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Tabuk University

Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3 rd Year – Level 5 – AY 1433-1434 Hematology – 2, MLT 307. Tabuk University. CHRONIC MYELOID LEUKEMIA (CML). By/ Dr. Walid ZAMMITI. Objectives Define CML, and know the causes.

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Tabuk University

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  1. Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3rd Year – Level 5 – AY 1433-1434 Hematology – 2, MLT 307 Tabuk University

  2. CHRONIC MYELOID LEUKEMIA (CML) By/ Dr. Walid ZAMMITI

  3. 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

  4. Whath is CML? • Clonal malignant myeloproliferative disorder characterized by increased proliferationof 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.

  5. Hematopoiesis : process by which blood cell (by bone marrow) lineages are produced • WBCs (WHITE BLOOD CELLS, or leukocyte) subdivided into • Myeloid lineages • Lymphoid lineages

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

  7. 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

  8. Leukaemogenisis 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

  9. BCR-ABL Oncogene • 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

  10. BCR-ABL Oncogene • BCR-ABL has tyrosine kinase activity and participates in intracellular signal transduction • Activityimpartsgrowthadvantage to leukaemiccells • - Increasedproliferationand cytokine growth • - Inhibition of apoptosis • - Alteration of adhesionpathways

  11. CML: Clinical manifestation • 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

  12. Splenomegaly in CML

  13. Stages of Chronic Myeloid Leukemia • Disease is biphasic, sometimes triphasic. • Chronicphase • Accelerated phase • Acute phase (Blast Phase)

  14. The chronic phase • 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)

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

  16. 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. Erytroblast Metamyelocyte Blast Myelocyte

  17. MelocyteMegacaryocyteMetamelocyte

  18. 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

  19. 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 .

  20. 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.

  21. CML Blast Basophil Neutrophils and precursors Promyelocyte

  22. Clinicalpresentaion of Ph+ and CML

  23. Classification • Chronic myeloid leukaemia, Ph. positive (CML, Ph+) (chronic granulocytic leukaemia, CGL) • Chronic myeloid leukaemia, Ph. negative (CML, Ph-) (atypical) • Juvenile chronic myeloid leukaemia • Chronic neutrophilicleukaemia • Eosinophilicleukaemia • Chronic myelomonocyticleukaemia (CMML)

  24. Laboratory Diagnosis • 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. • Platelet count may be increased (most frequently), normal or decreased. • Blood film shows various stages of granulopoiesis including promyelocytes, myelocytes,metamyelocytesand bandand segmentedneutrophils. Basophils are raised. • Bone marrow examination : hypercellular with granulopoieticpredominance. • Biochemical tests may reveal a raised serum uric acid, serum lactate dehydrogenase (LDH) or, less commonly, hypercalcaemia. • Ph. chromosome on cytogenetic analysis (conventional or FISH) of blood or bone marrow.

  25. CML vsLeukemoid Reaction

  26. 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?

  27. Thank you

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