1. Acute Myeloid Leukemia
Marcelo C. Pasquini, MD, MS
Associate Professor of Medicine
Adult BMT Program
Heme-Malignancies
Division of Hematology/Oncology

2. Acute Myeloid Leukemia Outline
Bone marrow as a blood forming organ
Biology of Acute Myeloid Leukemia
Treatment
Bone marrow Transplant

3. Bone Marrow: the source of blood production and the immune system
All blood cells arise from hematopoietic stem cells
Self renewing
Pluripotent
Blood production is highly regulated
Messages from the body (e.g. erythropoietin from kidney)
Microenvironments produce specific cells
Cytokines (SCF, IL3)
Growth factors (G-CSF)
Normal bone marrow

4. Hematopoiesis Scheme Lymphoid Compartment Stem Cell Compartment
Myeloid
Compartment

5. AML and Morphologic Differences

6. WHO AML
Classification

7. Prognostic factors in AML
Disease markers
Chromosomes
Genetic markers
Performance status
Age

8. Yearly incidence of AML per 100 000 inhabitants
Epidemiology  
Median age is 72 y
Peak incidence at y
      
At least 70% of patients up to age 80 have a PS of 0-II     
Yearly incidence of AML per inhabitants according to age and sex in Sweden 1997 to 2006, in the SEER registry (whites, ),24 and in the United Kingdom.25 United Kingdom data were given for 20-year age intervals (20-39, 40-59, 60-79, and 80+ years).
Yearly incidence of AML per inhabitants
Juliusson G et al. Blood 2009;113:
Juliusson G et al. Blood 2012;119:

9. Prognosis in AML-Age
Juliusson G et al. Blood 2009;113:

10. Life Expectancy Average life expectancy for: Newborn ~ 76 years
50 year old ~ 30 years (80)
55 year old ~ 25 years (80)
60 year old ~ 22 years (82)
65 year old ~ 18 years (83)
70 year old ~ 14 years (84)
75 year old ~ 10 years (85)
80 year old ~ 8 years (88)

11. Southwest Oncology Group Leukemia Committee percentage of patients in cytogenetic risk groups by age category.
Southwest Oncology Group Leukemia Committee percentage of patients in cytogenetic risk groups by age category. The percentage includes only patients with a known cytogenetic risk group.
Appelbaum F R et al. Blood 2006;107:

15. 4 3
Region 2 2 1
Short arm 'p' 3
Region 1 2 1
Centromere 1 2
Region 1 3
Long arm 'q' 1
Region 2 2 1 2 3
Region 3 4

16. Normal Male Karyotype: 46, XY
Prior to cell division, all the genetic material within the nucleus is packaged in chromosomes. We can collect blood, stimulate the nucleated cells to divide in culture and use agents to block cell division at this particular stages.

17. 47, XY, +8

18. Report Sample

19. Florescence In Situ Hybridization
How about FISH?
Florescence In Situ Hybridization

20. Cytogenetic Evaluation
Std Cytog.
FISH
Cells analyzed 20
Cell cycle
Metaphase
Metaphase and Interphase
Abnormality specific No
Yes
Cell culture

22. Overall Survival by SWOG Cytogenetic Risk Status
Slovak et al, Blood 2000; 96:

24. Genetic markers in AML

25. Dohner H, Hematology 2007, p

26. Molecular Markers and Prognosis
New Good Guys
NPM1 mutation without FLT3 ITD
CEBPA mutation
New Bad Guys
FLT3 ITD
MLL PTD
KIT mutation (Associated with t(8;21) or inv(16))
Overexpression of BAALC
WT1 mutations
IDH1/2

27. Frequencies and Distribution of the NPM1, CEBPA, MLL, FLT3, and NRAS Mutations, According to Mutation Class
Figure 1. Frequencies and Distribution of the NPM1, CEBPA, MLL, FLT3, and NRAS Mutations, According to Mutation Class. Frequencies are given for the 438 patients in whom data on all genes were available. ITD denotes internal tandem duplication, PTD partial tandem duplication, and TKD mutation of the tyrosine kinase domain.
Schlenk R et al. N Engl J Med 2008;358:

28. Favorable Intermediate Unfavorable NPM1pos+FLT3ITDneg CEEBPA mut
t(8;21) + c-kit mutation
Intermediate
FLT3 ITD
Unfavorable

29. AML and Genetic Variation

30. AML Up-Front Treatment
Induction
“7+3”
Post-Remission Therapy CR
Allogeneic BMT
Consolidation
Chemotherapy
Autologous BMT
Diagnosis
CR: Complete Remission

31. First report of “7 + 3”
Cancer Chemotherapy reports Part 1 Vol. 57, No. 4, Nov/Dec 1973

32. Induction therapy
7 + 3
Azacitidine
Decitabine
Clofarabine

33. Hematopoietic Cell Transplant
Preparative or Conditioning
Regimen:
Radiation and or Chemotherapy
HSCT D D R R D R D RL D RL D
Recipient
Donor
Complete Chimera

34. Indications for Hematopoietic Stem Cell Transplants in the US, 2012
Number of Transplants

35. Trends in Allogeneic Transplants by Recipient Age*
* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma

36. 100 20 40 60 80
Probability, %
Years
p <
Early (n=7,607)
Intermediate (n=2,124)
Advanced (n=2,578) 1 2 6 4 5 3
s25
Survival after HLA-identical Sibling Donor Transplants for AML,
By Disease Status

37. Survival after Unrelated Donor Transplants for AML, 2002-2012
100 20 40 60 80
Probability, %
Years 1 2 6 4 5 3
Early (n=7,365)
Intermediate (n=4,172)
Advanced (n=4,095)
p <
By Disease Status

38. Conclusions AML is a heterogeneous disease
Understanding prognosis helps in planning therapy
Understanding better the biology is helping the development of new treatments.
Transplants for AML are less toxic and able to help a greater number of patients.