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

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

  1. 1. Targeted therapies in leukaemia: New avenues Stephan Metzelder Ascona, 13.06.2011
  2. 2. τὸ λευκὸν αἷμα White Blood18 year old patient Healthy donor500.000 leukocytes 5.000 leukocytes
  3. 3. Targeted Therapies Principle:Targeting genetic lesions involved in tumorigenesis Characteristics: effective tumour-specific reduced treatment associated toxicities (economic)
  4. 4. „Older new Avenues“
  5. 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. 6. Arsenic Trioxide Monotherapy Four cycles consolidation One cycle consolidation Ghavamzadeh A et al. J Clin Oncol 2011; Jun 6 Epub
  7. 7. Arsenic Trioxide Zhang XW et al. Science 2010;5975:240
  8. 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. 9. BCR-ABL:The CMLoncogene
  10. 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. 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. 12. TKIs cure CML? STIM – Stop Imatinib 41% CMR after 1y Mahon FX et al. Lancet Oncology 2010;11:1029
  13. 13. Interferon: Signal transduction via IRFs
  14. 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. 15. Interferon after ImatinibRelapse free survival after STOP Imatinib Burchert et al., J Clin Oncol 2010
  16. 16. Model BCR/ABL dep. Imatinib IFN-aHSC no - +GMP yes + -CMP
  17. 17. CML study V Flow chart First diagnosis CML Randomisation TK-Inhibitor Induction TK-Inhibitor InterferonMaintenance TK-Inhibitor Interferon
  18. 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. 19. Sorafenib in vitro
  20. 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. 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. 22. Patients characteristics
  23. 23. Patients characteristics
  24. 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. 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. 26. „New Avenues grow old?“ Andreas Neubauer Andreas Burchert Colleagues in Marburg Colleagues providing patient data

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