CHRONIC MYELOID LEUKAEMIA 3.57.51 PM

CHRONIC MYELOID LEUKAEMIA 3.57.51 PM - CHRONIC MYELOID...

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Unformatted text preview: CHRONIC MYELOID LEUKAEMIA Dr Rosline Hassan Department of Haematology School of Medical Sciences Universiti Sains Malaysia Leukaemias 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 Types of Leukaemia Types of Leukaemia Lymphocytic (B or T lineage) Myeloid – granulocytes Erythroids Monocytes Acute : No maturation beyond blast ALL Chronic : Maturation beyond blast CLL AML CML Introduction­ CML 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 Introduction­ CML Introduction­ CML Incidence :1 per 100,000 (UK) Accounts for 7­15% of all leukaemia in adults Median age : 53 years All age groups, including children, can be affected Introduction­ CML 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 Leukaemogenesis Leukaemogenesis Leukaemogenesis Leukaemogenesis Philadelphia chromosome is an acquired cytogenetic anomaly that is characterizes in all leukaemic cells in CML 90­95% of CML pts have Ph chromosome Reciprocal translocation of chromosome 22 and chromosome 9 Leukaemogenesis 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, B­cells and sometimes T­cell proof that CML derived from pluripotent stem cell Leukaemogenesis Leukaemogenesis Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine kinase activity BCR­ABL 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 Clinical Features Disease is biphasic, sometimes triphasic 40% asymptomatic Chronic phase Splenomegaly often massive Symptoms related to hypermetabolism – – – – Weight loss Anorexia Lassitude Night sweats Clinical Features 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 Lab features 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 Lab features 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 30­40% Lab features Lab features Other lab features : – NAP reduced – Serum B12 and transcobalamin increased – Serum uric acid increased – Lactate dehydrogenase increased – Cytogenetic : Philadelphia chromosome Laboratory­ summary Laboratory­ summary Lab investigation to confirm diagnosis – Full blood picture – Neutrophil alkaline phosphatase – Bone marrow cytogenetic Phases 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 Phases 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) General Management General Management Discussion with family – The disease & diagnosis – Prognosis – Choices of treatment Cytotoxic drug vs bone marrow transplant Side effect CML ­ principles of 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) CML ­ principles of CML ­ principles of treatment Treatment cont… Eradicate malignant clone (curative) – allogeneic transplantation – alpha interferon ? – imatinib mesylate/STI 571 ?(Thyrosine kinase inhibitor) Chemotherapy Chemotherapy Busulphan – Alkylating agent – Preferred in older pts (not candidate for transplant) – Side effect : prolonged myelosuppression Pulmonary fibrosis Skin pigmentation infertility Chemotherapy 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 Chemotherapy 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 CML ­ prognosis CML ­ prognosis Median survival 3.5 yrs (range 2­8 yrs) Interferon + chemotherapy :6 years Transplant : 5+ years imatinib mesylate ? 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This note was uploaded on 12/24/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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