Page 1
Acute Myeloid Leukemia
Marcelo C Pasquini, MD, MSAssistant Professor of Medical College of Wisconsin, Milwaukee, USA
Vanderson Rocha, MD, PhDMedical Assistant of HSCT unit, Hopital Saint Louis, Paris, FranceChair of the Acute Leukemia Working Party of EBMTVisiting Professor of Medical College of Wisconsin, Milwaukee, USA
Page 2
OutlineOutline
Acute Myeloid Leukemia: overview
Classification
General aspects of AML treatment
HVD05_2.ppt
Page 3
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.
Page 4
Hematopoiesis Scheme
Stem CellCompartment
LymphoidCompartment
MyeloidCompartment
Page 6
Details of the Myeloid Compartment
Page 7
Marrow DisordersMarrow Disorders
-normal+/-Differentiation
+/-+/-+++Apoptosis
++++++Proliferation
Acute Leukemia
MPDMDS
MDS: Myelodysplasia; MPD: Myeloproliferative Disorder
Page 8
NormalHematopoiesis Leukemogenesis
Page 9
Acute Myeloid LeukemiaAcute 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
Page 10
Secondary AMLSecondary 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
MNC03_12.ppt
Page 11
• Lack of significant multilineagedysplasia;
• Good risk cytogenetics t(8;21), t(15;17), inv 16 or t(16;16);
• Favorable response to therapy;
MNC03_13.ppt
““De novoDe novo”” AMLAML
Page 12
FAB ClassificationFAB Classification
Page 13
AML and Morphologic Differences
Page 14
Cytogenetic Changes and AML Cytogenetic Changes and AML OutcomesOutcomes
Page 15
Region 2
Region 1
Region 1
Region 2
Region 3
4321321123
21
1234
Short arm 'p'
Centromere
Long arm 'q'
Page 16
Normal Male Karyotype: 46, XY
Page 18
Chromosomal abnormalities
Structural abnormalities- Translocation- Deletion- Inversion
Numerical changes- Hyperdiploidy 50- 65 chromosomes.
- Trisomie- Near haploidy 26-34 chromosomes,
- Monosomie
Page 19
Report SampleReport Sample
Page 20
Region 2
Region 1
Region 1
Region 2
Region 3
4321321123
21
1234
Short arm 'p'
Centromere
Long arm 'q'
Page 21
Chromosomal Morphologic AssociationAbnormality FAB- AML
Trisomy 8 VariableMonosomy 7 M2,M4,M5Monosomy 5, de(5q) M1,M2t(8;21)(q22;q22) M2,*M4t(15;17)(q22;q11-12) M3t(9;11)(p22;q23) M5,M4,M2del(11)(q22 –23) M5,M4,M2inv(16)(p13;q22), del(16q) M4Eo,M2,M5t(6;9)(p13;q34) M1,M2,M4; t(9;22)(q34;q11) M1
Page 22
FAB ClassificationFAB Classification
Page 23
AML M0AML M0
CD13+,CD33+.MPO<3%
Page 24
AML M1AML M1
MPO +
CD13+,CD33+,CD117+,CD65s+.
MPO
Page 25
AML M2AML M2
MPO +CD13+,CD33+,CD117+,CD65s+CD19+,CD56+.
t(8;21)(q22;q22) AML1 / ETO
Page 29
AML M5 aAML M5 a
CD34+,CD33+,CD117+,CD14+CD34+,CD33+,CD117+,CD14+
t(9;11)(p21;q23)t(9;11)(p21;q23)
AF9 / MLLAF9 / MLL
Page 30
Acute Acute ErythremiaErythremia
GlyGly A+A+
t(9;22)(q34;q11)t(9;22)(q34;q11)
ABL / BCR
Page 31
AML M7AML M7
CD34+,CD117+.CD34+,CD117+.
CD41a+,CD61+.CD41a+,CD61+.
Page 32
How about FISH?How about FISH?
FFlorescence lorescence IIn n SSitu itu HHybridizationybridization
Page 33
Cytogenetic EvaluationCytogenetic Evaluation
NoYesCell culture
YesNoAbnormality specific
Metaphase and Interphase
MetaphaseCell cycle
200-50020Cells analyzed
FISHStd Cytog.
