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 Remission-Induction Post-remission Refractory CRCure Relapse Death

9. Treatment of AML Remission-Induction Post-remission Refractory CRCure Relapse Death 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. < 5% Marrow Blasts in Normocellular Marrow Normal Peripheral Blood Counts No Extramedullary Disease Complete Remission Minimal Residual Disease (MRD) Post-remission Treatment Cure Relapse ~10 9 cells Pre-treatment ~10 12 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  -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. Induction Chemotherapy CR Allotransplant Observation ? Maintenance Consolidation Chemotherapy x 2

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

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. Blood, 2003 v102, 1232-1240 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

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 years26-35 years36-45 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. 46 % Normal, +8, +6, -Y, del(12p) Intermediate Indeterminate Standard

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

44. 15-25 years26-35 years36-45 years 1.Age …alloBMT cut-off 35-40 years? Suciu, S. et al. Blood 2003;102:1232-1240

45. 2. Presence of specific mutations

46. 2.iFLT3 mutations i. FLT3/ITD - “internal tandem duplication” in JM domain - activating - associated with high LKC - ~20-25% ii. FLT3/TKD - activating point mutation - second tyrosine kinase domain of FLT3 - ~7-10% iii. FLT3-JM-PM - activating point mutation in JM domain - ~2%

47. pp 1752-1759

48. 316899Unknown.51741923abn(3q).01722830-7.020016 -5.0050019 del(5q).00003214344Complex 867379Adverse.71721012+22.728215374+8.0050018 11q23.11021820del(7q).00013496185281Normal 30132302434Intermediate.003733942inv(16).0004966167t(8;21).002374984133t(15;17) 2458184242Favourable P%FLT3/ITD+FLT3/ITD+FLT3/ITD-TotalCytogenetics Suciu, S. et al. Blood 2003;102:1232-1240

49. 316899Unknown.51741923abn(3q).01722830-7.020016 -5.0050019 del(5q).00003214344Complex 867379Adverse.71721012+22.728215374+8.0050018 11q23.11021820del(7q).00013496185281Normal 30132302434Intermediate.003733942inv(16).0004966167t(8;21).002374984133t(15;17) 2458184242Favourable P%FLT3/ITD+FLT3/ITD+FLT3/ITD-TotalCytogenetics Suciu, S. et al. Blood 2003;102:1232-1240

50. <.00132%44%41%OS <.00123%39%35%EFS <.00130%46%42%DFS <.00164%44%49%RR Outcome at 5 y.411%9%10%RD.0411%7%8%ID.0578%84%82%CR 227627854No. of patients PFLT3/ITD+FLT3/ITD-Total Kottaridis, P. D. et al. Blood 2001;98:1752-1759

53. Should FLT3/ITD status define alloBMT?

54. 2.ii.MLL partial tandem duplications - partial internal tandem duplication usually involving exons 2-6 or 2-8 - ~10 of AML with normal cytogenetics - ~ 90% of AML with +(11)

56. No difference in presentation features No difference in CR rate

57. Remission duration PTD-positive (n = 16) vs. PTD-negative (n = 158) AML with normal cytogenetics Dohner, K. et al. J Clin Oncol; 20:3254-3261 2002

58. Overall survival PTD-positive (n = 18) vs. PTD-negative (n = 203) AML with normal cytogenetics Dohner, K. et al. J Clin Oncol; 20:3254-3261 2002

59. 2.iii.Nucleophosmin mutations - ~50-60% normal cytogenetics

60. pp 3733-3739

61. Kaplan-Meier analysis of AML with normal karyotype bearing mutated or WT NPM1 Schnittger, S. et al. Blood 2005;106:3733-3739

62. 2.iv.other CEBP  -  ~ 15-20% of normal cytogenetics - confers favourable prognosis RAS - ~ 10% of normal cytogenetics - neutral KIT - ~ 1% - unknown

63. 3. Overexpression of specific genes

64. 3.i.ERG (ETS - Related Gene) - overexpression ~25% normal cytogenetics

66. 4.other CEBP  -  ~ 15-20% of normal cytogenetics - confers favourable prognosis RAS - ~ 10% of normal cytogenetics - neutral KIT - ~ 1% - unknown

67. 4.other CEBP  -  ~ 15-20% of normal cytogenetics - confers favourable prognosis RAS - ~ 10% of normal cytogenetics - neutral KIT - ~ 1% - unknown

68. Outcome of patients grouped by ETS-related gene (ERG) expression into quartile 4 (Q4), the uppermost quartile, and quartiles 1 to 3 (Q1-3), the lower quartiles Marcucci, G. et al. J Clin Oncol; 23:9234-9242 2005

