ACUTE MYELOID LEUKIMIA

A Journal from NEJM, 1999

 ACUTE MYELOID LEUKIMIA

Hematopoietic
Myeloid arrest
Increase myeloid insufficiency with
in their
cell in the marrow or without
maturation
leukositosis

Increase Survival rates in

Incidence
progressively with patient less than
2.4/100.000
age 65 y.o = 40%

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 CLINICAL PRESENTATION

INFECTION AND FEVER

FATIGUE HEMORHAGE  ↓RBC, pletelets and
white cells

Leukemic infiltration of
various tissue 
Hyperleukocytosis  Metabolic
hepatomegaly,
leukostasis abnormalities are rare
spleenomegaly,
Lymfadenophaty

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 DIAGNOSIS
• AML  Leukemic myeloblast in preparation of
peripheral blood and bone marrow  stained with
Wright-Giemsa

Round to Very little

Myeloblast iregulr nuclei cytoplasm

Cytoplasm
azurophylic Auer bodies
granules

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 DIAGNOSIS

> 30 % leukemic blasts in a bone marrow

aspirate  definitive diagnosis of acute
leukemia

AML  myeloblast in the marrow >30%

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 DIAGNOSIS
AML distinguished with ALL :
• Cell morpholgic
• Immunohistochemical
• Immunologic methods
AML distinguished with MDS
or MDS-related AML :
• MDS  ineffective hematopoiesis
• Morphologic evidence of dysplastic
maturation
• Cytogenetic lesions : del5q, del 20q,
loss of Y
• Conventional theraphy of AML is
much less effective against MDS
related AML
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 DIAGNOSIS

AML has
Identify
variability soecific
AML is diagnosed morphologic and
morphologic
genetic subtype
subgroups

Subtypes based on : Classification of

morphologic of blasts, AML  9 AML group  FAB
reactivity with
histochemical stain, subtypes (French America
immunologic methods British) group

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 DIAGNOSIS

Morfologic, immunologic,
genetically based diagnostic

Modify therapy

Monitor patient’s response to

therapy

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DIAGNOSIS

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 MOLECULAR PATHOGENESIS

Sensitivity of the Improve the

therapeutic
Specific cytogenic leukemic blasts to
approach and
lession therapeutic outcome of AML
agents patients

Translocation Trans retinoic acids highly successful

therapeutic use of the
associated with targets chimeric
differentiation-
acute promyelocytic protein encoded by inducing agent
leukimia the t(15;17) alltrans-retinoic acid.

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 MOLECULAR PATHOGENESIS

Targets of AML- Protein fusion

DNA binding interfere in a
associated
chromosomal
transcription dominant manner
factors genes function of wildtye
translocation protein

Identify Critical insight

Three specific
subgroups  into
therapeutic
molecular
pathogenesis of
purpose genetic lessions
AML

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ALTERATIONS OF AML1-CBFb

Encoded the
AML-associated DNA-binding
t(8;21)  AML1 subunit of AML1-
CBFb

Essensial for Transcription factor

normal  regulates a
development of number of
hematopoietic hematopoiesis-
system specific genes

AML1-CBFb  most
frequent target of
chromosomal
rearrangement og
human leukimia
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 AML WITH ALTERATIONS OF THE
MIXED-LINEAGE LEUKEMIA GENE

Structural MLL interaction

>30 different 5' portion
alterations with putative
chromosomal 6q27, 9p22, of the antiphosphatas
band q23 of
loci 10p12, mixed- e Sbfl 
chromosom participate in a positive
17q21 or lineage
e 11  this 11q23 regulator in
19p13.1 leukemia or
common in translocation kinase signaling
MLL pathways.
AML

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 AML WITH ALTERATIONS OF THE
MIXED-LINEAGE LEUKEMIA GENE

MLL rearrangement
Other mechanism : Structural mutation
 AML 
alteration of  maturation
alteration in
growth-factor- subdomain of
transcriptional
signaling pathway receptor for G-CSF
cascade

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AML WITH ALTERATIONS OF THE
MIXED-LINEAGE LEUKEMIA GENE

Celullar
In AML, the nature
transformation 
of these lesien are
multistep process 
poorly defined
lead leukimia

>50% of AML cases Underlying

involve molecular genetic
chromosomal abnormalities
rearrangements should be idintified

