5 表一診斷試驗檢查結果 ( ) ( ) LDH t (9,22) BCR-ABL (qrt-pcr) t (9,22) (FISH) 伍疾病分期 2 圖一慢性骨髓性白血病的致病機轉 4 肆診斷 (fluorescence in situ hybridization, FISH) (rever

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1 繼續教育慢性骨髓性白血病藥物治療的進展吳雅惠 1 1,2 李建瑩中山醫學大學附設醫院藥劑科 1 2 中山醫學大學醫學系助理教授摘要 9 22 BCR-ABL (breakpoint cluster region-abelson) Imatinib imatinib BCR-ABL chronic myeloid leukemia BCR-ABL fusion gene tyrosine kinase inhibitor 臨床藥物治療學壹前言 (chronic myeloid leukemia, CML) 1960 Rudkin (Philadelphia chromosome) 80% 貳病因 9 74 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.3 Sep t (9:22) (q34; q11)9 ABL (abelson) 22 BCR (breakpoint cluster region) BCR-ABL (tyrosine kinase) ( ) 1,2 參發生率 15-20% ( ) 53 3

2 5 表一診斷試驗檢查結果 ( ) ( ) LDH t (9,22) BCR-ABL (qrt-pcr) t (9,22) (FISH) 伍疾病分期 2 圖一慢性骨髓性白血病的致病機轉 4 肆診斷 (fluorescence in situ hybridization, FISH) (reverse transcription polymerase chain reaction, RT- PCR) BCR-ABL ( ) 臨床藥物治療學 32 3 ( ) 6 (chronic phase) (accelerated phase) (blast crisis) MD Anderson Cancer Center 30%85% imatinib 表二依照世界衛生組織定義慢性骨髓性白血 6 病分期標準慢性骨髓性白血病分期世界衛生組織定義 10% /10-19% 20% Sep 藥學雜誌

3 繼續教育慢性骨髓性世界衛生組織定義白血病分期 ( 100,000/ L) ( 1,000,000/ L) (cytogenetic evolution) / 20% 陸治療反應與病情監測 ( ) 7,8 (Complete Hematologic Response, CHR) (Cytogenetic response) FISH (Molecular response) PCR BCR-ABL (European LeukemiaNet) ( ) 6 臨床藥物治療學7,8 表三慢性骨髓性白血病疾病緩解的定義與檢驗的時機點緩解定義檢查時間 (CHR) < 450,000/ L 15 CHR < 10,000/ L 3 < 5% 細胞遺傳學反應 3,6,12 > 95% CCyR 12 MMR 66-95% 36-65% (PCyR) 1-35% (CCyR) (PCR) 分子學反應 (PCR) MMR (BCR- (MMR) (IS) BCR-ABL ABL < 0.1%) 3-6 < 0.1% MR 4.0 BCR-ABL < 0.01% (IS) BCR-ABL MR 4.5 < % PCR BCR-ABL Sanger sequencing (Fluorescence IN Situ Hybridization,FISH)- 76 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.3 Sep

4 藥學雜誌一酪胺酸激酶抑制劑 (Tyrosine kinase inhibitors, TKIs) 2001 imatinib BCR-ABL tyrosine kinase ATP BCR-ABL imatinib 2006 nilotinib dasatinib ( 一 )Imatinib (Glivec) 6 圖二定義慢性骨髓性白血病治療反應等級柒藥物治療 MD Anderson Cancer Center , % hydroxyurea interferon imatinib 9 捌藥物個論臨床藥物治療學 mg 600 mg 800 mg (400 mg ) CYP3A4 imatinib CYP3A4 50% CYP3A4 2C6 2C19 warfarin D TKIs (leukapheresis) hydroxyurea 10 CML -interferon ( 二 )Nilotinib (Tasigna) imatinib 20 ABL V299L F317L CML 300 mg imatinib CML 400 mg Sep

5 繼續教育臨床藥物治療學 (20-30%) (10-15%) (10-15%) QT QT nilotinib ( mg ) imatinib (400 mg ) nilotinib CCyR (78-80% vs.65%) MMR (43-44% vs. 22%) 12 (< 1% vs.11%) 11 ( 三 )Dasatinib (Sprycel) SRC ABL imatinib 325 T3151 ABL Y253H, E255K/V, F359C/V 100 mg 140 mg 140 mg 180 mg (50%) (9%) (4%) (6%) (3%) dasatinib 100 mg imatinib 400 mg dasatinib 12 CCyR (83% vs.72%) MMR (46% vs. 28%) 12 ( 四 )Ponatinib (Iclusig) FDA TKIs T3151 FDA TKIs 45 mg 78 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.3 Sep CYP3A4/5 CYP3A4 30 mg ( 五 )Bosutinib (Bosulif) Src/Abl BCR-ABL imatinib c-kit and PDGFR (platelet derived growth factor receptor) FDA TKIs 500 mg mg 288 imatinib Bosutinib 24 86% 41%2 92% 13 (8%) (9%) (5-10%) 二蛋白質合成抑制劑 (Protein Synthesis Inhibitor)-Omacetaxine mepesuccinate (Synribo) 2012 FDA (ribosome) A- BCR-ABL1 BCR-ABL T

