Background: cMET (MNNG HOS Transforming gene) is a proto-oncogene encoding the hepatocyte growth factor receptor (HGFR) with HGF as the only known ligand. Whereas the role of cMET mutations in NSCLC patients remains debated controversively, amplification of cMET is considered as one of the molecular resistance mechanisms in EGFR-mutated NSCLCs treated with 1st or 2nd generation EGFR-TKIs. Further, at least for high-level amplifications, these aberrations might be a possible target for cMET-targeted therapy also in EGFR-wt patients. Nevertheless, much is unknown about the contribution and the impact of cMET amplifications regarding their prognostic or predictive value. Patients and Methods: Beside the screening of rebiopsied EGFR-TKI-resistant patients, cMET apmlification status as assessed by fluorescence in-situ hybridization (FISH) was also analyzed in therapy-naïve patients. A cohort of 588 patients was analyzed using FISH and next-generation sequencing (NGS). The amplifications were categorized as low-level, intermediate, and high-level amplifications. Results: 171 patients with cMET amplification were identified, whereof 11 (6.4%) had a high-level amplification. cMET amplifications cooccured with a large spectrum of other driver mutations (EGFR, KRAS, HER2, STK11, NRAS, BRAF) or amplifications (FGFR1) in both therapy-naïve and treated patients, and smoking status represented the known associations (i. e., low smoking association in patients with EGFR mutations, high association in patients with KRAS and NRAS mutations). The amplifications occurred in both adenocarcinoma and squamous cell carcinoma. Preliminary data suggests that low-level amplifications beside EGFR mutations in therapy-naïve patients do not alter the predictive value of the EGFR mutation. Conclusions: The preliminary data suggests a higher prevalence of cMET amplifications in a broad spectrum on NSCLC patients. Furthermore, cMET amplifications are not exclusive for EGFR-mutated patients with acquired resistance to EGFR-directed therapy. Preliminary data suggest that low-level amplification does not lead EGFR-TKI resistance. Disclosure: No conflict of interest disclosed. V34

Occurrence and characteristics of KEAP1-mutations in patients with non-small cell lung cancer (NSCLC) Frank R.1, Scheffler M.1, Michels S.1, König K.2, MerkelbachBruse S.2, Serke M.3, Ko Y.-D.4, Gerigk U.5, Geist T.6, Heukamp L.2, Büttner R.2, Wolf J.1,7 Uniklinik Köln, Lung Cancer Group Cologne, Köln, Germany, 2Uniklinik Köln, Institut für Pathologie, Köln, Germany, 3Lungenklinik, Hemer, Germany, 4Johanniter Krankenhaus, Bonn, Germany, 5Malteser Krankenhaus Bonn, Bonn, Germany, 6Schwerpunktpraxis für Lungen-und Bronchialheilkunde, Düsseldorf, Germany, 7Uniklinik Köln, Klinik 1 für Innere Medizin, Köln, Germany 1

Background: The Kelch-like ECH-associated protein 1 (KEAP1) suppresses the Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) under physiological conditions and therefore the antioxidative and anti-inflammatory effect during oxidative stress. Mutations in KEAP1 are described for diverse tumor entities with a relatively high frequency. Limited data is available on the clinical relevance, the exact frequency of occurrence

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and the association with specific characteristics of patients. This study was performed to characterize KEAP1-mutated NSCLC clinically and genetically. Patients and Methods: Tumor tissue collected from 446 patients within a regional screening network was analyzed for KEAP1 mutations using next-generation sequencing (NGS). Clinical, pathological and genetic characteristics of these patients are described and compared with a control group of patients without KEAP1 mutation. Results: So far, we identified 33 patients with KEAP1 mutations. Among these we found at least 19 different mutations, of which the majority was not previously described. KEAP1 mutations were not restricted to a special exon, and in 30 patients (90.9%), additional driver mutations in KRAS, FGFR1, STK11, ALK, DDR2, and NRAS could be detected, as well as mutations and polymorphisms in TP53. KEAP1 mutations occurred in both adenocarcinoma and squamous cell carcinoma histology. Results of the ongoing clinical characterization of the patients as well as the prognostic and predictive impact of KEAP1 mutations in a prospective cohort will be presented. Conclusions: Our data suggest a role of KEAP1 mutations as a cofactor in addition to classical driver mutations underlying the malignant phenotype of lung cancer cells. Further data analysis will reveal the role of these mutations for the outcome of these patients. Disclosure: No conflict of interest disclosed. V35

Palliative chemotherapy significantly prolongs survival in elderly and old patients with metastatic lung cancer Noskova I., Kasenda B., Zippelius A., Rothschild S.I. University Hospital Basel, Medical Oncology, Basel, Switzerland

Background: Lung cancer is the most frequent cause of cancer-related death. More than 50% of lung cancer patients (pts) are older than 65 years. However, elderly pts are usually underrepresented in clinical trials (Hutchins LF, NEJM 1999) and the knowledge on optimal management of this patient population is scarce. Methods: From our clinical database we identified consecutive pts older than 65 years diagnosed with stage IIIB/IV lung cancer between January 1997 and December 2012. Pts’ characteristics, treatment delivery, overall survival (OS) and established prognostic parameters were evaluated. We used the log-rank test to compare unadjusted survival probabilities and multivariable Cox regression to investigate potential prognostic factors with respect to OS. Results: We included 205 pts; the majority was male (69.3%); 84% were current or former smokers. Mean age was 72 years (range, 65–85 years). 79% of pts had non-small cell lung cancer with adenocarcinoma as the most frequent histological subtype (60%). 147 pts (72%) were between 65 and 74 years old and 58 pts (28%) were classified as very elderly pts with 75 years and older. In the elderly group, 59% of pts were in a good performance status (ECOG PS 0–1), whereas only 45% in the very elderly group had an ECOG PS 0–1. 173 pts (84%) had at least one line of cytotoxic chemotherapy (range, 1–6); of those 68% received a platinum-based chemotherapy. Very elderly pts received less chemotherapy compared to pts younger than 75 years (76% vs. 88%). Median OS of the whole patient cohort was 8.8 months. In the unadjusted analysis, application of chemotherapy was associated with improved OS (median OS 9.1 vs. 4.0 months, p < 0.0001). In multivariable analysis, application of chemotherapy was also associated with better OS (HR 0.27, 95% CI 0.15–0.49, p  60 years), autologous stem cell transplantation (ASCT +/-) and other factors upon overall survival (OS) and progression-free survival (PFS). Results: In patients treated with rituximab (n = 27), 3-year OS was 77.8% (95%-CI:62–93%). In contrast, in patients treated without rituximab (n = 52), 3-year OS was only 39.9% (CI:27–53%, Figure). The difference in OS was significant in the univariate (p = 0.002) as well as the multivariate analysis (p = 0.049, Hazard ratio (HR)=0.248). In the rituximab group, 80.8% were free of progression at the date of analysis (median not reached), whereas median PFS in the group without rituximab was only 17 months (CI:8–26), (p = 0.001). Patients ≤ 60 years of age (n = 28) had a 3-year OS of 78.2% (CI:63–94%) and a median PFS of 75 months, in patients > 60 years (n = 51) 3-year OS was 38.7% (CI:25–52%) and median PFS was 39 months (CI:6–72). Patients who received high dose therapy and autologous stem cell transplantation (ASCT) had a 3-year OS of 85.2% (CI:72–99%) and 65.1% were alive up to the time of analysis (range 9–131 months). Without ASCT median OS was only 16 months (CI:11–21) and 3-year OS was 35.2% (CI:22–48%). Age and ASCT were significantly associated with better OS in univariate (p = 0.002 and p = 0.001) as well in multivariate analysis (p = 0.004, HR = 0.023 and p = 0.001, HR = 0.014). Conclusion: Rituximab treatment, ASCT and age are independent prognostic factors for overall survival in the first line treatment of PCNSL.

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Fig. 1. Disclosure: No conflict of interest disclosed. V46

Secondary CNS involvement in malignant lymphoma: Data from a prospective registry Strehlow F.1, Schroers R.2, Schmidt-Hieber M.3, Schlegel U.4, Reimer P.5, Griesinger F.6, Höffkes H.-G.7, Jordan K.8, Meyer zum Büschenfelde C.9, Mezger J.10, Kreher S.1, Hirsch A.1, Mensen A.1, Fischer L.1, Korfel A.1 Charité Universitätsmedizin Berlin – Campus Benjamin Franklin, Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 2 Knappschaftskrankenhaus Bochum, Medizinische Universitätsklinik, Bochum, Germany, 3Helios Klinikum Berlin-Buch, Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 4Knappschaftskrankenhaus Bochum, Neurologie, Bochum, Germany, 5Kliniken Essen Süd, Hämatologie, Onkologie und Stammzelltransplantation, Essen, Germany, 6Pius Hospital Oldenburg, Hämatologie und Onkologie, Oldenburg, Germany, 7Klinikum Fulda, Tumorklinik, Fulda, Germany, 8 Universitätsklinikum Halle (Saale), Hämatologie und Onkologie, Halle, Germany, 9Asklepios Klinik Altona, Hämatologie, internistische Onkologie und Palliativmedizin, Hamburg, Germany, 10St.-Vincentius-Kliniken, Hämatologie, Onkologie, Immunologie, Palliativmedizin, Karlsruhe, Germany 1

Introduction: Secondary CNS involvement is extremely rare in malignant lymphoma and its optimal management is yet to be defined. In a prospective German registry data on patients with secondary CNS lymphoma (SCNSL) are collected. Methods: Patients with secondary CNS involvement of indolent or aggressive non-Hodgkin`s lymphoma (confirmed histologically or cytologically) with or without systemic involvement at the time point of CNS involvement are eligible. Results: Since July 2011 77 patients were included, of whom 69 have been analysed (median age 60 years, range 26–80). Eight patients (12%) had simultaneous CNS and systemic involvement at first diagnosis (cohort I) and 61 (88%) had CNS involvement at relapse (cohort II). Eleven patients (16%) in cohort II had simultaneous systemic disease. The histology at first diagnosis was aggressive B-cell lymphoma in 48 patients (70%), mantle-cell and T-cell lymphoma in 2 (3%) each and indolent B-cell lymphoma in 17 (25%). Median time from first diagnosis to CNS relapse in cohort II was 16 months. CNS lymphoma localisation was brain parenchyma in 39 patients (57%), meninges in 18 (26%), spinal cord in 2 (3%) and combination of these in 10 (14%). Therapy for CNS involvement was systemic chemotherapy in 37 patients (54%), systemic plus intrathecal chemotherapy in 30 (43%) and intrathecal chemotherapy alone in 2 (3%). High-dose chemotherapy with autologous stem-cell transplantation was given to 23 patients (33%). Median follow-up time was 17

Abstracts

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Rituximab, age and high dose therapy followed by autologus stem cell transplantation are independent prognostic factors for survival in the first line treatment of primary CNS-lymphoma

Disclosure: Felicitas Strehlow: No conflict of interest disclosed. Agnieszka Korfel: Financing of Scientific Research: Mundipharma, Riemser; Expert Testimony: Mundipharma, Riemser V47

Final analysis of a randomized phase II trial with prednisone, vinblastine, doxorubicin, and gemcitabine in patients with early unfavorable Hodgkin lymphoma -PVAG-14 pilotFuchs M.1, Wongso D.1, Plütschow A.1, Feuring-Buske M.2, Hertenstein B.3, Höffkes H.-G.4, Vogelhuber M.5, von Tresckow B.1, Biersack H.6, Link H.7, Topp M.S.8, Fischer N.9, Bredenfeld H.10, Sasse S.1, Behringer K.1, Böll B.1, Borchmann P.1, Engert A.1, German Hodgkin Study Group (GHSG) Universitätsklinik Köln, Klinik I für Innere Medizin, Köln, Germany, Universitätsklinikum, Ulm, Germany, 3Klinikum Bremen Mitte, Bremen, Germany, 4Klinikum, Fulda, Germany, 5Universitätsklinik, Regensburg, Germany, 6Universitätsklinikum Schleswig-Holstein, Lübeck, Germany, 7 Westpfalz Klinikum, Kaiserslautern, Germany, 8Universitätsklinikum, Würzburg, Germany, 9Klinikum Schwabing, München, Germany, 10 Evangelisches Krankenhaus, Düsseldorf, Germany 1 2

Introduction: Optimal treatment for early unfavorable Hodgkin lymphoma (HL) with the most efficacy and least toxicity is still open for debate. Therefore the German Hodgkin Study Group (GHSG) designed PVAG14, a new chemotherapy regimen that includes gemcitabine, an effective drug in relapsed or refractory HL patients. Methods: Patients with newly diagnosed early unfavorable HL were randomized to receive eight cycles of PVAG-14 (prednisone, vinblastine, doxorubicin and gemcitabine) with two different doses of doxorubicin (25 or 35 mg/m2) followed by 30 Gy involved-field radiotherapy. The aims of this phase-II trial were to assess toxicity and activity of PVAG-14 (benchmarks: < 50% hematological grade III/IV toxicities; >50% complete responders). Secondary objectives were feasibility, efficacy and safety. Results: Between November 2008 and May 2011, 41 patients were recruited in this trial. The median age was 38 years and 49% were male. Most patients (40/41) received eight cycles of PVAG-14 with a median dose intensity of 97%. Grade III/IV leukopenia occurred in 4/41 patients (< 10%) including one patient with grade IV leukopenia. No treatment-associated anemia or thrombocytopenia was documented. Three patients had grade III infections, no grade IV infection was observed. All in all, 37% of the patients experienced a grade III/IV toxicity (haematological and non-haematological). All patients except one (98%) achieved a complete remission (CR or CRu) as final treatment result. The lower 95%-confidence limit of the complete response rate is 87% and excludes the benchmark for inefficacy defined in the protocol. One patient had progressive disease at 5 months, another patient relapsed 15 months after the end of treatment. With a median observation time of 27 months, the 2-year PFS was 94% [95%-CI: 86%-100%] and the overall survival 100%. Due to the low number of patients a comparison of the different doxorubicin doses was not possible.

Abstracts

Conclusions: Both endpoints for efficacy and toxicity as predefined in the protocol were met despite the premature closure of the trial. Although fewer patients than expected were included in this trial, the results are compelling. PVAG-14 is an efficient and well tolerated regimen for patients with early unfavorable HL. The observed toxicity is remarkably low. Based on these results, PVAG-14 might challenge present treatments of choice in this group of patients. A randomized trial is thus warranted. Disclosure: No conflict of interest disclosed. V48

Synthetic lethal targeting of SUMOylation in Myc-driven lymphoma Höllein A.1, Fallahi M.2, Schaub F.2, Schoeffmann S.1, Steidle S.1, Rudelius M.3, Miething C.4,5, Peschel C.1, Cleveland J.2, Keller U.1 III. Medical Department, Division of Hematology and Oncology, Technische Universität München, München, Germany, 2Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States, 3Institut für Pathologie, Julius-Maximilians-Universität Würzburg, Würzburg, Germany, 4Memorial Sloan Kettering Cancer Center, New York, United States, 5Freiburg University Medical Center and Albert-LudwigsUniversity, Freiburg, Germany 1

Introduction: Myc oncoproteins (c-Myc, N-Myc and L-Myc) are transcription factors that regulate cell growth, cell division and metabolism under physiologic conditions. Myc overexpression is a hallmark of cancer, present in most advanced tumors, and associated with poor prognosis. We have previously shown that Myc overexpression results in specific cancer cell liabilities, e.g. during cell cycle progression, that constitute therapeutic targets for synthetic lethality approaches. Small Ubiquitin-like Modifier (SUMO) proteins covalently bind other proteins to modify their function. SUMOylation is involved in various cellular processes including transcription and cell cycle progression. Methods: Gene expression analysis of components of the SUMOylation machinery. Stable constitutive/inducible shRNA interference (RNAi) and pharmacologic inhibition of SUMOylation (SUMOi) in Myc-driven lymphomas in vitro. Assessment of the therapeutic potential in syngeneic and xenograft lymphoma models in vivo. Results: We observed a highly concordant expression of critical SUMOylation mediators and Myc in a conditional MYC-transgenic B cell model in vitro. The majority of SUMOylation pathway genes were identified as direct Myc targets. Using Myc-induced lymphoma as a model disease, we show a striking transcriptional activation of the SUMOylation machinery, resulting in hyperSUMOylation in manifest Eµ-Myc lymphomas. The activation of the SUMOylation machinery was also evident in molecular-defined human Burkitt lymphoma (BL) using transcriptome analysis. Immunohistochemistry of B cell lymphoma subtypes in tissue microarrays showed significant hyperSUMOylation of BL samples. Evaluating the therapeutic potential of specific RNAi revealed that the SUMO pathway is required for Myc-induced proliferation, for intact transitioning of the G2-M cell cycle checkpoint and through mitosis. The use of pharmacologic SUMOi resulted in cell cycle arrest, polyploidy and cell death. This therapeutic effect of SUMOi was Myc-specific as shown by use of genetically defined cell lines and conditional Myc-expression systems. Finally, in vivo loss of function studies in BL xenograft models and in syngeneic Eµ-Myc lymphoma recipients showed that inhibition of SUMOylation disrupts lymphoma maintenance. Conclusion: We provide correlative and experimental evidence that the Myc-associated expression of genes involved in SUMOylation constitutes a therapeutically exploitable liability in Myc-driven lymphoma. Disclosure: No conflict of interest disclosed.


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months. In cohort I, 3 patients progressed/relapsed after 7.0–11.5 months and one died after 16 months following diagnosis of CNS involvement. Median progression-free survival (PFS) and overall survival (OS) from CNS involvement in cohort II was 6.7 months (95%CI 3.7–9.5) and 15.7 months (95%CI 7.0–24.3), respectively. Median PFS and OS of patients with parenchymal involvement were significantly longer (both not yet reached) as compared to patients with meningeal involvement with 5.5 (95%CI 2.9–8.0) and 8.2 (95%CI 5.2–11.1) months, respectively (P< 0.001 for PFS and 0.007 for OS). Conclusions: The high frequency of isolated CNS relapse reflects the reduced effectivity of modern anti-lymphoma therapy to clear the CNS as compared to the systemic compartment. SCNSL patients, particularly those with meningeal involvement, remain to have poor outcome despite frequent usage of CNS-penetrating systemic chemotherapy.

V49

Targeting the tumors’ systems biology: Combined biomodulatory therapy in refractory Hodgkin´s lymphoma Ugocsai P., Klobuch S., Zaiss S., Dietz D., Wolff D., Holler E., Herr W., Reichle A. Med. Klinik III, Universität Regensburg, Regensburg, Germany

Introduction: Outcome for patients with Hodgkin’s lymphoma refractory to autologous stem-cell transplantation and rescue therapy with Brentuximab-vedotin is really poor. For this situation, we designed a novel therapy approach simultaneously targeting selected hallmarks of cancer, i.e. tumor metabolism, inflammation, angiogenesis and immune response. Methods: In a compassionate use program patients with either refractory or relapsed Hodgkin´s lymphoma following failure to Brentuximab-Vedotin were treated with an all-oral combined biomodulatory therapy approach in analogy to an ongoing melanoma trial, including low dose trofosfamide in combination with a PPARalpha/gamma agonist (pioglitazone), mTOR inhibitor (everolimus) and COX-2 inhibitor (etoricoxib), on daily basis. Low-dose dexamethasone was added in Hodgkin’s lymphoma and two patients received treosulfan instead of trofosfamide. Response was monitored using 18-FDG-PET in combination with high resolution CT every 4 weeks after start of therapy. Patients achieving at least a partial remission were scheduled for metronomic therapy until start of conditioning for allogeneic stem cell transplantation. Results: All patients, 27 to 39 years old, were refractory to high-dose chemotherapy and autologous stem cell transplantation, as well as to Brentuximab-Vedotin. Metronomic therapy was well tolerated as 4th or 5th line therapy, without any major adverse events. All three patients responded with complete or partial remission within 4 to 8 weeks, and all patients achieved PET negativity (involvement of lung, bone, lymph nodes). Consecutively, the patients proceeded to allogeneic stem cell transplantation. Eight weeks after transplantation all patients had a complete remission, which is ongoing 6 months+. Conclusions: Combined biomodulatory therapy provides an efficacious approach as bridging therapy to allogeneic transplantation. Long-term efficacy and safety should be evaluated also in patients not qualifying for allogeneic transplantation. Combined biomodulatory therapy targeting rationalizations, i.e. the physical constitution of single hallmarks of cancer within the tumor compartment, overcomes chemo-resistance and resistance to classic targeted therapy. Disclosure: No conflict of interest disclosed.

Disclosure: Boris Böll: Financing of Scientific Research: Celgene, Amgen Peter Borchmann: No conflict of interest disclosed.

