Acute Leukemia: Treatment Historical General Principles (AML) APL ALL Cases

1. Acute Leukemia: Treatment Historical General Principles (AML) APL ALL Cases

2. Acute Leukemia: Treatment Historical Prior to modern chemotherapy (1960s), average survival with acute leukemia ~ 2 months

3. General Principles Individualized and risk adapted Major supportive care component due to natural history of the disease and due to treatment toxicity Treatment with curative intent involves sequential remission Induction and post-remission phases

4. General Principles Individualized and risk adapted Individualized risk/benefit analysis. Since conventional leukemia treatment is associated with significant toxicity and mortality (10-40%), based on age, comorbidities, disease biology etc., not all patients should be treated aggressively.

5. General Principles Individualized and risk adapted Whereas even 10 years ago all patients treated aggressively were treated identically (overkill), due to a better molecular understanding of disease biology, and better prognostication (largely molecular and cytogenetic) the intensity of treatment (and hence the toxicity) is now tailored to the individual case).

6. General Principles • Major supportive care component • Protean signs and symptoms • Patients may present with or develop during treatment • life-threatening opportunistic infections (neutropenia) • septic shock, respiratory failure etc. • severe bleeding, often life threatening (thrombocytopenia +/- coagulopathy) • neurological symptoms (CNS infiltration or bleeding) • etc.

7. General Principles Treatment with curative intent involves sequential remission Induction and post-remission phases

8. Treatment of AML Death Death Remission-Induction Post-remission CR Cure Refractory Relapse

9. Treatment of AML Death Death Remission-Induction Post-remission CR Cure Refractory Relapse Chemotherapy x 2(3) Allotransplant Long-term follow-up (with assessment of minimal residual disease) Maintenance treatment? Chemotherapy x 1

10. Why Post-remission treatment?

11. CR: > 60-70% Long-Term Survival (>3 years): ~15%

12. > 50% of patients relapse

13. Cure Complete Remission Post-remission Treatment Pre-treatment Relapse ~1012 cells < 5% Marrow Blasts in Normocellular Marrow Normal Peripheral Blood Counts No Extramedullary Disease Minimal Residual Disease (MRD) ~109 cells

14. Treatment of AML Remission-Induction Prognostic factors (who gets treated?) Drugs

15. Remission-Induction Prognostic factors before therapy Age (>60 unfavourable; median 68) Secondary leukemia (unfavourable) Comorbidities (unfavourable) Cytogenetics Favourable Intermediate Poor risk Other elevated LDH presentation LKC Interrelated

16. Induction chemotherapy Supportive care Clinical trial No treatment

17. Drugs Cytosine Arabinoside, Cytarabine, Ara-C S-phase-specific cytotoxic antimetabolite Metabolized intracellularly into Ara-CTP DNA damage due to inhibition of a-DNA polymerase, inhibition of DNA repair, and incorporation into DNA. Anthracycline (Daunorubicin, Mitoxantrone, Idarubicin) DNA intercalation, inhibiting DNA synthesis and DNA- dependent RNA synthesis. Cytotoxic activity cell cycle phase non-specific, but maximal in S-phase.

18. Drugs Etoposide Cytotoxic topoisomerase II inhibitor, inhibiting DNA synthesis. Affects mainly the S and G2 phases

20. Remission?

23. Allotransplant Observation ? Maintenance Induction Chemotherapy Consolidation Chemotherapy x 2 CR

24. Prognostic factors after therapy Age (>60 unfavourable; median 68) Comorbidities Cytogenetics Favourable Intermediate Poor risk Other Time to CR Number of blasts on day 14-16 MRD

25. Prognostic factors after therapy Age (>60 unfavourable; median 68) Comorbidities Cytogenetics Favourable Intermediate Poor risk Other Time to CR Number of blasts on day 14-16 MRD

26. pp 4075-4083

27. Risk Status SWOG/ECOG % MRC AML 10 % Favourable Good inv(16)/t(16:16)/del (16q) t(15;17) +/- other aberrations; t(8:21) without del(9q) or complex karyotypes 20 inv(16)/t(16:16)/del (16q) t(15;17), t(8:21) +/- other aberrations 21 Intermediate Indeterminate Standard Normal, +8, +6, -Y, del(12p) 46 Normal, 11q23 abn, +8, del(9q), del(7q), +21, +22, all others 62 Unfavourable Poor del(5q)/-5, -7/del(7q), abn 3q abn 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22), complex karyotypes (>= 3 unrelated abn) 30 del(5q)/-5, -7, abn 3q abn 9q, 11q, 20q, 21q, 17p, complex karyotypes (>= 5 unrelated abn), t(6;9), t(9;22) 17

