3. CHRONIC MYELOID LEUKAEMIA
Dr Rosline Hassan
Department of Haematology
School of Medical Sciences
Universiti Sains Malaysia

4. Leukaemias What are Leukemias
Neoplasm of white blood cell and its precursor
Clonal proliferations and accumulation of cells in marrow
Classify as
Acute leukaemias
Chronic leukaemias

5. Types of Leukaemia Acute : No maturation beyond blast
Chronic : Maturation beyond blast
Lymphocytic (B or T lineage)
ALL
CLL
Myeloid – granulocytes
Erythroids
Monocytes
Platelets
AML
CML

6. Introduction- 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

8. Introduction- CML Incidence :1 per 100,000 (UK)
Accounts for 7-15% of all leukaemia in adults
Median age : 53 years
All age groups, including children, can be affected

9. Introduction- CML Etiology Not clear
Little evidence of genetic factors linked to the disease
Increased incidence
Survivors of the atomic disasters at Nagasaki & Hiroshima
Post radiation therapy

11. Leukaemogenesis

12. Leukaemogenesis
Philadelphia chromosome is an acquired cytogenetic anomaly that is characterizes in all leukaemic cells in CML
90-95% of CML pts have Ph chromosome
Reciprocal translocation of chromosome 22 and chromosome 9

14. Leukaemogenesis
BCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9
Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell

15. Leukaemogenesis
Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine kinase activity
BCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of cytokines
It protects hematopoietic cells from programmed cell death (apoptosis)

16. Clinical Features Disease is biphasic, sometimes triphasic
40% asymptomatic
Chronic phase
Splenomegaly often massive
Symptoms related to hypermetabolism
Weight loss
Anorexia
Lassitude
Night sweats

17. Clinical Features Clinical features cont… Features of anaemia
Pallor, dyspnoea, tachycardia
Abnormal platelet function
Bruising, epistaxis, menorrhagia
Hyperleukocytosis
thrombosis
Increased purine breakdown : gout
Visual disturbances
Priapism

18. Lab features Peripheral blood film Anaemia
Leukocytosis (usu >25 x 109/L, freq> 100 x 109/L
WBC differential shows granulocytes in all stages of maturation
Basophilia
thrombocytosis

21. Lab features Bone marrow Hypercellular (reduced fat spaces)
Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)
Myelocyte predominant cell, blasts less 10%
Megakaryocytes increased & dysplastic
Increase reticulin fibrosis in 30-40%

22. Lab features Other lab features : NAP reduced
Serum B12 and transcobalamin increased
Serum uric acid increased
Lactate dehydrogenase increased
Cytogenetic : Philadelphia chromosome

23. Laboratory- summary Lab investigation to confirm diagnosis
Full blood picture
Neutrophil alkaline phosphatase
Bone marrow cytogenetic

25. Phases Accelerated phase
Median duration is 3.5 – 5 yrs before evolving to more aggressive phases
Clinical features
Increasing splenomegaly refractory to chemo
Increasing chemotherapy requirement
Lab features
Blasts>15% in blood
Blast & promyelocyte > 30% in blood
Basophil 20% in blood
Thrombocytopenia
Cytogenetic: clonal evolution

26. Phases Blastic phase Resembles acute leukaemia
Diagnosis requires > 30% blast in marrow
2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase
Survival : 9 mos vs 3 mos (lym vs myeloid)

29. General Management Discussion with family The disease & diagnosis
Prognosis
Choices of treatment
Cytotoxic drug vs bone marrow transplant
Side effect

30. CML - principles of treatment
Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis
Hydration
Chemotherapy (bulsuphan, Hydoxyurea)
Control and prolong chronic phase (non-curative)
alpha interferon+chemotherapy
imatinib mesylate
chemotherapy (hydroxyurea)

31. CML - principles of treatment
Treatment cont…
Eradicate malignant clone (curative)
allogeneic transplantation
alpha interferon ?
imatinib mesylate/STI 571 ?(Thyrosine kinase inhibitor)

32. Chemotherapy Busulphan Alkylating agent
Preferred in older pts (not candidate for transplant)
Side effect :
prolonged myelosuppression
Pulmonary fibrosis
Skin pigmentation
infertility

33. Chemotherapy Hydoxyures
Fewer side effect
Acts by inhibiting the enzyme ribonucleotide reductase
Haematological remissions obtain in 80% for both drugs
However disease progression not altered and persistence of Ph chromosome containing clone

34. Chemotherapy Recombinant human α- Interferon
Prolong chronic phase and increase survival
Haematogical and cytogenetic remission
Side effect
Flu like symptoms
Fever and chills
Anorexia
Depression

36. CML - prognosis Median survival 3.5 yrs (range 2-8 yrs)
Interferon + chemotherapy :6 years
Transplant : 5+ years
imatinib mesylate ?

37. Thank you