Plenarsitzung NHL Aggressiv V52

Trends in the Management of DLBCL Pfreundschuh M., German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

German Hodgkin Study Group Phase I trial of Doxorubicin, Vinblastine, Dacarbazine, and Lenalidomide (AVD-Rev) for elderly Hodgkin Lymphoma patients Böll B.1, Plütschow A.1, Eichenauer D.A.2, Thielen I.1, von Tresckow B.1, Atta J.3, Pfreundschuh M.4, Feuring-Buske M.5, Vogelhuber M.6, Sökler M.7, Fuchs M.1, Engert A.1, Borchmann P.1, Deutsche Hodgkin Studiengruppe (GHSG) Uniklinik Köln, Klinik I für Innere Medizin, German Hodgkin Study Group, Köln, Germany, 2Uniklinik Köln, Klinik I für Innere Medizin, Köln, Germany, 3Uniklinik Frankfurt, Hämato-Onkologie, Frankfurt, Germany, 4 Universitätsklinikum des Saarlandes, Hämato-Onkologie, Homburg, Germany, 5Universitätsklinikum Ulm, Hämato-Onkologie, Ulm, Germany, 6 Universitätsklinik Regensburg, Innere Medizin III, Regensburg, Germany, 7 Universitätsklinik Tübingen, Hämato-Onkologie, Tübingen, Germany 1

Introduction: About 30% of all Hodgkin Lymphoma (HL) patients are ≥60 years old. ABVD is standard of care for these patients, although outcome and feasibility are poor, one limitation being bleomycin-induced pulmonary toxicity. We thus replaced bleomycin with lenalidomide (Revlimid®), and initiated the AVD-Rev phase-I trial (NCT01569204) for 60–75 year-old patients with 1st diagnosis of early unfavorable- or advanced-stage HL, good performance status (ECOG/WHO ≤2), and no severe organ dysfunction.


Universitätsklinikum Homburg, Homburg/Saar, Germany

The International Prognostic Index (IPI) has been confirmed to be the most valid prognosticator in the rituximab era. Therefore, it is justified to pursue specific strategies in patients belonging to different risk and age groups. Young patients with no risk factor according to the age-adjusted (aa) IPI and no bulky disease have been shown in the MInT study to have a high event-free and nearly 100% overall survival after 6 cycles of R-CHOP-21, suggesting that some of these patients are overtreated. For the first time in the history of DLBCL treatment prospective trials like the FLYER study evaluate reduction of treatment from 6 to only 4 cycles of CHOP with 6 applications of rituximab. For young patients with aaIPI=1 and/or bulky disease, best results have been achieved with 6xR-CHOP-21 plus involved-field radiotherapy to bulky disease or the more aggressive and more toxic R-ACVBP program without radiotherapy. For young poor-prognosis patients (aaIPI=2,3) best results have been achieved with 6xR-CHOEP-14, with a 3-year overall survival of aaIPI=2 patients of roughly 90%, demonstrating that this subpopulation is no high-risk population any more in the rituximab era. For young aaIPI=3 patients there is still room for improvement and ongoing trials evaluate primary high-dose chemotherapy with stem cell transplantation or the addition of new drugs to a CHOP(E)P-14 backbone. Elderly patients who represent up to two thirds of all DLBCL patients do best with 8 cycles of R-CHOP-21 or 6 cycles of R-CHOP-14 plus 2 additional rituximab

Abstracts

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V50

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Methods: Depending on stage and response at interim staging, patients received 4–8 cycles of AVD-Rev followed by radiotherapy with prophylactic anticoagulation (ASA or heparin). The daily lenalidomide dose for the first patient was 5mg; possible dose levels ranged from 5 to 40mg. Thromboembolism ≥CTC II°, hematological toxicity as severe cytopenia (ANC< 500/µl >7days with G-CSF and thrombocytopenia < 25.000/µl), and complications as neutropenic fever and prolonged therapy delay were considered as dose limiting toxicities (DLT) if they occurred during the first 4 cycles. Results: 25 patients (median age: 67, range 61–76) and a CIRS-G comorbidity score of up to 7 points (range 0–7) were assigned to dose levels 5mg (n = 1), 10mg (n = 1), 15mg (n = 1), 20mg (n = 6), and 25mg (n = 16). 15 patients were male, 68% had advanced stage-HL, and 80% had B-symptoms. After DLT evaluation of 20 patients, a pre-specified stopping criterion was reached with a recommended dose for a phase II trial of 25mg. Dose delivery was high with a median relative dose intensity of 97% (range 49%-104%; mean 91%). However, CTC III°-IV° toxicities occurred in all 22 patients treated at the 20mg and 25mg dose levels. DLTs were observed in 1 of 6 and 5 of 16 patients at 20mg and 25mg, respectively, and were mainly hematologic but included 3 thromboembolic events despite ASA prophylaxis. No DLT occurred in patients receiving < 20mg lenalidomide. Of note in these vulnerable patients, no treatment related deaths occurred. Overall response rates were 80% for all patients (20/25) and 86% (19/22) for patients receiving ≥20mg lenalidomide. At 19 months median observation time, 5 patients had disease progression and 4 patients died. The one-year estimates for progression-free and overall survival are 75% [95%-CI: 53–88%] and 92% [95%-CI: 71–98%], respectively. Conclusion: AVD-Rev is toxic but feasible and effective in this vulnerable population of elderly HL patients.

Disclosure: Michael Pfreundschuh: Advisory Role: Boehringer-Ingelheim, Celgene, Pfizer, Onyx, Millenium, Roche; Expert Testimony: Roche, Spectrum

Fortbildung

Mammakarzinom V54

Mechanisms of endocrine resistance and strategies to overcome Tesch H. Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien Krankenhaus, Frankfurt, Germany

About two third of breast cancer express estrogen or progresteron receptors and are considered as candidates for anti-hormonal treatment. However in the metastatic situation about 50% of tumors do not respond to endocrine therapy and nearly all develop a secondary endocrine resistance under treatment. The mechanisms of endocrine resistance are not fully understood yet. Preclinical and clinical studies revealed that tumor progression and resistance are associated with activation of the signal transduction pathways such as the PI3k/akt/mTOR , MAPK, raf and others. Mutations of PI3K and inactivation of the tumor suppressor gene PTEN are frequentl y observed in breast cancer and can lead to activation of mTOR. In addition this pathway is also activated by ER signaling and extensive crosstalk has been shown between ER and growth factor pathways. This led to the hypothesis that the dual combination of antihormonal treatment with an m-TOR inhibitor could overcome endocrine resistance and lead to improvement of clinical results. This concept war proven in the Bolero 2 trial which demonstrated that the combination of exemestane and the mTOR inhibitor everolimus significantly improved progression free survival in hormone receptor resistant breast cancer in postmenopausal patients. Current trials attempt to further elucidate the mechanisms and clinical benefits with specific and potent inhibitors of the PI3K /AKT pathway. Additional genetic pathways may also be involved in endocrine resistence and may lead to the identification of inhibitors with clinical relevance. Recently it has demonstrated that combination of antiendocrine treatment and inhibitors of cyclin dependent kinases, which play a key role in cell cycle progression can improve treatment results, thus opening a new avenue of research. Disclosure: Hans Tesch: Financing of Scientific Research: Novartis, Roche, GSK V55

Her2/neu in focus: novel therapeutic options Welt A. Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum, Universitätsklinikum, Essen, Germany

Results from clinical trials highlight the evolving treatment options for women with human epidermal growth factor receptor 2 (HER2-positive) breast cancer. Recently some of these trials using new monoclonal antibodies changed our daily practice. T-DM1 is an antibody-drug conju-

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gate that combines trastuzumab and the chemotherapy drug DM1. The EMILIA trial showed improved overall survival (OS) in women with advanced HER2-positive disease who had been previously treated with the HER2-targeted drug trastuzumab and taxane chemotherapy. Women who received T-DM1 had substantially better OS than women treated with capecitabine and lapatinib (30.9 versus 25.1 months). Patients treated with T-DM1 also had better progression-free survival (PFS) with less toxicity. Pertuzumab is a monoclonal antibody that is targeting a different part of the HER2 receptor than trastuzumab. In the CLEOPATRA phase III trial patients were randomized to receive either pertuzumab, trastuzumab, and docetaxel or trastuzumab, docetaxel, and a placebo. The median PFS of women receiving pertuzumab was more than 6 months longer than those treated with the placebo (18.5 versus 12.4 months). Updated results for OS will be presented in 2014. Several investigational drugs that disrupt signaling pathways thought to play an important role in tumor resistance to HER2-targeted agents. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a protein kinase central to a number of signaling pathways regulating cell growth and proliferation that may restore sensitivity to and enhance efficacy of HER2-targeted therapy. The BOLERO-3 phase III study was conducted to evaluate the addition of everolimus to trastuzumab plus vinorelbine in pretreated patients. Final PFS analysis showed a significant, but small improvement (5.8 months versus 7.0 month). Many ongoing trials are part this increasingly dynamic area of research for HER2-positive breast cancer. In early-stage disease, the optimal treatment duration in the adjuvant setting is still a matter of debate. Results from HERA (2 years of adjuvant treatment with trastuzumab versus 1 year of trastuzumab versus observation) and first results from the PHARE trial (12 versus 6 months of adjuvant treatment trastuzumab / non-inferiority trial) suggest that 12 months of treatment with trastuzumab should remain our standard of care. Disclosure: Anja Welt: Employment or Leadership Position: Oberärztin am Universitätsklinikum Essen; Advisory Role: Amgen, Roche, TEVA, Novartis, Eisai; Financing of Scientific Research: Pierre Fabre Pharma, Roche Pharma, Eisai, Amgen; Expert Testimony: Novartis

Fortbildung MPN V57

The CALR mutation – relevance in diagnosis and clinic Gisslinger H., Schalling M. Medizinische Universität Wien, Klinik für Innere Medizin I, Wien, Austria

Myeloproliferative Neoplasms are a group of disease entities which are characterized by an overproduction of malignant cells from the myloid linage. The classical definition inlcudes the three diseases essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The disease-causing mutations in all three of these entities occur mainly in the genes for JAK2 (Janus kinase 2) and MPL (thrombopoietin receptor). In December of 2013, a new mutation in the calreticulin (CALR) gene was found in most of the JAK2- negative ET and PMF patients. It has since been found to be the second most common mutation among these two diseases, with occurences of 25% in ET and 35% in PMF respectively. The CALR mutation is clinically associated with some common and hematologic parameters. Affected patients usually are younger when diagnosed. The CALR mutation is associated with a superior overall survival in PMF patients. CALR-positiv patients show, compared to JAK2-positiv patients, higher thrombocyte counts, lower rate of thrombosis and lower hemoglobin levels. A study done on PMF patients also showed, that the leukemia-free survival was significantly longer in CALR-positiv patients than in JAK2-positiv ones, even more so when being compared to triple-negative patients.

Abstracts

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administrations. Since further intensification of chemotherapy is hardly possible in the elderly population, improvement strategies evaluate new doses and schedules of rituximab based on the recent demonstration that rituximab is suboptimally dosed in all DLBCL patients except elderly females. Other improvement strategies include vitamin D substitution in vitamin D insufficient and deficient DLBCL patients, because vitamin D deficiency impairs ADCC, the most important mechanism of action of rituximab, as well as new drugs targeting specific molecules involved in the signal transduction pathway of the B-cell receptor. While the rate of patients dying from DLBCL has been cut into half during the last decade, these new approaches should further improve the cure rate of DLBCL in the near future.

Disclosure: Heinz Gisslinger: Advisory Role: AOPOrphan, Novartis, Celgene, Janssen-Cilag; Honoraria: EP 13.18.6939.8, EP 13.18.4632.1; Financing of Scientific Research: Vortragshonorare von: AOPOrphan, Novartis, Celgene, Janssen-Cilag; Expert Testimony: Novartis (Projekt-Finanzierung an die MedUniWien), Genetic Characterisation of MPNs, MPN Reclassification Project Martin Schalling: No conflict of interest disclosed. V58

Role of Jak2 inhibitors in the long-term treatment of myelofibrosis Grießhammer M. Johannes Wesling Klinikum, Minden, Germany

The discovery of JAK2 mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of JAK ATP-competitive inhibitors (JAKi) that indirectly inhibit the JAK-STAT pathway. These agents consistently alleviate constitutional symptoms and reduce spleen size in myelofibrosis (MF) and other MPN. Most data are available for Ruxolitinib but other JAKi such as Momelotinib (CYT387), Pacritinib (SB1518), CEP701, BMS-911543, INCB039110 and LY2784544 are now under investigation. Every inhibitor has different target specificity on JAK1, JAK2, JAK3, FLT3, CDK2, TYK, JNK1 and thus exerts variable clinical effects and toxicity. In trials with MF patients CYT387 additionally improves anaemia and for Ruxolitinib a significant reduction in bone marrow fibrosis was seen in some patients. Fedratinib (SAR302503) program and development was stopped because it caused Wernicke encephalopathy in a few PMF patients. Long-term outcomes of patients with MF receiving JAK1/JAK2 inhibitor Ruxolitinib within the COMFORT trials still demonstrated a significant clinically activity with rapid reductions in splenomegaly and constitutional symptoms that were sustained for ≥ 3 years of treatment in the majority of patients. Ruxolitinib was well tolerated, with nearly half of patients remaining on study after > 3 years of therapy. The rates of adverse events of special interest (anemia, thrombocytopenia, bleeding, and infections) generally decreased after the first 24 weeks of treatment with Ruxolitinib. Few new or worsening decreases in hemoglobin levels and platelet counts were observed with longer exposure to Ruxolitinib. Longer follow-up also continues to suggest a survival advantage with Ruxolitinib treatment compared with best available therapy (BAT) or placebo. Long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving Ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial showed similar results. Interestingly, MF patients with high-risk MF experienced the same overall survival with Ruxolitinib as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction. JAKi therapy has become a standard therapy for symptomatic MF with convincing long-term results concerning efficacy and safety for Ruxol-

Abstracts

itinib. Other JAKi may have the potential for similar results and are also tested in prospective trials. Disclosure: No conflict of interest disclosed.

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Hämostaseologie I V61

Pathophysiology-based therapy of thrombotic microangiopathy Knoebl P. Med. Univ. Vienna, Dept. Med 1, Div. Hematology & Hemostasis, Vienna, Austria

Thrombotic microangiopathies (TMA) are a heterogeneous group of disorders characterized by microangiopathic hemolytic anemia with red cell fragmentation, thrombocytopenia and organ dysfunction due to disturbed microcirculation. Thrombotic thrombocytopenic purpura (TTP) is characterized by a severe deficiency of ADAMTS13, an enzyme responsible for physiological cleavage of von Willebrand factor (VWF). Organ dysfunction can be severe and life-threatening, and immediate start of appropriate therapy is necessary to avoid permanent damage or death. The therapeutic options, however, are often limited to symptomatic measures, and are not standardized or based on high scientific evidence. During the last years, not only considerable progress has been made in better diagnosis of TMA, but also new therapeutic strategies have been established. Initial treatment still is based on plasma exchange and symptomatic measures to protect organ function, but new concepts (immunosuppression, targeted anti-VWF or anti-complement therapy, replacement with recombinant enzymes) are currently under development. Disclosure: Paul Knoebl: Advisory Role: Baxter, Alexion, Novo-Nordisk, CSL-Behring; Financing of Scientific Research: Vortragshonorare und Reiseunterstützungen Baxter, Alexion, Novo-Nordisk V63

HIT-when to consider and when to treat? Greinacher A. Universitätsmedizin Greifswald, Greifswald, Germany

Heparin-induced thrombocytopenia (HIT) is caused by immunogenic complexes of heparin and platelet factor 4 (PF4). Some of the resulting antibodies activate platelets via the FcγRIIa, leading to a prothrombotic state. Diagnosis of HIT is challenging. However, the previous problem of underdiagnosis has turned into a tendency to overdiagnose HIT. Anti-PF4/heparin antibodies can be found fairly frequently in heparin-treated patients, but only a minority of patients with these antibodies develops clinical HIT. HIT is a clinicopathologic syndrome, which demands both, the presence of clinical features (thrombocytopenia, thrombosis) and pathologic anti-PF4/heparin antibodies. Two approaches can help to rule out HIT: systematic assessment of the clinical presentation using scoring models that determine the pretest probability of HIT and in vitro demonstration of the absence of anti-PF4/heparin antibodies. The strength of all PF4/heparin antigen assays is to rule out HIT. For confirmation of HIT, functional assays employing washed platelets are better suited. The treatment principles of HIT are: Substitute heparin with a rapidly-acting non-heparin anticoagulant, in therapeutic doses; avoid phenprocoumon pending platelet count recovery; minimize prophylactic platelet transfusions; test for HIT antibodies; investigate for lower-limb DVT. Vitamin K should be given (5 to 10 mg by slow intravenous injection) if HIT is diagnosed in a patient who is receiving phenprocoumon, especially if DTI therapy is planned (warfarin raises the PTT and thus risks PTT confounding of DTI therapy). Also “isolated HIT” (thrombocytopenia, no thrombosis) requires therapeutic dose anticoagulation until the platelet


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Similar results were observed in ET patients. In a comparison between patients carrying one of the three most common mutations in MPNs, JAK2, CALR and MPL, it was found that MPL-positiv patients have the longest overall survival, followed by CARL-positive ones. With regrads to the thrombosis-free survival, CALR-positive patients showed to do considerably better than JAK2- or MPL-positive patients. Another study was done to investigate the impact of the CALR mutational status on the outcome of allogeneic stem cell transplantations. It was found, that CALR-positivity leads to a better overall survival. Also, the non-mortal relapse rate was lower in this group of patients. The data also suggested a higher incidence of stage 1 acute graft-versus-host disease and limited chronic graft-versus-host disease, making the CALR mutational status a potential diagnostic and prognostic marker. All of the data to date suggest, that CALR-positive patients have a slight advantage over JAK2-positive patients regarding overall survival as well as thrombosis-free survival and overall survival after alloHSCT. Additionally, CALR might be a very valuable target for therapy, like JAK2 before it.

Disclosure: Andreas Greinacher: Advisory Role: ja; Financing of Scientific Research: ja; Expert Testimony: ja

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Keimzelltumore – Zwischen Toxizitätsminimierung in frühen Stadien und Therapieinnovationen bei Hochrisikopatienten V65

Retroperitoneal Lymph Node Dissection (RPLND) – influence of new imaging modalities? Heidenreich A. Uniklinik RWTH, Aachen, Germany

Introduction: Whereas the role of primary nerve sparing RPLND is discussed extremely controversial in the management of stage I nonseminomas (NS), postchemotherapy (PC) RPLND plays an integral part in the treatment of advanced seminomas and NS. With the availability of modern imaging techniques such as magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), positron emission tomography (PET) the indication for and the extent of RPLND might be influenced significantly. Seminoma: In men with advanced seminoma treated with chemotherapy residual masses > 3cm will harbour viable cancer in about 35% of patients. Therefore, previous guidelines recommended PC-RPLND which usually was more challenging as in NS due to the extensive desmoplastic reations between residual tumour tissue and especially the large retroperitoneal vessels. Nowadays, FDG-PET/CT is performed in those cases to differentiate viable from fibrotic lesions. If performed adequately, sensitivity and specificity to detect viable cancer is in the range of 80% and 100%, respectively, indicating the need for additional therapy. Nonseminomas: For staging purposes, CT of the chest, abdomen and small pelvis is the method of choice. Besides the size of the lymph nodes their anatomical location has to be considered in detail. It has been shown in previous studies that lymph nodes of about 1cm in diameter located in the primary lymphatic landing zone of the tumour bearing testicle harbour an about 90% for occult metastatic disease. With a false negative rate of about 40% FDG-PET/CG has not been proven to be useful as staging modality. To evaluate therapeutic response after chemotherapy for advanced NS, CT of the retroperitoneum is performed. MRI is performed if involvement of the major vessels is suspected and it will influence the extent of RPLND. MRI and CT are also extremely helpful in patients with involvement of the vertebra to define the extent of resection. With a sensitivity of about 40% and 65%, FDG-PET/CT is not helpful to detect residual masses with viable cancer in the postchemotherapy setting. Conclusions: CT remains the main radiologic technique used prior to RPLND. MRI and PET have specific roles to identify vascular and skeletal involvement and their results heavily influence the surgical approach and the extent of resection. Disclosure: No conflict of interest disclosed.

