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LLA 2011 - S. Metzelder - Targeted therapy in leukaemia: New avenues
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LLA 2011 - S. Metzelder - Targeted therapy in leukaemia: New avenues



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  • 1. Targeted therapies in leukaemia: New avenues Stephan Metzelder Ascona, 13.06.2011
  • 2. τὸ λευκὸν αἷμα White Blood18 year old patient Healthy donor500.000 leukocytes 5.000 leukocytes
  • 3. Targeted Therapies Principle:Targeting genetic lesions involved in tumorigenesis Characteristics: effective tumour-specific reduced treatment associated toxicities (economic)
  • 4. „Older new Avenues“
  • 5. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocolDisease-Free Survival Induction-Consolidation / Maintenance ATRA-Dauno/AraC / ATRA Dauno/AraC / ATRA ATRA-Dauno/AraC / none Dauno/AraC / none Tallman M et al. Blood 2002;100:4298
  • 6. Arsenic Trioxide Monotherapy Four cycles consolidation One cycle consolidation Ghavamzadeh A et al. J Clin Oncol 2011; Jun 6 Epub
  • 7. Arsenic Trioxide Zhang XW et al. Science 2010;5975:240
  • 8. The „Magic Cancer Bullet“ 1845 RudolfVirchow 1960 Peter Nowell David Hungerford 1973 Janet Rowley 1987 Owen Witte David Baltimore 1999 Nick Lydon Alex Matter Jürg Zimmermann Elisabeth Buchdunger Brian Druker
  • 9. BCR-ABL:The CMLoncogene
  • 10. CML Survival 1983 - 2009 The Swiss / German CML study group N=3140 Imatinib:Percent survival 92% after 5 years (> 2001) Interferon or stem cell transpl. 71% after 5 years Interferon: 53% after 5 years Busulfan: 38% after 5 years Years after diagnosis
  • 11. New tyrosine kinase inhibitors: Are they better?Nilotinib/Dasatinib approved in Germany as first linetreatment in CML chronic phaseCompared to Imatinib:- Faster MMR/CCyR- Less Acceleration/BlastcrisisSome limitations:- Faster MMR not correlated with better OS- Higher rate of progress to AP/BC for Imatinib: 3,5% Dasision, 4,2% ENESTnd, vs. 1,5% IRIS Saglio G et al. NEJM 2010;362:2251 Kantarjian H et al. NEJM 2010;362:2260
  • 12. TKIs cure CML? STIM – Stop Imatinib 41% CMR after 1y Mahon FX et al. Lancet Oncology 2010;11:1029
  • 13. Interferon: Signal transduction via IRFs
  • 14. ICSBP (=IRF8): A potential tumor suppressor of CML 32D/BA-v 32D/BA-ICSBP Days after Inj.All Good Poor Schmidt et al., Blood 1998 Schmidt et al., J Clin Oncol 2000 Resp. Resp. Schmidt et al., Blood 2001 Burchert et al., Blood 2004
  • 15. Interferon after ImatinibRelapse free survival after STOP Imatinib Burchert et al., J Clin Oncol 2010
  • 16. Model BCR/ABL dep. Imatinib IFN-aHSC no - +GMP yes + -CMP
  • 17. CML study V Flow chart First diagnosis CML Randomisation TK-Inhibitor Induction TK-Inhibitor InterferonMaintenance TK-Inhibitor Interferon
  • 18. FLT3-ITD positive Acute Myeloid Leukemia• ∼20-30% in AML < 60J, ∼5% in AML > 60J.• High-Risk: - ∼90% relapse after conventional chemotherapy within 12 mo. - poor survival• Relapse after allogenic transplantation: desperate situation Kindler T et al. Blood 2010;116:5089
  • 19. Sorafenib in vitro
  • 20. Sorafenib in vivo: ♀, 40a therapy refractory FLT3-ITD+ AMLSorafenib p.o. before Sorafenib d+12 Sorafenib Metzelder S et al. Blood 2009;113:6567
  • 21. Sorafenib in vivo: ♀, 40a therapy refractory FLT3-ITD+ AML, Relapse post allo-SCTrelapse molecular no detectable FLT3-ITD Sorafenib p.o. allo-PBSCT
  • 22. Patients characteristics
  • 23. Patients characteristics
  • 24. Sorafenib in FLT3-ITD positive AMLOnly good when combined with graft vs leukemia Design of SORMAIN FLT3 ITD AML Allogen. BMT Random Placebo Sorafenib
  • 25. Summary• Arsenic is effective as monotherapy in APL and recruits PML-RARa to proteasomal degradation• IFNa therapy may deepen molecular remission in maintenance of CML (by IRF8 ?)• Sorafenib monotherapy might have curative potential in AML with FLT3-ITD (especially after BMT)
  • 26. „New Avenues grow old?“ Andreas Neubauer Andreas Burchert Colleagues in Marburg Colleagues providing patient data