Acute Myeloid Leukemia

Marcelo C Pasquini, MD, MS

Assistant Professor of Medical College of Wisconsin, Milwaukee, USA

Vanderson Rocha, MD, PhD

Medical Assistant of HSCT unit, Hopital Saint Louis, Paris, France
Chair of the Acute Leukemia Working Party of EBMT
Visiting Professor of Medical College of Wisconsin, Milwaukee, USA
 Outline

 Acute Myeloid Leukemia: overview

 Classification
 General aspects of AML treatment

HVD05_2.ppt
 Epidemiology: AML

• 10,500 New Cases in USA 2001

• Incidence is stable for the last 3
decades
• Median age: 63 years (70 y in Sweden)
• Most common acute leukemia in adults
• Sharp increase in incidence after the
6th decade of life.
Hematopoiesis Scheme
Lymphoid
Compartment

Stem Cell
Compartment

Myeloid
Compartment
Details of the Myeloid Compartment
 Marrow Disorders

MDS MPD Acute

Leukemia

Proliferation + +++ ++

Apoptosis +++ +/- +/-

Differentiation +/- normal -

MDS: Myelodysplasia; MPD: Myeloproliferative Disorder

Normal
Hematopoiesis Leukemogenesis
 Acute Myeloid Leukemia

• Two major distinctions:

– Secondary AML
• (MDS or therapy related);
– “de novo” AML .
• FAB classification (morphological)
– M0, M1, M2, M3, M4, M5, M6, M7
• WHO classification (“risk adapted”)

MNC03_11.ppt
 Secondary AML

• AML that arises from myelodysplasia and/or

secondary to previous chemotherapy:
– Multilineage dysplasia
– Poor risk cytogenetic findings
– Poor response to therapy
– Incidence increases with age
– Poor response to therapy
– Lower survival compared to “de novo” AML

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 “De novo” AML

• Lack of significant multilineage

dysplasia;
• Good risk cytogenetics t(8;21),
t(15;17), inv 16 or t(16;16);
• Favorable response to therapy;

MNC03_13.ppt
FAB Classification
AML and Morphologic Differences
Cytogenetic Changes and AML
Outcomes
 4
Region 2 3
2
1 Short arm 'p'
3
Region 1 2
1
Centromere
1

Region 1 2
3
Long arm 'q'
1
Region 2 2
1
2
3
Region 3
4
Normal Male Karyotype: 46, XY
47, XY, +8
 Chromosomal abnormalities

 Structural abnormalities
- Translocation
- Deletion
- Inversion

 Numerical changes
- Hyperdiploidy 50- 65 chromosomes.
- Trisomie
- Near haploidy 26-34 chromosomes,
- Monosomie
Report Sample
 4
Region 2 3
2
1 Short arm 'p'
3
Region 1 2
1
Centromere
1

Region 1 2
3
Long arm 'q'
1
Region 2 2
1
2
3
Region 3
4
Chromosomal Morphologic Association
Abnormality FAB- AML

Trisomy 8 Variable
Monosomy 7 M2,M4,M5
Monosomy 5, de(5q) M1,M2
t(8;21)(q22;q22) M2,*M4
t(15;17)(q22;q11-12) M3
t(9;11)(p22;q23) M5,M4,M2
del(11)(q22 –23) M5,M4,M2
inv(16)(p13;q22), del(16q) M4Eo,M2,M5
t(6;9)(p13;q34) M1,M2,M4;
t(9;22)(q34;q11) M1
FAB Classification
AML M0

CD13+,CD33+.MPO<3%
 AML M1

MPO +

CD13+,CD33+,CD117+,CD65s+.

MPO
AML M2

MPO +
CD13+,CD33+,CD117+,CD65s+
CD19+,CD56+.

t(8;21)(q22;q22) AML1 / ETO

M2
M3
M4eo
 AML M5 a

CD34+,CD33+,CD117+,CD14+

t(9;11)(p21;q23)

AF9 / MLL
Acute
Erythremia

Gly A+

t(9;22)(q34;q11)

ABL / BCR
AML M7

CD34+,CD117+.

CD41a+,CD61+.
How about FISH?

Florescence In Situ
Hybridization
 Cytogenetic Evaluation

Std Cytog. FISH

Cells analyzed 20 200-500

Cell cycle Metaphase Metaphase and

Interphase
Abnormality No Yes
specific
Cell culture Yes No
Overall Survival by SWOG Cytogenetic Risk Status

Slovak et al, Blood 2000; 96: 4075-4083

Overall Survival by MRC “Good” Cytogenetic Risk
Compared to Intermediate Risk

Grimwade et al, Blood 1998; 92: 2322-2333

WHO AML
Classification
 AML WHO CLASSIFICATION

• Recognizes three sub groups

– AML with recurrent genetic
abnormalities
– AML with multilineage dysplasia
• Includes secondary AML (MDS, therapy
related)
– AML not otherwise categorized

