1. Therapeutic Advances in Acute Myleoid Leukemia J Clin Oncol 29:487-494 (Volume 29. Number 5. February 10 2011) Samuel Aparicio, B.M., B.Ch., Ph.D., and Carlos Caldas, M.D. R3 변자민

2. INDEX I.Introduction II.Current Treatment Outcomes III.Treatment of Younger Patients IV.Treatment of Older Patients V.Need for Novel Drugs

3. Acute Myeloid Leukemia –Median age of presentation: late 60’s –Highly heterogenous “set of diseases” Morphology Cytochemistry of the leukemic population Immunophenotype Cytogenetics Molecular abnormalities 1)Essential for confirmation of subtype 2)Highly prognostic for outcomes of first line treatment 3)Navigate the direction of treatment after relapse 1)Additional prognostic information 2)Optimize existing treatments 3)Development of additional treatment INTRODUCTION

4. CURRENT TREATMENT OUTCOMES Patients ≤ 60 y.o 1-2 induction (70-80% CR) + consolidation → from diagnosis 40- 45% of the patients cured Older patients 40-65% achieve remission → 85% relapse within 2-3 years

5. TREATMENT OF YOUNGER PATIENTS I. Induction Therapy II. Postinduction Therapy III. Role of Transplantation IV. Molecular Genetic Implications for Diagnosis and Therapeutics V. Epigenetic Implications for Dx & Tx IV. Molecular Genetic Implications for Diagnosis and Therapeutics V. Epigenetic Implications for Dx & Tx

6. Anthracyline, usually daunorubucin -Dose equivalence between daunorubicin, mitoxantrone and idarubicin -Dose escalation of daunorubicin Cytarabine 7 days + Daunorubicin 3 days cytarabine Alternatives Third drug combination 1.Marrow blast < 5% & adequate recovery of peripheral counts 2.Failure to achieve peripheral counts recovery → poor px 3.Failure to achieve CR with 1 or 2 treatment courses → poor px

7. TREATMENT OF YOUNGER PATIENTS I. Induction Therapy II. Postinduction Therapy III. Role of Transplantation IV. Molecular Genetic Implications for Diagnosis and Therapeutics V. Epigenetic Implications for Dx & Tx Total of 4, including induction is sufficient! –High dose cytarabine: 3g/m 2 on days 1,3,5 –4 courses Amsacrine Etoposide Cytarabine → Mitoxantrone Cytarabine High Dose Cytarabine vs

8. TREATMENT OF YOUNGER PATIENTS I. Induction Therapy II. Postinduction Therapy III. Role of Transplantation IV. Molecular Genetic Implications for Diagnosis and Therapeutics V. Epigenetic Implications for Dx & Tx Standard: SCT from a well-matched sibling Low risk: delay SCT to second CR High risk: SCT is the best option Intermediate risk : controversial! –Risk of SCT depends on: age of the recipient & donor, CMV status, parity of female donor, degree of matching, comorbidities –Restrict to patients of 35 to 40 y.o –Matched sibling = Unrelated donor

9. TREATMENT OF YOUNGER PATIENTS I. Induction Therapy II. Postinduction Therapy III. Role of Transplantation IV. Molecular Genetic Implications for Diagnosis and Therapeutics V. Epigenetic Implications for Dx & Tx

10. 5-7% 2%: a/w monosomy 7, inv(3)(q21q26)/t(3,3)(q21;q26 ) 33% 10% ?

11. TREATMENT OF YOUNGER PATIENTS I. Induction Therapy II. Postinduction Therapy III. Role of Transplantation IV. Molecular Genetic Implications for Diagnosis and Therapeutics V. Epigenetic Implications for Dx & Tx Epigenetic mechanisms are important in the regulation of cellular process involved in cell growth and differentiation –DNA cytosine methylation: specific methylation a/w particular AML genotypes, such as t(8:21), t(15:17), mutations in C/EBPα, or high EVI1 –Candidates for demethylating therapies

12. TREATMENT OF OLDER PATIENTS Problems 1.High age itself 2.Reduced anthracycline sensitivity 3.More common unfavorable cytogenetics Prognostic factors for lower CR rates a)Increasing age b)Poor performance status c)Secondary leukemia d)Overexpression of P-glycoprotein e)Adverse cytogenetics f)Splenomegaly g)Extramedullary disease h)Monosomal karyotype

13. TREATMENT OF OLDER PATIENTS I. Remission Induction Treatment II. Postremission Treatment III. Nonfit Patients with AML Daunorubicin (45-50mg/m 2 ) for 3 days + Cytarabine (100-200mg/m 2 ) for 7-10 days –Mitoxantrone, etoposide, idarubicin (X) –Dose-response relationship for daunorubicin Up to 90mg/m 2 60-65 y.o: improvements in OS, CR rates, EFS High peak concentration > total dose

14. TREATMENT OF OLDER PATIENTS I. Remission Induction Treatment II. Postremission Treatment III. Nonfit Patients with AML No established postremission treatment –1) Low dose cytarabine vs. no maintenance / 2) 1 additional cycle of combination chemoTx for remission consolidation vs. 4 /3) 3 vs. 4 successive cycles of intensive chemoTx: no difference in OS –High dose cytarabine: too toxic –Reduced-intensity allogenic SCT: no prospective trials

15. TREATMENT OF OLDER PATIENTS I. Remission Induction Treatment II. Postremission Treatment III. Nonfit Patients with AML 1.Best supportive care << Low-dose cytarabine 2.Consider hypomethylation agents

16. NEED FOR NOVEL DRUGS