Chronic Myeloid Leukemia PDF Lecture Notes

CHRONIC MYELOID LEUKEMIA EBSUTH LECTURE  Introduction CML is a clonal malignant myeloproliferative disorder of the haematopoietic stem cell characterized by overproduction of myeloid cells and the presence of the Philadelphia chromosome It is characterized by marke...

CHRONIC MYELOID LEUKEMIA EBSUTH LECTURE  Introduction CML is a clonal malignant myeloproliferative disorder of the haematopoietic stem cell characterized by overproduction of myeloid cells and the presence of the Philadelphia chromosome It is characterized by marked increase in granulocytic proliferation in the marrow and granulocytic leucocytosis.  Results in increases in all granulocytic series and platelets in peripheral blood and marked myeloid hyperplasia in the bone marrow. Originates in a single abnormal haemopoietic stem cell. Untreated, CML progresses from a chronic phase to a rapidly fatal blast phase, generally over 3-5 years. Blast phase is often preceded by accelerated phase, which is marked by the acquisition of new cytogenetic abnormalities in 50-80% of patients.  EPIDEMIOLOGY Median age range at presentation is 45-55 years Incidence increases with age Up to 30% of patients are aged >60 years Less common in children with ≈ 10% of patients less than 20 years Slightly higher incidence in males Male-to-female ratio—1.3:1 At presentation 50% diagnosed by routine laboratory tests 85% diagnosed during chronic phase  PATHOGENESIS CML arises from a translocation between the BCR gene on chromosome 22 and the ABL gene on chromosome 9. This reciprocal translocation creates the Philadelphia chromosome (t 9;22) and the consequent formation of a unique BCRABL protein product. This protein has constitutive kinase activity that drives uncontrolled proliferation of hematopoietic stem cells.  Mutation resulting from balanced translocation of genetic material between chromosome 9 and 22 (Philadelphia Chromosome). BCR-ABL Mutation takes place at the level of the haemopoetic stem cell The resultant protein has a tyrosine kinase activity that persistently stimulates proliferation of granulocytes Granulocytes released from the marrow spill into the peripheral blood and infiltrates organs like spleen, and the liver.  Hyper-leukocytosis affecting end arteries in eye and ears may cause sudden loss of vision and hearing It may also cause hyper-viscosity syndrome. Splenic enlargement compresses the stomach causing easy satiety with weight loss due to reduced food intake. Basophilia with histamine release may cause pruritus. High cellular turnover causes fever, increased uric acid production,  CLINICAL PRESENTATION Asymptomatic Massive splenomegaly Symptoms of hyper-metabolism; weight loss, anorexia, weakness, night sweat Symptoms of hyper-viscosity; hearing loss, visual loss, headache, dizziness, thrombosis, priapism. Bleeding Fever Symptoms of anemia; weakness, palpitation, dizziness.  INVESTIGATIONS  Diagnostic test; FBC and peripheral blood film Conventional karyotyping. FISH for cytogenetics. Bone marrow aspiration for cytological assessment– Eosinophilia, basophilia, megakaryocyte hyperplasia. PCR for molecular diagnosis and Detection of resistance related mutations Bone marrow biopsy for– Exclusion of myelofibrosis – Cytogenetics/Karyotype  Ancillary tests; in preparation for treatment and for detecting potential for adverse reaction. Uric acid Liver function tests Lactate dehyrogenase Neutrophil specific alkaline phosphatase SE/Ur/Cr  TREATMENT Aim of treatment; Reduce leucocyte count to prevent hyperleucostasis. To eliminate the BCR-ABL clone. To sustain the chronic phase and slow the rate of acceleration phase  Supportive Uric acid–allopurinol,rasburicase Anaemia, Thrombocytopaenia/thrombocytopathy(bleeding) – platelet transfusion. Infection- antibiotics Leucoapheresis Exchange blood transfusion.  Specific therapy in the chronic phase Cytoreductive agents-hydroxyurea, interferon. Signal transduction inhibitors-Monoclonal antibodies e.g.Imatinib,dasatinib,nilotinib, ponatinib, bosutinib. Stem cell transplantation (uses graft versus leukaemia effect)  Assessment of response to therapy Haematological ; complete, partial, non- remission. Molecular. Cytogenetic.