CML CML CML. tyrosine kinase inhibitor CML. 22 t(9;22)(q34;q11) chronic myeloid leukemia CML ABL. BCR-ABL c- imatinib mesylate CML CML BCR-ABL

Transcription

1 1 Key Wordschronic myeloid leukemiaimatinib mesylate tyrosine kinase inhibitor chronic myeloid leukemia CML imatinib mesylate CML CML CML CML Ph CML α IFNα Ph Ph cytogenetic response CRmajor CR Ph 35% 10 38% complete CR Ph 5 30% % major CR % 1 IFNα Ara-C 1 major CR 21 35% % 2) IFNα CML Ph CML 90%9 22 t(9;22)(q34;q11) 9 ABL 22 BCR BCR-ABL 22 ABL 3) ABL SRC BCR-ABL BCR 4 BCR-ABL 4) BCR-ABL CML BCR-ABL ATP ATP ATP BCR- ABL ATP 5) CML 1 BCR-ABL c- kit platelet derived growth factor PDGF

2 1 IFNα CML II 1 6) 34 52% complete CR 4 82% 600 mg 400 mg 3 major CR % major CR 30 40% CML 1, IFNα + Ara-C 553 III IRIS study 7) 400 mg 3 12 minor CR Ph 36 65% 800 mg INFα + Ara-C IFNα 500 /m 2 Ara-C 20 mg/m II IFN 400 mg/ 600 mg/ % 27% 37% 16% 10% 13% 9% 27% 21% 27% major response Ph 35% 65% 16% 28% 16% complete response Ph 0% 52% 11% 19% 7% 75% 4y 16% 3y 40% 3y 7% 3y 82% 4y 35% 3y 55% 3y 14% 3y

3 2 CML α+ Ara-C IRIS study 18 IFNα+ Ara-C n = 553 n = % 69.0% p < major response Ph 35% 87.1% 34.1% p < complete response Ph 0% 76.2% 14.5% p < % 8.5% p < % 95.8% p = % 30.6% IFNα + Ara-C complete CR 76.2% CML IRIS study M.D. Anderson 8) CML 30 98% IFNα 88% p = 0.01 CML IRIS study 42 9) 75% IFNα + Ara-C 4% 18 98%91% major CR 84% complete CR 97% 94% major CR progression free survival PFS 84% % major CR 4.5% 2.4% 1.4% % 2 7.5% 3 4.6% 4 2.3% % 2% 6 42 PFS 91% 68% p < complete CR 93% 74%p < major CR 91% 66% p < IRIS study Sokal Sokal 42 complete CR 91% 84% 69% p < PFS 94% 88% 80% p = CML 80% complete CR PCR BCR-ABL minimal residual disease MRD PCR Nested PCR CML TARGET 2 PCR transcription mediated amplification TMA BCR-ABL Amp-CML PCR IRIS study IRIS study BCR-ABL 10) 12 39% complete CR BCR- ABL mrna 3 log 42 PFS 98% 136 complete CR 3 log PFS 90% 94

4 complete CR 75% 138 9) BCR-ABL 3 log major molecular response major molecular response 24 4 log ) molecular response CML MRD CML IFNα complete CR MRD MRD CML 12) MRD 98% 7) IRIS study 16.2% 9.3% 4.0% 5.4% 42 6% 9) IRIS study TIDEL study 13) CML 600 mg/ 800 mg/ 3 Ara-C 3 6 major CR 9 complete CR 12 BCR-ABL 4 log TIDEL study 600 mg/ IRIS study 400 mg/ 12 TIDEL study major molecular response 4 log TIDEL study 400 mg/ major molecular response (%) log 4 log mg/ major molecular response IRIS study

5 IRIS study 4% 10% BCR-ABL BCR-ABL BCR-ABL BCR-ABL BCR-ABL MRD multi-drug resistance α1-acid glycoprotein BCR-ABL 14) BCR-ABL BCR-ABL BCR-ABL phosphate binding loop p-loop imatinib binding site activation loop catalytic loop p-loop 15) MRD ABL ABL BMS ) SRC-family ABL BCR-ABL 260 T315I imatinib binding site BCR-ABL 86% 46% complete CR 17% p-loop / AMN107 17) ABL ABL BCR-ABL T315I BMS CML CML HLA 1 2 CML CML 1) Saweyer C: Chronic myeloid leukemia. N Engl J Med 340: 1330~1340, ) Guilhot F, et al.: Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 337: 223~229, ) Deininger MW, et al.: The molecular biology of chronic myeloid leukemia. Blood 96: 3343~3356, ) McWhirter JR, et al.: A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol 13: 7587~7595, ) Druker BJ, et al.: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2: 561~566, ) Richard T, et al.: Four year follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blastic crisis (BC) chronic myeloid leukemia (CML) treated with imatinib in three large phase trials. Blood 104: 11a, ) O'Brien SG, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med 348: 994~1004, ) Kantarjian HM, et al.: Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data. Cancer 98: 2636~2642, ) Guilhot F, et al.: Sustained durability of responses plus high rates of cytogenetic responses result in long-term benefit for newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) treated with imatinib (IM) therapy: Update form the IRIS study. Blood 104: 10a, ) Hughes TP, et al.: Frequency of major molecular responses to imatinib or interferon α plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349: 1423~1432, ) Hughes T, et al.: Long term significance of achieving a major molecular response for first and second line imatinib treated chronic phase patients with CML entered in the IRIS study. Abstract Book of 10th Congress of the European Hematology Association, ) Graham ST, et al.: Primitive, quiescent, Philadelphiapositive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99: 319~325, ) Huges T, et al.: Higher-dose imatinib (600 mg/day) with selective intensification in newly diagnosed CML

6 patients in chronic phase; cytogenetic response rates at 12 months are superior to IRIS. Blood 104: 10a, ) Shah NP, et al.: Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blastic crisis chronic myeloid leukemia. Cancer Cell 2: 117~125, ) Branford S, et al.: Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in ATP phosphate-binding loop (p-loop) are associated with poor prognosis. Blood 102: 276~283, ) Shah NP, et al.: Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305: 399~401, ) Weisberg E, et al.: Characterization of AMN107, a selective inhibitor of native and mutant BCR-ABL. Cancer Cell 7: 129~141,