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V66

The role of high-dose chemotherapy in metastatic germcell cancer Beyer J. UniversitätsSpital Zürich, Onkologie, Zürich, Switzerland

High-dose chemotherapy (HDCT) has been explored in metastatic germcell cancer either in patients (pts) with poor prognosis at initial presentation or in pts with relapsed or refractory disease for more than 25 years. Whereas most available evidence point to the superiority of HDCT over conventional-dose chemotherapy (CDCT) with about a 10–15% survival benefit in certain subgroups, the use of HDCT is still vividly debated. In the first-line setting two negative prospective randomized trials comparing HDCT to CDCT (Motzer JCO 2007, Daugaard Ann Oncol 2011) are contrasted by a more recent positive one (Fizazi ASCO 2013). Candidates for HDCT are pts with high serum AFP and/or HCG levels and a slow marker decline, pts with liver, bone or brain metastases at initial presentation as well as all pts with primary mediastinal non-seminomatous germ-cell cancer. In the first-salvage setting one negative prospective trial comparing HDCT to CDCT (Pico Ann Oncol 2005) is contrasted by a large international retrospective matched pair analysis (Lorch JCO 2011). The majority of pts, however, will profit from HDCT as intensification of first salvage treatment, particularly pts with brain metastases or other poor risk features (International Prognostic Factor Study Group JCO 2010). In the second or subsequent salvage setting HDCT can still cure patients with cisplatin-sensitive disease. However, when used late, the long-term survival rate drops to 17% or less (Lorch Ann Oncol 2012). In late relapse germ-cell cancer more than two years after cisplatin-based chemotherapy, HDCT should also be considered in individual pts with unresectable disease and a good performance status as long-term responses have been demonstrated (Lorch J Urol 2010). Conclusion: The majority of pts with metastastic germ-cell cancer can be cured using CDCT such as BEP, VIP or TIP and will not require HDCT. Yet, HDCT has the power to improve survival in pts with rare unfavorable clinical scenarios. As treatment decisions are complex in these scenarios, early contact/referral of pts to one of the few centers in Germany with known expertise in unfavourable germ-cell cancer is of independent prognostic significance (Colette JNCI 1999). Centers can be found and contacted via http://www.hodenkrebs.de. Early contacts/referrals should be considered mandatory and HDCT be used to salvage pts not limited hospital budgets or as a means of personal ambition at centers inexperienced in this disease. Disclosure: No conflict of interest disclosed. V67

Modern strategies for the follow-up of testicular cancer patients – late toxicities Rothermundt C. Kantonsspital St. Gallen, Onkologie/Hämatologie, St. Gallen, Switzerland

Despite being a rare disease (1% of new cancer diagnoses in men), testicular cancer (TC) is the most frequent malignancy in younger men between ages 15 and 40. The majority of TC patients can be cured, either by surgery alone followed by active surveillance, by chemotherapy or radiotherapy. With a 10-year rate of overall survival > 95% TC has an excellent prognosis [1;2]. However, there are a growing number of TC survivors, who experience long-term morbidity and sequelae: secondary malignancies, cardiovascular disease, impairment of renal, pulmonary, gonadal, neuronal, and cognitive function and psychosocial disorders [3]. With a trend to follow an increasing number of patients with stage I TC using active surveillance instead of giving adjuvant therapy, more relapses will occur. Adequate clinical, laboratory and radiologic assessments for early detection of relapses are important since early detection improves prognosis [4]. However, frequent CT scanning is associated with excessive radiation and the radiation exposure of each CT scan carries a

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count recovered to a stable plateau. HIT neither shows the characteristics of a primary nor of a secondary immune response. It is likely a misdirected host bacterial defense mechanism. Preimmunization by PF4/bacteria complexes (or PF4/nucleic acid complexes) may explain the early onset of the anti-PF4/heparin IgG response during heparin treatment as a secondary immune response. However, the rapid decline of antibody titers after cessation of heparin is not compatible with a classical secondary immune response. Thus the transient kinetics of the anti-PF4/heparin IgG response resembles neither that of recall antibodies nor that of autoantibodies, but indicates the involvement of a specific B-cell compartment, which has recently been identified as marginal zone B-cells in mouse models

References 1. Horner MJ et al.: SEER Cancer Statistics Review, 1975–2006. 2. Verdecchia A et al.: Lancet Oncol. 2007. 3. Travis et al.: J Natl Cancer Inst. 2010. 4. Beyer J et al.: J Clin Oncol. 1996. 5. Brenner DJ, Hall EJ: N Engl J Med. 2007. 6. Brenner DJ, Elliston CD: Radiology 2004. 7. Oldenburg J et al.: Ann Oncol. 2013. 8. Cathomas R et al.: Swiss Med Wkly. 2010. 9. Travis LB et al.: JNCI 2010. 10. http://www.sag-tccs.com. Disclosure: No conflict of interest disclosed.

Freier Vortrag

Multiples Myelom – klinisch V68

Outcome and prognostic factors of 17p deleted multiple myeloma patients Kull M.1, Teleanu V.1, Schwarzwälder P.1, Wildbihler K.1, Hayde D.1, Kolmus S.1, Greiner A.1, Liebisch P.2, Langer C.1 Universitätsklinikum Ulm, Innere Medizin III, Ulm, Germany, 2Onkologie Moers, Moers, Germany 1

Introduction: During the last decade, the outcome of patients (pts) with symptomatic multiple myeloma (MM) has markedly improved. However, there is still a significant proportion of pts who do not achieve a longtime control of their disease. In particular, pts presenting with a deletion 17p (del17p) still are regarded as high risk pts. We therefore sought to investigate the prognostic impact of the size of the del17p clone, additional genetic abnormalities, treatment modalities and the incorporation of the novel agents lenalidomide and bortezomib. Methods: We identified 51 MM pts diagnosed between 1998–2012 who had a del17p at diagnosis and were treated at the University Hospital of Ulm. The patients were screened for additional chromosomal aberrations by fluorescence in situ hybridization (FISH) performed on purified bone marrow plasma cells. Results: The median age at MM diagnosis was 58.5 years (57.4% male pts). At presentation the median del17p clone size was 82.5%. In the vast majority of cases (83%) the presence of a del17p was associated with the presence of a del13q14. Other concomitant genetic abnormalities detected by FISH were t(4;14) in 14.8%, t(11;14) in 20.4% and gain at 1q21 (+1q21) in 24.0% of cases. The median overall survival (OS) was poor (20.4 months) and did not change substantially over time (median survival in pts diagnosed before 2006 versus pts diagnosed thereafter). The clone size had no impact on OS in pts presenting with a del17p. Neither the presence of a t(4;14) nor a t(11;14) did impact on OS. In patients with an additional +1q21 OS was shorter (15 versus (v) 28 months; p = 0,07). The incorporation of one of the novel agents into first-line treatment did not change the outcome significantly. In contrast, pts receiving at least one autologous transplantation showed a significantly longer OS (33 v 11 months). 15 pts underwent an allogeneic transplantation. Although the only longtime survivors were identified in this subset of pts (maximum currently 12 y), OS was not significantly impacted by this procedure.

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In multivariate analysis ISS stage and implementation of an autologous transplantation remained significant prognostic factors for OS. Conclusions: The outcome of MM pts with a del17p remains poor, even after the introduction of lenalidomide and bortezomib into clinical practice. The development of novel therapeutic strategies therefore is urgently warranted. Disclosure: No conflict of interest disclosed. V69

Carfilzomib (30 min infusion) with and without dexamethasone in patients with relapsed and/or refractory multiple myeloma: Results from the phase 1b study PX-171–007 (NCT00531284) Badros A.Z.1, Papadopoulos K.P.2, Zojwalla N.3, Lee J.R.3, Siegel D.S.4 University of Maryland School of Medicine, Baltimore, United States, South Texas Accelerated Research Therapeutics, San Antonio, United States, 3Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, United States, 4John Theurer Cancer Center at Hackensack University Medical Center, Department of Myeloma, Hackensack, United States 1 2

Introduction: In the US, carfilzomib (K) (starting dose: 20 mg/m2; target dose: 27 mg/m2; 2‒10 min infusion) is approved in patients (pts) with relapsed and refractory multiple myeloma (MM). In this phase 1b dose escalation study (PX-171–007), the safety, tolerability, and efficacy of K (30 min infusion) ± low-dose dexamethasone (dex) was evaluated in pts with relapsed and/or refractory MM (RRMM). The primary objectives were to determine the maximum tolerated dose (MTD) of single-agent K and to evaluate the safety and tolerability of K ± dex in pts with RRMM. Methods: K was administered (30-min infusion) on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. During the dose escalation portion of the study, K (20 mg/m2) was administered on days 1–2 of cycle 1, followed by dose-escalation to 36, 45, 56, or 70 mg/m2. Additionally, K (45 or 56 mg/ m2) was combined with low-dose dex (40 mg/week; Kd). Safety was assessed (CTCAE v 3.0) and responses were determined (IMWG criteria). Results: Thirty-three pts were treated with single-agent K. In the 70 mg/ m2 dosing cohort, two dose-limiting toxicities were observed (renal tubular necrosis and proteinuria; both grade 3). The MTD of single-agent K was 56 mg/m2. Among pts who received single-agent K, 7 pts (21.2%) discontinued treatment due to an adverse event (AE), all from the 56 mg/m2 cohort; 11 pts (33.3%) in the overall population (including 5 pts [20.8%] in the 56 mg/m2 cohort) required dose reductions due to an AE. Nausea and fatigue (each 51.5%) and pyrexia (42.4%) were the most common treatment-related AEs. In the single-agent K cohorts, treatment-related hypertension occurred in 12% of pts; 4% of pts in the 56 mg/m2 cohort had treatment-related cardiac failure. In pts who received single-agent K (56 mg/m2), the overall response rate (ORR) was 50%. An additional 22 pts received Kd; 1 pt (4.5%) each discontinued treatment or was dose reduced due to an AE. The most common treatment-related AEs were thrombocytopenia and fatigue (each 40.9%) and anemia (27.3%). Treatment-related hypertension occurred in 23% of Kd pts (45 or 56 mg/ m2). One death occurred ≤30 days of completing treatment (not attributable to K). In 22 pts who received Kd (45 or 56 mg/m2 cohorts), the ORR was 55%. Conclusions: K (up to 56 mg/m2; 30-min infusion) ± low-dose dex was well tolerated and active in pts with RRMM. Kd is being evaluated versus bortezomib and low-dose dex in pts with relapsed MM in the randomized phase 3 study ENDEAVOR (NCT01568866). Disclosure: Ashraf Badros: No conflict of interest disclosed. David Siegel: Advisory Role: Consultancy, honoraria, advisory committee membership, Speaker’s Bureau for Millennium, Celgene & Onyx Pharmaceuticals Inc., an Amgen subsidiary; Financing of Scientific Research: Millennium, Celgene & Onyx Pharmaceuticals Inc., an Amgen subsidiary

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small carcinogenic risk, which is relevant in this young patient population [5;6].The ESMO 2013 guidelines therefore call for an effort to reduce the frequency of CT scans and limit their overall number [7]. Few data are available from prospective evaluations to inform on patterns of relapse and usefulness of the various follow-up examinations in TC patients. In a joint effort, interdisciplinary evidence-based recommendations for the follow-up of TC patients were formulated in 2010 [8]. Research strategies and recommendations in the field of TC survivorship were made by Travis et al. [9]. The Swiss Austrian German Testicular Cancer Cohort Study is an undertaking to determine the diagnostic performance and the clinical impact of a variety of tests, assess the pattern of care and the outcome of TC patients [10].

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V71

Bochtler T.1, Hegenbart U.1, Kimmich C.1, Seckinger A.1, Hose D.1, Goldschmidt H.1, Granzow M.2, Dreger P.1, Ho A.D.1, Jauch A.2, Schönland S.O.1

Domm A.-S.1, Kleber M.1, Hieke S.2, Schumacher M.2, Ihorst G.3, Koch B.4, Duyster J.1, Wäsch R.1, Engelhardt M.1

Detection of translocation t(11;14) by iFISH predicts long term hematologic remission and improved overall survival in patients with AL amyloidosis treated with autologous stem cell transplantation

Medizinische Klinik V, Universitätsklinik, Heidelberg, Germany, 2Institut für Humangenetik, Universität, Heidelberg, Germany 1

Introduction: Cytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are of prognostic significance for multiple myeloma patients. In AL amyloidosis (AL), a related plasma cell dyscrasia, the prognostic impact of cytogenetic aberrations has not yet been defined. The aim of this long term follow-up study was to assess the prognosis of AL patients (pts.) treated with autologous stem cell transplantation (ASCT) depending on iFISH results. Methods: We analyzed a consecutive cohort of 122 AL pts. from 02/2003 to 04/2014. Pts. with age up to 70 years, NYHA stage ≤ 2 and ECOG ≤ 2 were considered for ASCT. Median age was 55 years (37–70), median dFLC 151 mg/l (0–3194), median number of involved organs 2 (1–5), 68/122 (56%) had cardiac and 81/122 (66%) had renal involvement. 68/122 pts. received an induction and 101/122 a mobilisation chemotherapy prior to stem cell harvest. High dose therapy was administered with melphalan 2x100 mg/m2 with respective adjustments for renal function. iFISH cytogenetics was performed in plasma cells purified by auto-magnetic-activated cell sorting with CD138 immunobeads. For hybridization commercial two-color probe sets were used. Results: Translocation t(11;14) was the most prevalent aberration (59%), followed by deletion 13q14 (30%), gain 1q21 (21%), hyperdiploidy (13%) and the high risk aberrations t(4;14), t(14;16) or deletion 17p13 (7%). Detection of t(11;14) conferred a favorable prognosis with superior complete remission rates (45% vs. 26%, p = 0.039), longer hematologic event free survival (hemEFS) (median 65.0 vs. 28.1 months, p = 0.024) and longer overall survival (OS) (median not reached vs. 93.7 months, p = 0.041). In the Kaplan Meier hemEFS plots a plateau at 40% was observed for t(11;14) positive pts.. On the contrary, high risk aberrations conferred an inferior hemEFS (28.1 vs. 34.1 months, p = 0.10) and OS (46.0 vs. 97.3 months, p = 0.077), though statistical significance was not reached likely due to low pts. numbers. Gain 1q21 had a trend for a worse hemEFS (31.1 vs. 46.1 months, p = 0.063), which did not translate into poorer OS (p = 0.56). Deletion 13q14 and hyperdiploidy were prognostically neutral. Discussion: Previous studies have shown the efficacy of ASCT for eligible pts.. In this long term follow-up analysis, we demonstrate that t(11;14) positive pts. benefit in particular from ASCT and are those most likely to achieve long lasting remission and survival or even cure. Disclosure: No conflict of interest disclosed.

Comprehensive assessment of comorbidities (CM), general condition and multiple myeloma (MM)-specific risk factors (RF) within a refined Freiburg Comorbidity Index (rFCI) in 803 consecutive MM patients (pts) and comparison with established comorbidity indices

Uniklinik Freiburg, Klinik für Innere Medizin I – Hämatologie, Onkologie und Stammzelltransplantation, Freiburg, Germany, 2Uniklinik Freiburg, Department für Medizinische Biometrie und Medizinische Informatik, Freiburg, Germany, 3Uniklinik Freiburg, Zentrum Klinische Studien (ZKS), Freiburg, Germany, 4Uniklinik Freiburg, Institut für Klinische Chemie und Laboratoriumsmedizin, Freiburg, Germany 1

Introduction: In addition to disease-specific and age-related factors, type and severity of CM play a relevant role, influence the tolerance of anti-MM-treatment and overall survival (OS). We have identified an impaired Karnofsky Performance Status (KPS), lung- and renal-impairment as significant RF for inferior outcome. These variables were combined in a comorbidity score (initial Freiburg Comorbidity Index [iFCI]). Objectives of this analysis were to refine the iFCI by adding host- and disease-specific RF, physical function, quality of life and its comparison to well-established comorbidity indices (CI; Charlson Comorbidity Index [CCI], Hematopoietic cell transplantation-specific comorbidity index [HCT-CI] and Kaplan-Feinstein). Methods: We assessed 803 consecutive pts treated between 1997–2012, determining CM as weighted renal-, lung-, heart-, liver-, gastrointestinal diseases, KPS, disability, frailty, infection, pain, secondary malignancies, peripheral neuropathy, thrombosis and disease parameters (e.g. cytogenetics). We divided our cohort into a training (n = 553) and validation set (n = 250). Results: Our pts showed a median age of 63 yrs (range 21–93). 26% revealed less favorable cytogenetics defined as t(4;14), t(14;16), del(17p13), del(13q14) and chromosome 1 abnormalities. Each 50% of pts received either standard chemotherapy or SCT. Frequent CM (>30%) were KPS-, heart-, renal-, lung-impairment, disability and frailty. Univariate analysis revealed age, renal-, lung- and heart-disease, KPS, disability, frailty, pain and infections as significant. Multivariate risks were age (>70 yrs), renal-, lung-, KPS-impairment, frailty and cytogenetics with hazard ratios of 2.2, 1.8, 1.3, 3.2, 1.9 and 1.5, respectively. The rFCI allowed to distinguish low-, intermediate- and high-risk pts with largely different OS of 11.2, 4.8 and 2.6 yrs, confirmed via validation analysis with even more distinct OS differences of not reached, 6.5 or 1.4 yrs, respectively. The rFCI compared to other CI remained highly significant and comparison of all CI via training set showed superiority of the rFCI and CCI and in the validation again of the rFCI and HCT-CI. Conclusions: Age, renal-, lung-, KPS-impairment, frailty and cytogenetics are relevant RF included in our rFCI. Advantages of the rFCI vs. iFCI are the inclusion of MM-specific RF including cytogenetics, the more accurate assessment of pts´ physical conditions, lower prediction errors and simple applicability. Disclosure: No conflict of interest disclosed. V72

Clinical activity of PAT-SM6 monoclonal antibody in advanced and extramedullary Multiple Myeloma – results from a phase I study and a single patient treatment use Rasche L.1, Düll J.1, Castro I.2, Lapa C.3, Rosenwald A.2, Topp M.S.1, Knop S.1, Chatterjee M.1, Einsele H.1, Brändlein S.2 Universitätsklinik Würzburg, Hämatologie, Würzburg, Germany, Universität Würzburg, Institut für Pathologie, Würzburg, Germany, 3 Universitätsklinik Würzburg, Nuklearmedizin, Würzburg, Germany 1

Introduction: PAT-SM6 is a monoclonal IgM antibody, developed for the treatment of patients with various tumor types including multiple my-

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2

Disclosure: Leo Rasche: No conflict of interest disclosed. Stephanie Brändlein: Advisory Role: consultancy agreement with Patrys Ltd, Australia; Expert Testimony: receives, in part, research funding from Patrys Ltd, Australia V73

Dynamic contrast-enhanced magnetic resonance imaging for assessment of anti-angiogenic treatment effects in multiple myeloma Merz M.1,2, Ritsch J.1, Kunz C.3, Wagner B.1, Sauer S.1, Hose D.1, Moehler T.1, Delorme S.2, Goldschmidt H.1,4, Zechmann C.5, Hillengass J.1,2 Universitätsklinikum Heidelberg, Hämatologie, Onkologie und Rheumatologie, Heidelberg, Germany, 2Deutsches Krebsforschungszentrum, Radiologie, Heidelberg, Germany, 3Deutsches Krebsforschungszentrum, Biostatistik, Heidelberg, Germany, 4Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany, 5Rinecker Proton Therapy Center, München, Germany 1

Introduction: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a non-invasive imaging modality to quantify bone marrow microcirculation. DCE-MRI parameters amplitude A and exchange rate constant kep are associated with blood volume and vessel permeability, respectively. We performed the current prospective trial to correlate findings from DCE-MRI before and after therapy with treatment response in patients with newly diagnosed MM. Methods: 91 patients were enrolled to receive DCE-MRI before and after treatment for newly diagnosed MM. 82 patients were treated with highdose therapy (HDT) and autologous stem cell transplantation (ASCT), while 9 patients were treated with conventional chemotherapy. Analysis of DCE-MRI was performed according to the two-compartment model by

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Brix et al. quantifying amplitude A and exchange rate constant kep. Patients with stable or progressive disease were classified as non-responders to therapy, while patients in remission were grouped as responders. Changes in DCE-MRI parameters A and kep before and after therapy for responders and non-responders were analyzed with the paired Wilcoxon signed-rank test. The Kruskal Wallis test and the Jonckheere Terpstra trend test were performed to identify differences and trends for A and kep according to remission after therapy. Results: Non-responders showed significantly higher A-values before therapy compared to responders (p = 0.02). In both, responders and non-responders, A-values dropped significantly (p = 0.004 and < 0.001, respectively) after primary therapy while lower values for kep after treatment were only found in responders (p = 1 antigen; n =  37; 25.9%) unrelated. The median follow-up was 4.4y. Medical research council (MRC) classification was favorable (n = 3; 2.2%) intermediate (int, n = 99; 72.3%) or adverse (adv, n = 35; 24.5%). All pts were characterized for CEBPA (n = 18; 13.0%) & NPM1 (n = 32; 22.9%) mut & FLT3-ITD (n = 23; 16.7%) presence at diagnosis.