69. 3.ii.BAALC (Brain And Acute Leukemia, Cytoplasmic)

71. Figure 2. Kaplan-Meier analysis of OS, EFS, and DFS for de novo AML patients with normal cytogenetics

72. Combinatorial analysis?

73. Distribution of additional mutations in the NPM1-mutated group Schnittger, S. et al. Blood 2005;106:3733-3739

74. Mrozek, K. et al. Blood 2007;109:431-448

75. Kaplan-Meier analysis of AML with normal karyotype and different NPM1 and FLT3-ITD status NPM- FLT3/ITD- NPM+ FLT3/ITD- NPM- FLT3/ITD+ NPM+ FLT3/ITD+ Schnittger, S. et al. Blood 2005;106:3733-3739

76. Kaplan-Meier analysis of AML with normal karyotype and different NPM1 and FLT3-TKD status NPM- FLT3/TKD- NPM+ FLT3/TKD- NPM- FLT3/TKD+ NPM+ FLT3/TKD+ Schnittger, S. et al. Blood 2005;106:3733-3739

77. Mrozek, K. et al. Blood 2007;109:431-448

78. Induction Chemotherapy CR Allotransplant Observation Consolidation Chemotherapy x 2(3) ? Maintenance Chemo

79. 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

80. Monitoring MRD Stratification parameter Detection of impending relapse Multiparameter flow cytometry Detect low frequency aberrant immunophenotype Quantitative PCR Detect translocation-specific transcripts t(15;17) inv(16) t(8;21) Detect expression of leukemia associated genes WT1 EVI1 usually expressed as log reduction from diagnosis

81. Induction Chemotherapy CR Allotransplant Observation ? Maintenance Chemo Consolidation Chemotherapy x 2(3)

82. Maintenance Chemotherapy ? No accepted role in NA in non-M3 AML (but of key importance in APL and ALL)

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

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

85. APL While all of the “general principles” apply, APL has several unique features - most curable AML - most progress in outcome in last 15 years of all AMLs

86. DNR + ATRA DNR Tallman, M. et al., (2002) Blood,100:4298-4302 North American Intergroup Overall Survival

87. APL - most “deadly” up front due to life-threatening coagulopathy hemorrhage thrombosis retinoic acid syndrome

88. APL - 10 - 15% of adult AML - median age ~ 40 years - no increase in incidence with age - increased incidence among Hispanics, Philipinos

89. APL Prognostic factors - t(15;17) confers good prognosis - presence of additional cytogenetic abnormalities does not alter this risk - simultaneous presence of “bad risk” or complex abnormalities do not confer bad risk in the presence of t(15;17) - RAR  fusion partner PZLF-RAR  confers poor drugresponse - WBC count >10 bil/L (likely have FLT3/ITD mutation) - Platelet count <40 bil/L - CD56 +ve

90. Treatment - unique sensitivity to all-trans retinoic acid (ATRA) and arsenic trioxide - LKC < 10,000: start ATRA day 0 and daunorubicin day 5 - LKC > 10,000: start ATRA and daunorubicin simultaneously

91. Treatment - typically no role for alloBMT - maintenance: LKC < 10 bil/L, ATRA x 1 – 2 years LKC > 10 bil/L, ATRA + 6-mercaptopurine + methotrexate x 2 years - only AML in which autoBMT in CR2 as good as alloBMT

92. Treatment MRD assessment - following induction, usually PCR +ve - following final consolidation, >95% PCR -ve (PCR +vity at this point very bad) - following completion of consolidation chemo, MRD assessment every 3 months for 2-3 years - if -ve PCR becomes +ve, chance of overt relapse within 1 year > 95%

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

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

95. ALL While all of the “general principles” apply, ALL has several unique features Adverse prognostic factors: Age > 35 years > 4 weeks to CR LKC > 30 bil/L (B lineage) LKC > 100 bil/L (T lineage) CytogeneticsPh+ t(9;22) (30 % adults) translocations involving MLL, myc hypodiploidy (mostly pediatric)

96. ALL Distinct biology lymphadenopathy, splenomegaly much more likely mediastinal mass common CNS disease much more common

97. ALL Treatment of adult ALL is much more complicated than that of AML: - more drugsdoxorubicin cytarabine methotrexate vincristine/vinblastine L-asparaginase corticosteroids 6-mercaptopurine - prophylactic CNS treatment intrathecal chemo + XRT - treatment lasts several years in 3 week cycles of alternating drugs, and with periodic CNS treatment, and periodic dose intensification

98. ALL In adults, alloBMT currently restricted to Ph+ cases and to those with 11q23 abnormalities

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