3 Objectives Define CML, and know the causes. Describe clinical signs and symptoms of CMLClassify CMLExplain the prognostic significance of cytogenetic abnormalitiesCite methods for diagnosing CML
4 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 marrowOriginate 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 intoMyeloid lineagesLymphoid lineages
7 In CML granulocytes were massively expanded (granulocytes neutrophile, bsophile and monocyte)
8 CML EtiologyNot clearLittle evidence of genetic factors linked to the diseaseHigh level radiation/toxin exposureIncreased incidenceSurvivors of the atomic disasters at Japan (Nagasaki & Hiroshima)Post radiation therapy
9 Phyladelphia chromosome LeukaemogenisisPhyladelphia chromosomePhiladelphia chromosome is an acquired cytogenetic anomaly that is characterizes in all leukemic cells in CMLReciprocal translocation of chromosome 22 and chromosome 990-95% of CML patients have Ph chromosome
10 BCR-ABL OncogeneBCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9The resulting fusion gene (BCR-ABL) produce an altered protein believed to play a key role in development of CMLPh chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell
11 BCR-ABL Oncogene Activity imparts growth advantage to leukaemic cells BCR-ABL has tyrosine kinase activity and participates in intracellular signal transductionActivity imparts growth advantage to leukaemic cells- Increased proliferation and cytokine growth- Inhibition of apoptosis- Alteration of adhesion pathways
12 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
14 Stages of Chronic Myeloid Leukemia Disease is biphasic, sometimes triphasic.Chronic phaseAccelerated phaseAcute phase (Blast Phase)
15 The chronic phaseMajority (>80%) of cases of CML diagnosed in chronic phaseDefined byElevated WBC count (≥20 × 109 /L)Basophilia & EosinophiliaThe platelet count is normal or elevated, and may exceed 1,000 × 109/LRelative lack of blasts (<10% in periferal blood and bone marrow)
16 CML: chronic phaseCML: Peripheral blood film showing various of stages of granulopoiesis including promyelocytes, myelocytes, metamyelocytes and segmented neutrophils
17 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.ErytroblastMetamyelocyteBlastMyelocyte
19 The accelerated phase Second and intermediate phase of CML Defining criterion: ≥ 5% to ≥19% blast in blood and marrowPersistent thrombocytopenia (<100 × 109/L) or thrombocytosis (>1,000 × 109/L) despite treatment.Characterized by general and progressive anemia my mark onsetFever unknown originBone painSymptoms related to splenomegalyMedian duration : 3-18 months
20 Blast phaseFinal disease phase characterized by ≥20% to ≥30% blasts in peripheral blood or marrow they are lymphoid, usually precursor B lymphoblasts.Increasing symptomologyFatigue related to progressive anemiaBleedingInfectious complicationCNS dysfunctionPhase rapidly fatal, with median survival ranging from 3 to 12 months .
21 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.
22 Neutrophils and precursors CMLBlastBasophilNeutrophils and precursorsPromyelocyte
25 Laboratory DiagnosisCBC : 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, metamyelocytes and band and segmented neutrophils. Basophils are raised.Bone marrow examination : hypercellular with granulopoietic predominance.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.
27 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 /µL).What are the hematologic abnormalities present here?