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DNMT3A and IDH1/2 mutations in AML: incidence, prognostic influence and association with other molecular markers Blau I.W.1, Berenstein R.2, Baldus C.2, Westermann J.1, Pezzutto A.2, Dörken B.1, Blau O.2 Charité – Universitätsmedizin Berlin, Campus Virchow Klinikum, Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 2 Charite – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hämatologie und Onkologie, Berlin, Germany 1

Introduction: Abnormal epigenetic regulation has been implicated in oncogenesis. Mutations in the DNA methyltransferase 3A (DNMT3A) gene and in isocitrat dehydrogenase 1/2 (IDH1/2) genes were recently demonstrated in acute myeloid leukemia (AML) as a candidates for the initiating of lesions in AML with adverse clinical outcome. Methods: We analyzed bone marrow samples from 320 AML patients at the time of diagnosis. In all AML patients double induction therapy

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Isocitrate dehydrogenase (IDH) mutations (mut) in acute myeloid leukemia (AML) patients (pts) with adverse karyotype undergoing hematopoietic stem cell transplantation (HCT) after reduced intensity conditioning (RIC) are associated with an improved outcome

Disclosure: Igor Wolfgang Blau: Employment or Leadership Position: ja; Advisory Role: Celgene, Janssen Cilag, MSD; Financing of Scientific Research: Celgene, Janssen Cilag, MSD, Gilead, Genthium, Novartis, BMS Olga Blau: No conflict of interest disclosed.

tors) could be allocated to one patient. Accordingly, patients were divided into two risk groups: 34 patients scored 0–1 points and 45 patients scored 2–3 points. Subsequently, OS, RFS and cumulative incidence of relapse (CIR) were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the two risk groups (p 12 months; 26% continued on treatment). The prevalence rate of all-grade infection was highest (69%) in the first 6 months, declining thereafter. One SAE occurred at >24 months. Overall, patients with CRs had lower grade ≥3 infection rates than non-CR patients. No substantial changes occurred in serum immunoglobulin (Ig) levels (IgA, IgG, IgM). Median times to onset and resolution of diarrhea were 8 and 5 days, respectively. Rates of diarrhea were highest in the first 6 months (44% all-grade; 4.5% grade ≥3; 1% SAE), declining thereafter. No SAE of diarrhea occurred at >6 months. No case of colitis was reported. Bleeding events including all-grade bruising occurred in 51% of patients. All-grade bleeding was highest in the first 6 months (41%; 14% at >24 months). Protocol-specified major bleeding was ≤5% during each interval. Conclusions: In patients receiving continuous ibrutinib, rates of infection and diarrhea decreased over time, while the prevalence of bleeding events remained stable, with a major bleeding rate ≤5%; these findings further document a favorable safety profile of ibrutinib in patients with previously treated MCL.

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Survival of patients with AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma – results from the German HIV Lymphoma Cohort Study

Disclosure: Stephan Stilgenbauer: Advisory Role: Pharmacyclics, Janssen; Financing of Scientific Research: Pharmacyclics, Janssen; Expert Testimony: Pharmacyclics, Janssen Kristie Blum: No conflict of interest disclosed. V126

Increased rituximab (R) doses eliminate increased risk and improve outcome of elderly male patients with aggressive CD20+ B-cell lymphomas: The SEXIE-RCHOP-14 trial of the DSHNHL Held G.1, Murawski N.1, Zeynalova S.2, Zwick C.1, Haenel M.3, Truemper L.4, Dreyling M.5, Dierlamm J.6, Loeffler M.2, Schmitz N.7, Pfreundschuh M.1, Deutsche Studiengruppe für Hochmaligne Non-Hodgkin-Lymphome (DSHNHL) Universitätsklinikum des Saarlandes, Innere Medizin I, Homburg/Saar, Germany, 2Institut für Medizinische Informatik, Statistik und Epidemiologie der Universität Leipzig (IMISE), Leipzig, Germany, 3Klinikum Chemnitz, Klinik für Innere Medizin III, Chemnitz, Germany, 4Universitätsmedizin Göttingen, Abteilung Hämatologie und Onkologie, Göttingen, Germany, 5 Universitätsklinikum Grosshadern, Medizinische Klinik 3, München, Germany, 6Universitätsklinikum Hamburg-Eppendorf (UKE), II. Med. Klinik und Poliklinik, Hamburg, Germany, 7Asklepios Klinik St. Georg, Abteilung Hämatologie/Onkologie, Hamburg, Germany 1

Introduction: Elderly male patients have significantly lower R serum levels, shorter exposure times and a worse outcome in RICOVER-60, RICOVER-noRTh, and Pegfilgrastim trials (Blood 2012, 119:3276; Blood 2014, 123:640–646). Methods: To test increasing R doses, male patients received 500 instead of 375 mg/m2 in the SEXIE-R-CHOP-14 trial which also compared six cycles of CHOP-14 in combination with eight 2-week applications with eight upfront dose-dense applications of R (days -1, 0, 3, 7, 14, 21, 28, 42) in a randomized phase-II trial. 271 patients (61–80 years) were randomized, 268 patients are evaluable. 148 patients males received 500 mg/ m2, 120 females 375 mg/m2 R. Results: Protocol adherence was excellent with median relative doses of R and myelosuppressive drugs >98%. During the treatment period, the increased R dose in males resulted in slightly higher trough serum levels than in females; however, R levels dropped faster in males resulting in very similar serum levels thereafter and a only a marginally longer overall R exposure time. The increased R dose in males was not associated with increased toxicities. 3-year PFS was 74% in males and 68% in females (p = 0.396), 3-year OS was 80% in males and 72% in females (p = 0.111). In a multivariable analysis adjusting for IPI factors, male hazard was 0.9 (p = 0.817) for PFS, and 0.8 for OS (p = 0.317). In a historical comparison by multivariable analysis adjusting IPI risk factors and age >70 years, of 148 elderly males who received 500 mg/m2 in SEXIE-R-CHOP-14 and 250 males who received 375 mg/m2 in RICOVER-60, the increased dose of R was associated with a reduced risk for an event in PFS (HR = 0.7; p = 0.128) and in OS (HR = 0.7; p = 0.223). Conclusions: Increasing R dose by one third from 375 mg/m2 to 500 mg/ m2 eliminated the increased risk of elderly males. That the increased R dose significantly improves outcome not only of elderly male patients, but also of young male and female patients who have a R pharmacokinetics similar to elderly males should be confirmed in a larger randomized study of these subpopulations with aggressive CD20+ B-cell lymphomas. Supported by Roche and Deutsche Krebshilfe. Disclosure: Gerhard Held: No conflict of interest disclosed. Michael Pfreundschuh: Advisory Role: Roche, Onyx, Celgene; Expert Testimony: Roche, Spectrum

V127

Vitamin D deficiency (VDD) impairs rituximab-mediated cellular cytotoxicity and outcome of DLBCL patients treated with, but not without rituximab (R) Bittenbring J.T.1, Zwick C.1, Neumann F.1, Altmann B.2, Achenbach M.1, Reichrath J.3, Ziepert M.2, Geisel J.4, Regitz E.1, Held G.1, Pfreundschuh M.1 Universitätsklinikum des Saarlandes, Innere Medizin I, Homburg/Saar, Germany, 2Institut für Medizinische Informatik, Statistik und Epidemiologie der Universität Leipzig (IMISE), Leipzig, Germany, 3Universitätsklinikum des Saarlandes, Dermatologie, Venerologie, Allergologie, Homburg/Saar, Germany, 4Universitätsklinikum des Saarlandes, Zentrallabor, Homburg/ Saar, Germany 1

Introduction: Vitamin D deficiency has been reported to be associated with a worse outcome in patients with various malignant diseases. Methods: The aim of this study was to investigate impact and underlying mechanisms of vitamin D-deficiency (VDD) on outcome of elderly patients with diffuse large B-cell lymphoma (DLBCL). 359 pretreatment 25-OH-vitamin D serum levels from the RICOVER-60 trial and 63 from the RICOVER-noRTh study were determined by chemoluminescent immunoassay. Rituximab-mediated cellular cytotoxicity (RMCC) was determined by LDH release assay of CD20+ Daudi cells. Results: RICOVER-60 patients with VDD (≤8 ng/ml) treated with R had a 3-year event-free survival of 59% compared to 79% in patients with vitamin D levels >8 ng/ml; 3-year overall survival was 70% and 82%, respectively. These differences were also significant in a multivariable analysis adjusting for IPI risk factors with a hazard ratio (HR) of 2.1 (p = 0.008) for event-free and 1.9 (p = 0.040) for overall survival. EFS was not significantly different in patients with vitamin D levels ≤8 and >8 ng/ml (HR 1.2; p = 0.388) treated without R. This was confirmed in an independent validation set of 63 RICOVER-noRTh patients. While R improved 3-year EFS of VDD patients by only 16%, patients with better vitamin D levels benefitted nearly twice as much from the addition of rituximab (31%). RMCC increased significantly (p 10 days. They frequently do not respond to empirical antibacterial therapy. A causative pathogen remains undetected in the majority of cases, but early treatment improves overall survival. Aspergillus spp., Pneumocystis jirovecii, multi-resistant gram-negative pathogens, mycobacteria or respiratory viruses may be involved, while in patients at risk, who have received trimethoprim-sulfamethoxazole prophylaxis, filamentous fungal pathogens appear to be predominant. However, they are commonly not proven at the time of treatment decision. Methods: The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and an international group of experts have updated their evidence-based clinical guideline. Results: Microorganisms detected from blood cultures, bronchoalveolar lavage or respiratory secretions are not always relevant for the etiology of pulmonary infiltrates and should be interpreted critically. Laboratory tests for detecting Aspergillus galactomannan, beta-D-glucan or DNA from blood, bronchoalveolar lavage or biopsies may facilitate the diagnosis. As non-infectious causes, pulmonary side effects from cytotoxic drugs, radiotherapy, or pulmonary involvement by the underlying malignancy should be taken into consideration and may be diagnosed by invasive procedures. Early treatment with mould-active systemic antifungals improves clinical outcome, while other microorganisms are preferably treated when microbiologically proven. High-dose trimethoprim-sulfamethoxazole is first choice for treatment of Pneumocystis pneumonia, while cytomegalovirus pneumonia is treated preferably with ganciclovir or foscarnet. In a considerable number of patients, clinical outcome is favorable despite respiratory failure. Intensive care should be unrestrictedly offered to patients whose prognosis is not desperate due to other reasons. Conclusions: This updated multi-disciplinary, evidence-based guideline may help to improve clinical outcome in febrile neutropenic patients with lung infiltrates. Disclosure: Georg Maschmeyer: Advisory Role: Gilead, Pfizer, F2G, Celgene; Financing of Scientific Research: Gilead; MSD; Pfizer; Astellas; Janssen-Cilag; Merck; Bristol-Myers Squibb; ADKA; LAGO; Bundesapothekerkammer; Expert Testimony: Pfizer

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V135

General recommendations regarding vaccination of cancer patients. General recommendations regarding prophylaxis against hepatitis B von Lilienfeld-Toal M.1, Sandherr M.2 Klinik für Innere Medizin II, Universitätsklinikum Jena, Hämatologie und internistische Onkologie, Jena, Germany, 2Gemeinschaftspraxis für Hämatologie und Onkologie, Weilheim, Germany 1

Vaccination of patients but also of their household members may prevent transmission of potentially lethal infections. Recent data have illustrated that many cancer patients respond to vaccinations despite their treatment-induced immunosuppression. For this reason, current guidelines recommend annual influenza-vaccination if possible 2–4 weeks prior to start of immunosuppressive therapy. After completion of therapy, patients should receive necessary vaccinations including annual influenza vaccination and pneumococcal vaccine 3–6 months after therapy. For household members, especially children, annual influenza vaccination and strict adherence to general vaccination schedules are recommended. Cancer patients may be at increased risk for reactivation of hepatitis B because of their disease or because of immunosuppressive therapy. In particular, patients who receive rituximab appear to have a high risk of reactivation. Importantly, this is true for all serological constellations. Thus, even patients without evidence of HBs-antigen or HBV-DNA but positive results for anti-HBc and anti-HBs may reactivate. The ID working party of the DGHO has developed an algorithm to guide management of cancer patients with a history of hepatitis B as depicted in figure 1.


Central venous catheter-related infections – updated guidelines Hentrich M. Klinikum Harlaching, Klinik für Hämatologie, Onkologie und Palliativmedizin, München, Germany

Introduction: Central venous catheters (CVC) are widely used in patients with malignancies. However, cancer patients are at increased risk for central venous catheter-related infections (CRI). Thus, a comprehensive, practical and evidence-based guideline on CRI in patients with malignancies is warranted. Methods: A panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) has developed a guideline on CRI in cancer patients. Literature searches of the PubMed, Medline and Cochrane databases were performed and consensus discussions were held. Results: CRI can be subdivided in catheter colonization, different types of local CRI, infusate-related bloodstream infections (BSI), and catheter-related BSI (CRBSI). Distinguishing between definite, probable and possible CRBSI removal of the catheter is recommended if the patient’s clinical state deteriorates or if S. aureus, Gram-neg. bacilli or Candida

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Aditionally the likelihood to get cancer is increasing too. Older patients require more resources of the haelth care system than younger patients. These includes more need of specialized care i.e. because of comorbities and more effective therapies („personalized therapy“). The possible solutions to serve the increasing demands will be discussed in detail during the presentation i.e. move to oncologic nurse practioners, development of a network of health care providers to share the increasing workload.

spp. are isolated from blood cultures. By contrast, the catheter may be preserved if coagulase-neg. staphylococci or Corynebacterium jeikeium are found. Antibiotic-lock technique for 10–14 days might be a treatment option for highly needed infected catheters. Prospective surveillance programs along with intensive training strategies to improve the handling of CVC are able to reduce CRI rates in neutropenic patients with hematologic malignancies. Hand hygiene procedures (alcohol-based hand rub), aseptic technique, and maximal sterile barrier precautions are important factors in preventing CRI. For cutaneous antisepsis an alcohol containing >0.5% chlorhexidine-based solution should be used with alcoholic polyvidone-iodine solutions or 70% propanolol being safe alternatives if there is a contraindication to chlorhexidine. Although not generally recommended, the use of antimicrobial-impregnated catheters may be useful in patients with long-term CVC if the CRI rate remains high despite implementation of educational programs and appropriate process control. Conclusions: This guideline is an evidence-based approach to the diagnosis, management and prevention of CRI in cancer patients. The strength of the recommendation and the level of evidence will be presented.

CML

these TKIs exert superior anti-leukemic effects in newly diagnosed CML patients compared to imatinib. These TKIs also counteract early transformation to AP and BP more effectively compared to imatinib. The superior effects of these TKIs may result from their strong effects on BCR/ ABL1 and BCR/ABL1 mutant-bearing subclones, but also from their effects on additional drug targets. Notably, in contrast to imatinib, most of these novel TKIs recognize a wide variety of additional kinase targets in leukemic cells. However, such additional targets are also expressed in non-hematopoietic cells and may thus be responsible for non-hematologic adverse events. Whereas in many cases, side effects are mild and manageable without organ damage, some of these patients have major problems and develop overt intolerance or even life-threatening adverse events (AEs) during treatment, which is a critical aspect as in most patients these novel TKIs are still prescribed on a life-long basis. Each novel TKI has a unique profile of severe adverse events. Patients receiving dasatinib may develop pleural and pericardial effusion as well as pulmonary hypertension, patients receiving nilotinib are at high risk to develop arterial occlusive disease (AOD) and patients treated with ponatinib may develop both AOD and venous thromboembolic events. All EA seem to accumulate over time and depend on the TKI dose applied. The mechanisms underlying these adverse events are currently being examined. In the current presentation, we provide a summary of our knowledge about severe adverse events occurring in patients treated with novel TKIs, with special emphasis on potential mechanisms and management.

V138

Disclosure: Peter Valent: Advisory Role: Novartis, BMS, Ariad, Pfizer; Financing of Scientific Research: Novartis, BMS, Pfizer, Ariad; Expert Testimony: Novartis


Fortbildung

Treatment-free remission – when to stop TKI treatment? Universitätsmedizin Mannheim, III. Med. Klinik, Abteilung für Hämatologie und Onkologie, Mannheim, Germany

More and more patients on tyrosine kinase inhibitor (TKI) treatment achieve deep responses. In these patients we face a paradigm shift from life-long treatment towards a life without specific treatment. Stopping TKI treatment has been necessary in patients with intolerable side effects without having alternative medication. Several prospective studies have been performed in order to quantify the chance of successful stopping of TKI therapy and to determine risk factors for a molecular relapse. Current trials try to answer the question how deep molecular remissions should be and how long they need to persist for predicting the outcome. These and other factors contributing to better outcome of treatment-free remission trials will be reviewed and discussed. Proper standardized and very sensitive molecular monitoring is the key methodology for guiding rational decisions in these “best of the best” responding patients. Disclosure: Martin Müller: Advisory Role: Novartis, BMS, Ariad, Pfizer; Financing of Scientific Research: Novartis, BMS, Ariad, Pfizer; Expert Testimony: Novartis, BMS V139

Relevant toxicities of novel BCR/ABL1 TKI: Clinical data, mechanisms and management Valent P. Medical University of Vienna, Wien, Austria

The BCR/ABL1 tyrosine kinase inhibitor (TKI) imatinib is considered the gold-standard of treatment of patients with freshly diagnosed CML. However, despite convincing efficacy and safety, resistance against imatinib may occur during therapy, often in association with BCR/ABL1 mutations. Treatment of imatinib-resistant CML is a challenge in clinical hematology. For these patients, more effective second- and third-generation TKIs have been developed, including nilotinib, dasatinib, busotinib and ponatinib. These TKIs received approval by major health authorities, based on their impressive effects on leukemic cells in imatinib-resistant CML. In addition, nilotinib and dasatinib are approved for first-line treatment of patients with Ph+ CML. Notably, it has been shown that

Abstracts

Fortbildung

Hepatische und Gallenwegstumore V143

Cholangiocarcinoma – state of the art 2014 Vogel A. Medizinische Hochschule Hannover, Hannover, Germany

Cholangiocarcinoma (CC) is the second most common primary liver cancer. The incidence in western countries increases and currently up to 1/ 100.000 people are diagnosed with CC per year. CC defines all tumors originating from gallway epithelium, including intrahepatic CC (ICC) and extrahepatic CC (ECC), as well as gallbladder carcinoma (GC). ECC can be divided into perihilar carcinoma and distal ECC. Radical resection is the only curative treatment option. However, high rates of irresectable patients and recurrence after resection result in overall poor prognosis. Because of the low prevalence and incidence of CC, conducting large prospective studies is difficult in CC. Only few randomized phase III-trials exist and so, many questions remain open in the treatment of CC, for example the role of adjuvant treatment or second line chemotherapy. In cases with a potentially curative surgery, 5-year survival rates of 25%30% are reported. Currently, two studies have been initiated in Germany to determine the role of adjuvant therapy after surgery. The randomized cli ACTICCA study funded by the Deutsche Krebshilfe evaluates the role of adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma. The ProDuct trail determines the feasibility and efficacy of adjuvant gemcitabine chemotherapy after liver transplantation for proximal bile duct cancer. In the palliative setting the intent of therapy is to extend life, relieve symptoms of obstructive jaundice and improve quality of life. Subclinical or frank cholangitis is associated with increased morbidity and mortality and endoscopic biliary drainage is an established procedure for palliation of unresectable malignant hilar biliary strictures. The role of intraductal radiofrequency ablation and photodynamic therapy, which consists of a photosensitizing agent in combination with laser irradiation, is currently evaluated in prospective trails such as the randomized Phase-III Pinnacle-PHO1201 trail. In metastatic disease, chemotherapy improves quality of life and survival, and the combination of gemcitabine and cisplatin


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Müller M.C.

represents the standard of care. However, all patients ultimately progress on this therapy, so clinical trials of new and better agents are essential to expand the existing treatment options for patients with biliary cancer. Disclosure: Arndt Vogel: Financing of Scientific Research: Roche, Amgen, Celgene, Bayer, FALK

Fortbildung

Multiples Myelom – spezielle Aspekte V144

Management of patients with impaired renal function Weisel K.C. University of Tübingen, Medical Center, Hematology, Oncology and Immunology, Tübingen, Germany

Acute kidney injury and renal impairment are one of the most common complications in multiple myeloma disease. More than half of the myeloma patients suffer from renal impairment during primary diagnosis or further disease course. Main cause of acute kidney injury is cast nephropathy which occurs when free light chains bind to Tamm-Horsfall protein resulting in a mechanical occlusion of the distal tubule. Additional cofactors, such as dehydration and the use of non-steroidal antiphlogistic agents might enhance kidney injury. Despite the introduction of novel agents in myeloma treatment, renal impairment remains a prognostic factor and still correlates with impaired prognosis. However, all current treatment strategies are available for renally impaired patients. Key issue is the rapid and consequent treatment introduction allowing effective myeloma contol and consecutive depletion of toxic light chains responsible for kidney injury. For primary diagnosed patients, so far bortezomib containing inuction regimens are recommended. Renally impaired patients in a transplant-eligible age should undergo a high-dose treatment strategy and autologous stem cell transplantation. Due to a still markedly higher early mortality rate patients with renal impairment should be closely monitored. In the relapse and refractory setting, all available drugs can be administered in case of impaired renal function. Current treatment concepts lead to sustained renal recovery in a large proportion of patients including those with dialysis dependent renal failure. In patients with primary dialysis dependent renal failure, extracorporeal light chain removal with high-cut off dialysis shows promising results, the exact role has still to be determined. Disclosure: Katja Weisel: Advisory Role: BMS, Celgene, Janssen, Noxxon, Onyx; Financing of Scientific Research: Celgene, Janssen, Onyx

