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Tabuk University

Faculty of Applied Medical Sciences

Department Of Medical Lab. Technology

3rd Year – Level 5 – AY 1433-1434

HEMATOLOGY – 2, MLT 307

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By/Dr. Walid ZAMMITI

CHRONIC MYELOID LEUKEMIA (CML)

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Objectives Define CML, and know the causes.

Describe clinical signs and symptoms of CML

Classify CML

Explain the prognostic significance of cytogenetic

abnormalities

Cite methods for diagnosing CML

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Whath is CML? Clonal malignant myeloproliferative disorder characterized

by increased proliferation of the granulocytic cell line without

the loss of their capacity to differentiate.

Results in increases in myeloid cells, erythroid cells and

platelets in peripheral blood and marked myeloid

hyperplasia in the bone marrow

Originate in a single abnormal haemopoietic stem cell

accounts for around 15% of leukaemias and may occur at

any age.

Most frequently between the ages of 40 and 60 years.

Progress slowly (runs a slow course)

Not immediately fatal.

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Hematopoiesis : process by which blood cell (by bone marrow) lineages are produced

• WBCs (WHITE BLOOD CELLS, or leukocyte) subdivided into

• Myeloid lineages• Lymphoid lineages

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In CML granulocytes were massively expanded(granulocytes neutrophile, bsophile and monocyte)

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CML Etiology Not clear

Little evidence of genetic factors linked to the

disease

High level radiation/toxin exposure

Increased incidence

Survivors of the atomic disasters at Japan

(Nagasaki & Hiroshima)

Post radiation therapy

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Phyladelphia chromosome

Philadelphia chromosome is an acquired cytogenetic anomaly that is characterizes in all leukemic cells in CML

Reciprocal translocation of chromosome 22 and chromosome 9

90-95% of CML patients have Ph chromosome

Leukaemogenisis

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• BCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9

The resulting fusion gene (BCR-ABL) produce an altered protein believed to play a key role in development of CML

• Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell

BCR-ABL Oncogene

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BCR-ABL Oncogene

• Activity imparts growth advantage to leukaemic cells

- Increased proliferation and cytokine growth- Inhibition of apoptosis - Alteration of adhesion pathways

• BCR-ABL has tyrosine

kinase activity and

participates in intracellular

signal transduction

Symptoms related to hypermetabolism (e.g.weight loss, anorexia or night sweats).

Splenomegaly (massive)

Features of anemia may include pallor and tachycardia.

Bruising, epistaxis or haemorrhage from other sites because of abnormal platelet function.

Gout or renal impairment caused by hyperuricemia from excessive purine breakdown may be a problem.

Rare symptoms include visual disturbances.

In up to 50% of cases the diagnosis is made incidentally from a routine blood count.

40% asymptomatic

CML: Clinical manifestation

Splenomegaly in CML

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Stages of Chronic Myeloid Leukemia

• Disease is biphasic, sometimes triphasic.• Chronic phase

• Accelerated phase

• Acute phase (Blast Phase)

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• Majority (>80%) of cases of CML diagnosed in chronic phase

• Defined by

– Elevated WBC count (≥20 × 109 /L)

– Basophilia & Eosinophilia

– The platelet count is normal or elevated, and may exceed 1,000 × 109/L

Relative lack of blasts (<10% in periferal blood and bone marrow)

The chronic phase

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CML: chronic phase

CML: Peripheral blood film showing various of stages of granulopoiesis including promyelocytes, myelocytes, metamyelocytes and segmented neutrophils

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CML: During the chronic phase, large numbers of

granulocytes are present in the bone marrow and

peripheral blood, but the cells retain normal functions.

It takes between 5

and 8 years after

the formation of

the first CML cell

for clinical signs

and symptoms to

develop.

Myelocyte

Blast

Metamyelocyte

Erytroblast

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Melocyte Megacaryocyte Metamelocyte

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The accelerated phase• Second and intermediate phase of CML • Defining criterion: ≥ 5% to ≥19% blast in blood and

marrow • Persistent thrombocytopenia (<100 × 109/L) or

thrombocytosis (>1,000 × 109/L) despite treatment. • Characterized by general and progressive anemia

my mark onset – Fever unknown origin– Bone pain– Symptoms related to splenomegaly

• Median duration : 3-18 months

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Blast phase • Final disease phase characterized by ≥20%

to ≥30% blasts in peripheral blood or marrow they are lymphoid, usually precursor B lymphoblasts.

• Increasing symptomology

– Fatigue related to progressive anemia

– Bleeding

– Infectious complication

– CNS dysfunction

• Phase rapidly fatal, with median survival ranging from 3 to 12 months .

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The blastic phase, which takes place 2 to 4 years after diagnosis, is characterized by further malignant transformation to immature cells, which act similarly to cells in acute leukemia.

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Basophil Blast

Neutrophils and

precursors Promyelocyte

CML

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Clinical presentaion of Ph+ and CML

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1. Classification

2. Chronic myeloid leukaemia, Ph. positive (CML,

Ph+) (chronic granulocytic leukaemia, CGL)

3. Chronic myeloid leukaemia, Ph. negative (CML,

Ph-) (atypical)

4. Juvenile chronic myeloid leukaemia

5. Chronic neutrophilic leukaemia

6. Eosinophilic leukaemia

7. Chronic myelomonocytic leukaemia (CMML)

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Laboratory Diagnosis1. CBC : TWBCs : Leucocytosis is usually >50 x 109/L and

sometimes >500 x 109/L. A complete spectrum of myeloid cells is seen in the peripheral blood.

2. Platelet count may be increased (most frequently), normal or decreased.

3. Blood film shows various stages of granulopoiesis including promyelocytes, myelocytes, metamyelocytes and band and segmented neutrophils. Basophils are raised.

4. Bone marrow examination : hypercellular with granulopoietic predominance.

5. Biochemical tests may reveal a raised serum uric acid, serum lactate dehydrogenase (LDH) or, less commonly, hypercalcaemia.

6. Ph. chromosome on cytogenetic analysis (conventional or FISH) of blood or bone marrow.

Characteristic feature

CML Leukemoid Reaction (leuckocytoisis)

Age >40 yrs Any age

Leukocytosis >100,000 30,000 – 50,000

Absolute Basophilia Present May not

Splenomegaly Prominent May not

Philadelphia Chromosome

Present Absent

LAP / NAP Very low / Absent High

Transformation to Acute leukemia

Yes No

CML vs Leukemoid Reaction

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Home work• Describe the main differences between CML and AML

• A 50-year-old man presents with a two-month history of fatigue and early satiety. His complete blood count shows the following:WBC:75,000/µL, Hgb:14 g/dL, Platelets:550,000/µL, Differential: Segmented neutrophils (granulocytes): 33,000/µL (normal range: 1,800-7,000/µL) ,Bands:1,500/µL (normal range: 0-700/µL) Metamyelocytes:11,000/µL (normal: 0),Myelocytes:7500/µL (normal: 0),Basophils: 3,750/µL (normal range: 0-200/µL),Lymphocytes:3,000/µL (normal range 1,000-4,800/µL),Monocytes:750/µL (normal range 0-800/µL).

What are the hematologic abnormalities present here?

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Thank you