Page 35
Overall Survival by SWOG Cytogenetic Risk Status
Slovak et al, Blood 2000; 96: 4075-4083
Page 36
Overall Survival by MRC “Good” Cytogenetic RiskCompared to Intermediate Risk
Grimwade et al, Blood 1998; 92: 2322-2333
Page 38
WHO AMLClassification
Page 39
AML WHO CLASSIFICATIONAML 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
MNC03_15.ppt
Page 40
• 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 CLASSIFICATIONAML WHO CLASSIFICATION
Page 41
• 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
MNC03_17.ppt
AML WHO CLASSIFICATIONAML WHO CLASSIFICATION
Page 42
• 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
MNC03_18.ppt
AML WHO CLASSIFICATIONAML WHO CLASSIFICATION
Page 43
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
Page 45
Risk Stratification with Molecular Markers
• More complex to tease out.• Combination of different
abnormalities• Location of a mutation• Development of molecular
signatures (microarray)
Page 46
Additional Risk Factors for Poor Outcome
• Age• WBC at diagnosis, blasts in bone
marrow.• Platelet count• Remission duration
Page 47
Initial AML TreatmentInitial AML Treatment
InductionInduction PostPost--Remission TherapyRemission Therapy
CR
Allogeneic BMTAllogeneic BMT
ConsolidationConsolidationChemotherapyChemotherapy
Autologous BMTAutologous BMT
DiagnosisDiagnosisDiagnosis
Primary Induction Failure
CR: Complete Remission
Page 48
Cassileth et al, NEJM 1998; 339: 1649-56
AML OS by Different Treatment Strategies:US Intergroup
Page 50
Definitions of Response and RelapseDefinitions 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)
Page 51
Active DiseaseActive Disease
HematologicHematologic
CytogeneticCytogenetic
MolecularMolecular
Treatment
Dis
ease
Bu
rden
Dis
ease
Bu
rden
CML Model
Page 53
AML Salvage treatment
• Mylotarg (gemtuzomab ozogomycin)• Decitabine• Auto HCT• Allogeneic HCT• Other investigational agents: p-
glycoprotein inhibitor (vorinostat), FLT3 inhibitors, temozolamide, tipafarnib.
Page 54
0
20
40
60
80
100
Pro
bab
ilit
y,
%
Early (N=3,174)
0 2 61 3
Years
4 5
SUM06_16.ppt
Probability of Survival after HLA-identical Sibling Donor Transplants for AML with Myeloablative Conditioning, 1998-2004
- by Disease Status -
P < 0.001
Intermediate (N=785)
Advanced (N=1,278)
Slide 24
Page 55
0
20
40
60
80
100
Pro
bab
ilit
y,
%
Early (N=1,063)
0 2 61 3
Years
4 5
SUM06_17.ppt
Probability of Survival after Unrelated Donor Transplants with Myeloablative
Conditioning for AML, 1998-2004- by Disease Status -
P < 0.001
Intermediate (N=1,066)
Advanced (N=1,251)
Slide 25
Page 56
0
20
40
60
80
100
Pro
bab
ilit
y,
% Early (N=804)
0 2 61 3
Years
4 5
SUM06_18.ppt
Probability of Survival after HLA-identical Sibling Transplants with Myeloablative
Conditioning for AML, Age <20 Years, 1998-2004- by Disease Status -
P < 0.001
Intermediate (N=174)
Advanced (N=165)
Slide 26
Page 57
0
20
40
60
80
100
Pro
bab
ilit
y,
%
Early (N=2,369)
0 2 61 3
Years
4 5
SUM06_19.ppt
Probability of Survival after HLA-identical Sibling Transplants with Myeloablative
Conditioning for AML, Age ³20 Years, 1998-2004- by Disease Status -
P < 0.001
Intermediate (N=611)
Advanced (N=1,113)
Slide 27
Page 58
0
20
40
60
80
100
Pro
bab
ilit
y,
%
Early (N=428)
0 2 61 3
Years
4 5
SUM06_20.ppt
Probability of Survival after HLA-identical Sibling Transplants with Reduced Intensity
Conditioning for AML, 1998-2004- by Disease Status -
P < 0.001
Intermediate (N=164)
Advanced (N=232)
Slide 28
Page 59
0
20
40
60
80
100
Pro
bab
ilit
y,
%
Early (N=249)
0 2 61 3
Years
4 5
SUM06_21.ppt
Probability of Survival after Unrelated Donor Transplants with Reduced Intensity
Conditioning for AML, 1998-2004- by Disease Status -
P < 0.001
Intermediate (N=184)
Advanced (N=260)
Slide 29
Page 60
0
20
40
60
80
100
Pro
bab
ilit
y,
%
Early, RIC (N=278)
0 2 61 3
Years
4 5
SUM06_22.ppt
Probability of Survival after HLA-identical Sibling Transplants for AML, Age >50 Years, 1998-2004
- by Disease Status and Conditioning Regimen Intensity -
P = 0.54
Intermediate, Myeloablative (N=133)
Intermediate, RIC (N=113)
Early, Myeloablative (N=467)
Slide 30
RIC = Reduced Intensity Conditioning
Page 61
Thanks for your attention