Acute Leukemia

Rahmawati Minhajat
A. Fachruddin Benyamin
Division of Hematology and Medical Oncology
Dept. of Int. Medicine, Medical Faculty
Hasanuddin Univ.

Outline
1

Concepts, biology

Epidemiology

Clinical & lab. manifestations

Diagnosis

Management and prognosis

Leukemia
Is a malignant hematologic disorder
characterized by a proliferation of abnormal
white cells that infiltrate the bone marrow,
peripheral blood & organs
4 main types of leukemia
Acute or chronic
Myelogenous or Lymphocytic

Types of Leukemia
Chronic
Acute
Excessive build up of rel.
Rapid growth of immature
mature blood cells
blood
cells
Hence
we have
MostlyLeukemia(ALL)
in older patients
Mostly
in children,
Acute
Lymphocytic/Lymphoblastic
:
Monitoring
before treatment
youngmost
adults
common type in young
children;
Needs immediate
treatment
also affects
adults, > 65
Acute Myelogenous/ Myeloid Leukemia(AML)
more commonly in adults than in children.
Chronic Lymphocytic leukemiaMyeloid
(CLL)
Lymphoid
most oftenand
affects adults
over the
age of 55
Affects lymphocytes
Affects
eosinophils,
Chronic
Myelogenous leukemia (CML)
plasma
cells
neutrophils, basophils
occurs
mainly in adults Myelogenous leukemia
Lymphocytic
leukemia
208,080 = Total number of leukemia patients today

Leukocytes = White Blood Cells

Phagocytic Leukocytes

PMNs

Polymorphonuclear
Neutrophilic
Leukocytes, a.k.a.,
PMNs. They are
shorter lived than
macrophages but
have greater killing
power.

Non-Phagocytic Granulocytes

Eosinophils are involved

in allergic responses,
inflammation, and
release of Histamine;
Histamine is released by
Basophils.

Mediators of Adaptive Immunity

Immune Specific

ALL

nave

germinal center

B-lymphocytes
Plasma
cells

Lymphoid
progenitor

T-lymphocytes

AML
Hematopoietic
stem cell

Myeloid
progenitor

Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells

Myeloid maturation

myeloblast promyelocyte

myelocyte

metamyelocyte

band

neutrophil

MATURATION
Adapted and modified from U Va website

Acute Leukemia

Accumulation of blasts in the marrow

How to distinguish AML vs CML

from looking at peripheral blood
Myeloid cell
CML
Blasts
q
q
Promyelocytes
q
Myelocytes
q
Metamyelocytes q
Bands
q
Neutrophils
q
#

AML

normal

gnificance of adult acute leukemia

A hematologic urgency
Usually fatal within weeks to months
without chemotherapy
With treatment, high mortality due to
disease or treatment-related complications
(unlike childhood acute leukemia)
Notify Hematologist promptly if acute
leukemia is suspected

Classification of acute leukemias

ALL
Mainly children
M>F
Curable in 70%
of children
Curable in minority
of adults

AML
Mainly adults
M>F
Curable in minority
of adults

Classification of AML
___________________________________
M 1 : L Mieloblastik akut
M 2 : L Mieloblastik akut + deferensiasi
M 3 : L Promielositik akut
M 4 : L Mielo-monositik akut
M 5 : L Monoblastik akut
M 6 : Eritroleukemia
___________________________________

wo-hit model of leukemogenesis

Loss of function of
transcription factors
needed for differentiation

eg. FLT3, c-KIT mutations

N- and K-RAS mutations
BCR-ABL
TEL-PDGFR

eg. AML1-ETO
CBF-SMMHC
PML-RAR

differentiation
block

Gain of function mutations of

tyrosine kinases

enhanced
proliferation

Acute
Leukemia

Causes of acute leukemias

Idiopathic (most)
Underlying hematologic disorders
Chemicals, drugs
Ionizing radiation
Viruses (HTLV I)
Hereditary/genetic conditions