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 AML WHO CLASSIFICATION

• AML with recurrent genetic

abnormalities
– AML with t(8;21)
– AML with t(16;16) or inv 16
– APML or AML with t(15;17)
– AML with 11q23 abnormalities
• Favorable response to therapy

MNC03_16.ppt
 AML WHO CLASSIFICATION

• AML with multilineage dysplasia

– Following MDS
– Without antecedent MDS, but with
dysplasia in at least 50% of cells in 2 or
more myeloid lineage
– Therapy related MDS or AML
• Alkylating agent, irradiation-related,
topoisomerase II inhibitor

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 AML WHO CLASSIFICATION

• AML, not otherwise categorized

• Defined almost identically as in the FAB
classification
• Based on identification of major cell
lineage(s) involved and degree of
maturation

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 AML with normal cytogenetics

• New Good
– NPM1 mutation without FLT3 ITD
– CEBPA mutation
• New Bad
– FLT3 ITD
– MLL PTD
– KIT mutation (t(8;21))
– Overexpression of BALLC
 Risk Stratification with Molecular
Markers

• More complex to tease out.

• Combination of different
abnormalities
• Location of a mutation
• Development of molecular
signatures (microarray)
 Additional Risk Factors for Poor
Outcome

• Age
• WBC at diagnosis, blasts in bone
marrow.
• Platelet count
• Remission duration
 Initial AML Treatment

Induction Post-Remission Therapy

Allogeneic BMT
Diagnosis Consolidation
Chemotherapy
CR
Autologous BMT

Primary Induction
Failure
CR: Complete Remission
AML OS by Different Treatment Strategies:
US Intergroup

Cassileth et al, NEJM 1998; 339: 1649-56

Definitions of Response and Relapse

• Important milestones that predict

future outcomes
• Complete remission: no evidence
of disease
• Levels of relapse/remission:
– Hematological (Increase blasts in the
BM, blood, extramedullary disease)
– Cytogenetics [t(15;17); t(8;21)]
– Molecular (PML/RARα, RUNX/MTG8)
 CML Model
Active Disease Treatment
Hematologic
Disease Burden

Cytogenetic

Molecular
 AML Salvage treatment

• Mylotarg (gemtuzomab ozogomycin)

• Decitabine
• Auto HCT
• Allogeneic HCT
• Other investigational agents: p-
glycoprotein inhibitor (vorinostat), FLT3
inhibitors, temozolamide, tipafarnib.
 Probability of Survival after HLA-identical
Sibling Donor Transplants for AML with
Myeloablative Conditioning, 1998-2004
- by Disease Status -
100

80
Probability, %

Early (N=3,174)
60

40 Intermediate (N=785)

20
Advanced (N=1,278)

P < 0.001
0
0 1 2 3 4 5 6

Years
Slide 24
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 Probability of Survival after Unrelated
Donor Transplants with Myeloablative
Conditioning for AML, 1998-2004
- by Disease Status -
100

80
Probability, %

60

Intermediate (N=1,066)
40

Early (N=1,063)

20
Advanced (N=1,251)
P < 0.001
0
0 1 2 3 4 5 6

Years
Slide 25
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 Probability of Survival after HLA-identical
Sibling Transplants with Myeloablative
Conditioning for AML, Age <20 Years, 1998-2004
- by Disease Status -
100

80
Probability, %

Early (N=804)
60

Intermediate (N=174)

40

20 Advanced (N=165)

P < 0.001
0
0 1 2 3 4 5 6

Years
Slide 26
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 Probability of Survival after HLA-identical
Sibling Transplants with Myeloablative
Conditioning for AML, Age ³20 Years, 1998-2004
- by Disease Status -
100

80
Probability, %

Early (N=2,369)
60

40 Intermediate (N=611)

20
Advanced (N=1,113)

P < 0.001
0
0 1 2 3 4 5 6

Years
Slide 27
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 Probability of Survival after HLA-identical
Sibling Transplants with Reduced Intensity
Conditioning for AML, 1998-2004
- by Disease Status -
100

80
Probability, %

60

Early (N=428)
40
Intermediate (N=164)

20

P < 0.001 Advanced (N=232)

0
0 1 2 3 4 5 6

Years
Slide 28
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 Probability of Survival after Unrelated
Donor Transplants with Reduced Intensity
Conditioning for AML, 1998-2004
- by Disease Status -
100

80
Probability, %

60

40 Early (N=249)

20 Intermediate (N=184)

Advanced (N=260)
P < 0.001
0
0 1 2 3 4 5 6

Years
Slide 29
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 Probability of Survival after HLA-identical Sibling
Transplants for AML, Age >50 Years, 1998-2004
- by Disease Status and Conditioning Regimen Intensity -

100

80
Probability, %

60
Early, Myeloablative (N=467)

40

Early, RIC (N=278)

20
Intermediate, Myeloablative (N=133)
Intermediate, RIC (N=113)
P = 0.54
0
0 1 2 3 4 5 6
RIC = Reduced Intensity
Conditioning Years
Slide 30
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Thanks for your attention