Acute Leukemia

Acute Myelogenous Leukemia

Sahyuddin

Dept. of Int. Medicine, Faculty of Medicine , Hasanuddin Univ.

 Outline

1 Concepts, biology
2 Epidemiology

3 Clinical & lab. manifestations

4 Diagnosis

5 Management and prognosis

 Leukemia

 Is a malignant hematologic disorder characterized

by a proliferation of abnormal white cells,
differentiatiob block , that infiltrate the bone
marrow, peripheral blood & organs
 4 main types of leukemia
 Acute or chronic
 Myelogenous or Lymphocytic
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 CLL Lymphomas MM
naïve

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML Myeloproliferative disorders

Hematopoietic Myeloid Neutrophils

progenitor
stem cell
Eosinophils

Basophils

Monocytes

Platelets

Red cells
 Types of Leukemia

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

208,080 = Total number of leukemia patients today

Three-hit model of leukemogenesis

Gain of function mutations Loss of function of Loss of Apoptosis

of tyrosine kinases transcription factors
needed for differen. eg.:
eg. FLT3, c-KIT mutations
N- & K-RAS mutations eg. AML1-ETO Bcl-2 over expression
BCR-ABL CBFb-SMMHC
TEL-PDGFbR PML-RARa

enhanced differentiation Suppression

proliferation + block + apoptosis

Acute
Leukemia
 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 AML normal

Blasts q q
Promyelocytes q
Myelocytes q
Metamyelocytes q
Bands q
Neutrophils q # q
Significance 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 AML
 Mainly children  Mainly adults
M>F M>F
 Curable in 70%  Curable in minority
of children of adults
 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
___________________________________
 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. Leukostasis
3. Tissue infiltration
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
 Gingival 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
 Myeloid 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 : Dyspnea, chest pain, hypoxemia,
pulmonary infiltrates
 CNS : Headaches, altered mentation,
ocular symptoms, stroke
 Priapism
 Myocardial infarction
 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)
AML
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
 Chemotherapy for acute leukemias

 Phases of ALL treatment

 induction
 intensification
 CNS prophylaxis Post-remission therapy

 maintenance
 Phases of AML treatment
 Induction remission
 consolidation (post-remission therapy)
Hematopoietic 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 Myelogenous Leukemia

Sahyuddin
 I. Introduction :

 Chronic Myelogenous Leukemia ( CML )

- Belongs to Myeloproliferative Disorders
- Adult & elderly
- Relatively slow clinical progression
- Relatively better live expectancy than
acute leukemia.
 II. Etiology of CML :

 Not clear yet.

- Cytotoxic drugs ?
- Viruses ?
- Radiation ?
- Pollutants ?
 III. Clinical picture of CML :
 Adult & elderly
 Male > female
 Splenomegaly ( Schuffner VII / VIII )
 Sometimes hepatomegaly
 Complaints : abd. fullness/dyspneu
abdominal mass
early satiety
Clinical progression in CML :

I. ChronicPhase
relatively stabil, lasting months / years

II. Accelerated Phase

decreased clin condition, weeks /months
blood smear : increased of blast cells

III. Blast Crisis Phase

worsened condition & laboratory findings
as an acute leukemia
 Pathogenesis of CML :

 Majority : Philadelphia chromosome (+)

 t (9:22) : resiprocal transversion of genetic
material from chrom 9 to 22 (vv)
 new abnormal protein
 initiating abnormal proliferation of myeloid cells
in bone-marrow  CML.
Sebuah Kariotip dengan translokasi kromosom 9 dan 22 : Philadelphia chromosome
 IV. Diagnosis of CML :

 Clinical pictures : adult/elderly, splenomegaly

 Routine blood : Hb low/normal/increased
Platelet normal / increased
WBC quite increased
Blood smear : immature WBC ( blast cells ),
intermediate (rods),mature WBC
granulocytes all are increased
 Peripheral blood smear :

 Blast cells < 5 % or

 Blast + promyelocytes < 10 %

Other marker : Leukocyte Alkaline Phospatase <

 Bone marrow aspiration :

 Increased of BM cellularity ( hypercellularity )

 Common BM appearance :
- erythropoiesis normal / increased
- megakaryopoiesis normal / increased
- granulopoiesis : hyperactive
( increased of granulocytes in all of stage
of maturation )
BMA in the CML case ( hypercellularity and increased of granulocytes in all of stage
of maturation)
 BMA in the CML case
( hypercellularity & increased of granulocytes in all of stage of maturation)
The differences with Acute Leukemia :

 Acute leukemia : - monotonous picture

(dominated by blast cells/immature)
- hiatus Leukemicus
( very little amount of intermediate form cells )
 V. Treatment of CML (1) :

 1. Glivec : ( Imatinib Mesylate ) per-oral.

Can eradicate Philadelphia chrom.
Very expensive
 2. Myleran : ( Busulfan ) per-oral
Potent & cheap, but toxic
 3. Hydrea : ( Hydroxy Urea ) per-oral
Fair / not expensive
 Treatment of CML (2) :

 4. Alpha Interferon inj :

- imunomodulator & antiproliferative effect
- can be given alone or simultaneously with
Cytosine Arabinoside ( Cytarabin ) inj.
Duration of treatment : 1 – 4 yr
Relatively very expensive
 Treatment of CML (3) :

 New technic :
Peripheral Blood Stem-cell Transplantation ( PBSCT )
 Advantages :
- no need operating theatre
- relatively simple & easy procedure
- low cost
- most ideally procedure (?)
 VI. Prognosis of CML :

 Depends on : - 1. age (>60 yo)

- 2. splenomegaly (>10 cm bac)
- 3. blast > 3 % in blood smear
or > 5 % in BM
- 4. platelet > 700.000 / mm3
All above are Negative Prognosis Factors
 Life expectancy of CML :

 Survival Rate : Median survival 4 yrs

10 % died in the 2nd yr
Yearly after : increased by 20 %
6. Vessel wall with activated endothelium
(colour-enhanced scanning electron micrograph)
This scanning electron micrograph shows how the endothelium has reacted to
compression and damage during surgery. The endothelial cells are activated
and the clotting cascade has started. The formation of thrombin is the pivotal
step in fibrin formation and thrombus development.
 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
1 (CML,Ph+)(chronic granulocytic leukemia)

2 (CML,Ph-)

3 Juvenile CML

4 Chronic neutrophilic leukemia.

5 Esinophilic leukemia

6 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

63
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-a.
 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.