Abnormalitas Sitogenetik
___________________________________
Abnormalitas kromosom 5 & 7
Sindroma Mielodisplasi (MDS) toksin /
kemotx leukemia.
___________________________________

Clinical manifestations

Symptoms due to :
1. Marrow failure
2. Tissue infiltration
3. Leukostasis
4. Constitutional symptoms
5. Other (DIC) L.Promielositik & L.Monositik

Usually short duration of symptoms

1. Marrow failure

Neutropenia : Infections, sepsis

Anemia
: Fatigue, pallor
Thrombocytopenia : Bleeding

2. Infiltration of tissues/organs

Enlargement of liver, spleen, lymph nodes

Gum hypertrophy
Bone pain
Other organs: CNS, skin, testis, any organ

Gum hypertrophy

ingival Infiltration in Monocytic

AML M4 eos) Variant of AML

Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright 2008 Massachusetts Medical Society

Chloromas

A
B
C

NEJM 1998

yeloid sarcoma
Extramedullary disease (myeloid sarcoma)
Can also have involvement of lymph nodes,
intestine, mediastinum, ovaries, uterus

3. Leukostasis

Accumulation of blasts in microcirculation

with impaired perfusion
Lungs : hypoxemia, pulmonary infiltrates
CNS : stroke
Only seen with WBC >> 50 x 109/L

4. Constitutional symptoms

Fever and sweats common

Weight loss less common

Laboratory features

WBC usually elevated, but can be

normal or low
Blasts in peripheral blood
Normocytic anemia
Thrombocytopenia
Neutropenia
DIC

Bone marrow in acute leukemia

Necessary for diagnosis

Useful for determining type
Useful for prognosis
Acute leukemias are defined by the
presence of > 20% blasts in bone marrow
(% of nucleated marrow cells)

ML

ALL

Distinguishing AML from ALL

Light microscopy
AML : Auer rods, cytoplasmic granules
ALL : no Auer rods or granules.

Flow cytometry
Special stains (cytochemistry)

Auer rods in AML

Treatment of acute leukemias

Choice of Rx is influenced by :
1. Type (AML vs ALL)
2. Age
3. Curative vs palliative intent

Principles of treatment
1. Combination chemotherapy
First goal is complete remission
Further Rx to prevent relapse
Combination Daunorubicin + Cytarabin

2. Supportive medical care

Transfusions, antibiotics, nutrition

3. Psychosocial support
Patient & family

emotherapy for acute leukemias

Phases of ALL treatment

induction
intensification
CNS prophylaxis
maintenance

Post-remission therapy

Phases of AML treatment

Induction remission
consolidation (post-remission therapy)

atopoietic stem cell transplantation

Permits Rescue from otherwise

excessively toxic treatment
Additional advantage of graft-vs-leukemia
effect in allogeneic transplants
Trade-off for allogeneic transplantation:
greater anti-leukemic effect but more toxic

Prognosis

Children w/AML have poorer prognosis than

w/ALL
WBC < 20,000, mm is more favorable the
20-49,000 mm, > 50 worst prognosis
Age, tumor burden at time of diagnosis,
drug sensitivity of cells are more important
prognostic indicators than cell morphology

Chronic Myeloid Leukemia

Definition of CML :
Is a clonal disorder of a pluripotent
stem cell and is classified as one of the
myeloproliferative disorder.
Constitute six different types of leukemia.
The disease accounts for around 15% of
leukemia.

Types of Chronic CML:

Type

name

(CML,Ph+)(chronic granulocytic leukemia)

(CML,Ph-)

Juvenile CML

Chronic neutrophilic leukemia.

Esinophilic leukemia

Chronic myelomonocytic leukemia

Philadelphia chromosome :

Is the chromosome which result from the

t(9;22)(q34;q11)part of the Abelson

proto-oncogene ABL is moved to the BCR
gene on chromosome 22 & part of
chromosome 22 moves to chromosome 9.

The abnormal chromosome 22is the Ph.