Freier Vortrag

Allogene Transplantation – klinisch I

CXCR4 (X4) chemokine receptor. Homozygosity for a 32 base pair deletion in the CCR5 allele (CCR5 delta32) prevents the cellular entry of R5 tropic HIV-1 strains and has been associated with a decreased risk of acquiring HIV-1. In 2009 a first case of an HIV patient with acute myeloid leukemia (AML) was reported who received an allogeneic stem cell transplantation (AlloSCT) from a donor who was homozygous for the CCR5 delta32 mutation. Methods: We here present the case of an HIV patient with large cell anaplastic T-cell-lymphoma who was treated with AlloSCT from a donor with homozygosity for the CCR5 delta32 mutation. The CCR5 delta32 homozygosity was proven by Sanger sequencing. The HIV-1 tropism was repeatedly analyzed by sequencing the V3 gene and by using the “geno2pheno-coreceptor tool”, which calculates the false positive rate of HIV-1 V3 sequences indicating the probability of classifying an R5-virus falsely as X4. Results: The genotypic analyses of HIV-1 variants during interruptions of the antiretroviral treatment showed a shift from a dominantly R5 tropic HIV infection prior to the AlloSCT towards a clear X4 tropic variant and high viral rebounds after AlloSCT. The HIV-1 variants, which were genotypically classified as extremely X4-capable, yielded twice high viral loads at times of treatment interruptions after AlloSCT. There appeared to be no obvious correlation with the administration of immunosuppressants and the HIV load or the CD3+/CD4+ cell count. Conclusions: Presumably the shift of tropism towards an extremely X4-capable virus was selected by the AlloSCT with stem cells homozygous for the CCR5 delta32 mutation. However, the HIV-1 infection was not controlled by the transplanted new immune system lacking a functional CCR5 receptor. This case shows that homozygous CCR5 delta32 deletion does not protect against replication of CXCR4 tropic HIV and disease progression. Thus, the beneficial effect of AlloSCT with donors homozygous for the CCR5 delta32 mutation can be hampered by the selection of X4-tropic HIV-1 variants. It will be crucial to define what levels of X4-tropic viruses would not jeopardize treatment strategies based on CCR5 coreceptor antagonism to prevent the cellular entry of HIV-1. Disclosure: No conflict of interest disclosed. V148

Azacitidine and Donor Lymphocyte Infusions as treatment for AML or MDS relapse after allogeneic stem cell transplantation – a retrospective multicenter analysis in 154 patients on behalf of the German Cooperative Transplant Study Group Schroeder T.M.1, Rachlis E.2, Bug G.3, Stelljes M.4, Klein S.5, Wolf D.6, Ringhoffer M.7, Czibere A.1, Nachtkamp K.1, Dienst A.1, Kondakci M.1, Stadler M.8, Platzbecker U.9, Uharek L.10, Luft T.11, Fenk R.1, Germing U.1, Bornhäuser M.9, Kröger N.12, Beelen D.W.13, Haas R.1, Kobbe G.2, Deutsche Kooperative Transplantationsstudiengruppe University of Düsseldorf, Medical Faculty, Hematology, Oncology and Clinical Oncology, Düsseldorf, Germany, 2Universitätsklinik Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie, Düsseldorf, Germany, 3Department of Medicine II, University Hospital, Frankfurt, Germany, 4University of Münster, Dept. of Medicine A, Hematology and Oncology, Münster, Germany, 5Universitätsmedizin Mannheim, Med. Klinik III, Mannheim, Germany, 6University Hospital Bonn, Med. Klinik III, Bonn, Germany, 7Karlsruhe Hospital, Dept. of Medicine III, Karlsruhe, Germany, 8Hannover Medical School, Hannover, Germany, 9University Hospital Carl Gustav Carus, Dresden, Germany, 10Charité, Hematology, Berlin, Germany, 11University Hospital Heidelberg, Dept. of Medicine V, Heidelberg, Germany, 12University Hospital Hamburg-Eppendorf, Hamburg, Germany, 13Clinic for Bone Marrow Transplants, University Hospital Essen, Essen, Germany 1

Shift of HIV-Tropism in a HIV-patient with large cell anaplastic T-cell-lymphoma undergoing allogeneic stem cell transplantation from a donor with homozygosity for the CCR5 delta32 mutation Kordelas L.1, Verheyen J.2, Beelen D.W.1, Horn P.A.3, Heinold A.3, Kaiser R.4, Trenschel R.1, Schadendorf D.5, Dittmer U.2, Esser S.5 University Hospital, University of Duisburg-Essen, Department of Bone Marrow Transplantation, Essen, Germany, 2University Hospital, University of Duisburg-Essen, Institute of Virology, Essen, Germany, 3University Hospital, University of Duisburg-Essen, Institute for Transfusion Medicine, Essen, Germany, 4University of Cologne, Institute of Virology, Cologne, Germany, 5University Hospital, University of Duisburg-Essen, Clinic for Dermatology, Essen, Germany 1

Introduction: HIV replication is initiated by attachment of the virus to the CD4 receptor and then interacting with either the CCR5 (R5) or the

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Introduction: Since two prospective studies and small retrospective series have demonstrated clinical efficacy of Azacitidine (Aza) as salvage therapy for relapse of AML or MDS after allo-HSCT, it has become a relevant treatment alternative in this setting. Nevertheless, the limited pa-

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V147

Disclosure: Thomas Schroeder: Financing of Scientific Research: Celgene; Other Financial Relationships: Celgene Reiseunterstützung Guido Kobbe: Financing of Scientific Research: Celgene; Expert Testimony: Research Funding Celgene V149

was diagnosed according to the Glucksberg criteria and by endoscopic biopsies. Cytomegalovirus, adenovirus, rotavirus and Clostridium difficile infection as potential cause of symptoms were excluded. The following symptoms were considered key symptoms and were preselected before data analysis: abdominal pain, cramps, bloating, diarrhea, urgency, upper abdominal pain, fullness, early satiety, nausea and vomiting Results: Out of 76 patients 40 showed intestinal aGvHD consequently diagnosed by endoscopic biopsies. GI-GVHD stages at the time of manifestation were I° n = 10, II° n = 12, III° n = 10 and IV° n = 8. In 12 patients presenting with GI-symptoms aGvHD was excluded by endoscopy and patients were enrolled as control subjects. After endoscopic diagnosis and symptom evaluation, patients with GI-GvHD received standard highdose corticosteroid therapy. Histological grading of colonic biopsies correlated with calprotectin levels (r = 0.76, p 95%). Gene expression levels were analyzed by Affymetrix array technology (GeneChip U133 Plus 2.0 arrays) and confirmed for a panel of select genes by qPCR. A stringent cut-off (p 3.0) was used to define differences in mRNA expression levels. A total number of 1,180 mRNA species were found to be differently expressed in EryPC in MDS (72 up-regulated, 1,108 down regulated) compared to normal BM EryPC. In the validation phase of our project, we identified the major Coxsackie-Adenovirus Receptor (CAR) as a rather specifically regulated protein-product in dysplastic EryPC. In fact, as assessed by FCM, a significantly lower or even absent expression of CAR was found on EryPC in 20 of 30 patients with MDS (67%), including 3/4 patients with RCUD, 1/4 with RARS, 6/10 with RCMD, 8/9 with RAEB, and 2/3 with 5q- syndrome, compared to normal BM or non-neoplastic controls (p  3 months. After admission for treatment of a newly diagnosed pneumonia, the patient developed rapidly progressive signs and symptoms of heart failure. A transthoracic echocardiography revealed a moderate circumferential pericardial effusion with hemodynamic compromise and three pericardial masses up to 5.9 × 8.0 cm. Cardiac magnetic resonance imaging confirmed moderate circumferential pericardial effusion and a diffuse infiltration of the left atrium and both ventricular walls. A myocardial biopsy was performed, histopathological examination of the sample revealed a chronic myocarditis, but no signs of infection or the suspected AML. Both laboratory examination of peripheral blood and bone marrow aspiration revealed no evidence for AML relapse. The patient died shortly after developing a perforated sigmoid diverticulitis with multi-organ failure. Autopsy confirmed an extramedullary AML relapse with infiltration of the myocardium. Immunohistochemical studies confirmed the same phenotype as on initial presentation in the bone marrow. In conclusion, we report a case of a patient with cardiac and pericardial infiltration by an extramedullary AML as manifestation of relapse that underlines the difficulty of diagnosing cardiac myeloid sarcoma even in the setting of a high clinical suspicion.

We have previously shown that the transcription factor Gfi1 is essential for the initiation and progression of acute lymphoid leukemia. Targeted loss of Gfi1 leads to regression of lymphoblastic leukemia without affecting the other hematopoietic cells. There is evidence that Gfi-1 plays also a regulatory role in maintenance of AML. In this study we examined the role of Gfi1 in myeloid leukemia and the suitability of the compound SH-2251, which targets Gfi1 expression, in different in vitro and in vivo leukemia models. Using different Gfi1 expressing human and murine AML cell lines, such as Kasumi1, KG1 and HL-60 and C1498, we could show that the presence of SH-2251 downregulates Gfi1 expression in these cells and impeded their growth. Non-Gfi1 expressing cell lines like embryonic kidney cells (293-T) were not affected by SH-2251, thus excluding the possibility of unspecific toxic effects. After these promising in vitro results we used different murine AML cell models mimicking human leukemia. We transplanted mice with murine leukemia expressing the human oncofusion protein AML1/ETO9a. After 3 weeks we started feeding the mice with 50mg/kg body mass SH2251. In a preliminary experiment with three control mice and three mice receiving the drug, SH-2251 delayed leukemia development. No toxic effects were observed when treating mice with SH-2251. On a molecular level, Gfi1 inhibits the function of p53 in leukemic cells. Loss of Gfi1 function leads to an overactive function of p53 and subsequently to massive apoptosis specifically in leukemic cells without affecting the non-leukemic cellsSH-2251 could be a new promising approach to treat AML patients, for whom no other therapeutic options are available. Disclosure: No conflict of interest disclosed. P179

AML patients in cytogenetic remission have significantly shortened telomeres: Possible implications on the origin of AML Crysandt M., Ziegler P., Ventura Ferreira M.S., Kaufmann J., Hummel S., Wilop S., Jost E., Brümmendorf T.H., Beier F. Medizinische Klinik IV, Medical Faculty, RWTH Aachen University, Dept. of Hematology, Oncology and Stem Cell Transplantation, Aachen, Germany

Acute myeloid Leukemia is a malignant disease of the hematopoietic system. Despite intensive therapy less than 30% of all leukemic patients can be cured. Especially elderly comorbid patients, for whom aggressive therapeutic approaches are often not suitable, have a very poor survival. Therefore new approaches to treat AML are warranted.

Introduction: Acute myeloid leukemia (AML) is a malignant disease primarily occurring in later adulthood. The close relationship to aging is not well understood and the question whether AML originates from prematurely aged hematopoietic stem cells is still unanswered. Telomere length (TL) shortens with each cell division and represents an established marker for tissue aging. Critical short telomeres have been found to play an important role in malignant transformation. In this study, we address this issue by sequentially analyzing TL in AML patients. Methods: TL of bone marrow (BM, n = 83) and peripheral blood (n = 9) of 45 newly diagnosed AML patients was analyzed using monochrome multiplex quantitative-PCR. Mean age of the AML patients was 50,4 years (range 21–75). Follow-up included the following timepoints: at diagnosis (n = 20), after two cycles of induction chemotherapy (IC, n = 42), after three additional cycles of consolidation chemotherapy (CC, n = 30). Peripheral blood leukocytes of 87 healthy controls were used for age-adaption of TL. Results: Newly diagnosed AML patients showed a significantly shortened age-adapted TL (mean±SE: -0.65±0.2 T/S ratio, p = 0.001). After IC and compared to TL at diagnosis, TL increased in patients with cytogenetic remission (CR, -0.33±0.1 T/S ratio, n = 34), but still remained moderately shortened compared to age-matched controls (p = 0.001). In comparison, patients with persistent AML showed no change in TL (-0.61±0.2 T/S ratio, n = 8). TL of patients in CR remained stable following three additional cycles of CC (-0.23±0.1 T/S ratio, n = 27, p = 0.03). Patients with relapse after CC remained substantially shortened (-1.0±0.2 T/S ratio, n = 4, p = 0.04). To exclude treatment related effects as a predominant reason for TL shortening, we longitudinally followed selected individual

Abstracts


Disclosure: No conflict of interest disclosed. P178

SH-2251 as a novel approach for leukemia therapy Lams R.F., Botezatu L., Hönes J., Michel L., Köster R., Dührsen U., Khandanpour C. Universitätsklinikum Essen, Klinik für Hämatologie, Essen, Germany

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Our data indicate cellular respiration as an early, sensitive and reliable surrogate parameter of mitochondrial function in viable cells that might be able to measure prospectively sensitivity or resistance of primary cancer cells towards specific anticancer drugs.


Functional inhibition of mesenchymal stromal cells (MSC) results in insufficient hematopoietic support in acute myeloid leukemia (AML) Geyh S.1, Cadeddu R.-P.2, Jäger P.2, Wilk M.2, Fenk R.2, Germing U.2, Kobbe G.2, Haas R.2, Schroeder T.2 University of Düsseldorf, Medical Faculty, Hematology, Oncology and Clinical Oncology, Düsseldorf, Germany, 2Universitätsklinik Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie, Düsseldorf, Germany 1

Introduction: Patients (pts) with acute myeloid leukemia (AML) generally suffer from hematopoietic insufficiency representing the major cause of morbidity and mortality. The molecular mechanisms of hematopoietic suppression in AML are poorly understood and often mechanistically summarized as marrow replacement by infiltrating leukemic cells. Therefore, it also remains unclear whether AML cells directly inhibit normal hematopoietic stem and progenitor cells (HSPC) or whether this is mediated via the BM microenvironment. Methods: Considering the role of mesenchymal stromal cells (MSC) in normal hematopoiesis we investigated the functional capacities of MSC in 42 pts with AML at diagnosis (n = 31) and/or during course of disease. In addition, we incubated healthy MSC with conditioned media (CM) of 4 AML cell lines (THP-1, HL-60, MV4–11, MOLM-13) and subsequently investigated MSC growth and differentiation. Results: At diagnosis, hematopoietic insufficiency was present in 31 AML pts as indicated by a median ANC of 1216/µl, median hemoglobin of 9.1 g/dl, a median platelet count of 71.000/µl and 72% of the pts having bi- or pancytopenia. MSC of these pts exhibited significantly impaired growth capacities as shown by an altered morphology, reduced CFU-F activity, a lower number of passages and cumulative population doublings. Cytochemical stainings, reduced osterix and osteocalcin (OC) mRNA levels as well as OC serum levels indicated a significantly reduced osteogenic differentiation potential of AML-MSC. Functionally, this translated into a significantly diminished ability of AML-MSC to support healthy CD34+ HSPC in LTC-IC assays. This defective stromal support was reversible and correlated with disease status, as LTC-IC frequency returned to normal values in pts in remission, but remained low in pts with refractory disease. In line with this, cultivation of healthy MSC in CM of 4 AML cell lines resulted in reduced proliferation and osteogenic differentiation suggesting a direct suppressive effect of AML cells on the BM microenvironment. Conclusion: Our data show that AML-derived MSC are structurally and functionally altered resulting in an impaired stromal support, which contributes to hematopoietic insufficiency in AML. The correlation between remission status and stromal support function together with the finding, that healthy MSC can adopt an AML-like phenotype when exposed to AML-CM suggest an instructive role of the leukemic precursor cells. Disclosure: Stefanie Geyh: No conflict of interest disclosed. Thomas Schroeder: Financing of Scientific Research: Celgene; Other Financial Relationships: Reiseunterstützung

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P181

Prognostic influence of CD4/20- ratio of bone marrow lymphocytes in aplasia and in complete remission after induction therapy in patients with AML Tschanter P.1, Evers G.2, Becker E.3, Büchner T.3, Sauer T.3, Müller-Tidow C.1, Berdel W.E.3, Koschmieder S.4, Krug U.5 Department of Medicine IV Hematology and Oncology, University HalleWittenberg, Halle (S.), Germany, 2Department of Medicine A Hematology, Oncology and Pneumology, University Münster, Münster, Germany, 3 Department for Hematology, Oncology and Pneumology; University Münster, Münster, Germany, 4RWTH Aachen, Aachen, Germany, 5Klinikum Leverkusen, Leverkusen, Germany 1

Acute myeloid leukemia (AML) is a heterogenous disease with different biological features. In recent years many prognostic markers could be identified. Published results report a correlation of lymphcyte recovery after induction therapy and prognosis. To analyse a possible impact of lymphocyte subpopulations on prognosis in AML we retrospectively analysed results of cell flow cytometry (CFC) in 243 AML patients. CFC was routinely performed at time of diagnosis, aplasia (d15) and at response assessment after induction chemotherapy. Further clinical parameters of the patients were observed: age, sex, FAB classification, type of chemotherapy, LDH, initial WBC, cytogenetic risk group, molecular risk factors, and blast percentage on day 15. Continous variables were analysed by

Mann-Whitney-U-Test, categorised variables by Chi-Square-Test. Overall (OS), event-free (EFS) and relapse-free survival (RFS) were estimated by the Kaplan Meier method and univariately compared by logrank test. For all multivariate statistics a Cox-regression was applied. In this retrospective study we identified the CD4/CD20- ratio in aplasia and in CR as a prognostic marker in AML: A high CD4/20- ratio (>34.5) is significantly associated with longer OS and EFS, but not with RFS, day 15 bone marrow blasts or remission rate. However, in multivariate Cox- regression analyses involving all clinical parameters, the only independent risk factors for OS and EFS were age and cytogenetic risk, but not the CD4/20- ratio. In contrary, a high CD4/20- ratio (>13.88) is associated with poorer prognosis in samples of patients in complete remission. In Cox regression analyses CD4/ 20- ratio, age and cytogenetic risk have a significant independent influence on OS, but no significant influence on RFS. In conclusion, flow cytometric determination of CD4/20 ratio at the time of CR achievement might add prognostic information in patients with AML in CR after induction treatment. If prospectively validated, such a determination could easily be incorporated into routine monitoring of AML bone marrow samples. Disclosure: No conflict of interest disclosed. P182

Human Equilibrative Nucleoside Transporter 1 (hENT1) – Expression assessed by flow cytometry in acute myeloid leukemia and correlation to clinical outcome Bellos F.1, Davis B.H.2, Culp N.B.2, Booij B.3, Schnittger S.1, Haferlach C.1, Haferlach T.1, Kern W.1 MLL Münchner Leukämie Labor, München, Germany, 2Trillium Diagnostics, Maine, United States, 3Clavis Pharma, Oslo, Norway 1

Introduction: Cellular hENT1 expression is essential for cell entry and cytotoxic activity of nucleoside analogues. Low hENT1 levels seem to correlate with poor response to therapies in solid tumors, data on AML is scarce. We examined hENT1 expression by flow cytometry in AML patients (pt) and correlated results to morphologic, cytogenetic (CG) and molecular genetic (MG) findings and clinical outcome in pt given intensive cytarabine-based chemotherapy (CHT) or demethylating agents (decitabine or 5-azaC, DM). Methods: 145 pt at diagnosis of AML were included (median age 67.3 years, CG done in 130 pt). Median hENT1 fluorescence intensities (MFI)

Abstracts

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patients. Thereby, we found no evidence for accelerated TL shortening in CR after IC (-0.28±0.1 T/S ratio, n = 24) and after CC (-0.18±0.1 T/S ratio, n = 24) arguing against a major impact of chemotherapy on TL in CR. Conclusion: We show that AML at diagnosis has substantially short telomeres, which increases – reaching cytogenetic remission – mostly due to a shift from leukemic cells (with shortened TL) to non-clonal cells. However, age-adapted TL is still significantly shortened in patients with first CR and remains stably shortened after further treatment. In summary, our data provides first evidence that AML possibly originates from HSC with prematurely shortened TL.

