1. Case 1 82 y/o WF. MDS for one year ( ? cytogenetics). On EPO and Transfusion PRN.  transfusion dependence and  WBC PTA. WBC 115K, Hb 6.7, PLT 72K. Bone marrow revealed AML (M1). She refused chemotherapy. Hydoxyurea + supportive care. Last WBC 50K. She developed A.fib., CHF and pulmonary edema. She expired on day 10.

2. Case 2 73 y/o WM. MDS(RAEB) for 11 months and transformed into AML. WBC 0.9K, Hb 7, PLT 15K, ANC 0.1. He received full dose of Cytarabine + Idarubicine(7+3) +G-CSF. Day 14, marrow was hypocellular. He had profound pancytopenia, and developed pneumonia and sepsis. He was intubated and went into multi- organ failure. He died on day 21 post- induction.

3. Case 3 63 y/o health Asian female. Dx AML on 8/02 in Jakarta, Indonesia. She was treated with chlorambucil and hydroxyurea. She visited daughter in U.S. and developed fever. WBC 15.2K and blasts 11%. Hb 8.9, PLT 44K. Peripheral blood flowcytometry confirmed AML (M2). She received standard induction chemotherapy with Ara-C and idarubicin (7+3). The course was complicated by persistent fever, bacteremia, GI bleeding, ileus, CHF, pulmonary edema, pneumonia, A.Fib, V-tach. She received granulocyte transfusion for 3 weeks and TPN for one week. The 14 day marrow showed no leukemia. Her WBC started to recover on day 25 post-induction. She stayed in hospital for a total 35 days.

4. Management of AML in Elderly Minxiang Gu, MD November 1,2002

5. Acute Myeloid Leukemia Incidence: increases with age - All age: 2.3/100,000 - Age  60: 13.7/100,000 - Median age: 65-70 years old

7. Outcome of the treatment in elderly AML Age< 60  60 CR 70 %45-55 % MS11 months6-9 months 5 year survival35-40 %5-8 %

8. Response Rate and Mortality of Induction Chemotherapy Hiddemann, W et al, JCO 17(11) 1999 49% 34% 64% 15%

9. Why are Elderly AML doing poorly?

10. Major Prognostic Factors in AML For response: –Cytogenetics /molecular genetics –WBC count –MDR phenotype –Secondary AML –Age For relapse: –Cytogenetics /molecular genetics –Time towards completed response –WBC count –flt-3 mutations –Autonomous proliferation –Secondary AML –Age

11. Karyotype and the Prognosis

12. Elderly AML have higher incidences of unfavorable chromosomal abnormalities and lower incidences of favorable chromosomal abnormalities 60 years No. of Patients % No. of Patients % Favorable10817104 Intermediate4276517563 Unfavorable123189433 Frequency of Karyotypes and Age : Hiddemann, W et al, JCO 17(11) 1999

13. Elderly AML has high prevalence of MDR expression MDR (multidrug resistance gene) MDR1: P-glycoprotein, 170 kDa, chromosome 7 ATP-dependent transport protein Binds to a variety of substrates (anthracycline, epipodophylotixin) Reversal agents: calcium channel blocker (verapamile), Cyclosporine A, Quinidine, PSC 833. Expressed in 70% of AML patients > 60 and only 37% in patients <60. Correlated to lower CR, short remission duration and poor survival.

14. Elderly AML and Secondary AML Higher incidence of secondary AML in elderly. The de novo AML in elderly is cytogeneticly similar to secondary AML.

15. The similarity between advanced MDS and elderly AML CytogeneticsMDSElderly AML Normal karyotypes31% 27% Single abnormality14% 13% Double abnormality17% 14% Complex karyotypes37% 46% Abnormal 520% 31% Abnormal 727% 27% Rossi G, et al.; Leukemia 14, 2000

16. Biological characteristics distinguishing secondary AML (t-AML and AML in the elderly) from true de novo AML t-AML/t-MDS Elderly ‘de novo’ AMLTrue ‘de novo’ AML Age Typical cytogenetic abnormality Multilineage dysplasia/dys poiesis Multi drug resistant phenotype (MDR1) Common in elderly Elderly common in younger -5/del(5q), inv(3) t(3:21), -7/del(7q), 17/I 17q, complex, -20q, t(11q23), +8, +13. +8, -5/del(5q), -7, del(7q), Complex t(15:17), t(8:21), inv(16). Complex >55 years 79% >55 years, 64% Uncommon High frequency; > 70% High frequency; >70% Low frequency; MDR1 usually absent in t(15:17), inv(16) and t(8:21) Dann.E J, et al Best Practice & Research Clinical Haematology, 14(1) 2001

17. Why are Elderly AML doing poorly? ( summary ) Higher incidence of unfavorable cytogenetics. Higher incidence of MDR expression. Increased prevalence of antecedent hematological disease. Limited proliferative capacity of hemapoietic stem cell. Comorbility and different metabolism cause high treatment related mortality.