Fig

44

Clinical Presentation:

It can occur in any age .But the most age

presentation is between 40-60.
Symptoms related to hyper metabolism:
(weight loss,lassitude,anorexia or night
sweats).
(Gout or renal impairment caused by
hyperuriceamia ).
Bone marrow failure:
Anemia.

Cont:

Bruising ,epistaxis,menorrhagia or
hemorrhage from any site because of
platelet dysfunction.

Organ infiltration:
Splenomegally almost always present and
is frequently massive.
Rare symptoms include visual disturbance.

Investigation:

CBC:
Wbc is usually >50X10/l & some times
>500X10/l.
Normocytic normochromic anemia.
Platelets .

peripheral blood film:

circulating basophil.

Cont:

Neutrophil alkaline phosphatase score is

invariably low.
BM: is hyper cellular with granulopoietic
predominance.
Cytogenetics: ph chromosome.
Serum vitamin B12 & vitamin b12-binding
capacity are.
Serum uric acid is usually.

Phases of CML:

1. Chronic phase :
2. Accelerated phase:
3. Blast phase:

Treatment:

Chemotherapy:
Tyrosine kinase inhibitor:
Interferon-.
Stem cell transplant.

Course & prognosis:

Usually shows excellent response to

chemotherapy in the chronic phase.

Death usually occur from terminal acute

trasformation ,hemorrhage or infection.

Chronic lymphocytic Leukemia

CLL is the most common of the chronic

lymphoid leukemias.
Peak incidence between 60-80yrs.
It is characterize by chronic persistent
lymphocytosis which later infiltrate
different organs.

Clinical presentation:

The disease occurs in older subject,rare

before 40 yrs.
M:F is 2:1.
Many cases discover routinely.
Symmetrical enlargement of superficial
lymph node is the most frequent clinical
sign.
Feature of anemia.

Fig(1)

Cont:

Splenomegaly & hepatomegaly usual in

later stage.

Repeated bacterial or fungal infection.

Thrombocytopenia.

Investigation:

CBC:
Wbc:.
Diff:lymphocytosis ,the absolute lymphocyte
count is>5x109/l and may be up to 300x109/l
or.More.
Anemia : normocytic normochromic anemia
is present in later stages, autoimmune
haemolysis.
Platelets : thrombocytepenia may occur.

Cont:
Blood film:
70-99% of white cells mature lymphocyte.
Smudge or smear cells also present.
Immunophenotyping:
Shows that the lymphocyte are B
cells(CD19)expressing one form of light
chain( or only)cells are also
CD5&CD23+ve.

Cont:

Bone marrow aspiration:

Lymphocytic replacement of normal
marrow.
Immunoglobulinelectrophoresis:
of Ig more marker with advance disease.
Cytogenetic :
The 4 most common abnormalities are;
deletion of13q14,trisomy 12,deletion
of11q23&structural abnormality of 17p
involving the p53 gene.

Treatment :

Since cure is rare,the treatment aim is

only symptoms control.
Indication for treatment:
Troublesome organomegaly.
Hemolytic episodes.
Bone marrow suppression.

Modality of Treatment:

1-chemotherapy:
Chlorambucil: 6mg/m2 daily for 10 days monthly for 2-4
month after which remission will be obtain.
Fludarabine:more effective as single agent.
Corticosteroid :indicated in bone marrow failure,also
indicated in autoimmune hemolytic anemia and
thrombocytopenia.

Cont:

2-Radiotherapy:
Is useful in reducing the size of lymphnode
not responsive to chemo.
3-Monoclonal antibody:
Both campath IH(anti CD52)and
Rituximab(anti CD20)produce response
in proportion of patient.

Cont:

4-Splenectomy :
For immune-mediated cytopenia or painful
bulky splenomegally.
5-immunoglobulin replacement:
250mg/kg /month by IV for patient with
hypogammaglobulinemia and recurrent
infection.
5- Stem cell transplant:
Under clinical trial.