6 藥學雜誌 mg/m mg/m (58%) (36%) (44%) (32%) (26%) (21%) 三異體造血幹細胞移植 (Human leukocyte antigen, HLA) 12 imatinib 臨床藥物治療TKIs 學 (International Bone Marrow Transplant Registry, IBMTR) 6, % % 玖結論 imatinib imatinib nilotinib dasatinib BCR-ABL RT-PCR 32 3 Sep The New Evolution of Therapeutic Drug for Chronic Myeloid Leukemia Ya-Hui Wu 1, Chien-Ying Lee 1,2 Department of Pharmacy, Chung Shan Medical University Hospital 1 Department of Medicine, Chung Shan Medical University 2 Abstract Most patients with chronic myeloid leukemia carry a genetic abnormality referred to known as the Philadelphia chromosome, resulting of a reciprocal translocation between chromosomes 9 and 22, fusion gene that encodes a constitutively active BCR-ABL tyrosine kinase protein. This situation causes the excess proliferation and split of myeloid cells. Tyrosine kinase inhibitors(tkis) are the initial treatment for patients with chronic myeloid leukemia (CML), it could significantly increase long-term survival and achieve molecular

7 臨床藥物治療學繼續教育 responses rapidly. Imatinib was the agent approved for the treatment of chronic myeloid leukemia. Some patients may acquire resistance or intolerance to imatinib. The timing of second-line TKIs treatment after failure of initial treatment may have a signiﬁcant impact on long-term outcome. Thus, second generation TKIs is an another choice and may attainment of better results. 參考資料 Jones D, Kamel-Reid S, Bahler D, et al: Laboratory prac- 4. resistance mutations in chronic myelogenous leukemia and material-for-patient-advocates/eln-cml-recommendations- acute lymphoblastic leukemia: a report of the Association summary-2013/470-treatment-recommendations-for- for Molecular Pathology. J Mol Diagn 2009;11:4-11. people-living-with-cml-traditional-chinese/ﬁle. Accessed Savage DG, Antman KH: Imatinib mesylate--a new oral September 3, targeted therapy in chronic myeloid leukemia: a popula- CA Cancer J Clin. 2006;56: tion-based study of patients diagnosed in Sweden from Boice JD Jr, Day NE, Anderson A, et al: Second cancers 1973 to J Clin Oncol 2011;29: Cancer Inst 1985;74(5): Baccarani M, Pileri S, Steegmann JL, et al: Chronic my- pregnancy outcome. Blood 2008;111: diagnosis, treatment and follow-up. Ann Oncol.2012;23( N Engl J Med 2010;362: Robert S Negrin, Charles A Schiffer: Overview of the 07, Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362: Cortes JE, Kantarjian HM, Brümmendorf TH, et al: Safety A patient-friendly summary of the European LeukemiaNet and efﬁcacy of bosutinib (SKI-606) in chronic phase Phil- recommendations (2013) for the management of Chronic adelphia chromosome positive chronic myeloid leukemia Myeloid Leukemia. Available patients with resistance or intolerance to imatinib. Blood net/education/eln-recommendations/391. Accessed: Sep- 2011; 118: tember 5, Saglio G, Kim DW, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. treatment of chronic myeloid leukemia. UpToDate : Aug 7. Pye SM, Cortes J, Ault P, et al: The effects of imatinib on eloid leukaemia: ESMO Clinical Practice Guidelines for Suppl 7): Björkholm M, Ohm L, Eloranta S, et al: Success story of Jemal A, Siegel R, Ward E, et al: Cancer statistics, following radiation treatment for cervical cancer.j Natl 5. 給與慢性骨髓性白血病一同生活的人的治療建議 targeted therapy. N Engl J Med.2002;346(9): tice guidelines for detecting and reporting BCR-ABL drug THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.3 Sep

Therapeutics of Clinical Drugs CML 4 肆臨床病程 CML ( ) 1. (chronic phase) 2. (accelerated phase) 3. (blast phase) 85% 10% 2 5~10% 2 20% 3-6 20% (acute

Therapeutics of Clinical Drugs 慢性骨髓性白血病中山醫學大學附設醫院藥劑科藥師陳玉美中山醫學大學藥理學科講師李建瑩蔡敏鈴摘要 90% 3-5 1. 2. 3. chronic myeloid leukemia Philadelphia chromosome tyrosine kinase

5 表一診斷試驗 檢查結果 ( ) ( ) LDH t (9,22) BCR-ABL (qrt-pcr) t (9,22) (FISH) 伍 疾病分期 2 圖一慢性骨髓性白血病的致病機轉 4 肆 診斷 (fluorescence in situ hybridization, FISH) (rever

5 表一診斷試驗檢查結果 ( ) ( ) LDH t (9,22) BCR-ABL (qrt-pcr) t (9,22) (FISH) 伍疾病分期 2 圖一慢性骨髓性白血病的致病機轉 4 肆診斷 (fluorescence in situ hybridization, FISH) (rever