Faculty of Applied Medical Sciences Department Of Medical Lab. Technology 3rd 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. • Describe clinical signs and symptoms of CML • Classify CML • Explain the prognostic significance of cytogenetic abnormalities • Cite methods for diagnosing CML
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.
Hematopoiesis : process by which blood cell (by bone marrow) lineages are produced • WBCs (WHITE BLOOD CELLS, or leukocyte) subdivided into • Myeloid lineages • Lymphoid lineages
In CML granulocytes were massively expanded (granulocytes neutrophile, bsophile and monocyte)
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
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
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
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
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
Stages of Chronic Myeloid Leukemia • Disease is biphasic, sometimes triphasic. • Chronicphase • Accelerated phase • Acute phase (Blast Phase)
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)
CML:chronic phase CML: Peripheral blood film showing various of stages of granulopoiesis including promyelocytes, myelocytes, metamyelocytes and segmented neutrophils
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
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
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 .
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.
CML Blast Basophil Neutrophils and precursors Promyelocyte
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)
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.
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?