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

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 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 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

Phyladelphia chromosome 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 Activity imparts growth advantage to leukaemic cells BCR-ABL has tyrosine kinase activity and participates in intracellular signal transduction Activity imparts growth advantage to leukaemic cells - Increased proliferation and cytokine growth - Inhibition of apoptosis - Alteration of adhesion pathways

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

Splenomegaly in CML

Stages of Chronic Myeloid Leukemia Disease is biphasic, sometimes triphasic. Chronic phase 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

Melocyte Megacaryocyte Metamelocyte

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.

Neutrophils and precursors CML Blast Basophil Neutrophils and precursors Promyelocyte

Clinical presentaion of Ph+ and CML

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 neutrophilic leukaemia Eosinophilic leukaemia Chronic myelomonocytic leukaemia (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, 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.

CML vs Leukemoid Reaction Characteristic feature CML Leukemoid Reaction (leuckocytoisis) Age >40 yrs Any age Leukocytosis >100,000 30,000 – 50,000 Absolute Basophilia Present May not Splenomegaly Prominent Philadelphia Chromosome Absent LAP / NAP Very low / Absent High Transformation to Acute leukemia Yes No

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?

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