Overview of Chronic Leukemia and Myeloproliferative Neoplasms

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Objectives
:
To understand the general features of Myeloproliferative
neoplasms
To understand the clinicopathological differences
between acute myeloid leukemia (AML) and chronic
myeloid leukemia (CML)
To understand the diagnostic approach for chronic
leukemia and the major differential diagnosis of CML
To recognize the importance of genetic study in diagnosis
and treatment of CML.
 To understand the general aspect of myelodysplastic
syndrome (MDS) including definition, pathogenesis,
clinical features and prognosis
To understand the general aspect of chronic
myelomonocytic leukemia (CMML) including definition,
pathogenesis, clinical features and prognosis.
 
 
 
 
 
 
 
 
 
References:
436 girls & boys’ slides
435 teamwork slides
 
 
 
Do you have any suggestions? Please contact us!
@haematology436                            E-mail: Haematology436@gmail.com
                              
or simply use this 
form
Chronic Leukemia
 
Chronic leukemias
● Heterogeneous group of hematopoietic neoplasms
●Uncontrolled proliferation and decreased apoptotic activity with variable degrees of
differentiation 
this the main difference between MPN and MDS where MDS there is
proliferation but apoptosis is enhanced
Composed of relatively mature cells 
the retain the ability to differentiate unlike AM
L
● Indolent 
(progress slowly)
(If untreated, the course is in 
months or years,
 
patient
might be asymptomatic for years)
● Occurs mainly in adults
 
 
 
 
 
 
 
 
 
 
The cells affected or the disease manifestation is in this stage
 
-
Main Types of Leukemia:-
 
HEMATOLOGY TEAM 436
 
2
 
When we have 
more than 20% 
blasts it is 
acute
 leukemia, and when there is 
less than 20%
 it
is 
chronic
 leukemia
 
Acute
leukemia
 
Chronic
leukemia or
lymphoma
 
-
Chronic Myeloid Leukemia (CML):
Stem cell MPN.
Predominant 
proliferation 
of 
granulocytic cells
.
Consistently associated 
with the 
BCR-ABL1 fusion gene 
(Most important feature of CML)
located 
in 
the 
Philadelphia (Ph)  
chromosome 
(abnormal 
chromosome) 
which 
results
from 
t(9;22)
The main types of cells that found in CML are: Myelocyte & Neutrophils
 
-
Before we start you have to know the classification of Myeloid Neoplasm
According to WHO :-
 
Main divisions
chronic myeloid
leukemia (CML)
 
Sub divisions
Chronic myelomonocytic
leukaemia(CMML)
 
-
Myeloproliferative Neoplasms (MPN):-
Malignant proliferation of myeloid cells (maturing cells) in blood and bone marrow.
Occur mainly in 
adults
Slow onset and long course
 (may be silent)
 
MPN features:- 
important!
Cytoses
 
increase in the number of cells (may be more than one lineage)
Organomegaly (mainly splenomegaly) 
due to accumulation of the cells and the extra
hematopoietic role of the spleen
High uric acid 
the cells are defective and destroyed forming the uric acid from the
purines of DNA
Hypercellular bone marrow 
the bone marrow is about 50% cellular but in case of
MPN proliferation ( malignancy) increases and could lead to fibrosis
Progression to acute leukemia ( mainly AML) 
the parameter is blast count if above
20% it is considered as acute
 
HEMATOLOGY TEAM 436
 
3
 
.
 
-
Clinical Presentation:
Asymptomatic 
presentation (20-40%)
Routine CBC : 
marked leukocytosis
Common symptoms : 
Fatigue ,weight loss 
or 
night sweating
Abdominal 
discomfort 
due 
to splenomegaly
Splenomegaly 
(Massive
) 
الدمام عنده كبير !!
 
