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Chronic myelogenous leukemia-CML

Chronic myelogenous leukemia-CML


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

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
· 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


· Not clear
· Little evidence of genetic factors linked to the disease
· Increased incidence
o Survivors of the atomic disasters at Nagasaki & Hiroshima
o Post radiation therapy


· 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
· 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
· 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)

Clinical Features

o Disease is biphasic, sometimes triphasic
o 40% asymptomatic
o Chronic phase
o Splenomegaly often massive
o Symptoms related to hypermetabolism
o Weight loss
o Anorexia
o Lassitude
o Night sweats
o Features of anaemia
o Pallor, dyspnoea, tachycardia
o Abnormal platelet function
o Bruising, epistaxis, menorrhagia
o Hyperleukocytosis
o thrombosis
o Increased purine breakdown : gout
o Visual disturbances
o Priapism
o Lab features

o Peripheral blood film
o Anaemia
o Leukocytosis (usu >25 x 109/L, freq> 100 x 109/L
o WBC differential shows granulocytes in all stages of maturation
o Basophilia
o thrombocytosis
o Bone marrow
o Hypercellular (reduced fat spaces)
o Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)
o Myelocyte predominant cell, blasts less 10%
o Megakaryocytes increased & dysplastic
o Increase reticulin fibrosis in 30-40%
o Other lab features :
o NAP reduced
o Serum B12 and transcobalamin increased
o Serum uric acid increased
o Lactate dehydrogenase increased
o Cytogenetic : Philadelphia chromosome

Laboratory- summary

Lab investigation to confirm diagnosis
Full blood picture
Neutrophil alkaline phosphatase
Bone marrow cytogenetic


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
Cytogenetic: clonal evolution
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)

General Management

o Discussion with family
o The disease & diagnosis
o Prognosis
o Choices of treatment
§ Cytotoxic drug vs bone marrow transplant
§ Side effect
o CML – principles of treatment
o Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis
o Hydration
o Chemotherapy (bulsuphan, Hydoxyurea)
o Control and prolong chronic phase (non-curative)
o alpha interferon+chemotherapy
o imatinib mesylate
o chemotherapy (hydroxyurea)
o CML – principles of treatment
o Treatment cont…
o Eradicate malignant clone (curative)
o allogeneic transplantation
o alpha interferon ?
o imatinib mesylate/STI 571 ?(Thyrosine kinase inhibitor)
o Chemotherapy
o Busulphan
o Alkylating agent
o Preferred in older pts (not candidate for transplant)
o Side effect :
§ prolonged myelosuppression
§ Pulmonary fibrosis
§ Skin pigmentation
§ infertility
o Chemotherapy
o Hydoxyures
o Fewer side effect
o Acts by inhibiting the enzyme ribonucleotide reductase
o Haematological remissions obtain in 80% for both drugs
o However disease progression not altered and persistence of Ph chromosome containing clone
o Chemotherapy
o Recombinant human α- Interferon
o Prolong chronic phase and increase survival
o Haematogical and cytogenetic remission
o Side effect
§ Flu like symptoms
§ Fever and chills
§ Anorexia
§ Depression
o CML – prognosis
o Median survival 3.5 yrs (range 2-8 yrs)
o Interferon + chemotherapy :6 years
o Transplant : 5+ years
o imatinib mesylate ?

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