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PROGNOSTIC FACTORS

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 PROGNOSTIC FACTORS

Favorable
• ±20 % patients ≤60 y.o
• Leukemic blast with t(15;17), t(8;21) or inv(16)
• In younger patient complete remission, low risk relaps
Standard
• Leukemic blasts  normal karyotype/ cytogenic abnormalities
• >60 y.o poor prognosis, probability of survival rate at 5 years <10%
Unfavorable
• ± 15% patient 15-60 y.o
• Presence of leukemic blasts  cytogenic abnormalities  >two chromosomees,
monosomies of chromosome 5 and 7, del 5q
• No current treatment approach is statisfactory

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 SECONDARY AML

Patients with have no risk factors to have primary

AML

Patients with a hematologic disorder (severe

congenital neutropenia)

3 to 10 percent of patients who receive alkylating agents as part

of their therapy for ovarian cancer, breast cancer, or multiple
myeloma

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 SECONDARY AML

The risk of this complication peaks 5 to 10 years

after the start of chemotherapy

The prognosis for these patients is considerably

worse than that for patients with pri- mary AML

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 TREATMENT

induce remission
The primary objective
treatment
thereafter prevent relapse

Induction of Remission
two phases of treatment
Postinduction Therapy

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INDUCTION TREATMENT

For past - Daunorubicin

30 years - Cytarabine

In recent Idarubicin or Mitoxantrone is more

years effectivethan daunorubicin

There is some evidence that the addition of etoposide to

combinations of daunorubicin and cytarabine can further
increase remission rates.
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 INDUCTION TREATMENT

Daunorubicin

The treatment is given Once have a dose of 40 to 60 mg per

three times square meter of body-surface area

cytarabine

Dose:
intravenously - 100 to 200 mg per square meter per day
- by continuous infusion over a period of 7 to 10 days.
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 POSTINDUCTION THERAPY

Once remission is induced, further intensive treatment of

patients with AML is essential to prevent relapse.

Three options are available for younger patients:

1. Allogeneic bone marrow transplantation
2. Autologous bone marrow transplantation
3. chemotherapy.

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ALLOGENEIC BONE MARROW
TRANSPLANTATION

Transplantation from an HLA-matched sibling

Cure 50 to 60 percent of recipients

The limited comparative data available do not always

show a benefit after allogeneic transplantation

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AUTOLOGOUS BONE MARROW
TRANSPLANTATION

Autologous Stem cell transplantation supporting

Myeloablative treatment

Non randomized studies indicate survival rates of

45 to 55 percent

The risk of relapse was reduced among children who underwent

allogeneic bone marrow transplantation, but this was
counterbalanced by a high risk of death

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 CHEMOTHERAPY

The overall survival rate cytarabine at a dose of 3 g per

square meter twice daily for
four years after three out of five days was
randomization was 46 superior to equivalent courses of
percent in the high- 400 or 100 mg per square meter
given as a continuous infusion
dose group over a period of five days.

The comparative value of

high dose cytarabine
regmens and autologous
transplantation in the various
prognostic subgroups
remains the subject of study.

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 RELAPSE

When treatment fails in patients with AML, the available options are dictated by
age, duration of the first remission, and cytogenetic findings, among other factors

Patients were in remission for more than one year before relapse have an
approximately 20 percent chance of survival after subsequent therapy

The survival rate after either autologous transplantation or allogeneic

transplantation with an HLA-matched donor for patients with AML in first
relapse or second remission is about 30 percent.

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OLDER PATIENTS WITH AML

More than 3/4 of Older patients

patients with AML cannot tolerate
are older than 60 intensive
years chemotherapy well

Low dose
Prognostic factors
maintenance
are 20 percent of
Chemotherapy better
survival rate
use for older patients

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USE OF HEMATOPOIETIC
GROWTH FACTORS

Hematopoietic growth factors use to accelerate

hematopoietic recovery

Prevent infection has attracted wide

attention.

Some studies have evaluated the use of G-CSF or GM-CSF as an

adjunct to induction or consolidation cycles of chemotherapy

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 CONCLUSIONS

The treatment of patients with AML is toward the

modification of therapy.

The treatment focus on targeting of the malignant

cells with molecular and immunologic therapeutic
strategies.

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TERIMA KASIH