Translocation of the ABL segment on chromosome 9 to BCR locus on
chromosome 22 fusing together in the chromosome the result is named
Philadelphia chromosome 22 chromosome
 
This fusion gene has a binding site for ATP(the activity of Imatinib
treatment is binding to this site and blocking it) that initiate the process
of phosphorylation- activation- by tyrosine kinase of a substrate like
JAK-2 involved in the transduction pathway that give rise to a state of
uncontrolled proliferation
 
 
-
Pathogenesis of Chronic myeloid leukemia:
 
It acts like ON/OFF
Button in many
processes and
proliferation is one
of them
 
Splenomegaly
 
HEMATOLOGY TEAM 436
 
4
 
These are normally
present in the blood but if
we find any of the
precursors it is 
abnormal.
How do they enter the
blood? The bone marrow
becomes hypercellular and
the cells become crowded
and start leaving and enter
the blood.
 
Very important finding!
 
- 
Neutrophil Alkaline Phosphatase (NAP)score:
 
Cytochemical stain that 
estimate the 
amount of alkaline phosphatase enzyme 
in
neutrophils
.
CML dysfunction cell do not have alkaline phosphate . But leukmoid is function cell
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.
CML= Low
Leukemoid = High
 
-
Main Differential Diagnosis:
 
(كيف أفرق بين الكرونيك مايلويد لوكيميا والأمراض الثانية)
:-
 
1.
Chronic myelomonocytic 
leukemia (CMML)
 
(
monocytosis 
,
BCR-ABL –ve
)
 
.
 
2.
Leukemoid 
reaction
: Leukocytosis 
due 
to physiological response to stress 
or 
infection
.
 
HEMATOLOGY TEAM 436
 
5
 
-
Chronic Myeloid Leukemia
 Phases:- 
المريض ينتقل من مرحلة لمرحلة اذا ما علجناه وكل مرحلة اخطر من اللي قبلها
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
Treatment:
 
1
st line
 
targeted
 therapy (tyrosine kinase inhibitors like
 
Imatinib)
-Excellent 
response 
(5 
years survival 
90%) 
2nd line therapy If 
no response
 
:
stem cell
 
transplantation.
This drug bind to ATP site of BCR-ABL competing with tyrosine kinase stopping its action
 
مثال لتسهيل المفاهيم: تخيل ان فيه مصنع سيارات صغير في مدينة صغيرة كان يصنع على قد حاجة المدينة 10 سيارات
في اليوم مثلا (نورمال) فجأة جاء ميوتيشن داخل المصنع فـ زاد الإنتاج من 10 سيارات صار ينتج 100 سيارة في اليوم
، اولاً بتزدحم شوارع المدينة بالسيارات                        وثانياً بيزدحم المصنع نفسه لأن الإنتاج فوق طاقته
الاستيعابية                    هذا هو اللي يصير في         .
اما اللي يصير في        نفس مثال المصنع اللي فوق بس لما صار ميوتيشن هنا انهبلت المكائن وصارت تصنع سيارات
مشوهة مثلاً تسوي سيارة بمكينتين أو سيارة بدون قير أو بدون كفرات فلما تطلع للشوارع بتخرب اول ما تطلع فبيجي
المرور                   ويوقف هذي السيارات ويتلفها لأن ما منها فايدة فبيصير عندي مصنع قاعد يصنع سيارات
خربانة ومزدحم من كثرتها                ،أما الشوارع بتكون فاضية لأن المرور قاعد يتلف السيارات
 
CML
 
MDS
 
(Apoptosis)
 
HEMATOLOGY TEAM 436
 
6
 
(Peripheral blood)
 
)
Bone Marrow
(
 
)
Bone Marrow
(
 
(Peripheral blood)
 
- MDS 
subtypes 
classified 
according to:
-
 
1- Blast count
. 
prognosis depends on the number of blast  the higher blast count
prognosis is worse.
2- 
Degree of
 
dysplasia.
3- 
Genetics:
 
Variable genetic 
abnormalities 
mainly 
-5
q
 
(
good prognosis
 
more in
female)
 
, 
-7
q 
(
bad
 
prognosis
 more in male)
 
- 
Treatment
:
supportive +/-
 
chemotherapy
 
- Myelodysplastic syndromes (MDS):- 
ضروري تقرون المثال نهاية السلايد اللي قبل هذا
Group of myeloid neoplasm's 
characterized
 
by:
1- Peripheral cytopenia 
(low 
Hemoglobin 
±
 low 
WBC 
& low
 
PLT).
2- Dysplasia 
(abnormal
 
morphology).
 