Disclosure: Frauke Bellos: Employment or Leadership Position: Arbeitnehmer MLL Münchner Leukämie Labor GmbH Wolfgang Kern: Employment or Leadership Position: Geschäftsführer MLL Münchner Leukämie Labor GmbH

to the parental cells. Modeling ASPP2 attenuation via specific siRNA knockdown in leukemia cell lines (K562 and Kasumi1) resulted in significantly increased cellular proliferation. Similarly, ASPP2-interference in pro-B Ba/F3 cells lead to perturbed proliferation and an increase of polyploid cells with a dramatic change in morphology with megaloid cells, indicating mitotic failure. This effect was even more pronounced after stress induction with daunorubicin. Lentiviral shRNA-ASPP2 knock-out was performed in Ba/F3 cells to follow cells in long term cultures for malignant transformation. Gamma irradiated ASPP2-lacking strains were successfully IL3 weaned as an indicator of autoactivated cellular proliferation – arguing for acquisition of oncogenic mutations (which we are currently screening for). In summary, we provide evidence that ASPP2 has a pivotal role in early hematopoiesis, and loss of ASPP2 is a driver mechanism to fuel leukemogenesis. Disclosure: No conflict of interest disclosed. P184

Base excision repair glycosylase activity is impaired in a subgroup of acute myeloid leukemia resulting in increased levels of oxidative base lesions Olipitz W.1, Lind K.2, Monsberger N.2, Katschnig A.2, Mangerich A.3, Hofer S.2, Schulz E.2, Quehenberger F.4, Schlembach D.5, Robier C.2, Wölfler A.2, Zebisch A.2, Sill H.2 LMU München, Medizinische Klinik und Poliklinik III, München, Germany, Medizinische Universität Graz, Klinische Abteilung für Hämatologie, Graz, Austria, 3Universität Konstanz, Molecular Toxikology Group, Department of Biology, Konstanz, Germany, 4Medizinische Universität Graz, Institut für Medizinische Informatik, Statistik und Dokumentation, Graz, Austria, 5 Medizinische Universität Graz, Klinik für Geburtshilfe und Gynäkologie, Graz, Austria 1 2

Inactivation of the p53 pathway is a universal event in human cancers. As p53 mutations are rare in de novo acute leukemias, the p53-pathway must be inactivated by other mechanisms instead. ASPP2 is a haploinsufficient tumor suppressor, which is attenuated in acute leukemia. We now provide evidence that ASPP2 regulates pathways involved in early hematopoiesis, and attenuated expression perturbs malignant transformation. Gene-chip microarrays were performed on ASPP2+/+ versus +/- mouse embryonic fibroblasts (MEFs) (knockouts are not viable) and pathway analysis was performed using Affimetrix software. ASPP2 expression was silenced in IL3-dependent Ba/F3 pro-B cells and leukemia cell lines using standard siRNA protocols. Cellular proliferation was assessed using XTT-based assays. To evaluate for malignant transformation, long term cell cultures with stably retrovirally silenced Ba/F3 cells (+/- stress inforcment using gamma irradiation, 4x 5Gy) were employed. IL3 weaning was performed as an indicator of autoactivated cellular proliferation. Microarray mRNA analysis revealed that attenuated ASPP2 expression resulted in significant alterations in pathways involved in mediating cellular growth, proliferation and tissue differentiation. Subanalysis proofed involvement of genes playing a major role in embryogenesis, the development of the hematopoietic system and leukemogenesis (homeobox (HOX) family members, NOTCH, BCL, IRF7 and EGR1). Population doubling times were significantly increased in ASPP2+/- MEFs compared

Base excision repair (BER) is the primary DNA repair mechanism dealing with oxidative base lesions. Oxidative DNA base lesions are the predominant type of DNA damage in mammalian cells. Deficiencies in glycosylases, the BER initiating enzymes, have been associated with increased genomic instability and increased frequencies of cancer. Here we investigated the role of oxidative BER in acute myeloid leukemia (AML). We determined oxidative BER activity in 99 primary AML blast cell samples, 34 CD34+ umbilical cord blood cell samples and 27 AML cell lines using the alkaline comet assay. Oxidative base lesion levels were determined in 10 AML cell lines using a modified version of the Comet assay with the bacterial enzymes Fpg and Endo III as well as using liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS). Using nuclear protein extracts in an oligonucleotide incision assay we tested the enzymatic activity of oxidative glycosylases. Mutational analysis, gene expression analysis and protein expression of oxidative glycosylases was performed using Sanger sequencing, real time PCR and western blot of nuclear extracts, respectively. We found DNA strand incision of oxidatively damaged bases significantly impaired in primary AML cells as compared to UCB cells (p =  0.003) suggesting a deficiency in BER glycosylases. In addition, 5/27 AML cell lines showed impaired DNA strand incision activity. We hypothesized that BER impaired cells harbor an increased number of oxidative base lesions compared to BER proficient cells. Using a modified comet assay and LC-MS/MS we were able to show that increased numbers of unrepaired oxidative base lesions were indeed present in glycosylase deficient AML cells (comet assay: p =  0.0001; mass spec: p =  0.03). We then evaluated the activity of the predominant oxidative DNA glycosylase, OGG1, and found significantly decreased DNA strand incision activity in BER impaired cells as compared to proficient cells (p =  0.002) further supporting the fact that glycosylases are deficient in BER impaired cells. Determining causes of BER deficiency preliminary experiments showed significantly decreased expression of nuclear OGG1 protein in BER impaired cells but did not reveal novel non-synonymous mutations or a difference in gene expression.

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P183

ASPP2 attenuation is a first step in leukemogenesis facilitating acquisition of leukemia driver mutations Schittenhelm M.M.1, Akmut F.1, Illing B.1, Lopez C.D.2, Kanz L.1, Kampa-Schittenhelm K.M.1 Medizinisches Universitätsklinikum Tübingen, Hämatologie, Onkologie, Rheumatologie, Immunologie und Pulmologie, Tübingen, Germany, 2 Oregon Health and Science University/Knight Cancer Institute, Portland, United States 1

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in myeloid progenitors (MP) was correlated to hENT1 MFI in lymphocytes to derive hENT1 index (index). Results: CG (MRC) was favorable in 21, intermediate in 75, adverse in 34 pt. 75 pt received CHT, 13 DM. According to CG, MP index was higher in favorable vs intermediate and adverse pt (3.05 vs 2.58 and 2.53, p = 0.034 and 0.023, respectively). According to MG, higher index for MP was found in FLT3-ITDmut (18/111; 3.19 vs 2.62, p = 0.012) and CEPBAmut (4/26, 3.15 vs 2.35, p = 0.004) and lower MP index in RUNX1mut pt (13/65; 2.17 vs 2.59, p = 0.031). Using lowest quartile of MP index (2.1185) as cut-off, pt below this cut-off vs those above treated with CHT tended to inferior event free survival (EFS, 1yr EFS 45 vs 66%, p>0.05, median follow up 13 months). Within the MRC intermediate group, both overall survival (OS) and EFS were lower in pt with MP index below vs above cut-off (1yr OS 61 vs 79% and 45 vs 62%, respectively, p>0.05 each). Longer OS was reached for MRC intermediate treated with CHT vs DM (1yr OS 73 vs 56%, p = 0.014). Strikingly, in this group, better OS with CHT vs DM was not achieved in pt with MP index below cut-off (1yr OS 61 vs 60%) while it was in those above cutoff (1yr OS 79 vs 50%, p = 0.03). Conclusions: Favorable CG AML had higher hENT1 expression in MP suggesting a mechanism for better response to CHT and outcome. AML with poor risk MG (RUNX1mut) showed lower hENT1 in MP. In pt treated with CHT non-significantly shorter OS and EFS in AML with MRC intermediate and low MP hENT1 index was observed. In these pt, CHT showed no benefit vs DM while it did in pt with MRC intermediate and high MP index. Determining hENT1 index might therefore aid in decision making for therapy in the big group of intermediate risk pt. Further analyses are warranted to explore the significance of hENT1 expression in AML.

Taken together we found impaired BER glycosylases in a substantial number of primary AML samples and AML cell lines resulting in increased levels of potentially mutagenic oxidative DNA base lesions. Disclosure: No conflict of interest disclosed. P185

Comparative examination of various molecular genetic methods for DNMT3A and IDH1/2 mutations identification in acute myeloid leukemia Berenstein R.1, Blau I.W.2, Kar A.3, Cay R.3, Sindram A.4, Seide C.4, Blau O.1,4 Charite – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hämatologie und Onkologie, Berlin, Germany, 2Charité – Universitätsmedizin Berlin, Campus Virchow Klinikum, Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany, 3Beuth Hochschule für Technik, Biotechnologie, Berlin, Germany, 4Labor Berlin, Hämatologie und Onkologie, Berlin, Germany 1

Background: Mutations in epigenetic modifiers were reported for acute myeloid leukemia (AML) including changes in DNA methyltransferase 3A (DNMT3A) in 20% to 30% and isocitrat dehydrogenase 1/2 (IDH 1/2) in 5% to 15% of cases. Novel studies indicate that changes in DNMT3A and IDH1/2 influence prognosis, thereby increasing the need to detect these mutations in laboratory daily routine. DNA sequencing used for the identification of these mutations is time consuming and cost-intensive. In contrast another lately introduced method, high resolution melt (HRM) analysis, is sometimes difficult to interpret and requires special equipment. Methods: In this study we developed an endonuclease restriction method for identification of the most common DNMT3A R882H mutation and an amplification-refractory mutation system (ARMS) for analysis of IDH2 R140Q mutations. Furthermore we compared our methods with HRM analysis and evaluated the latter for detection of IDH1 mutations. Results: Analysis of 230 AML patient samples led to identification of DNMT3A mutations in 30 cases (13%), IDH2 R140Q mutations in 16 cases (7%) and IDH1 mutations in 36 cases (16%). Sensitivity assays performed by serial dilutions of mutated DNA revealed a sensitivity of 4,5% for ARMS analysis and 0,05% for endonuclease restriction compared with 5,9% to 7,8% sensitivity for HRM analysis of different mutations. To account for the heterogeneity of IDH1 mutations we identified HRM as the best method for analysis. Furthermore the generated methods for IDH2 and DNMT3A showed a perfect concordance (100%) with Sanger sequencing, whereas HRM analysis had near perfect conformity about 98%. Conclusion: Our study suggests that all developed methods are rapid, specific, and easy in application and interpretation. PCR-based methods are the useful tool for routine laboratory applications for prognostic relevant mutations. We propose that early screening of mutations in AML patients with normal karyotype could facilitate risk stratification and improve treatment opportunity for AML patients. Disclosure: No conflict of interest disclosed.

Posterdiskussion CLL

P186

1st-line treatment with BR or FCR in patients with chronic lymphocytic leukaemia: First outcome data from the German prospective TLN Registry Knauf W.1, Abenhardt W.2, Engel E.3, Grugel R.4, Harde J.4, Jänicke M.4, Marschner N.5, TLN Registergruppe Onkologische Gemeinschaftspraxis, Frankfurt a. M., Germany, 2Münchner Onkologische Praxis, München, Germany, 3Hämatologisch – Onkologische Praxis Altona (HOPA), Hamburg, Germany, 4iOMEDICO, Freiburg i. Br., Germany, 5Praxis für interdisziplinäre Onkologie & Hämatologie, Freiburg i. Br., Germany

1

Introduction: FCR is currently considered as standard of care for medically fit patients (pts) with untreated chronic lymphocytic leukaemia (CLL). However, due to its significant toxicity other, potentially less toxic regimens are currently under investigation. First results of the phase III trial CLL10 of the German CLL-Study Group (GCLLSG) comparing FCR to BR were presented recently. Here, we investigated effectiveness of BR and FCR in unselected pts with CLL treated in routine practice. Methods: The open, longitudinal, multicentre, clinical registry on lymphoid neoplasms (TLN Registry, ClinicalTrial.gov NCT00889798) prospectively collects data on the treatment of pts with lymphoid B-cell neoplasms as administered by German office-based haematologists. Pts are followed for 5 years. A broad set of data regarding patient and tumour characteristics, comorbidities, all systemic treatments and response rates, progression-free survival and overall survival are recorded. Since May 2009, 115 sites have actively recruited a total of 3,383 pts. 485 pts with CLL, recruited at the onset of 1st-line therapy and treated with BR (72%) or FCR (28%), were included in this analysis. Results: Clinical and tumour characteristics differ between pts receiving BR or FCR: Pts treated with BR are older than pts with FCR (mean 70 vs. 63 yrs; p 20% 10–20% Day 7: 30%). The duration of filgrastim therapy was 6.5±9.3 days (median: 5 days). In later cycles, filgrastim started earlier. In PP cycles, patients received filgrastim earlier and longer than in SP and TX cycles. The global incidence of FN was 3.9%/cycle; 10.2% of all patients experienced FN and in 2.2% FN led to hospitalization. In cycle 1, 38% of patients applied antibiotics (prophylactic: 29%; TX: 13%) and 13% developed infection. The incidence decreased over cycles. Overall, 42 patients (25%) experienced adverse events (AEs), 11 of these serious (7%) and 10 filgrastim-related (6%). Filgrastim-related AEs were musculoskeletal pain and nausea; none was serious. Conclusions: Interim data confirm earlier experiences that filgrastim is generally given as prophylaxis to patients with medium to high FN risk and is thus in accordance with guidelines. On the other hand, filgrastim was started comparatively late in the CT cycle and administration was shorter than recommended. FN rates were in line with other published data. Future analyses will concentrate on filgrastim treatment patterns and their influence on infections and use of antibiotics.

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recent clinical trials. Gynecologists who are associated in the BNGO document all patients by using an online registry in order to control, maintain and improve treatment quality and measure outcome. The objective of this analysis was to evaluate the efficacy of PAL-based antiemetic prophylaxis with or without the NK1A aprepitant (APR) in BC patients (pts) receiving A-based chemotherapy in BNGO practices. Methods: From 11/2008 until 3/2014, 2329 BC patients receiving A-containing chemotherapy and antiemetic prophylaxis based on PAL have been documented using the ODM Quasi® GYN online documentation system. Severity, frequency, duration and onset of nausea (N) and vomiting (V) were assessed after the 4th antiemetic treatment cycle. Efficacy criteria were complete control (CC: no V, no rescue medication (RM), only mild N); complete response (CR: no V, no RM) and RM. Results: 2329 pts with a median age of 55 years received a PAL-based antiemetic prophylaxis and were documented in 47 practices. In 78% of pts the A component of the CT schedule was epirubicin. Response was evaluated after cycle 4. Efficacy of all PAL-based antiemetic regimens (n =  2329): CC: 64,6%, CR 79,4%, Rescue Medication was needed in 6,3% of pts. Efficacy of the triplet therapy of PAL plus APR plus DEX (n = 544): CC 73,3%, CR 84,9%, RM 6,6%. 75% of pts had no or only mild N in the overall risk phase, 78,2% of pts had no nausea in the delayed phase. Only 5,2% of all pts had severe N during the overall phase. No additional side effects were observed with the triplet therapy. Conclusions: Antiemetic prophylaxis based on the 5HT3-RA PAL is effective in breast cancer pts receiving AC chemotherapy. The addition of APR to PAL enhances the efficacy in the reduction of vomiting and nausea in the acute and the delayed phase. The triplet therapy is well tolerated.

P509

Efficacy and patient satisfaction with a fentanyl buccal tablet for breakthroug pain (BTP) in cancer patients treated in German urological practices Schulze M.1,2, Geiges G.3 IQUO e.V., Neuenhagen, Germany, 2Urologische Praxis, Markkleeberg, Germany, 3Urologische Praxis, Berlin, Germany 1

Introduction: With modern principles of analgesic therapy 80% of patients (pts) achieve pain control. A remaining problem is breakthrough pain (BTP). It is difficult to manage, especially in the ambulant setting. In Germany, many pts with urological cancers (UC) are treated in urological practices. Urologists who are members of the German association of urologists in practices (IQUO) document all UC patients by using an online system in order to control, maintain and improve treatment quality and measure outcome. The objective of this retrospective analysis was to evaluate the efficacy of a fentanyl buccal tablet (FBT) in BTP and to assess patient satisfaction. FBT is indicated for BTP in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain. Methods: For documentation the online ODM QuaSi® URO system was used, for pt satisfaction a printed questionnaire. Documentation started on first application of FBT and was repeated after 1 wk and 4 wks. From 5/2009 until 4/2014 89 pts with UC receiving FBT for BTP treated in 31 practices of the IQUO were analysed retrospectively. Results: 89 pts (87 m, 2 f) with urological cancers (74 prostate, 11 renal cell, 4 bladder) were evaluable, 82 pts (92%) met. disease. Median age 69 y (range 39–91). All pts had BTP with mean 3 pain episodes per day (range 1–5) despite opioid treatment. Pain aetiology: 15% neuropathic, 15% nociceptive, 70% mixed. Pain was assessed by VAS scale from 0–11. 26% of pts had a median pain score (MPS) > 5 on opioid basic therapy with median 3 pain episodes in all pts. 68/89 pts (76%) of pts had MPS due to BTP ≥ 6 before treatment of BTP. 70 patients had been pretreated for BPT at the onset of FBT therapy. Starting dose (µg) of FBT: 100 (50%), 200 (30%), 400 (19%), 800 (1%). Dose after 4 weeks: 100 (41%), 200 (22%), 400 (30%), 600 (6%), 800 (1%). Efficacy of FBT (% of pts after 1 wk/ 4 wks): no pain 12/20, pain intensity (PI) 2–3 52/57, PI 4–5 27/19, PI ≥ 6 8/4. Estimate of pain reduction (% after 1 wk/ 4 wks) very good 35/37, good 53/50, moderate 9/12, insufficient 3/1. Time to response (% after 1 wk/ 4 wks) < 5 min 7/11, 5–10 min 38/39, 11–15 min 38/35, ≥ 16 min 17/15. Patient satisfaction (%) after 4 wks: very good 41, good 45, moderate 9, bad 5%. Patient preference for FBT to other BTP medication: 77%. Conclusion: FBT showed high and rapid efficacy in reducing BPT in urological cancer patients. 77% of pts preferred FBT to other BPT medications. Disclosure: No conflict of interest disclosed. P510

Ifosfamide (IF) encephalopathy (IF-E) and the relevance of preventive measures: real-life analysis and precise recommendations for various cancer patients (pts) Szymaniak-Vits M.1,2, Reinhardt H.1, Kaiser S.1,2, Urban J.1, Otte P.1,2, Groß B.1,3, Hug M.3, Duyster J.1, Wäsch R.1, Engelhardt M.1 Klinik für Innere Medizin I, Hämatologie, Onkologie und Stammzelltransplantation, Freiburg, Germany, 2Universitätsklinikum Freiburg, CCCF, Freiburg, Germany, 3Universitätsklinikum Freiburg, Klinikumsapotheke, Freiburg, Germany 1

Introduction: As an alkylating agent, IF is currently integral part of numerous chemotherapy (CTx) protocols for sarcoma, lymphoma and other

Abstracts

tumor pts (Das Blaue Buch [BB] 2014). Neurotoxicity is a well-known side effect (SE) and encephalopathy is stated as a very commonly occurring event (>1/10) in the IF SPC (Holoxan®, Baxter Oncology 2008). As a potentially fatal toxicity, IF-E occurs most often during or shortly after drug administration. The most frequently reported manifestation of IF-E is confusion (80% of pts), ranging from transient lethargy or drowsiness to delirium, followed by hallucinations (Ajithkumar T et al. Clin Onc 2007). We meticulously analysed our in-house data on IF-E in 2008–2010, here performed a follow-up analysis from 2011–2013 and updated our BB/ clinical pathway (CP) guidelines. This analysis was complemented by a literature review with special focus on the role of thiamine and methylene blue (MB) in the prevention of IF-E. Methods & Results: Our in-house data was collected via the pharmacy Zenzy-, electronic prescribing software Chemo-AS- and Clinic-On-database, with direct access to pts’ e-notes. Moreover, an extensive literature search was performed (Pubmed). Therein, we found 4 case reports of thiamine prophylaxis (TP) used prior to IF therapy, with pt numbers ranging from 1 to 11, all of which recommending TP. However, the evaluation performed by Richards et al (J Onc Pharm Pract 2011) in 63 pts, 29 with TP, showed no benefit of TP. In 2011–2013, we had 155 pts treated with IF and 19 cases of neurotoxicity (12%); the frequency of IF-E of all IF-applications ranging between 0.5–1% in 2006–2013. In adherence with our BB/CP-guideline, all pts were treated with i.v. MB and fully recovered. Two received TP, but developed IF-E nevertheless. MB prophylaxis was employed in none of our pts. The analysis of specific CTx-protocols and risk factors (RF) revealed that IF-E frequently occurred in sarcoma and multiple myeloma pts, with increasing (high-dose [HD]) IF-doses and RF predisposing to IF-E, such as reduced performance status, renal/liver organ dysfunction, increased age and specific CTx-protocolls. Conclusions: IF-E is an important SE to be aware of when commencing pts on HD-IF therapy. TP and/or MB might be considered, however, its effectiveness cannot be relied on. The presence of RF for IF-E of individual pts need to be thoroughly reviewed. In accordance with these results, we have updated our IF-CP (online BB 5/2014). Disclosure: No conflict of interest disclosed. P511

Febrile neutropenia and bacterial septicemia after TBIbased allogeneic stem cell transplantation – protective effect of Palifermin for prophylaxis of mucositis? Schmidt V.1, Klink A.1, Treschl A.1, von Lilienfeld-Toal M.1, Hochhaus A.1, Sayer H.G.1,2 Klinik Innere Medizin II, Universitätsklinikum Jena, Hämatologie und Internistische Onkologie, Jena, Germany, 2HELIOS Klinikum Erfurt, 4. Medizinische Klinik, Hämatologie und Internistische Onkologie, Hämostaseologie, Erfurt, Germany 1

Introduction: Oral mucositis is the most frequent und debilitating adverse effect of myeloablative conditioning followed by allogeneic stem cell transplantation (alloSCT). Irrespective of the need for opioid-containing analgesia, parenteral nutrition and prolonged hospitalization, mucosal ulcers represent a major risk for bacterial invasion and life-threatening infections. Recombinant human keratinocyte growth factor 1 (Palifermin) is recommended for prophylaxis of mucositis for myeloablative autologous SCT, but there is no published guideline for the allogeneic setting due to lack of evidence. Here, we report our experience with Palifermin focusing on infectious complications. Methods: In our center, 34 patients (22–59 years, 17 male) received total body irradiation (TBI, 12Gy) and cyclophosphamide (120 mg/kg b.w.) followed by alloSCT for hematologic malignancies. Within the OSHO#76 trial (EudraCT No. 2006–003683–54), Patients were randomized (2:1) for mucosal prophylaxis with Palifermin (3 × 60 µg/kg before conditioning and after alloSCT each; 23 patients) and standard supportive care (control, 11 patients). The oral cavity was inspected for mucosal ulcers daily by a trained nurse. Febrile neutropenia was defined as a body temperature of >38.3 °C together with a polymorphonuclear cell count < 0.5x109/l.


