1. ACUTE MYELOID LEUKEMIA Irit Avivi

2. What is an Acute Myeloid Leukemia ?
Accumulation of early myeloid progenitors (blast cells) in bone marrow and blood
Definition requests presence of 20% or more blasts in BM
Normally- less than 5%

4. AML Aggressive disease with an acute onset Can occur De Novo or
following a known leukomogemic trigger (radiation, chemotherapy, diseases):
Secondary AML

5. Malignant Transformation Proliferation and Accumulation
Leukemia
Malignant Transformation
Proliferation and Accumulation
Peripheral blood Blasts in BM
Visceral organs Cytopenias

6. Bone Marrow - Normal (low power)

7. BM - Acute Leukemia (low power)

8. BM - Normal (high power)

9. Bone Marrow - acute leukemia (high power)

10. Inhibition/Enhancements of regulatory genes
Myeloid
Stem Cell
Pathophysiology
Radiation chromosomal damage
Chemotherapy
Viruses
t(8;21),M2
t(15;17) M3
Inv 16;M4e
Protooncogen
Inhibition/Enhancements of regulatory genes
Inhibition of
suppressor genes
Inhibition
of apoptosis
Enhancements
of proliferation

11. Epidemiology

12. Predisposing factors Environmental Benzen, herbicies
Chemotherapy :AK ; NU;PRC
Radiation
Acquired diseases Meyloproliferative(CML;PV..)
Aplastic anemia
Genetic Congenital abnormality
to repair DNA :
Down syndrome
Ashkenazi Jews >> orientals
Relatives(1st degree x3)

13. Clinical symptoms of Acute Leukemia
Bone marrow expansion Bone pain
Bone marrow failure Leucopoenia infections
Thrombopenia bleeding
Anemia
Leucostasis >50,000 blasts
Dispnea,
CNS

14. Clinical symptoms Extramedullary (Chloroma) Skin , CNS Gingiva Kidney

15. Extramedullary: Gingival hypertrophy

16. Clinical symptoms DIC Bleeding Thrombosis
Metabolic Hyperuricemia Tumor lyses syndrome K
Lactic Acid

17. Diagnosis >20% blasts in bone marrow/peripheral blood)
Normal bone marrow
AML ;blasts B M

18. Acute leukemia - AUER Rods ( FAB;AML M3 )
Aggregation
of granules

19. Acute Lymphoblastic Leukemia

20. Acute promyelocytic leukemia - AML M3

21. Myeloblasts - AML
Auer rod

22. AML M2 blasts

23. French American British (FAB) classification
-Based on morphology and staining (cytochemistry)
-Divides patients into 7 AML subtypes
-A morphological rather than biological classification
-Correlation between morphological and biological characteristics may exist , but not always

24. Myeloblasts - myeloproxidase positive
Cytochemistry
Myeloblasts - myeloproxidase positive

25. Diagnosis Diagnosis :>20% blasts in BM Cytochemical stains :
ALL TdT +, MPO -
AML TdT -, MPO+
Classified into subgroups based on
cell surface markers and cytogenetics 19 3 15 5
B cells
T cells
Myeloblast
FACS 22 22 13 3 33 7 13 20

26. Diagnosis : Karyotype, cytogenetics chromosomal abnormalities: M3

27. AML M2

28. Chromosomal abnormalities (cytogenetics)

29. Prognosis Risk factors
Cytogentics
Flt-3 mutation
Age
White blood cell count at presentation
FAB classification
De-novo /secondary
Response to first course of chemotherapy

30. Cytogenetic Classification
SWOG
MRC ; As for SWOG, except:-
t(15;17)
Inv(16)
t(8;21)-
Favorable
t(8;21) –– other abnormality + _
11q23
del(9q), del(7q) –– alone
Complex karyotypes (> 3 abn, but
< 5 abn)
All abnormalities of unknown
prognostic significance +8
normal karyotype
Intermediate
-5/del(5q), -7/del(7q),
inv(3q), 11q23, 20q,
21q, del(9q), t(6;9)
t(9;22), 17p,
Complex (> 3 abn)
Unfavorable
Complex karyotypes (> 5 abn)
All other clonal chromosomal
aberrations with less than 3 abn
Unknown

31. Cytogenetic and prognosis
100
Favorable n=377 75
67%
64%
62% 50
Overall Survival (%)
Intermediate n=1,072
41% 25
Adverse n=163
15%
11%
Years 1 2 3 4 5
D. Grimwade, et al, Blood, 1998

32. Treatment % Still Alive Years 50 40 30 20 10 1970-74 1975-79 1980-84
Years

33. Treatment of acute leukemia (I)
Supportive care :
Hydration
Allopurinol to prevent hyperuricemia
Cytopharesis
Blood products
Patient workup:
History for occupational exposure or exposure
Bone marrow aspiration and biopsy
Bone marrow sample for cytogenetic, FACS, PCR

34. Treatment in the Younger AML Patient<60yrs
Course I of chemotherapy
INDUCTION
Intensive
Chemotherapy
Allogeneic
Stem Cell
Transplantation
Autologous
Stem Cell
Transplantation

35. Outcome at 5 years Allo Chemotherapy Relapse 20-30% 40-60%
Overall survival % %
TRM % %

36. So how to choose which therapy to a specific patient?
use the prognostic factors to estimate
relapse rate and survival

37. Unfavorable Cytogenetics
100%
Allogeneic BMT
Autologous BMT
80%
Chemotherapy
60%
Survival
44%
40%
20%
15% 0% 2 4 6 8
Years
Slovak M., et al, Blood, 2000

38. What is the best treatment?
Patients with poor risk
and standard risk younger than 35/40 years in CR1
Patients in CR2 or beyond
Favourable/standard risk patients who relapsed, responded again to chemotherapy and have no matched donor
Patients in CR1 ?
Who should have a matched related Allo SCT ?
Who should have an
Auto SCT?

39. AML in Elderly patients(>60 years)
The majority of the patients are older than 60
Lower remission rate
Higher treatment –related morbidity & mortality
Very poor outcome
higher frequency of poor risk cytogenetics & resistance to chemotherapy

40. Future directions Identify new prognostic factors
New therapies : Modulation of drug resistance
Biological, specific treatments:
Monoclonal antibodies
ATRA in APL, t (15;17)

41. Summary
The majority of patients still die of their disease (significantly poor outcome in elderly patients)
Further improvement is needed:
Better ability to predict patients outcome
Tailoring treatment to patient’s risk factors
Improving therapy & supportive care
New strategies for elderly patients

42. Suggested Reading Hoffbrand Hematology Williams Hematology
Harrison’s Text book of Internal Medicine
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