خلايا مشوهة
3
Ineffective
 hematopoiesis 
(hypercellular bone marrow
)
4
Progression to AML 
(preleukaemic disease).
5
Enhanced 
apoptosis
. 
in the 
per
i
pheral blood cause
 
cytopenia
Normal
Dysplastic
 
No Granules! and 
 number of lobes
BM
: Hypercellular
with dysplasia
Blood: Pancytopenia with dysplasia.
 
- Chronic Myelomonocytic Leukemia (CMML)
- Clonal Hematopoietic 
malignancy characterized by 
proliferation of both monocytes
and
 
neutrophils it is classified as MDS/MPN disease.
MDS/MPN disease:
 
has both 
(takes features from both)
 :-
-Features of MDS (dysplasia & enhanced
 
apoptosis).
-Features of MPN ( marked 
proliferation).
Philadelphia chromosome 
must be
 
negative.
Blast must be 
less than
 
20%,
Aggressive course (survival 
rate around 
2.5
y)
Treatment: 
Chemotherapy
 
±
SCT
 
HEMATOLOGY TEAM 436
 
7
 
(if it is +ve then it is CML)
 
(more than 20% 
 acute)
 
 proliferation - 
 apoptosis = Ineffective hematopoiesis
 
- Difference between Chronic Myeloid Leukemia & Acute Myeloid Leukemia
Effective proliferation
Ineffective proliferation
 
HEMATOLOGY TEAM 436
 
8
 
M
C
Q
s
:
 
T
e
a
m
 
m
e
m
b
e
r
s
:
A
b
d
u
l
l
a
h
 
A
l
-
T
w
e
r
k
i
Z
i
a
d
 
A
l
-
A
n
a
z
i
 
1. The mutation responsible for the effects and manifestations of CML is :
A.   t(15;17)
B.   Philadelphia chromosome
C.   Chromosome 5 monosomy
D.   Chromosome 7 monosomy
 
2. The distinguishing feature of AML is:
A.
Blast > 20%
B.
Cytosis
C.
bone marrow failure
D.
Hepatomegaly
 
3. A 55 year old patient came to the clinic for a regular check up. He does not complain
of any symptoms. His results are as follows:
High WBC count, Mainly bands, High NAP score. What is the most likely diagnoses:
A.
CML
B.
AML
C.
CMML
D.
infection
 
4. CMML is presented with cytopenia and decreased apoptosis:
A.
True
B.
False
 
5. Which one of the following genes Must be positive in CML?
A.
APC
B.
BCR-ABL
C.
REKA-B
D.
P53
 
Answers: 1. B , 2. A , 3. D , 4. B, 5. B
 
Team Leaders
 
Abdulaziz Al-Hussainy
Safa Al-Osaimi
 
Good Luck !
 
HEMATOLOGY TEAM 436
 
9
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This comprehensive guide covers the general features, diagnostic approach, and clinicopathological variances between acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), along with insights into myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). It emphasizes the importance of genetic studies in CML diagnosis and treatment, presenting key distinctions and classifications within myeloid neoplasms. Various types of leukemia, including acute and chronic forms, are discussed, shedding light on the unique characteristics and progression of chronic leukemias.


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  1. Chronic Leukemia Objectives: To understand the general features of Myeloproliferative neoplasms To understand the clinicopathologicaldifferences between acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) To understand the diagnostic approach for chronic leukemia and the major differential diagnosis of CML To recognize the importance of genetic study in diagnosis and treatment of CML. To understand the general aspect of myelodysplastic syndrome (MDS) including definition, pathogenesis, clinical features and prognosis To understand the general aspect of chronic myelomonocyticleukemia (CMML) including definition, pathogenesis, clinical features and prognosis. Color code: Important. Extra. Doctor s Notes References: 436 girls & boys slides 435 teamwork slides Editing file Do you have any suggestions? Please contact us! @haematology436 E-mail: Haematology436@gmail.com or simply use this form

