CML: Chronic Myelogenous Leukemia PDF

CML Chronic Myelogenous Leukemia  CML is a clonal myeloproliferative disorder characterized by Specific genetic abnormality i.e BCR-abl fusion gene Leukocytosis with complete left shift Basophillia Spleenohepatomegaly Myeloproliferative disorder The chronic my...

CML Chronic Myelogenous Leukemia  CML is a clonal myeloproliferative disorder characterized by Specific genetic abnormality i.e BCR-abl fusion gene Leukocytosis with complete left shift Basophillia Spleenohepatomegaly Myeloproliferative disorder The chronic myeloproliferative disorders (CMPDs) are a group of disorders that are considered clonal malignancies of the hematopoietic stem cells. Other common features shared by these disorders are splenomegaly, hepatomegaly, increased leukocytosis, thrombocytosis, and erythrocytosis. These disorders include chronic myelogenous leukemia (CML), myelofibrosis with myeloid metaplasia (MMM), polycythemia vera (PV), and essential thrombocythemia (ET) Synonyms chronic granulocytic leukemia chronic myelocytic leukemia Chronic meylogenous leukemia Classification Based on the presence or absence of Philadelphia chromosome and the cell precursors involved: 1. Classical CML with Philadelphia positive 2. CML without Philadelphia chromosome 3. CML of neutrophilic cell 4. CML of eosinophilic cell 5. CML of myelomonocyte 6. Juvenile CML Epidemiology CML occurs in all age groups Most common in the middle-aged and elderly. Incidence 1–2 per 100,000 people More common in men Represents 15–20% of all cases of adult leukemia in Western populations. Increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki. Long-term exposure to benzene may also contribute Clinical features CML Splenomegaly Gout like symptoms Anaemia Hyperurecemia Bruising Epistaxis Menorrhagia Hemorrhages from other sites Visual disturbance Clinical presentation CML is a malignant blood disorder Involves early haematopoietic cells Become clonally expanded. Disease originates from a single abnormal haematopoietic stem cell which proliferates over months and years so that at diagnosis blood granulocytosis and marrow granulocytopoiesis are apparent. The bone marrow becomes hypercellular. CML may be clinically categorized as follows: Phases of CML Chronic phase Accelerated phase Blast crises Chronic phase…? Chronic phase Approximately 85% of patients are in the chronic phase at the time of diagnosis. Asymptomatic or have only mild symptoms Blast less than 10% No spleenomegaly No anemia thrombocytosis Duration is variable May progress to an accelerated phase Chronic phase 50x Accelerated phase…? Accelerated phase 10–19% blasts in the blood or bone marrow >20% basophils in the blood or bone marrow Platelet count 20% myeloblasts or lymphoblast in the blood or bone marrow Large clusters of blasts in the bone marrow on biopsy Development of a chloroma (solid focus of leukemia outside the bone marrow) Myeloid blast crises 200x Myeloid blast crises 1000x Lymphoid blast crises Pathophysiology Every cell contains chromosomes To be more specific, 23 pairs of chromosomes  Cont… The most important cause of CML is a translocation of two of them: chromosome 9 (the ABL gene) chromosome 22 (the BCR gene). During the division of the cells Cont… These two chromosomes criss -cross, break, and fuse to each other In doing so, they create so called Philadelphia chromosome  Cont… Philadelphia chromosome is made up of two parts Also called BCR-ABL.  Cont… This new gene produces a specific 210kD tyrosine kinase.  Cont… Fusion Tyrosine kinase stimulates uncontrolled production of abnormal blood cells by B/M.  Cont… Normally, WBCs grow and divide in a controlled way In leukemia the process gets out of control, cells divide too quickly but do not mature Too many myeloid cells produced and released into the blood When immature are unable to work properly, known as blasts. Blasts fill up the bone marrow and prevent it from making blood cells properly. Can’t make enough healthy red cells and platelets Leads to an increased risk of infection.  Cont… Enhanced tyrosine kinase activity increases phosphorylation within the cells Regulates metabolic pathways and serve as a receptor for growth factors Oncogenic role of p210 is found in association with increased G-CSF and platelet- derived growth factor Its activation may also suppress apoptosis in hemopoietic cells Lab diagnosis Lab diagnosis 1. CBC 2. Biochemical tests 3. Bone marrow 4. Immunological markers 5. Cytogenetics 6. Molecular assays Lab investigation of CML 1.CBC Blood cell count WBC count ranges between 50 to 500 x109/l Platelet count thrombocytosis  Cont… Peripheral blood film examination Normocytic, normochromic anaemia Neutrophils show left shift Eosinophils normal or some time increased NRBCs are seen Absolute Basophilia  Cont… Moderate thrombocytosis Macrocytosis Hypogranulated myeloid cells  Cont… 2. Bone marrow Hypercellular Increased M:E ratio i.e: 10:1 With mature neoplastic myeloid cells Erythroid precursors decreased Megakaryoblasts normal or increased  Cont… Immature myeloid precursor can be found away from bony trabeculae Blasts not more than 10% in chronic phase Eosinophilic and basophilic granules are abnormal Nuclear to cytoplasmic asynchrony  Cont… 3. Biochemical findings Serum Uric acid Increased due to increased purine destruction Serum iron Increased Serum B12 and B12 binding capacity Increased NAP score Decreased Serum LDH Elevated Ca++ increase  Cont… 4. Immunological Markers CD13 + CD14 + CD15 + CD33 +  Specialized Techniques Chromosome analysis i.e. cytogenetics Ph positive BCR-ABL positive