1 Key Wordschronic myeloid leukemiaimatinib mesylate tyrosine kinase inhibitor chronic myeloid leukemia CML imatinib mesylate CML CML CML CML Ph 10 1 30 50 3 5 CML α IFNα Ph Ph cytogenetic response CRmajor CR Ph 35% 10 38% complete CR Ph 5 30%5 52 63% major CR 7 10 80% 1 IFNα Ara-C 1 major CR 21 35% 5 68 70% 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
1 IFNα CML II 1 6) 34 52% complete CR 4 82% 600 mg 400 mg 3 major CR 181 20 4 70% major CR 30 40% CML 1,106 553 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 2 10 18 2 1 II IFN 400 mg/ 600 mg/ 454 62 119 229 95% 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
2 CML α+ Ara-C IRIS study 18 IFNα+ Ara-C n = 553 n = 553 95.8% 69.0% p < 0.001 major response Ph 35% 87.1% 34.1% p < 0.001 complete response Ph 0% 76.2% 14.5% p < 0.001 3.3% 8.5% p < 0.001 97.4% 95.8% p = 0.23 2.9% 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% 15 16 42 6.1% major CR 4.5% 2.4% 1.4% 1 1 3.4% 2 7.5% 3 4.6% 4 2.3% 42 4.0% 2% 6 42 PFS 91% 68% p < 0.001 12 complete CR 93% 74%p < 0.001 major CR 91% 66% p < 0.001 IRIS study Sokal Sokal 42 complete CR 91% 84% 69% p < 0.001 PFS 94% 88% 80% p = 0.003 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
complete CR 75% 138 9) BCR-ABL 3 log major molecular response major molecular response 24 4 log 24 42 2 11) 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 (%) 100 90 80 70 60 50 40 30 20 10 0 3 log 4 log 3 6 9 12 18 24 27 30 33 36 39 42 2 400 mg/ major molecular response IRIS study
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-354825 16) 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 10 50 T315I BMS-354825 CML CML HLA 1 2 CML CML 1) Saweyer C: Chronic myeloid leukemia. N Engl J Med 340: 1330~1340, 1999 2) Guilhot F, et al.: Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 337: 223~229, 1997 3) Deininger MW, et al.: The molecular biology of chronic myeloid leukemia. Blood 96: 3343~3356, 2000 4) 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, 1993 5) 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, 1996 6) 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, 2004 7) 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, 2003 8) 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, 2003 9) 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, 2004 10) 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, 2003 11) 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, 2005 12) 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, 2002 13) Huges T, et al.: Higher-dose imatinib (600 mg/day) with selective intensification in newly diagnosed CML
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