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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