  2. HEMATOLOGY TEAM 436 Chronic leukemias Heterogeneous group of hematopoietic neoplasms Uncontrolled proliferation and decreased apoptotic activity with variable degrees of differentiation this the main difference between MPN and MDS where MDS there is proliferation but apoptosis is enhanced Composed of relatively mature cells the retain the ability to differentiate unlike AML Indolent (progress slowly)(If untreated, the course is in months or years, patient might be asymptomatic for years) Occurs mainly in adults When we have more than 20% blasts it is acute leukemia, and when there is less than 20% it is chronic leukemia Acute leukemia Chronic leukemiaor lymphoma The cells affected or the disease manifestation is in this stage -Main Types of Leukemia:- Acute Chronic Lymphoid ALL LPN(CLL) MPN/MDS (CML) Myeloid AML Acute Mixed Biphenotypic Acute Non 2 Undifferentiated

  3. HEMATOLOGY TEAM 436 -Before we start you have to know the classification of Myeloid Neoplasm According to WHO :- Myeloid Neoplasm Main divisions Myeloproliferative neoplasms (MPN) Myelodysplastic syndromes (MDS) acute myeloid leukemia (AML) MDS/MPN Sub divisions chronic myeloid leukemia (CML) Chronic myelomonocytic leukaemia(CMML) -Myeloproliferative Neoplasms (MPN):- Malignant proliferation of myeloid cells (maturing cells) in blood and bone marrow. Occur mainly in adults Slow onset and long course (may be silent) MPN features:- important! Cytoses increase in the number of cells (may be more than one lineage) Organomegaly (mainly splenomegaly) due to accumulation of the cells and the extra hematopoietic role of the spleen High uric acid the cells are defective and destroyed forming the uric acid from the purines of DNA Hypercellularbone marrow the bone marrow is about 50% cellular but in case of MPN proliferation ( malignancy) increases and could lead to fibrosis Progression to acute leukemia ( mainly AML) the parameter is blast count if above 20% it is considered as acute -Chronic Myeloid Leukemia (CML): Stem cell MPN. Predominant proliferation of granulocytic cells. Consistently associated with the BCR-ABL1 fusion gene (Most important feature of CML) located in the Philadelphia (Ph) chromosome (abnormal chromosome) which results from t(9;22) The main types of cells that found in CML are: Myelocyte& Neutrophils 3

  4. HEMATOLOGY TEAM 436 These are normally present in the blood but if we find any of the precursors it is abnormal. How do they enter the blood? The bone marrow becomes hypercellular and the cells become crowded and start leaving and enter the blood. -Pathogenesis of Chronic myeloid leukemia: It acts like ON/OFF Button in many processes and proliferation is one of them Translocation of the ABL segment on chromosome 9 to BCR locus on chromosome 22 fusing together in the chromosome the result is named Philadelphia chromosome 22 chromosome This fusion gene has a binding site for ATP(the activity of Imatinib treatment is binding to this site and blocking it) that initiate the process of phosphorylation-activation-by tyrosine kinase of a substrate like JAK-2 involved in the transduction pathway that give rise to a state of uncontrolled proliferation . -Clinical Presentation: Asymptomatic presentation (20-40%) Routine CBC : marked leukocytosis Common symptoms : Fatigue ,weight loss or night sweating Abdominal discomfort due to splenomegaly Splenomegaly (Massive) Splenomegaly 4 !! Very important finding!

  5. HEMATOLOGY TEAM 436 -Main Differential Diagnosis: ) ( :- 1.Chronic myelomonocytic leukemia (CMML) (monocytosis ,BCR-ABL ve). 2.Leukemoid reaction: Leukocytosis due to physiological response to stress or infection. CML Leukaemoid Age Adult Any age WBC count High High but <100,000 Mainly myelocytes and segmented and neutrophils. Differential Mainly Bands Morphology Hypogranular Toxic + Splenomegaly -/+ (massive) NAP score Low High +ve CML BCR/ABL -ve Onset Chronic Acute - Neutrophil Alkaline Phosphatase (NAP)score: Cytochemical stain that estimate the amount of alkaline phosphatase enzyme in neutrophils. CML dysfunction cell do not have alkaline phosphate . But leukmoid is function cell . CML= Low Leukemoid = High 5

