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

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 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.

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

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

8. 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

9. 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

10. 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

11. 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

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

13. Splenomegaly in CML

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

15. 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)

16. CML: chronic phase
CML: 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.
Erytroblast
Metamyelocyte
Blast
Myelocyte

18. Melocyte Megacaryocyte Metamelocyte

19. 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

20. 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 .

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
CML
Blast
Basophil
Neutrophils and precursors
Promyelocyte

23. Clinical presentaion of Ph+ and CML

24. 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)

25. 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.

26. 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

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?

28. Thank you