28. Proportions of different cytogenetic subtypes in each age group Bacher, U. et al. (2005) Haematologica 90: 1502-1510

29. 1: 21-30 years 2: 31-40 years 3: 41-50 years 4: 51-60 years 5: 61-70 years Bacher, U. et al. (2005) Haematologica 90: 1502-1510

30. Slovak, M. L. et al. Blood 2000;96:4075-4083

31. So who gets transplanted ? (Who gets observed?)

32. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial Stefan Suciu, Franco Mandelli, Theo de Witte, Robert Zittoun, Eugenio Gallo, Boris Labar, Gennaro De Rosa, Amine Belhabri, Rosario Giustolisi, Richard Delarue, Vincenzo Liso, Salvatore Mirto, Giuseppe Leone, Jean-Henri Bourhis, Giuseppe Fioritoni, Ulrich Jehn, Sergio Amadori, Paola Fazi, Anne Hagemeijer, and Roel Willemze, for the EORTC and GIMEMA Leukemia Groups Blood, 2003 v102, 1232-1240

33. Autologous BMT in CR1 identical to chemotherapy alone… Allogeneic BMT vs. Autologous BMT Allogeneic BMT vs. chemotherapy alone

34. DFS from CR according to donor availability Good Risk Suciu, S. et al. Blood 2003;102:1232-1240

35. Allo BMT? Good Risk… NO

36. DFS from CR according to donor availability Bad Risk Suciu, S. et al. Blood 2003;102:1232-1240

37. Allo BMT? Bad Risk… YES

38. DFS from CR according to donor availability Intermediate Risk Suciu, S. et al. Blood 2003;102:1232-1240

39. DFS from CR according to donor availability in 3 age groups 15-25 years 26-35 years 36-45 years Suciu, S. et al. Blood 2003;102:1232-1240

40. Allo BMT? Intermediate Risk… Maybe

41. How to further stratify intermediate risk group?

42. Intermediate Indeterminate Standard 46 % Normal, +8, +6, -Y, del(12p)

43. Intermediate Indeterminate Standard 46 % Normal, +8, +6, -Y, del(12p) ~1/3

44. 1. Age 15-25 years 26-35 years 36-45 years Suciu, S. et al. Blood 2003;102:1232-1240 …alloBMT cut-off 35-40 years?

45. 2.Presence of specific mutations

46. 2.i FLT3 mutations • i. FLT3/ITD • - “internal tandem duplication” in JM domain • - activating • - associated with high LKC • - ~20-25% • ii. FLT3/TKD • - activating point mutation • - second tyrosinekinase domain of FLT3 • - ~7-10% • iii. FLT3-JM-PM • - activating point mutation in JM domain • - ~2%

47. pp 1752-1759

48. Cytogenetics Total FLT3/ITD- FLT3/ITD+ %FLT3/ITD+ P Favourable 242 184 58 24 t(15;17) 133 84 49 37 .002 t(8;21) 67 61 6 9 .0004 inv(16) 42 39 3 7 .003 Intermediate 434 302 132 30 Normal 281 185 96 34 .0001 del(7q) 20 18 2 10 .1 11q23 18 18 0 0 .005 +8 74 53 21 28 .7 +22 12 10 2 17 .7 Adverse 79 73 6 8 Complex 44 43 1 2 .00003 del(5q) 19 19 0 0 .005 -5 16 16 0 0 .02 -7 30 28 2 7 .01 abn(3q) 23 19 4 17 .5 Unknown 99 68 31 Suciu, S. et al. Blood 2003;102:1232-1240

49. Cytogenetics Total FLT3/ITD- FLT3/ITD+ %FLT3/ITD+ P Favourable 242 184 58 24 t(15;17) 133 84 49 37 .002 t(8;21) 67 61 6 9 .0004 inv(16) 42 39 3 7 .003 Intermediate 434 302 132 30 Normal 281 185 96 34 .0001 del(7q) 20 18 2 10 .1 11q23 18 18 0 0 .005 +8 74 53 21 28 .7 +22 12 10 2 17 .7 Adverse 79 73 6 8 Complex 44 43 1 2 .00003 del(5q) 19 19 0 0 .005 -5 16 16 0 0 .02 -7 30 28 2 7 .01 abn(3q) 23 19 4 17 .5 Unknown 99 68 31 Suciu, S. et al. Blood 2003;102:1232-1240

50. Total FLT3/ITD- FLT3/ITD+ P No. of patients 854 627 227 CR 82% 84% 78% .05 ID 8% 7% 11% .04 RD 10% 9% 11% .4 Outcome at 5 y RR 49% 44% 64% <.001 DFS 42% 46% 30% <.001 EFS 35% 39% 23% <.001 OS 41% 44% 32% <.001 Kottaridis, P. D. et al. Blood 2001;98:1752-1759