Shinichiro Okamoto MD, PhD Keio University School of Medicine Tokyo Japan
vincristine) Berberidaceae etoposide VP-16)
MRD 10 12 PCR 10 10 10 8 10 6 10 4 10 2 ( CR) ( CR)
AML Study n Ind Consol % 3 5yr CALGB 474 DA/HiDACx3 or HiDACx1, E, CTX or diaziquone, M 72 34 GAMLCG 535 TAD, HAM/TAD 74 39 HOVON 253 DA, AMSA A/ME 77 38 ALFA 345 DA MA AMSA A; MEC 82 38 ALLG 298 ICE ICE or IcEx2 80 47 JALSG 1,057 IA or DA MA, DA, ACR-A, A-triple-V or HiDACx3 78 48
2 1. 2.
/ P P PI3K/Akt
Mylotarg (gemtuzumab ozogamicin) gemtuzumab ozogamicin internalization CD33 calicheamicin DNA
ATP BCR-ABL 9 9 BCR-ABL (q+) 1 2 3 1 5 6 7 8 9 10 11 12 22 Ph (22q-) 13 14 15 16 17 18 Effector 19 20 21 22 X Y abl bcr Effector bcr-abl
CML Imatinib IRIS Study % 100 8 80 60 CML 8 93 8 40 20 12 24 36 48 60 72 84 96 108 1126 ASH 2009
Affinity of Three TKIs to Abl Imatinib Nilotinib Dasatinib 1 30 325
III AP24534 II Dasatinib Nilotinib AP24534 325 30 400 500 SRC ABL1 ABL1 SRC ABL1 VEGF T315I T315I E255V E255K V V299L F317L E255K V Y253F H Q252H F359V T315I E255V
AML Farnesyl tranferase FLT3 P CD33 Tipifarnib PKC412 CEP-701 Bortezomib Decitabine Azacytidine Clofarabine Cloretazine Bcl-2 Oblimeresen sodium Zosuquidar GO
P15 P21 P15 P21 MAP P15 P210 AKT0 P15 P21 MAP MAP MAP C-KIT RAS ERK ERK PKC ERK IL ERK STAT BCR-ABL
( Ph + ALL N=28 100 (3 100 (3 + (N=25 Probability (%) 80 60 40 20 78.1 11.6% 38.7 8.8% 80 60 40 20 78.1 11.6% 38.7 8.8% Including one CR after Salvage Tx + Imatinib P <.001 12 24 36 48 60 72 P <.001 12 24 36 48 60 72 Blood 2005; 105: 3449-3457
2009 600 400 200 0 200 400 JMDP) 600 Nations
/ 100 100 80 80 Probability % 60 40 76.2% 37.2% 60 40 85.5% 57.5% 46.7% 17.5% 20 14.1% 20 10.2% 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 BBMT 14: 651-657, 2008, BMT 39; 217-221, 2007
AML LFS OS % 100 % 100 Leukemia-free survival 75 50 25 Transplant group No transplant group Overall survival 75 50 25 Transplant group No transplant group P=0.0002 P=0.0003 21 42 63 84 21 42 63 84 Leukemia 23: 194-196, 2009
Painting its brighter future
GVHD
UVAR XTS TM or CELLEX TM Photopheresis Systems
Extracorporeal Photopheresis (ECP)
A Multicenter Prospective Phase 2 Randomized Study of Extracorporeal Photopheresis for Treatment of Chronic Graft-Versus-Host Disease Median % Change in Steroid Dose 50 0 50 75 By 12W 50% reduction of PSL is achieved in 20.8% ECP group vs 6.4% Control p <0.04 ECP Control Probability of a Response 1.0 0.8 0.6 0.4 0.2 / p <0.0001 ECP Control W2 W4 W6 W8 W10 W12 Study Week 3 6 9 12 Study Week Blood 2008; 112: 2667-2674
ECP Complete and Partial Response Rate % 70 60 50 40 30 20 10 27% 65% 12 50% 43% 36% 27% 12% 7% Complete and Partial Response Rate % 70 60 50 40 30 20 10 43% 70% 24 50% 50% 47% 42% 29% 26% Original Randomized Non-ECP Cross-over Open-Label ECP Study Original Randomized ECP Crossover Open-Label ECP Study
Nitch
G-CSF CXCR4 CD44 HA SDF- VLA-4 VCAM-1 c-kit KL MMP9 NE+ CG Plerixafor (AMD3100)
AMD3100 Washington University School of Medicine MD Anderson Cancer Center Dana Farber Cancer Institute Washington University School of Medicine Multicenter Multicenter Phase II. HLA plerixafor Phase I/II. plerixafor Phase I/II. AML MEC plerixafor Phase I/II. CLL plerixafor Phase I. plerixafor
Shh AMD3100 AMD3465 SDF-1 VEGF C CXCR4 FLT4 Notch Cell cycling p27 Kip1 PI3K/Akt & MAPK signaling mtor S6 kinase Bcl-2 expression Sorafeni b Sorafenib FLT3 KIT KL CD44 CD62L VLA-4 Natalizuma b BIO5192 VCAM-1 Osteopontin Fibronectin Collagen Hyaluronin PSGL GMI-1070 Blood 2009; 113: 6045-6046
Thank you for your attention!!