18. Complete Remission Rate by Disease Status, Cytogenetic Status, and MDR1 Expression in Elderly AML (SWOG9031) Secondary AMLDe Novo AML Unfavorable intermed/favorable Unfavorable intermed/favorable Pts CRs %CR Pts CRs %CR MDR1 expression Bright/moderate positive (>0.15) Dim positive (0.10-0.14) Negative (<0.10) 15 2 139 1 11 17 4 24 40 19 48 2 0 0 3 1 33 6 3 50 16 10 63 2 0 0 7 4 57 2 0 0 27 22 81 Leith,C P. et al, JCO 89(9) 1997 - 211patients > 55, median age 68 years - Induction: 7+3 - MDR1 expression 71% in elderly - A important prognostic factor for likelihood of CR in induction chemotherapy

19. Should we treat elderly AML with intensive chemotherapy? - Supportive Care verses Anti-leukemia Chemotherapy

20. 60 AML Pts (age 65-82, median age 72, PS 0-4) ARM A (31)ARM B (29) Management 1-2 cycles of daunorubicin, vincristine and cytarabine. + one more cycle if achieve CR “wait and see” + cytoreductive agent (hydroxyurea +cytarabine) for leukocytosis related complication CR 58 % 0 % 2 Y survival 17%0 % Mean survival 21 weeks11 weeks Median % of days in H55%50% Löwenberg, B, et al. JCO 7(9) 1989 On the Value of Intensive Remission-Induction Chemotherapy in Elderly Patients of 65+ Years With Acute Myeloid Leukemia: A Randomized Phase III Study of the European Organization for Research and Treatment of Cancer Leukemia Group

21. What modification should be made to increase the response rate and reduce the treatment-related mortality

22. Remission induction Chemotherapy

23. Add New Agents and Change the Dose of Cytarabine Hiddemann, W et al, JCO 17(11) 1999 RBZ, rubidazone; 6-GT, thioguanine

24. Daunorubicin Dose and Treatment Response to the Induction Therapy(1) Hiddemann, W et al, JCO 17(11) 1999

25. Daunorubicin Dose and Treatment Response to Induction Therapy(2) DNR Dose No. of CR(%) ED(%) DFS at (mg/m2/course) Patient 5Y(%) < 901456 45 26 14 > 90877 54 25 26 Hiddemann, W et al, JCO 17(11) 1999

26. Remission Induction Chemotherapy (summary) Agents and Intensity: Add etoposide or 6-TG - not beneficial Increase or decrease the dose of cytarabine - not beneficial Reduce DNR dose: impact on CR rate and long- tern outcome Conclusion: As a population, favor intensive therapy (standard dose) to improve initial CR and long- tern survival.

27. Postremission Therapy

28. Intensive Postremission Chemotherapy in Adults with Acute Myeloid leukemia Likelihood of 4 Y survival: Age% <4038 40-6027 >60 9 Mayer et al, N Engl J Med 6:896, 1994 -1088 Pts 7+3 induction 693 in CR 596 Pts consolidation -Dose of Ara-C100mg/m 2, 400mg/m 2 or 3000mg/m 2 Q12 day 1, 3, 5.  Only 29% patients >60 finished 4 courses versus 62% of younger patients.

29. Cytarabine dose and patients age versus CR in 4 years AraC dose(mg/m 2 )CR in 4 years (%) 60 100 24  16 400 29  16 3000 44  16 Conclusion: Consolidation chemotherapy with HDAC (3g/m2) improves disease free and overall survival only in patient < 60 years of age.

30. Mitoxantrone Versus Daunorubicin in Induction-Consolidation Chemotherapy --- The Value of Low Dose Cytarabine for Maintenance of Remission, and an Assessment of Prognostic Factors in Acute Myeloid Leukemia Cooperative Group of the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato- Oncology Cooperative Hovon Group Randomized Phase III Study AML Lowenberg et al, JCO 16(3), 1998 489 Pts (median age 68) Induction Chemotherapy (DNR + AraC or MTZ + AraC) 147 CR Pts AraC 10 mg/m 2 SC Q12 Hr day 1-12, Q42 days interval x 8 cycles or disease relapse. No further treatment 5Y DFS 13% 7 %P = 0.006 OAS 18% 15%P = 0.29

31. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine 205 Pts in CR(  60) 169 medically well AraC alone (100mg/m2/day, 5 days/month) X 4 ID AraC (500 mg/m2/12 hr) + mitoxantrone(5mg/m2/12hr) X 6 7.7 Y follow up AraCAraC + mitoxantrone Relapse 77% 82% Median DFS 11 M 10 M Median Survival 20 M 16 M Richard et al, Blood 98(3),2001

32. Conclusion No standard consolidation regimen for elderly AML. May benefit from standard dose or lower dose Ara-C therapy.