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Disclosure: Edgar Jost: Employment or Leadership Position: Hexal AG Dietmar Bulenda: Employment or Leadership Position: selbständiger Consultant; Advisory Role: u.a. Sandoz, Hexal; Financing of Scientific Research: u.a. Sandoz, Hexal

Disclosure: Volker Schmidt: Expert Testimony: Die Studie wurde unterstützt von Sobi (Swedish Orphan Biovitrum) Herbert Sayer: Expert Testimony: Die Studie wurde unterstützt von Sobi (Swedish Orphan Biovitrum) P513

Patient satisfaction during treatment with Sancuso for CINV Musch R.1, Maessen D.2 Krebsheilkunde Lichtenberg, Berlin, Germany, 2ProStrakan Pharma GmbH, Düsseldorf, Germany 1

Introduction: Sancuso (transdermal Granisetron patch) has demonstrated efficacy for prevention of CINV in patients receiving multi-day moderately to highly emetogenic chemotherapy. The objective of this study is to examine patient satisfaction with Sancuso in clinical practice. Methods: The study is being conducted in 19 oncology units in Germany. All patients scheduled to receive Sancuso at the prescribing physician´s discretion for prevention of CINV in moderately or highly emetogenic multi-day chemotherapy are observed. Patients are asked to record on a visual analogue scale (VAS [0–100]) their ´general satisfaction´ with Sancuso treatment, for each cycle of chemotherapy where Sancuso was used. Basic demographic and clinical information is also collected about each patient. Results: Overall, the study is planned to recruit 250 patients. Of the first 75 patients observed, 43 (57%) were male. The average age of patients to date was 70. The maximum number of cycles of chemotherapy for an individual patient was five (one patient only). In all, information was collected on 110 cycles. The most common cancers were colorectal/anal and urological. FOLFOX and FOLFIRI were the most common regimens; 74% of cycles were moderately emetogenic. Additional anti-emetics were co-administered in 68% of cycles. Complete control was achieved in 88% of cycles and complete response in a further 8%. The influence of the chemotherapy administered and a guideline conformal CINV prophylaxis will be discussed. Average general satisfaction with Sancuso was 93 (VAS). Updated results will be presented. Conclusions: Overall, general patient satisfaction with Sancuso was high. Disclosure: Reinhard Musch: Financing of Scientific Research: Vortragshonorar von ProStrakan Pharma GmbH erhalten Dirk Maessen: Employment or Leadership Position: Medical Director, ProStrakan Pharma GmbH

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P514

A case report: Mucormycosis in a neutropenic patient Kraft F.1, Müller S.2, Fritsch A.1, Schulz K.1, Junghanß C.1, Gläser G.1 University of Rostock, Clinic of Hematology, Oncology and Palliative Care, Rostock, Germany, 2University of Rostock, Institute of Microbiology, Virology and Hygiene, Rostock, Germany 1

Introduction: Mucormycosis is a rare angioinvasive infection with increasing incidence. It is commonly seen in patients affected by immunosuppression, diabetes or penetrating trauma. Mucomycosis is difficult to diagnose and characterized by mortality rates up to 95% in disseminated disease. The individual prognosis dependents from the time point of initiation of therapy. Antifungal chemotherapy, control of the underlying predisposition condition and surgery are the cornerstones of clinical management. Case report: A 55-year-old male patient was diagnosed with secondary myeloid leukemia (emerged of a myelodysplastic syndrome). Induction chemotherapy with idarubicin and cytarabine with the objective of an allogeneic hematopoietic stem cell transplantation was induced. The patient received an antimycotic prophylaxis with posaconazole. Despite an immediate broad-spectrum antibiotic treatment (piperacilline and tazobactam) the patient developed recurring fever attacks with dysphagia and croakiness during neutropenia. A computer tomography scan of the chest showed a massively thickened esophagus wall located tight to the aortic arch with clear signs of a mediastinitis. Antibiotic treatment was switched to meropenem and linezolid, while the antimycotic treatment was changed to caspofungin. The esophagus had to be resected and a salivary fistula was applied. Microbiologic analysis of the biopsy revealed rhizopus. Antimycotic treatment was switched to Amphotericin B. The patient died due to a multi-organ dysfunction 5 days after surgery. Conclusion: There is still a lack of knowledge concerning the management of mucormycosis infection. This case report shows the importance of an early diagnosis and treatment therefore guidance has to be improved. Disclosure: No conflict of interest disclosed. P515

Pneumocystis jirovecii pneumonia associated with Ruxolitinib therapy in a patient with myelofibrosis Knödler A.1, Schmiedel S.2, Schäfer G.2, Bokemeyer C.1, von Amsberg G.1 Universitätsklinikum Hamburg-Eppendorf, Onkologisches Zentrum, II. Medizinische Klinik, Hamburg, Germany, 2Universitätsklinikum HamburgEppendorf, I. Medizinische Klinik, Sektion Tropenmedizin, Hamburg, Germany 1

Background: JAK1/JAK2 inhibitor Ruxolitinib, is considered effective and safe in the reduction of splenomegaly and consitutional symptoms in patients with myelofibrosis (MF). However, different opportunistic infections have been observed to date. We report on a patient who developed pneumocystis jirovecii pneumonia (PJP) when treated with ruxolitinib for MF. Case report: A 68-years old male patient had been treated with Ruxolitinib for post polycythemia vera MF for over one year, when he started to complain about progressive dyspnoea on exertion. Diagnostic workup included chest x-ray, blood gas analysis, lung function tests, exercise testing and echocardiography, all without pathological findings. In contrast, CT scan of the chest revealed bilateral ground glass opacities. Consequently, flexible bronchoscopy with broncho-alveolar lavage was performed and PJP was diagnosed by quantitative pneumocystis jirovecii PCR examination. Lactate dehydrogenase levels were found to be constantly elevated to about 900 U/L for the past two years due to the patient’s underlying hematological condition. Remarkably, while total leucocytes were within the normal range, a depletion of T-lymphocytes (218/µl; reference 900 to 2900/µl) was detected. Treatment with clindamycin and daraprim was

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Peripheral and central blood cultures were obtained at each onset of fever up to 4 times a day. Results: For Palifermin, duration of mucosal ulcers was reduced from 10.6±8.0 (mean±sd, control) to 8.0±6.9 days. Febrile neutropenia occurred for 3.0±2.7 days (Palifermin) and for 4.8±4.6 days (control), respectively. Similarly, duration of intravenous antibiotics dropped from 23.4±9.9 to 19.0±8.5 days. However, due to the small number of patients and a wide range, these differences failed statistical significance. Positive blood cultures were found in 8 of 23 patients (34.8%, Palifermin) and in 6 of 11 patients (54.5%, control). The most common pathogens were gram-positive cocci. While all patients with Palifermin survived until day +100, 2 patients of the control group died of severe pneumonia and septic multiorgan failure (p = 0.09; Fisher´s exact test). Conclusion: Although our results failed statistical significance, they indicate a concordant trend towards reduction of clinical and microbiological infections by Palifermin in patients after TBI-based alloSCT. These findings encourage further evaluation of the use of Palifermin in the setting of alloSCT.

initiated, the latter due to chronic renal insufficiency. As the patient’s condition failed to ameliorate, daraprim was switched to primaquin. Dyspnoea rapidly improved over the following days and left the patient free of symptoms within a week. Conclusion: In conclusion, to the best of our knowledge this is the first case of PJP in a patient treated with ruxolitinib. Interestingly, a depletion of T-lymphocytes was observed at the time of infection suggesting an impaired immune status. In fact, a decrease of T regulatory cells has been reported in patients with MF treated with ruxolitinib by Barosi et al. Thus, clinicians should be aware of the risk of intracellular or opportunistic infections associated with ruxolitinib and prophylactic therapy for opportunistic infections should be discussed for those patients developing T-cell depression when treated with ruxolitinib. Disclosure: No conflict of interest disclosed.

Posterdiskussion

Tumore des Gastrointestinalen Traktes II P516

Differentiation and detection of markers for discrimination between primary and secondary adenocarcinoma using gene expression profiling Hass H.G.1, Nehls O.2, Scheurlen M.3, Vogel U.4, Jobst J.5 Paracelsus-Klinik, Scheidegg, Germany, 2Praxis of Gastroenterology and Tumor Medicine, Stuttgart, Germany, 3University of Würzburg, Department of Gastroenterology, Hematology, Oncology and Rheumatology, Würzburg, Germany, 4University of Tübingen, Department of Pathology, Tübingen, Germany, 5Matrigene GmbH, Reutlingen, Germany 1

Background: Cholangiocellular carcinoma is the second most common liver cancer with an unfavorable prognosis, reasonable to a late diagnosis in most cases and a chemotherapy-resistance in the palliative setting. In clinical routine a differentiation between this adenocarcinoma, especially by intrahepatic location, against secondary adenocarcinomas of the liver (e.g. metastases of gastrointestinal cancers, CUP syndrome) may be not so clearly, leading to false diagnosis and treatment decisions. Methods: In this study, we used oligonucleotide microarrays (Affymetrix Hu133A ©) for gene expression analysis of primary (CCC; n = 11) and secondary adenocarcinomas (colorectal metastases; n = 6) of the liver. In a second step the estimated specific gene expression profiles and detected dysregulated biomarkers were used for 2-dimensional cluster analysis allowing a fast and secure differentiation between these tumors. Results: Using this analytical approach 338 genes were detected significantly dysregulated (gene expression/fc ≥2; dysregulation in ≥ 60%) in both tumor groups. By 2-dimensional cluster analysis using these dysregulated genes a fast, clear and reproduciable differentiation between intrahepatic CCC and colorectal metastases were in all cases possible. As potentional biomarkers for differentiation between the tumors groups 12 genes (CCC: INBA, KOC1, KRT7, SNAP25, DBN1, KCNJ16; metastases: DPEP1, MYB, TDGF1, BCL11A, HOXA9, TFF3) could be established as candidate genes and will used for further investigations. Conclusions: By gene expression analysis a specific genetic pattern for intrahepatic CCC and colorectal liver metastasis was established allowing a clear and secure differentiation of these tumors. Using 2-dimensional cluster analysis candidate genes for clinical use (e.g. immunhistochemistry, RT-PCR) were also described here for the first time. Disclosure: No conflict of interest disclosed. P517

Gene expression analysis for evaluation of different biomarkers in hepatocellular carcinoma Hass H.G.1, Nehls O.2, Scheurlen M.3, Vogel U.4, Jobst J.5 Paracelsus-Klinik, Scheidegg, Germany, 2Praxis of Gastroenterology and Tumor Medicine, Stuttgart, Germany, 3University of Würzburg, Department of Gastroenterology, Hematology, Oncology and Rheumatology, Würzburg, Germany, 4University of Tübingen, Department of Pathology, Tübingen, Germany, 5Matrigene GmbH, Reutlingen, Germany 1

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Background: Hepatocellular carcinoma is the fifth most common and the third most common cause of deaths by cancer worldwide with increasing incidence in western countries, reasonable to the high prevalence of chronic hepatitis C and NASH. The still worse prognosis of hepatocellular carcinoma and the lack of screening markers with higher sensitifity and specifity as AFP underline the need for more investigations to establish other biomarker for human hepatocarcinogenesis. Methods: In this study, we analyzed the gene expression levels of 10 actual postulated biomarkers of HCC (AFP, GPC3, OPN, IGF1, HGF, SPINK1, KPNA, FUCA1, CgA, HSP90) in 38 HCCs of different etiolo-


The role of proinflammatory cytokines TNFα and IL-6 on OATP4A1 in colorectal cancer Sheikh M.1, Katic A.1, Zotter S.1, Larijani A.1, Bajna E.1, Bauer H.2, Mollik M.3, Reiner A.3, Ausch C.2, Zeillinger R.4, Sebesta C.2, Kriwanek S.5, Buxhofer-Ausch V.2, Thalhammer T.1 Institut für Pathophysiologie und Allergieforschung, Wien, Austria, 22. Medizinische Abteilung, Donauspital, Wien, Austria, 3Pathologisches Institut, Donauspital, Wien, Austria, 4Ludwig Boltzmann Institut, Translationale Onkologie, Wien, Austria, 5Chirurgische Abteilung, Donauspital, Wien, Austria 1

Introduction: The transport protein OATP4A1, which mediates the uptake of steroid and thyroid hormones, prostaglandins and cyclic nucleotides, was previously found to be higher expressed in colorectal cancer than in non-malignant colon. To get further insight in the role of this transporter, we investigated OATP4A1 expression in specimens from early colorectal cancer (Stage I/II) and in diverticulitis samples. The effect of proinflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) was assessed in the C205 colon cancer cell line. Methods: Quantitative microscopic image analysis on paraffin-embedded tissue sections stained by immunohistochemistry (IHC) was done to assess the expression in tumor, stroma and immune cells, separately. The newly developed software StrataQuest was applied to automatically evaluate selected areas based on cell nuclei staining with hematoxylin (H). To further identify OATP4A1-expressing cells, double-immunofluorescence staining (IF) with appropriate cellular markers was done. A potential proinflammatory effect of TNFα and IL-6 on OATP4A1 expression was assessed by qRT-PCR and immunofluorescence analysis in the colon cancer cell line C205. Results: OATP4A1 expression (immunoreactive score per number of cells) was higher in immune, tumor and stroma cells of patients who did not suffer from a relapse within 5 years than in relapse-suffering patients. Regarding the immune cells, OATP4A1 was detected in CD45+ leucocytes, CD3+ T- and CD20+ B-cells, macrophages, dendritic cells and CD34+ -precursor cells. Surprisingly, treatment of C205 cells with TNFα (10 ng/ml) and IL-6 (100 ng/ml) reduced OATP4A1 mRNA (50% inhibition after 24 hrs) and protein expression time-dependently, whereby

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treatment with the single agent was even more effective than the combination of cytokines. Conclusions: High levels of OATP4A1 are associated with a better prognosis in early colon cancer as data from the tissue sections of colon cancer patients revealed. In the C205 cells, derived from a late stage metastasizing colon tumor, however, proinflammatory cytokines inhibited transporter expression. Therefore, the sole of chemokines in colon cancer cells from tumors of different stage and in immune cells has to be further evaluated. Disclosure: No conflict of interest disclosed. P519

miRNA expression differences in colon cancer stages I/ II and III Rammer M.1, Webersinke G.1, Haitschi-Petnehazy S.2, Bauer E.2, Hackl H.3, Charoentong P.3, Trajanoski Z.3, Malli T.1, Petzer A.L.4, Rumpold H.4 Krankenhaus der Barmherzigen Schwestern Linz, Labor für Molekularbiologie und Tumorzytogenetik, Linz, Austria, 2Krankenhaus der Barmherzigen Schwestern Linz, Institut für Klinische Pathologie und Prosektur, Linz, Austria, 3Medizinische Universität Innsbruck, Biozentrum Innsbruck: Sektion für Bioinformatik, Innsbruck, Austria, 4Krankenhaus der Barmherzigen Schwestern Linz, Abteilung für Innere Medizin I: Internistische Onkologie, Hämatologie und Gastroenterologie, Linz, Austria 1

Introduction: In recent years studies have confirmed the regulatory potential of microRNAs. Alterations of miRNA expression can be associated with cancer types and could have a prognostic and predictive value. Aim of the study is to evaluate miRNA expression patterns correlating with colon carcinoma stages. The main focus lies on comparing primary tumor tissue from lymph node negative with lymph node positive tumors. Material and methods: Total RNA was extracted from 142 FFPE samples using the RecoverAll FFPE kit (Ambion). From 40 samples miRNA array analysis (Affymetrix) was conducted, investigating expressions of 1,733 human mature miRNAs in each sample. For array data validation of selected miRNAs, qPCR was carried out using TaqMan miRNA assays (ABI). Results: Comparison of the array data of twenty lymph node negative (stage I/II) and twenty lymph node positive samples (stage III) showed no miRNAs with a significant differential expression. Furthermore, qPCR results of 100 validation samples confirmed the lack of miRNA expression differences when comparing nodal status. The array data was also analyzed considering differences between the T stages (acc. to UICC criteria) regardless of nodal positivity or negativity; here significant expression differences could be detected. Conclusions: Regarding miRNA expression according to lymph node status array analyses as well as validating qPCR analyses do not display significant differences. Hence, in our 142 samples none of the miRNAs investigated could be utilized to distinguish stage III from stage I/II colon cancer. Nevertheless, the significant differences of miRNA expression levels between the T stages according to array analyses indicate impact in tumor progression, which will be validated in the larger cohort as part of an ongoing project. These findings could further enhance our understanding of the role of miRNAs in disease biology. The study was funded by Krebshilfe Oberösterreich. Disclosure: No conflict of interest disclosed.

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gies (HCV, HBV, alcohol-induced HCC) by gene expression (Affymetrix Hu133A ©) and RT-PCR (LightCycler©) analysis. Results: The Expression of 4 of the chosen candidate genes (FUCA1, HGF, IGF1, CgA) was not significantly overexpressed, median fold change (fc) of these genes ranged between 0.2 up to 0.8 in a maximum up to 15% of all analyzed tumor probes and were significantly lower expressed when compared with the expression of AFP. These genes were not considered for further analysis. The median gene expression of AFP was 2.4 and significantly overexpressed in 30% of all tumor probes. In Patients with high AFP expression levels serum AFP concentrations were also in over 90% significantly elevated measurable. In comparison to the expression level of AFP, 5 genes (OPN, SPINK1, GPC3, HSP90, KNPA2) showed significantly more often an overexpression in 64% up to 82% with a median gene expression (fc) between 2.9 and 8.3 in comparison to the non-malignant corresponding liver tissue. The elevated expression levels of OPN, SPINK1, GPC3 and KNPA2 were also analyzed by RT-PCR with similar results. Conclusions: In comparison to the literature we could not estimate the impact of FUCA1, HGF, IGF1 or CgA as potentional markers for HCC by gene expression analysis. Despite of these genes our results underline the importance of the genes coding for OPN, SPINK1, GPC3 and KNPA2 as potentional markers for HCC with significantly increased overexpression compared with expression levels of AFP. So, gene expression analysis enables the detection of potentional biomarkers for better screening of patients witch elevated risk for HCC.

P520

Tumor infiltrating lymphocytes in colorectal adenocarcinoma: How does the immune response progress through the tumor stages? Stamm M.1, Hallas C.2, Falk M.2, Tiemann M.2 1 2

Asclepios Medical School, Campus Hamburg, Hamburg, Germany, Institut für Hämatopathologie Hamburg, Hamburg, Germany

Introduction: Tumor infiltrating lymphocytes (TIL) have been linked to prognosis in colorectal adenocarcinoma. Nevertheless, there is considerable discrepancy about the type and the exact location of TIL thought to be relevant for a prognostic impact. An exact qualitative and quantitative description of the sequence of lymphocyte infiltration regarding cell type and tumor stage is still lacking. Methods: B-cells (CD19+ and CD20+, resp.), T-cells (CD3+, CD4+, and CD8+, resp.), activated T-lymphocytes (CD25+), and tissue macrophages (CD68+) were stained by immunohistochemistry and counted in 131 colorectal adenocarcinomas in three representative fields of view each. Only TIL along the invasive margin of the tumor were counted. Lymphocytes in the stroma or organized in follicular structures were excluded. Results: As expected, the immune response in the tumors was dominated by T-cells, but CD4+ cells were significantly more abundant than CD8+ cells in all TNM stages except T2. CD8+ T-cells accounted for less than 35% of infiltrating cells in T1 and less than 25% of lymphocytes in T4. The significantly highest number of CD8+ T-cells was found in T2 tumors where they accounted for almost 50% of TIL. This was correlated with a significant increase in activated lymphocytes and tissue macrophages. Median CD4/CD8 ratio was 1.25 in T1, 1.17 in T2, 1.45 in T3 and 2.3 in T4. In 86% of all carcinomas stage T4 more CD4+ than CD8+ cells were found. The strongest B-cell response, however, was found in T1 (p  2) were low (maximum 10% each for diarrhea and nausea/vomiting), but 35% of the pts had at least one episode of hospitalization due to toxic side effects. At time of evaluation 82/92 pts (89%) had died. Median overall survival (OS) from start of 2nd line CT reached 7.3 months (mo) and 27% of pts survived 1 year. The calculated OS since start of 1st line CT was 14.4 mo. Progression free survival (PFS) was 2.9 mo. There was no difference in OS and PFS for pts > 70y and younger ones. Peritoneal carcinomatosis (p T1 48.7 vs. 36.5%; p = 0.023) or lymph node involvement (N+ 36.5 vs. 26.7%; p = 0.02). Treatment related follow-up impairments as lymph edema (18.7 vs. 11.8%; p = 0.045) or polyneuropathy (42.5 vs. 14.9%; p = 0.001) and duration of illness (until start of rehabilitation; 9.0 vs. 6.5 months, p = 0.004) were also seen more often in patients with TNBC. Disclosure: No conflict of interest disclosed.

