aml patho physiology & classification - v roccha

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

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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”)

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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

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• Lack of significant multilineagedysplasia;

• Good risk cytogenetics t(8;21), t(15;17), inv 16 or t(16;16);

• Favorable response to therapy;

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““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

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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

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• 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

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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

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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

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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

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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)

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0

20

40

60

80

100

Pro

bab

ilit

y,

%

Early (N=1,063)

0 2 61 3

Years

4 5

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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)

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0

20

40

60

80

100

Pro

bab

ilit

y,

% Early (N=804)

0 2 61 3

Years

4 5

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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 -

P < 0.001

Intermediate (N=174)

Advanced (N=165)

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0

20

40

60

80

100

Pro

bab

ilit

y,

%

Early (N=2,369)

0 2 61 3

Years

4 5

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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 -

P < 0.001

Intermediate (N=611)

Advanced (N=1,113)

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0

20

40

60

80

100

Pro

bab

ilit

y,

%

Early (N=428)

0 2 61 3

Years

4 5

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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)

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0

20

40

60

80

100

Pro

bab

ilit

y,

%

Early (N=249)

0 2 61 3

Years

4 5

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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)

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0

20

40

60

80

100

Pro

bab

ilit

y,

%

Early, RIC (N=278)

0 2 61 3

Years

4 5

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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 -

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