33. Salvage Therapy for Relapsed or Persistent AML in Elderly

34. Aggressive Salvage Treatment is not Appropriate for the Majority of Elderly Patients with Acute Myeloid Leukemia Relapsing from First Complete Remission 150 patients with relapsed AML after CR1, median age 66 (61-79). Treatment group (99): HDAC or FLAG (fludarabine+AraC+G- CSF) or IDAC +idarubicin/or mitoxantrone. Control group(51): No treatment. Best supportive care + Hydrea for leukocytosis. Outcome: Ferrara F et al, Blood 2000, 96: 324a

35. WBC, cytogenetics and age > or < 70 had no inference on SFR. BSC group required less hospitalization(p=.003), less transfusion (p=.004 and.006) and less antibiotics(p=.001). Conclusion: –Aggressive salvage chemotherapy results in a true survival benefit only for a minority of elderly AML( CR1>12M). The remaining ones should be managed with BSC or allocated into experimental trial. Ferrara F et al, Blood 2000, 96: 324a

36. Efficacy and Safety of Gemtuzumab Ozogamicia (Mylotarg) in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse Humanized Anti-CD 33 antibody conjugated with calicheamicin. 142 patients median age 61. Dose: 9 mg/m2 IV over 2 hours, Q 14 days for 2 doses. Outcome: –CR= 23%;CRp = 19%;OR = 42% –RFS of CR+CRp = 6.8 months –Median survival: CR=12.6 M; CRp=11.1M; NR=2.9M; Average = 5.9M. Sievers,EL et al, JCO 19(13) 2001

37. Treatment-Emergent Adverse Events (Grade 3 and 4) Infusion related: –Chill 11% –Fever7% –Hypotension 4% –1 st dose 34%; 2 nd dose 12 % Treatment related: –Sepsis16% –fever15% –Chill13% –N/V11% –Dyspnea9% –Hypertension 9% –Hypotension 7% –Pneumonia 7% –Hyperbilirubinemia 33% –Elevated ALT and ALT 17% –Mucositis 4% –Myelosuppression Neutropenia 93 % Thrombocytopenia 99% Bleeding 15% –Epistaxis: 3% –ICH:4%

38. The Role of Hematopoietic Growth Factors

39. A Controlled Study of Recombinant Human Granulocyte Colony-stimulating Factor in Elderly Patients after Treatment for Acute Myelogenous Leukemia Dombret. H et al, N Eng J Med 332(25) 1995 1 8 28 7+3 induction Lenograstin(5ug/kg/day) or Placebo Neutrophil recover Treatment failure Max 28 days Days - 173 AML Pts, age  65 - Main end point: 8 weeks

40. G-CSF given after the induction chemotherapy for AML patients  65 year old: Did not decrease the mortality rate at 8 weeks. Did not improve the overall survival. Did not cause persistent or early relapse of disease Did shorten the duration of neutropenia. Did improve CR.

41. Granulocyte-Macrophage Colony-stimulating Factor after Initial Chemotherapy for Elderly Patients with Primary Acute Myelogenous Leukemia GM-CSF given after the induction chemotherapy for AML patients  60 year old: Did not decrease the severe myelosuppression Did not stimulate re-growth of leukemia Did not improve CR Stone, RM et al N Eng J Med 332(25), 1995 -388 Pts,  60, median age 69

42. Summary Elderly AML represent a discrete population in terms of the biology of the disease, prognosis and treatment- related complications. It should be managed differently from the younger age population. The cytogenetics, MDR expression, secondary AML, performance status and comorbility play important roles in the clinical decision making. If there is no contraindication, the standard induction chemotherapy is favored to achieve better CR rate and long-term survival.

43. Hematopoietic growth factors can be used safely to shorten the duration of critical neutropenia, but not improve CR rate and overall survival. The standard regimen for postremission therapy has not been established. Standard or low dose of Ara-C can be considered. Aggressive chemotherapy in relapsed AML only show survival benefit in small group of patients. Mylotarg shows benefit in this setting.

44. Diagnosis Unfavarable biology (Cytogenetics, MDR, 2 nd AML) Yes No Contraindication against intensive(standard) therapy YesNo Supportive care only New approaches Intensive (standard) therapy Hiddemann, W et al, JCO 17(11) 1999 Decision making in Elder AML

45. Future Reversal of drug resistance: PSC833(a cyclosporine analogue). Non-myeloablation SCT Post-translational protein modulator: –Farnesyl transferase inhibitor –Histone deacetylase inhibitor