Wissenschaftliches Symposium CML V543

Stem cell biology of CML and its clinical implications Wolf D. Med III, Uniklinikum Bonn (UKB), Bonn, Germany

The introduction of tyrosine kinase inhibitors (TKIs) for the treatment of Chronic Myelogenous Leukemia (CML) has dramatically improved the prognosis, but only a small proportion of CML patients can be permanently cured by TKIs. Data from the STIM study suggest that approximately 40% of patients remain disease-free characterized by a sustained deep molecular remission after TKI discontinuation. So far, however, the follow-up of the STOP-studies is still too short to draw definite conclusions whether a significant proportion of CML patients can indeed be long-term cured by


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after a new code is introduced and if the coding behaviour depends on a revenue-relevance of that code. This analysis aimed to show the adoption of newly introduced OPScodes, 1–941.0 and 1–941.1, into the DRG system. Methods: Data from the InEK DRG browser were analysed for the years 2007–2012. 1–941.0 and 1–941.1 (=1–941) codes were identified in all R60 (AML) and R61 (lymphoma and non-acute leukaemia) DRGs. 1–941 coding of all inlier patients was analysed descriptively for each DRG and year. Revenue-relevance of 1–941 codes was identified by screening the definition tables of the respective DRG for these codes. In these DRGs, differences of 1–941 coding frequencies between 2 years before revenue-relevance and 2012 were analysed. Results: Over the years a steady increase in coding frequency could be observed in DRGs R60A (16.90% (2007) up to 64.59% (2012)) and R60B (0% (2007) up to 27.28% (2012)). In revenue-relevant DRGs, 1–941 coding frequency increased in all DRGs: R60C (2010: 10.52%, 2012: 26.70%), R61B (2009: 0%, 2012: 5.22%) and R61G (2009: 0%, 2012: 1.21%). Conclusion: The largest annual increase of 1–941 coding could be noticed in R60A. As R60A describes patients with intensive chemotherapy at initial diagnosis, these codes should have been used in nearly all patients. Yet, we observed these codes in only around 2/3 of the patients. In DRGs where coding of 1–941 is relevant for remuneration, an increase in coding could only be detected in a small number of patients. Therefore budget impact of 1–941 seems of little relevance for coding behaviour. The small number of patients in whom the codes are revenue relevant makes the existing approach questionable. Introduction of additional remuneration seems to be a better way to compensate hospitals for the initial diagnostic workup.

Disclosure: Dominik Wolf: Advisory Role: BMS, Novartis, Pfizer; Financing of Scientific Research: BMS, Novartis, Pfizer; Expert Testimony: Novartis V544

Mechanisms of drug resistance and clonal evolution in CML Balabanov S. Universitätsspital Zürich, Klinik für Hämatologie, Zürich, Switzerland

Although the high efficacy of tyrosine kinase inhibitors (TKIs) has been proved in a number of successful clinical trials, resistance against TKIs represents a relevant clinical problem in treatment of chronic myelogenous leukemia (CML). In that context, kinase domain mutations represent a frequent mechanism of drug resistance against all clinical used TKIs, particular in more advanced phases of the disease. Based on that knowledge new TKIs have been introduced in to the clinic and can be classified as second generation (such as nilotinib, dasatinib and bosutinib) or third generation (also covering T315I such as ponatinib) TKIs. Furthermore, new TKIs binding BCR-ABL apart from the kinase domain, like allosteric inhibitors, have demonstrated strong preclinical BCR-ABL inhibitory activity for the wild type and mutated kinase and are currently tested in clinic trials. However, mutations in BCR-ABL only account for about half of the cases of treatment failure under TKIs and other mechanisms bypassing BCR-ABL activity and thereby supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling have been described (e.g. activation of SRC-family kinases dependent pathways). Of special interest are activated signaling pathways that can be inhibited by multi-kinase inhibitors or by a combination of certain TKIs ideally upfront or as a second line therapy. Mathematical models and first experimental in vivo and in vitro studies validate this approach as a feasible therapeutic strategy. Furthermore, clonal evolution is increasingly recognized as a central driving force in disease progression and drug resistance under TKI treatment. The combination of new next generation sequencing technologies and mathematic modelling, in particular evolutionary modelling, represents a promising approach to understand the population growth and decline of resistant clones. Furthermore, information about inter-clonal interaction, clonal dominance and clonal fitness can be derived from thus experiment and can provide crucial information for the development of new optimized treatment schedules. Therefore, an accurate understanding of the different resistance mechanisms based on the combination of clinical, experimental and theoretical approaches will be the prerequisite to overcome or prevent clinical resistance and for the successful use of combinations of targeted inhibitors in the future therapy of CML patients. Disclosure: Stefan Balabanov: Advisory Role: Beratungstätigkeit für ARIAD Pharmaceuticals

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Effects of long-term treatment with TKI on incidence, prevalence and overall survival in CML patients Saußele S. Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

Actually, survival of chronic myeloid leukemia (CML) patients in imatinib studies exceeds 86% at 8 years (Hehlmann JCO 2014). This leads to increasing prevalence of CML. In addition new questions and problems in the management of CML arise as patients will live a long time with their disease. With new treatment options QoL data might be essential for decision making also after failure of first-line therapies and the decision before a possible SCT. Quality of life data in CML are rare). Data of a QoL assessment in a cross sectional survey including 422 patients in Italy using the SF36 questionnaire showed that especially younger CML patients on imatinib treatment have an impaired QoL in regards of role emotional and social functioning compared to general population (Efficace 2011). The most common symptom was fatigue. The occurrence of symptoms was correlated with fatigue (Efficace 2013). Another aspect is that randomized trials can be complicated by comorbidities and their influence in CML has not been studied so far. In an evaluation of the CML-Study IV, a randomized five-arm trial to optimize imatinib therapy, the impact of comorbidities had been evaluated (Saussele ASH 2013). Therefore all patients were grouped according the Charlson Comorbidity Index (CCI, Charlson 1987), a validated weighted index which includes the number as well as the severity of comorbidities and the age of patients. For analyses patients were grouped in CCI 2, CCI 3–4, CCI 5–6 and CCI ≥7. In 1519 patients 521 index comorbidities were reported resulting in i) CCI 2: 589, ii) CCI 3–4: 599, iii) CCI 5–6: 229 and iv) CCI ≥7: 102 patients respectively. There were no significant differences in remission rates according to CCI, neither for time to complete cytogenetic remission, to major molecular remission nor for the cumulative incidences of accelerated phase and blast crisis. Significant differences in overall survival (OS) were observed. In a multivariate analysis CCI was the most powerful predictive factor for OS. Conclusion: OS alone is not any more an appropriate measure for the effectiveness of a specific treatment for CML. Moreover the comorbidities an QoL of CML patients have to be taken in account for valid comparative analysis and interpretation of OS observed with different TKIs in CML patients Disclosure: Susanne Saußele: Advisory Role: Novartis, BMS, Pfizer; Financing of Scientific Research: Novartis, BMS, Pfizer; Expert Testimony: Novartis, BMS; Other Financial Relationships: Novartis, BMS, Pfizer

Wissenschaftliches Symposium

Niere, Harnleiter und Blase – Forschung beim Urothelkarzinom 2014 V549

Prognostic and predictive genetic alterations in upper tract urothelial carcinoma: Gakis G. University Hospital Tübingen, Dept. of Urology, Tübingen, Germany

Introduction: Urothelial carcinomas of the upper and lower urinary tract show stage-specific discrepancies in outcomes. The aim of the present study was to evaluate the impact of genetic markers in terms of their predictive and prognostic significance in upper tract urothelial carcinoma (UTUC). Methods: A PubMed search was conducted for genomic alterations reported in UTUC between 2000 to 2014. Literature search was based on the following key words: gene, expression, marker, predictive, prognos-

Abstracts

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sole TKI-based therapy concepts. The persistence of so-called CML repopulating stem cells (CML-SC) is currently regarded as the main cause of disease persistance. The CML-SC pool is characterized by expression of CD34 and absence of CD38. It is believed that in patients, still 1 out of 100 to 1000 CD34+CD38- CML-SC are still BCR-ABL positive at the time the total BCR-ABL load is getting negative. Interestingly, despite effective BCR-ABL kinase inhibition in CML-SC by TKIs, this compartement remains almost unaffected. This observation indicates that CML-SC are BCR-ABL independent and explain why these cells can rapidly give rise to disease recurrence after treatment discontinuation. Thus, effective targeting of this cell population by novel and innovative substances is a prerequisite for long-term cure of CML. Various directly CML-SC targeting strategies (eg inhibitors of ß-catenin/wnt pathway, HDAC, autophagy-, or Hedghog JAK2 inhibitors, direct targeting by antibodies such as Mabcampath), but also stroma-modifying therapies (eg immune activation by interferon-α, checkpoint antibodies, modification of the stem cell niche by parathyroid hormone, or immune-activating vaccines) provided promising results in vitro and in preclinical models in vivo and are currently being evaluated in phase 1–3 clinical trials. After the introduction of TKIs, successful elimination of CML-SC will mark the next major and probably final milestone on the path towards cure of the disease.

tic, upper tract urothelial carcinoma. Studies were evaluated in terms of their clinical implications. Primary study endpoints included correlation to tumor stage at radical nephroureterectomy and recurrence-free survival. A total of 92 studies were initially identified out of which four will be highlighted in the following. Results: In a case-control series including 261 patients with UTUC and 261 healthy controls the single-nucleotide polymorphism rs9642880 (genotype: TT) in the PSCA gene conferred susceptibility for UTUC (OR: 1.72; 95%-CI: 1.1–1.28). Additionally, the TT genotype was associated with tumor stage and grade at RNU while an association for urothelial carcinoma of the bladder (UCB) was not found. A supervised analytic approach using gene expression microarray chips reported a small number of differentially expressed genes which were likely limited to a single pathway--the chloride ion binding activity pathway that which was more frequently found in UTUC compared to UCB. In another study HER2- gene amplification was present in 18% of UTUC patients, which was associated both with tumor grade and stage and recurrence-free survival after RNU. Conclusions: Urothelial carcinomas of the upper and lower urinary tract show distinct stage-specific discrepancies in their genetic profile. These finding may be utilized in future for targeted therapies in the neoadjuvant and adjuvant setting.

to the substance at the same time. Autophagy might be exerted via the PI3K/AKT/mTOR pathway as a result of the inactivation of p-Akt. The global proteome analysis revealed regulation of several proteins previously reported to be involved in metastasis formation, tumor cell invasion, and malignant growth. Among others, alterations in keratin 81 isoforms, up-regulation of CrkII, and both precursor and mature forms of IL-1β, as well as down-regulation of the active form of cathepsin B were observed. Frondoside A significantly reduced tumor volume in vivo without causing major side effects. A remarkable increase of the lymphocyte count in the blood of treated animals suggests that in vivo anticancer activity of Frondoside A could at least in part be mediated by immune stimulatory effects. Conclusion: In conclusion, Frondoside A is a promising novel substance for the treatment of CRPC, showing high efficacy and low toxicity in vitro and in vivo. Regulation of anti-apoptotic pathways, induction of autophagy, and potentially immune-mediated effects are supposed modes of action of the substance. Acknowledgement: This research is supported by the Eppendorfer Krebs- und Leukämiehilfe and the Hamburger Krebsgesellschaft. Both first and both last authors contributed equally Disclosure: No conflict of interest disclosed.

Disclosure: No conflict of interest disclosed. V553

Prostatakarzinome V552

Marine triterpene glycoside frondoside a exhibits high in vitro and in vivo activity in prostate cancer Dyshlovoy S.1,2, Menchinskaya E.1,2, Rast S.1, Venz S.3, Hauschild J.1, Jacobsen C.1, Kalinin V.2, Silchenko A.2, Avilov S.2, Bokemeyer C.1, Schumacher U.4, Stonik V.2, Aminin D.2, Honecker F.1,5, von Amsberg G.1 University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald -Tumorzentrum, Hamburg, Germany, 2G.B. Elyakov Paciﬁc Institute of Bioorganic Chemistry, Vladivostok, Russian Federation, 3 University of Greifswald, Department of Medical Biochemistry and Molecular Biology, Interfacultary Institute of Genetics and Functional Genomics, Department of Functional Genomics and Department of Otorhinolaryngology, Head and Neck Surgery, Greifswald, Germany, 4 University Medical Center Hamburg-Eppendorf, Department of Anatomy and Experimental Morphology, Hamburg, Germany, 5Tumor and Breast Center ZeTuP, St. Gallen, Switzerland 1

Introduction: Despite of the progress in the treatment of castration resistant prostate cancer (CRPC), patients face a dismal prognosis due to the development of resistance. We examined the efficacy and toxicity of Frondoside A – a marine natural compound belonging to the group of triterpene glycosides, in a human prostate cancer model. Methods: Anticancer activity of Frondoside A was investigated using the CRPC cell line PC3. The effects on cell viability and cell cycle were investigated using trypan blue staining and flow cytometry. Mode of action was analysed using Western blot analysis and a global proteome screening approach by 2D-PAGE followed by mass spectrometry analysis. For determination of in vivo efficacy and toxicity a mouse model with s.c. transplanted PC3 cells was used. Results: Frondoside A significantly inhibited proliferation of PC3 cells in a dose dependent manner at low micromolar concentrations. It induced caspase-3 and -9-dependent apoptosis, lead to down-regulation of the anti-apoptotic factors p-ERK and survivin, and induced a G2/M cell cycle arrest. Up-regulation of LC3B-II, a marker of type II cell death, suggests that autophagy-associated processes are involved in the cellular response

Abstracts

Effects of radium-223 dichloride (Ra-223) on total alkaline phosphatase (ALP) and prostate-specific antigen (PSA) in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases from the phase 3 ALSYMPCA trial Strauss A.1, Heinrich D.2, Parker C.3, Shan M.4, Wilhelm S.4, Garcia-Vargas J.4, O’Bryan-Tear C.G.5, Sartor O.6 Universitätsmedizin Göttingen, Klinik für Urologie, Göttingen, Germany, Akershus University Hospital, Lorenskog, Norway, 3The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom, 4Bayer Healthcare, Whippany, United States, 5Algeta ASA, Oslo, Norway, 6Tulane University Cancer Center, New Orleans, United States 1 2

Introduction & Objectives: Ra-223 is approved for the treatment of patients with CRPC and symptomatic bone metastases (m-CRPC) and no known visceral metastases. In ALSYMPCA, Ra-223, compared with placebo (pbo), significantly improved median OS by 3.6 months (HR = 0.70; 95% CI, 0.58–0.83; P < 0.001) and was well tolerated. ALP, a recognized marker of bone metastases, appeared to be a potential marker of Ra-223 effect in m-CRPC patients in early studies. Unlike androgen- receptor targeting agents for which PSA can indicate effect, the Ra-223 mechanism of action suggests a primary effect on ALP. Here we report plasma ALP and PSA data from ALSYMPCA. Materials and methods: Patients were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV every 4 wk) or matching pbo. The treatment period was from the first injection of study drug (wk 0) to 4 weeks after the last injection (wk 24), and follow-up visits continued until 3 years after each patient’s first injection. ALP and PSA measurements were recorded at each treatment and follow-up visit. Patients with ALP measurements at baseline and week 12 were included in an exploratory analysis of changes in ALP levels. Results: At week 12, Ra-223 treatment was associated with a significant decline from baseline ALP levels, which persisted during treatment and follow-up (Ra-223 vs pbo; P < 0.001). This decrease was seen in 87% (433/497) of Ra-223 patients compared with 23% (49/211) of pbo patients. On average, Ra-223 patients experienced a 32% decrease from baseline ALP, whereas pbo patients had a 37% increase (P < 0.001). Ra223 also significantly prolonged the median time to ALP progression (7.4 vs 3.8 mo; HR = 0.17; 95% CI, 0.13–0.22; P < 0.001). Ra-223 patients with a confirmed ALP decline at week 12 had a significantly longer median OS than Ra-223 patients with no confirmed ALP decline (17.8 vs 10.4 mo; HR = 0.45; 95% CI, 0.34–0.61; P < 0.0001). Mean PSA levels


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Freier Vortrag

increased from baseline during treatment and follow-up periods more rapidly among pbo patients than among Ra-223 patients, and Ra-223 significantly prolonged the median time to PSA progression (HR = 0.64; 95% CI, 0.54–0.77; P < 0.001). Conclusion: Ra-223 significantly improves OS in men with m-CRPC and has a major impact on serum ALP levels, but a relatively modest effect on PSA kinetics. PSA levels should not be used as a marker of response to Ra-223. ALP requires further study as a possible biomarker of response. Disclosure: Arne Strauss: Financing of Scientific Research: Bayer, Pfizer, Amgen, Novartis, Janssen-Cilag O. Sartor: No conflict of interest disclosed. V554

Prognostic value of free testosterone (FT) levels during salvage chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxelresistant prostate cancer (mDRPC) Reuter C.1, Morgan M.A.1, Ivanyi P.1, Grünwald V.1, von Kloth C.2, Merseburger A.2, Ganser A.1 Medizinische Hochschule Hannover, Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Hannover, Germany, 2 Medizinische Hochschule Hannover, Urologie und urologische Onkologie, Hannover, Germany 1

Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Our recent data suggest that carboplatin is effective in combination with docetaxel in DRPC. Platinum(II)-complexes have been shown to interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n = 59) and during carboplatin/ docetaxel chemotherapy (n = 52). Results: Of the 84 pts. treated since February 2005, 95.2% had bone metastases, 41.7% had lymph node, 27.4% liver and 17.9% lung involvement. At the time of the current analysis, the median follow-up time was 15.1 months, 64 pts. had died and 75 had progressive disease. The objective response rate was 40.0% and the disease control rate 62.0% in the 50 pts. with measureable disease. Response of prostate-specific antigen (≥50%) was observed in 40/84 (47.6%) patients. Median progression-free survival (PFS) for all patients was 6.9 months (CI 95% 6.0, 7.8) and median OS was 17.9 months (CI 95% 12.6, 23.0). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (42.9/38.1%). Median free testosterone levels were 0.69 pg/ml before and < 0.18 pg/ml during carboplatin/docetaxel treatment (nadir levels, p 

2014 - Herbsttagung und Jahrestagung der Arbeitsgruppe Rhythmologie vom 09. - 11. Oktober 2014 in Düsseldorf .

Das Referenzzentrum für Neuroradiologie für die Hirntumorstudien der deutschen Gesellschaft für pädiatrische Onkologie und Hämatologie (GPOH).

49. Jahrestagung der Deutschen Gesellschaft für Neuroradiologie : 23.-25. Oktober 2014 Gürzenich, Köln.

Mitgliederbefragung der Deutschen Gesellschaft für internistische Intensivmedizin und Notfallmedizin zur Ausrichtung der künftigen Jahrestagungen.

Der Schmerz Kulturphänomen und Krankheit : Kulturphänomen und Krankheit.

Wissenschaftsgeschichte und das Revival der Begriffsgeschichte.

Nachtrag zur Liste der vom Robert Koch-Institut geprüften und anerkannten Desinfektionsmittel und -verfahren (16. Ausgabe).

Augenlidschwellung und Belastungsdyspnoe.

Freud und Sechs.

Mobbing - Wenn der Arbeitsplatz zur Hölle wird - Ursache und Wirkung von Mobbing.

Probiotika: Anforderungen und Wirkmechanismen.

Chorioretinale Erkrankungen und Fluoreszenzangiographie.

Das Ganze und das Einzelne.

Rede zur Eröffnung auf dem 20. Kongress 'Armut und Gesundheit' am 05.03.2015 in der TU Berlin.

"He is a Mysterious Man": : Der ungarisch-jüdische Mathematiker John von Neumann zwischen Wissenschaft und Politik.

Mysterium Glaskörper : Aufbau, Alterung und Ersatzstrategien.

In der Enge und im Kleinen kann man nichts verstecken: "Small formats" im Museum Gugging.

Vergleichende Untersuchungen mit der oralen und intravenösen Glucosebelastung zur Erfassung einer verminderten Kohlenhydrattoleranz.

6th Congress of the GTH (Gesellschaft für Thrombose- und Hämostaseforschung). Kiel, February 21-24, 1990. Abstracts.

Seltene hochkontagiöse und lebensbedrohliche Erkrankungen.

Abgrenzung zwischen Arzneimitteln und Lebensmitteln.

Erratum zu: Empfehlungen zur Prävention und Kontrolle von Methicillin-resistenten Staphylococcus aureus-Stämmen (MRSA) in medizinischen und pflegerischen Einrichtungen : Empfehlung der Kommission für Krankenhaushygiene und Infektionsprävention (KRINKO) beim Robert Koch-Institut.

Stellungnahme der Deutschen Ophthalmologischen Gesellschaft zur Glaukomfrüherkennung.