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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
OutlineOutline
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
Stem CellCompartment
LymphoidCompartment
MyeloidCompartment
Details of the Myeloid Compartment
Marrow DisordersMarrow Disorders
-normal+/-Differentiation
+/-+/-+++Apoptosis
++++++Proliferation
Acute Leukemia
MPDMDS
MDS: Myelodysplasia; MPD: Myeloproliferative Disorder
NormalHematopoiesis Leukemogenesis
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
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
• 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
FAB ClassificationFAB Classification
AML and Morphologic Differences
Cytogenetic Changes and AML Cytogenetic Changes and AML OutcomesOutcomes
Region 2
Region 1
Region 1
Region 2
Region 3
4321321123
21
1234
Short arm 'p'
Centromere
Long arm 'q'
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 SampleReport Sample
Region 2
Region 1
Region 1
Region 2
Region 3
4321321123
21
1234
Short arm 'p'
Centromere
Long arm 'q'
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
FAB ClassificationFAB Classification
AML M0AML M0
CD13+,CD33+.MPO<3%
AML M1AML M1
MPO +
CD13+,CD33+,CD117+,CD65s+.
MPO
AML M2AML M2
MPO +CD13+,CD33+,CD117+,CD65s+CD19+,CD56+.
t(8;21)(q22;q22) AML1 / ETO
M2M2
M3M3
M4eoM4eo
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
Acute Acute ErythremiaErythremia
GlyGly A+A+
t(9;22)(q34;q11)t(9;22)(q34;q11)
ABL / BCR
AML M7AML M7
CD34+,CD117+.CD34+,CD117+.
CD41a+,CD61+.CD41a+,CD61+.
How about FISH?How about FISH?
FFlorescence lorescence IIn n SSitu itu HHybridizationybridization
Cytogenetic EvaluationCytogenetic Evaluation
NoYesCell culture
YesNoAbnormality specific
Metaphase and Interphase
MetaphaseCell cycle
200-50020Cells analyzed
FISHStd Cytog.
Overall Survival by SWOG Cytogenetic Risk Status
Slovak et al, Blood 2000; 96: 4075-4083
Overall Survival by MRC “Good” Cytogenetic RiskCompared to Intermediate Risk
Grimwade et al, Blood 1998; 92: 2322-2333
WHO AMLClassification
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
• 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
• 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
• 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
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 TreatmentInitial AML Treatment
InductionInduction PostPost--Remission TherapyRemission Therapy
CR
Allogeneic BMTAllogeneic BMT
ConsolidationConsolidationChemotherapyChemotherapy
Autologous BMTAutologous BMT
DiagnosisDiagnosisDiagnosis
Primary Induction Failure
CR: Complete Remission
Cassileth et al, NEJM 1998; 339: 1649-56
AML OS by Different Treatment Strategies:US Intergroup
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)
Active DiseaseActive Disease
HematologicHematologic
CytogeneticCytogenetic
MolecularMolecular
Treatment
Dis
ease
Bu
rden
Dis
ease
Bu
rden
CML Model
AML Salvage treatment
• Mylotarg (gemtuzomab ozogomycin)• Decitabine• Auto HCT• Allogeneic HCT• Other investigational agents: p-
glycoprotein inhibitor (vorinostat), FLT3 inhibitors, temozolamide, tipafarnib.
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
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
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
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
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
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
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
Thanks for your attention