Prof J Passweg Klinik Hämatologie

Transkript

1 Prof J Passweg Klinik Hämatologie

2 Leukozytose Ausschwemmung aller Vorstufen Thrombozytose Splenomegalie

3 1 Genetische Anomalie -> 1 Maligne Erkrankung Klonale Evolution Gezielte Therapie: Tyrosinkinaseinhibitor

4 Chronische Phase Früh Spät Fortgeschrittene CML Akzelerierte Phase Blastenkrise Mediane Dauer 5 6 J Dauer 6 9 Mt Ueberleben 3 6 Mt

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8 Grb2 SH2 SH3 Sos Raf MAPKs SEK Fos P Y? β Shc Ras Bcr Fes p210 Crkl BCR-ABL a IL-3 OD Ser/Thr kinase DBL PH SH3 SH2 Tyr kinase NLS DNA Actin BD BD Bcl-2 SHIP Grb2 Grb2 Sos SH3 Ras Raf SHP-2 MAPKs Cbl PI3K Akt Myc STATs STATs JAKs Shc MEKK JNK/SAPK Jun IL-3 BCR-ABL Signalisationswege

9 Die Kinase aktiviert ein Substratprotein, zb, PI3 durch Phosphorylierung Substrate Das aktivierte Substrat initiiert eine Signalisationskaskade welche zur Zellteilung und zum Zellüberleben führt Bcr- Abl Effector ADP P P P P ATP P P P ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate. SIGNALING Savage and Antman. N Engl J Med. 2002;346:683 Scheijen and Griffin. Oncogene. 2002;21:3314.

10 Der Tyrosinkinase Inhibitor besetzt die ATP bindende Tasche der Abl Kinase Domäne Keine Substratphosphorylierung, keine Signalübermittlung Bcr- Abl ima+nib nilo+nib dasa+nib P ATP P P SIGNALING P Savage and Antman. N Engl J Med. 2002;346:683.

11 Entwicklung CML Behandlung Arsenic Spleen irradia+on Busulfan Hydroxyurea Stem cell transplanta+on Interferon alpha Ima+nib Nilo+nib, Dasa+nib Others

12 Imatinib, (CML IV) 5-J Survival 92% Survival probability Interferon / Stammzelltransplantation, (CML IIIA) 71% Interferon / Stammzelltransplantation, (CML III) 63% N = 3140 Interferon, , 53% (CML I, II) Hydroxyurea, Busulfan, , 38% German CML Study Group. Data on file. Year after diagnosis

13 Hämatologische Remission Normalisiertes Blutbild Zytogenetische Remission Keine Philadelphia Chromosom positiven Metaphasen Molekulare Remission Kein bcr-abl Transkript Heilung?

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16 Kaplan-Meier Estimates of the Cumulative Best Response to Initial Imatinib Therapy Druker BJ et al. N Engl J Med 2006;355:

17 Rate of Progression to the Accelerated Phase or Blast Crisis on the Basis of Cytogenetic Response after 12 Months or Molecular Response after 18 Months of Imatinib Therapy Druker BJ et al. N Engl J Med 2006;355:

18 Major Molecular Responses at 24 months BCR-ABL/ABL 0.1% IS patients (ITT) 71% 71% Preudhomme C. et al. NEJM, 2010 in press

19 Overall Survival after progression to AP/BC on Imatinib (IRIS) Alive following progression, % Estimated % alive at 12 months 43% 24 months 30% Months Since AP/BC Treatment At 12 months, 57% of patients who progressed on imatinib died

20 Resistenz gegen Tyrosinkinase Inhibitoren

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22 Ueberleben nach Stammzelltransplantation: Patienten mit guter Risikokonstellation N = N = N = 594

23 Häufigkeit allogene Stammzelltransplantation CML 1200 CML cp allo 900 CML non 1st cp allo 600 CML cp auto 300 CML non 1st cp auto

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25 Nilotinib und Dasatinib in chronischer Phase: major molecular response nach 12 Mt P <.0001 P <.0001 P < % MMR by 12 Months ENESTnd DASISION 0 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Dasatinib 100 mg QD Saglio G, et al. N Engl J Med 2010;362: Kantarjian H, et al. N Engl J Med 2010;362:

26 Nilotinib und Dasatinib in chronischer Phase: Transformation zu Akzeleration/Blastenkrise Note: these data are from separate trials and should not be directly compared. % Progressed to AP/BC ENESTnd p=0.0095* p=0.0037* DASISION /282 1/281 11/283 5/259 9/260 NS 0 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Dasatinib 100 mg QD *p-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC Saglio G, et al. N Engl J Med 2010;362: Kantarjian H, et al. N Engl J Med 2010;362:

27 Imatinib Compliance undbehandlungserfolg In a study of 87 patients with CML-CP in CCyR, lower adherence to IM treatment ( 90%) is a significant predictor for worse response 90% adherence = missing 3 or 4 days of treatment per month 1.0 Adherence >90% (n=64) Cumulative incidence of MMR P< Adherence 90% (n=23) Months from start of imatinib therapy Marin D, et al. J Clin ONcol, 2010; 28:

28 Absetzen von Imatinib nach kompletter molekularer Remission: STIM survival without molecular relapse At M12, the probability of persistent CMR is 41% (95% CI: 29-52%) n=69 pts Mahon F-X., et al. Lancet Oncol 2010

29 Assumptions: Population 500 million, mortality 2% per year, incidence constant.

30 Literatur Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. Druker BJ, Guilhot F, O'Brien SG, Gratwohl A, et al. IRIS Investigators. N Engl J Med Dec 7;355(23): Milestones and monitoring in patients with CML treated with imatinib. Deininger MW. Hematology Am Soc Hematol Educ Program 2008: Review. Resistance and relapse with imatinib in CML: causes and consequences. Deininger M. J Natl Compr Canc Netw Mar;6 Suppl 2:S11-S21. Review.

31 Literatur Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-{alpha} in Newly Diagnosed Chronic Myeloid Leukemia. Hehlmann R, Lauseker M, Gratwohl A, et al. J Clin Oncol Apr 20;29(12): Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. Kantarjian H, Shah NP, Hochhaus A, et al. N Engl J Med Jun 17;362(24): Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Kantarjian HM, Giles FJ, Bhalla KN, et al. Blood Jan 27;117(4):