CHRONIC MYELOID LEUKEMIACML

Chronic Myeloid Leukemia

• Abbreviated as CML

• Synonyms:

1- Chronic myelogenous leukemia

2- Chronic granulocytic leukemia

⚫ Is characterized by an unregulated proliferation of myeloid elements in the bone marrow, liver and spleen, leading to marked leukocytosis and organomegaly.

⚫ Incidence

◼20% of all leukemias

◼Primarily affects adults 25-60 years old, with a peak incidence at 40-59.

CML

Etiology

Anything that can induce chromosomal aberrations such as ionizing radiation, alkylating agents, and exposure to other biologically active chemicals.

CML◼Appears to be a clonal hematopoietic stem cell

disorder

⚫90% of CML have a Philadelphia (Ph’) chromosome (reciprocal translocation between chromosome 22 and chromosome 9 by cytogenetic karyotype studies.

⚫A BCR/ABL hybrid/fused gene is created when the breakpoint is in the major breakpoint cluster region of chromosome 22. The gene product (p210) has enhanced tyrosine kinase activity that results in

◼ Increased granulocyte-colony stimulating factor

◼ Increased platelet derived growth factor

◼Suppression of apoptosis in hematopoietic cells

⚫The remaining 5-10% are positive for the translocation using more sensitive DNA studies such as RT-PCR or FISH techniques.

⚫The Ph’ chromosome is found in all hematopoietic cells except T lymphocytes.

⚫The Ph’ cells have a growth advantage over normal cells

At diagnosis

• The following features will alert us toward CML:

• 1- Splenomegaly

• 2- Granulocytic Leukocytosis

• 3- Presence of Ph chromosome in all leukemic cells.

• Note: Normal cells lack Ph Ch.

CML is a triphasic disease

1- Chronic phase: Stable phase that lasts usually from 2 to 6 yrs, but it may take as long as 15 or 20 yrs then it will enter:

2- Accelerated phase: It involves increase in blast cells. After short period: months to one yr, it will transform to:

3- Acute blastic transformation: AML or ALL, or Biphenotypic

Clinical Course: Phases of CML

Chronic phase

Median 4–6 yearsstabilization

Accelerated phase

Median durationup to 1 year

Blastic phase (blast crisis)

Median survival3–6 months

Terminal phase

Advanced phases

In CML usually

• Myelopoiesis that involve primarily the granulocytic series is increased.

• Also, common, megakaryopoiesis is increased and manifested as high PLT count.

• But erythroid hyperplasia and polycythemia occur only rarely

CML cells

• CML cells are very sensitive to G-CSF and IL3.

• CML cells produce elastases that inhibit response of normal cells to G-CSF.

• Also CML cells are insensitive to inhibitory growth factors.

• Moreover, CML cells are less adhesive to endothelium due to abnormality in Integrins.

Cytogenetics

• In more than 90% of CML cases Philadelphia chromosome is present in the leukemic cells. This leads to the formation of BCR-ABL gene that would be translated to a novel chimeric protein with oncogenic activity.

Philadelphia Chromosome

1 2 3 4 5

6 7 8 10 119 12

13 14 15 16 17 18

19 20 21 22 x Y

PHILADELPHIA CHROMOSOME t(9;22)

Spectral Karyotyping

BCR-ABL

• ABL gene is normally found in Ch. 9.

• This gene normally encodes for a tyrosine kinase.

• But after fusion with BCR gene on ch.22, the chimeric protein (P210 kda) oncoprotein has very far greater TK activity than the normal ABL gene product.

Some patients

• Some patients have in addition to Ph chromosome they have additional chromosomal abnormalities, that would worsen the prognosis.

Accelerated phase

• Acceleration looks like to involve additional genetic abnormalities. Especially in ch.8 (trisomy), ch.17 and 19.

Clinical Findings

• Symptoms are related to:

– Splenomegaly

– Hemorrhage from different sites

– Anemia

50% of CML cases

• 50% of CML cases are diagnosed accidentally:

– During pregnancy

– Before blood donation

– After RTA

– Other causes that let the patient to visit physicians.

Symptoms• Loss of energy-Easy Fatigability

• Shortness of breath on exertion.

• Weight loss

• Night sweat

• Fever

• Hemorrhage from various sites

• Left Upper quadrant discomfort

• Splenomegaly

• Hepatomegaly

• Lymphoadenopathy

• Bone tenderness

Splenomegaly

Hematological Findings• Anemia but not severe

• TWBC range: 20-200x109/L, but counts as high as 1000x109/L have been reported. – ¾ have WBC counts > 100 x 109/L

• BF shows left shift- full spectrum of normally appeared cells in the granulocytic series (but they are not functionally normal, however), ranging from blast forms to mature neutrophil.

• But myelocytes and polymorphs predominate- Myelocyte peak, and PMN peak

Cont’d Hematological Findings

• Blasts are usually less than 10%.

• Basophilia

• For your knowledge: Basophilia may alert us for a malignancy.

• Eosinophilia

• PLT are usually increased (300-600 x109/L), but may be normal or decreased.

