1. AML NCCN guidelines 2009 Presented by CR 謝燿宇

2. Introduction Treatment of AML: age, hx of prior MDS or cytotoxic therapy and performance status The most predictable factor for disease free survival: cytogenetic status 60 y/o: divergence point (Frederick R. et. al. Blood 2006 107: 3481-3485.)

4. P’ts < 60 y/o: induction Standard induction: < 60 y/o p’ts without antedecent hematologic disease Anthracycline [daunorubicin or idarubicin (more intracellular retension time)] + Cytarabine, no benefit of adding etoposide Dose intensive v.s. standard: more treatment related morbidity and mortality, but longer remission duration (SWOG, ALSG) Neurotoxicity and renal toxocity

5. SWOG study

11. CALGB study CALGB trial: 44% remission rate with SDCA + Daunorubicin plus high dose cytarabine consolidation High dose cytarabine induction: may be influenced by consolidation strategy, fewer high dose cytarabine consolidation or for early going auto-HSCT (category 2B)

12. Induction therapy 20-45% p’ts will not enter remission, which is strongly influenced by cytogenetics

13. EBMT trial in secondary AML or MDS 45% 34%

14. Post induction therapy

16. Evaluation: 7~10 days after completion of induction Both lymphoid and myeloid marker: may response to ALL therapy if failure to induction

18. Post remission therapy 3-4 courses of high dose consolidation: non-protocol standard for p’ts < 60 y/o and good or intermediate cytogenetic

19. CALGB trial Robert J. Mayer et. al., N Engl J Med 1995; 332:334-335, 44% 12% severe neurotoxicity and 5% treatment related mortality, 60% disease free survival in good risk; 30% in intermediate risk; 12% in poor risk

20. Post remission One or more cycles of high dose cytarabine followed by auto-HSCT or allo- HSCT? Consider: expected relapse rate, transplantation related morbidity and mortality, salvage option, features of disease at diagnosis, numbers of cycles of induction to achieve remission

21. Post remission therapy Good risk: no single preferred suggestion Treatment related mortality 8-10% Clara D. Bloomfield, et. al. CANCER RESEARCH 58. 4173-4179. CBF: t(8;21) inv(16), t(16;16), and del(16) 50-60%

22. Post remission therapy

23. EORTC/GIMEMA-AML10 BLOOD, 2003 VOLUME 102, 1232-1240 No significance

24. Post remission therapy Multiple cycles of dose intensive consolidation (category 1), one cycle of dose intensive consolidation followed by auto-HSCT (category 2B) CBF mutation with c-Kit mutation (20-30%): high risk for relapse (60-70% v.s. 30%), but no impact on remission rate, consider clinical trial

25. Post remission therapy Normal risk: transplant based (matched sibling or 1-2 cycles of dose intensive cytarabine followed by auto-HSCT), also multiple courses of high or intermediate dose of cytarabine Normal karyotype with isolated NPM1 mutation: good prognosis Normal karyotype with isolated FLT3-ITD mutation: poor prognosis

26. Post remission therapy

27. EORTC/GIMEMA-AML10 BLOOD, 2003 VOLUME 102, 1232-1240 No significance

28. CALGB study Farag SS, et. al. JCO 2005;23:482-193

30. Post remission therapy Poor risk: matched sibling or matched UR- HSCT, as well as clinical trial Auto-HSCT v.s. chemotherapy: comparable with 18% DFS

31. EORTC/GIMEMA-AML10 BLOOD, 2003 VOLUME 102, 1232-1240 Significance!

33. AML in elderly patient: induction therapy 60 y/o as divergence point P’ts > 75 y/o, 60-75 y/o with significant co- morbidites, PS >2: especially poor

34. Intensive Chemotherapy in AML and MDS, Kantarjian et al. CANCER 2006;106:1090-1098

35. British MRC AML14 trial (Burnett et al. CANCER 2007;109:1114-1124) low dose cytarabine: 30 days mortalities 26%

37. AML in elderly patient: induction therapy Pancytopenia with modest marrow infiltration (20-40%): may wait cytogenetic if clinically stable Remission rate: 25% in poor risk group with 25% mortality rate, highly suggest clinical trial; whereas 40~50% CR rate in normal karyotype (favor idarubicin) ALFA 9801 study, Blood, 2007;110:55a

38. Phase II Study of Decitabine for Front-line Treatment of Older Patients with AML Patients age > 60, no prior therapy for AML Primary endpoint: complete remission rate Treatment with decitabine 20 mg/m 2 iv x 5 days q4 weeks All patients will be treated with 2 cycles unless they have progression of peripheral blast count Patients with a complete or partial response after 2 cycles can get additional cycles until progression

39. Phase II Study of Decitabine for Front-line Treatment of Older Patients with AML Bone marrow collection at baseline, day 5 of cycle 1 and day 28 of cycle 2 for correlative studies  RNA profiling as part of the Genomics of AML project  DNA methylation profiling  Pilot proteomics study CR rate: 29% 3 of 10 poor risk patients also have CR Clofarabine: previously used in refractory pediatric ALL, proved to use in adult AML as well

41. Post induction therapy Evaluation: 7-10 days after completion of induction Full normalization of PB count often does not occurred in elderly patients due to previous antedecent myelodysplasia CRi: marrow blast < 5% with mild residual cytopenia

42. Post induction therapy ALFA 9803 trial v.s. CALGB trial: dose intensive cytarabine? Myeloablative HSCT: too risky RIC HSCT: still of interest

43. 28% v.s.17% in 2yrs DFS Ambulatory better than single dose intensive therapy ALFA 9803 trial, BLOOD, 2007;109:5129-5135

44. Elihu Estey et al. BLOOD, 2007;109:1395-1400

46. Post-remission surveillance and salvage Followed-up: CBC qM-q3M in the first two years after completion of consolidation then q3M-q6M for total 5 years BM study: only if abnormal CBC count noted or cytopenia Transplantation in first CR or first relapse

47. Post-remission surveillance and salvage Gemtuzumab ozogomicin: single agent use, 29% of p’ts with CD33+ expression obtained marrow clearance and transfusion dependence Fever, chills, hypotension during infusion, persistent thrombocytopenia without leukemia relapse, hepatotoxicity, increased VOD like syndrome if exposure within 3- 4months after HSCT

48. Auto-HSCT only in non-APL patient with no allogenic donor, no suggested in poor risk patient

49. CNS leukemia CNS leukemia: <3% involvement compared with ALL No routine LP surveillance Neurological symptoms on diagnosis: imaging for r/o mass effect, if negative, consider LP

50. May substitute high dose cytarabine for intrathecal Do not combine R/T with high dose cytarabine!

51. Supportive care G-CSF: 抽 BM 前七天要停 輸血：照光加減白！ High dose cytarabine: monitor renal function, correlated neurotoxiticy (nystagmus, ataxia, dysmetria), change all subsequent high dose to standard dose Retinoic acid syndrome: fever, fluid retension, WBC > 10000, treat with dexamethasone 10mg bid for 3-5 days taper within 2 weeks, may restart ATRA later Arsenic trioxide: QT prolong, EKG monitor, keep Ca ≧ 9.0, K ≧ 4.0, Mg ≧ 1.8