  6. HEMATOLOGY TEAM 436 - Chronic Myeloid Leukemia Phases:- Leukocytosis(12-1000 10 /L). Mainly neutrophils and myelocytes. Blasts 10% ,Basophils 20% Stable course (years) Chronic phase Increasing counts 10-19% blasts (basophils 20%) (Why 19% ? because if it is 20 it will be AML) Unstable course (months) Accelerated phase ( 20% blasts = AcuteLeukemia) (80% AML & 20% ALL) Coarse (Weeks) Blastic phase (AML or ALL) - Treatment: 1st line targetedtherapy (tyrosine kinase inhibitors like Imatinib) -Excellent response (5 years survival 90%) 2nd line therapy If no response : stem celltransplantation. This drug bind to ATP site of BCR-ABL competing with tyrosine kinase stopping its action 10 10 100 : ( )Bone Marrow( ) . (Peripheral blood) CML MDS (Apoptosis) (Peripheral blood) )Bone Marrow( 6

  7. HEMATOLOGY TEAM 436 - Myelodysplastic syndromes (MDS):- Group of myeloid neoplasm's characterizedby: 1- Peripheral cytopenia (low Hemoglobin low WBC & lowPLT). 2- Dysplasia (abnormal morphology). 3 Ineffective hematopoiesis (hypercellular bone marrow) 4 Progression to AML (preleukaemic disease). 5 Enhanced apoptosis. in the peripheralblood cause cytopenia Dysplastic Normal No Granules! and number of lobes BM: Hypercellular with dysplasia Blood: Pancytopenia with dysplasia. proliferation - apoptosis = Ineffective hematopoiesis - MDS subtypes classified according to:- 1- Blast count. prognosis depends on the number of blast the higher blast count prognosis is worse. 2- Degree of dysplasia. 3- Genetics: Variable genetic abnormalities mainly -5q (good prognosis more in female) , -7q (bad prognosismore in male) -Treatment: supportive +/- chemotherapy - Chronic Myelomonocytic Leukemia (CMML) - Clonal Hematopoietic malignancy characterized by proliferation of both monocytes and neutrophils it is classified as MDS/MPN disease. MDS/MPN disease: has both (takes features from both) :- -Features of MDS (dysplasia & enhancedapoptosis). -Features of MPN ( marked proliferation). Philadelphia chromosome must benegative. Blast must be less than 20%, Aggressive course (survival rate around 2.5y) Treatment: Chemotherapy SCT (if it is +ve then it is CML) (more than 20% acute) 7

  8. HEMATOLOGY TEAM 436 Effective proliferation Ineffective proliferation - Difference between Chronic Myeloid Leukemia & Acute Myeloid Leukemia CML AML Indolent course . Symptoms appear after a long period onset Rapid Three phases 1.Chronic phase 2.Accelerated phase 3.Blastic phase phases No known phases Gene mutation known as Philadelphia gene T(9;22) Many mutations e.g. t(15;17) etiology Marked ( sometimes severe or massive especially spleen) hepatosplenomegaly moderate Blasts Fewer than 20% > 20% Cell count Cytosis Cytopenia 8

  9. HEMATOLOGY TEAM 436 MCQs: 1. The mutation responsible for the effects and manifestations of CML is : A. t(15;17) B. Philadelphia chromosome C. Chromosome 5 monosomy D. Chromosome 7 monosomy 2. The distinguishing feature of AML is: A. Blast > 20% B. Cytosis C. bone marrow failure D. Hepatomegaly 3. A 55 year old patient came to the clinic for a regular check up. He does not complain of any symptoms. His results are as follows: High WBC count, Mainly bands, High NAP score. What is the most likely diagnoses: A. CML B. AML C. CMML D. infection 4. CMML is presented with cytopenia and decreased apoptosis: A. True B. False 5. Which one of the following genes Must be positive in CML? A. APC B. BCR-ABL C. REKA-B D. P53 Answers: 1. B , 2. A , 3. D , 4. B, 5. B Good Luck ! Team members: Abdullah Al-Twerki Ziad Al-Anazi Team Leaders Abdulaziz Al-Hussainy Safa Al-Osaimi 9

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