Acute Myeloid LeukemiaMarcelo C. Pasquini, MD, MS

Associate Professor of MedicineAdult BMT ProgramHeme-Malignancies

Division of Hematology/Oncology

Acute Myeloid Leukemia Outline

• Bone marrow as a blood forming organ• Biology of Acute Myeloid Leukemia• Treatment• Bone marrow Transplant

Bone Marrow: the source of blood production and the immune

system• All blood cells arise from

hematopoietic stem cells–Self renewing–Pluripotent

• Blood production is highly regulated–Messages from the body (e.g.

erythropoietin from kidney)–Microenvironments produce

specific cells• Cytokines (SCF, IL3)• Growth factors (G-CSF)

Normal bone marrow

Hematopoiesis Scheme

Stem CellCompartment

LymphoidCompartment

MyeloidCompartment

AML and Morphologic Differences

WHO AMLClassification

Prognostic factors in AML

• Disease markers

– Chromosomes– Genetic markers

• Performance status• Age

Juliusson G et al. Blood 2012;119:3890-3899

 • Median age is 72 y

• Peak incidence at 80-84 y

      • At least 70% of

patients up to age 80 have a PS of 0-II     

Yearly incidence of AML per 100 000 inhabitants

Epidemiology

Juliusson G et al. Blood 2009;113:4179-4187

Prognosis in AML-Age

Juliusson G et al. Blood 2009;113:4179-4187

Life Expectancy• Average life expectancy for:

– Newborn ~ 76 years– 50 year old ~ 30 years (80)– 55 year old ~ 25 years (80)– 60 year old ~ 22 years (82)– 65 year old ~ 18 years (83)– 70 year old ~ 14 years (84)– 75 year old ~ 10 years (85)– 80 year old ~ 8 years (88)

http://www.ssa.gov/OACT/STATS/table4c6.html

Southwest Oncology Group Leukemia Committee percentage of patients in cytogenetic risk groups by age

category.

Appelbaum F R et al. Blood 2006;107:3481-3485

Region 2

Region 1

Region 1

Region 2

Region 3

4321

321

1

23

21

1234

Short arm 'p'

Centromere

Long arm 'q'

Normal Male Karyotype: 46, XY

47, XY, +8

Report Sample

How about FISH?

Florescence In Situ Hybridization

Cytogenetic Evaluation

Std Cytog. FISH

Cells analyzed 20 200-500

Cell cycle Metaphase Metaphase and Interphase

Abnormality specific

No Yes

Cell culture Yes No

Overall Survival by SWOG Cytogenetic Risk Status

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

Genetic markers in AML

Dohner H, Hematology 2007, p412-419

Molecular Markers and Prognosis

• New Good Guys– NPM1 mutation without FLT3 ITD– CEBPA mutation

• New Bad Guys– FLT3 ITD– MLL PTD– KIT mutation (Associated with t(8;21) or inv(16))– Overexpression of BAALC– WT1 mutations– IDH1/2

Schlenk R et al. N Engl J Med 2008;358:1909-1918

Frequencies and Distribution of the NPM1, CEBPA, MLL, FLT3, and NRAS Mutations, According to

Mutation Class

Favorable

Intermediate

Unfavorable

NPM1pos+FLT3ITDneg

CEEBPA mut

t(8;21) + c-kit mutation

FLT3 ITD

AML and Genetic Variation

AML Up-Front Treatment

Induction“7+3”

Post-Remission Therapy

CR

Allogeneic BMT

ConsolidationChemotherapy

Autologous BMT

DiagnosisDiagnosis

CR: Complete Remission

First report of “7 + 3”

Cancer Chemotherapy reports Part 1 Vol. 57, No. 4, Nov/Dec 1973

Induction therapy

• 7 + 3• Azacitidine• Decitabine• Clofarabine

DRL

RRL

RR D

DDD

HSCT

D

D

D

D

Complete ChimeraRecipient

Donor

Hematopoietic Cell TransplantPreparative or Conditioning

Regimen: Radiation and or Chemotherapy

Indications for Hematopoietic Stem Cell Transplants in the US, 2012

Myeloma/PCD

AML ALL CML NHL HD MDS/MPD

CLL Aplastic Anemia

Other Non-Ma-lig Dis

Other Cancer

0

1000

2000

3000

4000

5000

6000

7000

Allogeneic (Total N=7,554) Autologous (Total N=11,145)

34

Nu

mb

er

of T

ran

spla

nts

Trends in Allogeneic Transplants by Recipient Age*

1992-1998 1999-2005 2006-20120

20

40

60

80

100

120

< 60 years ≥ 60 years

* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma 35

Tra

nsp

lant

s, %

Survival after HLA-identical Sibling Donor Transplants for AML, 2002-2012

By Disease Status 36

100

0

20

40

60

80

Pro

babi

lity,

%

Years

p < 0.0001

Early (n=7,607)

Intermediate (n=2,124)

Advanced (n=2,578)

10 2 64 53

s25

Survival after Unrelated Donor Transplants for AML, 2002-2012

By Disease Status 37

s26

100

0

20

40

60

80

Pro

babi

lity,

%

Years10 2 64 53

Early (n=7,365)

Intermediate (n=4,172)

Advanced (n=4,095)

p < 0.0001

Conclusions

• AML is a heterogeneous disease• Understanding prognosis helps in planning

therapy• Understanding better the biology is helping

the development of new treatments. • Transplants for AML are less toxic and able to

help a greater number of patients.