CML. Myeloproliferation. CML Klinischer Verlauf. CML: Modellerkrankung. Philadelphia Chromosom. Chronische Phase. Blastenkrise

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1 CML Myeloproliferation rof J assweg Klinik Hämatologie Leukozytose Ausschwemmung aller Vorstufen Thrombozytose Splenomegalie CML: Modellerkrankung CML Klinischer Verlauf Klonale Evolution 1 Genetische Anomalie -> 1 Maligne Erkrankung Klonale Evolution Chronische hase Früh Spät Fortgeschrittene CML Akzelerierte hase Blastenkrise Gezielte Therapie: Tyrosinkinaseinhibitor Mediane Dauer 5 6 J Dauer 6 9 Mt Ueberleben 3 6 Mt Chronische hase Blastenkrise hiladelphia Chromosom

2 BCR-ABL Shc N = 314 Year after diagnosis IL-3 βββ hiladelphia Chromosome BCR-ABL Signalisationswege IL-3 OD Ser/Thr kinase DBL H SH3 SH2 Tyr kinase NLS DNA BD Actin BD a SH2 Grb2 SH3 Sos SH-2 SHI Y? Bcr Fes p21 Crkl Cbl JAKs Shc Grb2 SH3 Sos Ras MEKK I3K STATs Ras Raf MAKs SEK JNK/SAK Akt MAKs Raf Fos Jun Myc STATs Bcl-2 Signalisationswege Tyrosinkinaseinhibitoren: Wirkmechanismus Die Kinase aktiviert ein Substratprotein, zb, I3 durch hosphorylierung Das aktivierte Substrat initiiert eine Signalisationskaskade welche zur Zellteilung und zum Zellüberleben führt AD AD = adenosine diphosphate; AT = adenosine triphosphate; = phosphate. Savage and Antman. N EnglJ Med. 22;346:683 Scheijenand Griffin. Oncogene. 22;21:3314. AT Substrate Effector SIGNALING Der Tyrosinkinase Inhibitor besetzt die AT bindende Tasche der Abl Kinase Domäne Keine Substratphosphorylierung, keine Signalübermittlung Savage and Antman. N EnglJ Med. 22;346:683. imatinib nilotinib dasatinib AT SIGNALING Entwicklung CML Behandlung Verbesserung der rognose der CML Arsenic Spleen irradiation Imatinib, (CML IV) 5-J Survival 92% Busulfan Hydroxyurea Stem cell transplantation Interferon alpha Survival probability Interferon / Stammzelltransplantation, (CML IIIA) 71% Interferon / Stammzelltransplantation, (CML III) 63% Imatinib Nilotinib, Dasatinib Others Interferon, , 53% (CML I, II) Hydroxyurea, Busulfan, , 38% German CML Study Group. Data on file.

3 Therapieziele Hämatologische Remission Normalisiertes Blutbild Zytogenetische Remission Keine hiladelphia Chromosom positiven Metaphasen Molekulare Remission Kein bcr-abl Transkript Heilung? Number of leukaemic cells rozent BCR-ABL Transcript korreliert mit Anzahl leukämischer Zellen 1% 1% 1%.1%.1%.1% Mean value observed at diagnosis (1% h+) Complete Haematologic Response Complete Cytogenetic Response Major Molecular Response Complete Molecular Response Behandlungsziel BCR-ABL% (according to IS) 1% 1% 1%.1%.1%.5%.1% Kaplan-Meier Estimates of the Cumulative Best Response to Initial Imatinib Therapy Rate of rogression to the Accelerated hase 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 26;355: Druker BJ et al. N Engl J Med 26;355: Major Molecular Responses at 24 months BCR-ABL/ABL.1% IS patients (ITT) Overall Survival after progression to A/BC on Imatinib (IRIS) 71% 71% Alive following progression, % Estimated % alive at 12 months 43% 24 months 3% Months Since A/BC Treatment At 12 months, 57% of patients who progressed on imatinib died reudhomme C. et al. NEJM, 21 in press

4 Resistenz gegen Tyrosinkinase Inhibitoren BCR-ABL Mutationen: Imatinib Resistenz J Apperley Lancet Oncol 27 Ueberleben nach Stammzelltransplantation: atienten mit guter Risikokonstellation Häufigkeit allogene Stammzelltransplantation CML 12 CML c allo N = N = N = CML non 1st c allo CML c auto CML non 1st c auto Tyrosinkinase Inhibitoren der 2. Generation Nilotinib und Dasatinib in chronischer hase: major molecular response nach 12 Mt <.1 <.1 < % MMR by 12 Months ENESTnd DASISION Nilotinib 3 mg BID Nilotinib 4 mg BID Imatinib 4 mg QD Dasatinib 1 mg QD Saglio G, et al. N Engl J Med 21;362: Kantarjian H, et al. N Engl J Med 21;362:226 7

5 2/282 1/281 11/283 5/259 9/26 % rogressed to A/BC Nilotinib und Dasatinib in chronischer hase: Transformation zu Akzeleration/Blastenkrise Note: these data are from separate trials and should not be directly compared ENESTnd p=.95* p=.37*.7.4 DASISION Nilotinib 3 mg BID Nilotinib 4 mg BID Imatinib 4 mg QD Dasatinib 1 mg QD *p-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to A/BC NS Saglio G, et al. N Engl J Med 21;362: Kantarjian H, et al. N Engl J Med 21;362:226 7 Imatinib Compliance undbehandlungserfolg In a study of 87 patients with CML-C in CCyR, lower adherence to IM treatment ( 9%) is a significant predictor for worse response 9% adherence = missing 3 or 4 days of treatment per month Cumulative incidence of MMR Adherence >9% (n=64) <.1 Adherence 9% (n=23) Months from start of imatinib therapy Marin D, et al. J Clin ONcol, 21; 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 CML rävalenzmodell Europa 25 Der Erfolg der TKI Behandlung Mahon F-X., et al. Lancet Oncol 21 Assumptions: opulation 5 million, mortality 2% per year, incidence constant. 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. 26 Dec 7;355(23): Milestones and monitoring in patients with CML treated with imatinib. Deininger MW. Hematology Am Soc Hematol Educ rogram 28: Review. Resistance and relapse with imatinib in CML: causes and consequences. Deininger M. J Natl Compr Canc Netw. 28 Mar;6 Suppl 2:S11-S21. Review. Literatur Tolerability-Adapted Imatinib 8 mg/d Versus 4 mg/d Versus 4 mg/d lus Interferon-{alpha} in Newly Diagnosed Chronic Myeloid Leukemia. Hehlmann R, Lauseker M, Gratwohl A, et al. J Clin Oncol. 211 Apr 2;29(12): Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. Kantarjian H, Shah N, Hochhaus A, et al. N Engl J Med. 21 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. 211 Jan 27;117(4):