Cont’d Hematological Findings

• Occasional NRBC may be seen

• ALP/NAP is absent or low.

Interphase FISH

BCR/ABL Fusion

Normal

signals

Fused BCR/ABLChromosome 9

ABL gene

Ch# 22

BCR gene

mRNA

minor

major

Case Study

➢ RBC= 2.96 x1012/L

➢ WBC= 230.0 x109/L

➢ Hemoglobin = 9.9 g/dl

➢ Hematocrit = 30.2%

➢ Platelet= 105x109/L

➢ WBC Histogram is giving abnormal flags

➢ PLT Histogram is giving abnormal flags

➢ RBC Histogram is giving abnormal flags

Manual WBC Differential Count

• Segmented Neutrophils= 30%

• Band Neutrophils = 16%

• Metamyelocytes= 10%

• Myelocytes= 13%

• Promyelocytes= 4%

• Blasts= 1%

• Basophils= 7%

• Eosinophils= 2%

• Lymphocytes= 17%

• NRBC’s/100 cells= 3

Advance disease: Accelerated phase diagnosis

• Accelerated phase:

• Blasts: 10-19% in PB and/or BM

• More basophilia >20%

• Thrombocytopenia (<100) or thrombocytosis (>1000)

• Increase in splenic size

Blast Transformation Diagnosis

• Blasts >20% on PB or BM

OR

• Clusters of blast cells in BM

OR

• Both

• ~ 70% of patients have blasts classifiable generally as myeloid, AML.

• ~20% of patients have lymphoid blast cells.

• ~10% of patients the blast cell transformations have mixed myeloid and lymphoid characteristics, biphenotypic

Of course you remember…….Say yes yes

CML: chronic phase

Accelerated phase

Blast Transformation

CML Management.

• Tyrosine kinase inhibitors (GLEEVEC® )

• Is indicated for the treatment of patients with CML in blast crisis, accelerated phase, or in chronic phase.

Course and prognosis.

• CML usually shows an excellent response to chemotherapy in the chronic phase.

• The median survival is 5-6 years.

• Death usually occurs from terminal acute transformation or from recurrent hemorrhage or infection.

Variants of CML.

• Ph-negative CML.• About 5% of patients with hematologically

acceptable CML lack the Ph chromosome.• ~1/2 of these patients have a BCR-ABL gene that is

molecularly identical to the BCL-ABL gene of Ph-positive CML.

• These patients have a clinical course similar to those with Ph-positive CML.

Variants of CML.

• Ph-negative CML (cont)

• Patients with no BCR-ABL gene frequently have hematological features that are subtly different from Ph-positive disease.

• They may lack basophilia, lack myelocyte peaks in the leukocyte differential count or show dysplastic features.

• Have some degree of monocytosis.

Variants of CML.

• Ph- negative CML (cont.).

• Survival is inferior to that of Ph-positive patients.

Variants of CML.

• Juvenile CML.

• Rare.

• Affecting children <12 year-old.

• Clinical features: anemia, lymphadenopathy with hepatosplenomegaly, skin rashes.

• Lab findings – leukocytosis with variable numbers of blast in the peripheral blood. Marrow is hypercellular but lacks chromosomal abnormalities.

• Responds poorly to standard cytotoxic drugs.

Variants of CML.

• Eosinophilic leukemia.

• High number of immature eosinophilic cells in the blood and marrow.

• May progress to blastic transformation in a manner similar to Ph-positive CML.

CHRONIC LYMPHOCYTIC LEUKEMIA

CLL

⚫ This is predominantly a disease of the elderly; > 90% are over 50 and 2/3 are over 60; male:female ratio is 2:1

⚫ Is characterized by peripheral and bone marrow lymphocytosis and a survival of a few years to > 10 years

⚫ This is a B cell abnormality

⚫ The lymphocytes appear normal, but are immunologically incompetent. However, some functionally normal B cells remain and there is a normal T cell pool

⚫ Etiology

◼Genetic factors are important since it runs in families

⚫ Clinical course

◼The pace of the disease varies and is dependent on the rate of accumulation of abnormal lymphocytes

◼Median survival is 3-4 years, but 10-15% survive > 10years

◼There is no tendency for blast transformation, but complications of advanced disease result from progressive accumulation of long-lived, poorly functional lymphocytes.

⚫ Signs and symptoms

◼Organomegaly and lymphadenopathy

◼Often discovered accidentally

◼Fatigue

⚫ Lab features

◼Absolute lymphocytosis of 10-150 x 109/L

◼Lymphocytes usually appear normal, but they are markedly fragile and smudge cells are seen on the peripheral smear

◼It is not necessary to do a bone marrow biopsy for diagnosis.

◼Anemia occurs late in the disease and may be due to decreased production secondary to marrow infiltration, hypersplenism, or autoimmune hemolytic anemia: the same things may cause neutropenia or thrombocytopenia

◼Hypogammaglobulinemia as the disease progresses

CLL WITH SMUDGE CELLS

Smudge cell

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