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Unformatted text preview: CHRONIC MYELOID LEUKAEMIA. LEUKAEMIA. CLINICAL FEATURES. CLINICAL Rare below the age of 20 years, but Rare occurs in all decades, with a median age of onset of 40-50 years. age The incidence is slightly higher in The males than in females. males In most cases there are no In predisposing factors but the incidence was increased in survivors of the atom bomb exposures in Japan. Japan. Clinical features. Clinical The clinical features include: Symptoms related to hypermetabolism e.g Symptoms weight loss, lassitude, anorexia or night sweat. sweat. Splenomegaly is nearly always present and Splenomegaly is frequently massive – can be associated with considerable discomfort, pain or indigestion. indigestion. Features of anaemia – pallor, dyspnoea Features and tachycardia. and Bruising, epistaxis, menorrhagia or Bruising, haemorrhage from other sites because of abnormal platelet function. abnormal Clinical features. Clinical Gout or renal impairement caused by Gout hyperuricaemia. hyperuricaemia. Visual disturbance and priapism. In more advanced disease – bone In tenderness or signs of infection. tenderness In established blastic transformation – In spleen is enlarged and may be painful, massive hepatomegaly, lymphadenopathy, fever or very rarely, lytic lesions of bone. fever In up to 50% of cases the diagnosis is In made incidentally from a routine bld count. made Haematological findings. Haematological Chronic phase. Early phase, Hb usually normal Low Hb when the patient develops Low splenomegaly. splenomegaly. WBC count is increased, usually 50200×109/l, sometimes upto 200-800×109/l. PBF – a full spectrum of cells in the granulocyte series ranging from blast forms to mature neutrophils with predominant myelocytes and neutrophils. The % of eosinophils and basophils are The increased. increased. Haematological findings. Haematological Chronic phase (cont.) Platelet count usually increased Platelet (300-600×109/l) but may be normal (300-600×10 or even low. NAP score is low or absent. B.marrow biopsy shows a complete loss of fat spaces, with dense hypercellularity. The cellular composition resembling that of the CML blood. Haematological findings. Haematological Chronic phase (cont.) Examination of the bone marrow by Examination aspiration or trephine biopsy is not necessary to confirm the diagnosis of CML, but it is carried out to assess: CML, The degree of marrow fibrosis To perform cytogenetic analysis To exclude occult transformation. Haematological findings. Haematological Advanced phase The haematological findings are very The variable. variable. It may differ little from the chronic It phase, but blast cell numbers may be increased disproportionately. be There may be anaemia in the There presence of a normal leucocyte count. count. Haematological findings. Haematological Advanced phase (cont.) Platelet count may be greatly Platelet increased (>1000×109/l) or increased reduced (< 100×109/l) in a manner not accounted for by treatment. Marrow shows increased number of blast cells and/or increased fibrosis. Haematological findings. Haematological Blast phase. Blastic transformation is defined by the Blastic presence of >30% blast or blast plus promyelocytes in the blood or marrow. promyelocytes The morphology of blast cells is very The variable: variable: ~ 70% of patients have blasts classifiable 70% generally as myeloid, which resemble to a degree the cells that characterize AML. degree ~20% of patients have lymphoid blast cells. ~10% of patients the blast cell ~10% transformations have mixed myeloid and lymphoid characteristics. lymphoid Biochemical changes. Biochemical Non specific. Chronic phase: Slightly increased serum uric acid. ALP normal or slightly increased. LDH is high. Spurious hyperkaelemia. Serum vit. B12 and B12 binding Serum capacity are increased due to increased level of Transcobalamin 1. increased Biochemical changes. Biochemical In transformation phase: Serum uric acid may be raised, Serum sometimes substantially. sometimes LFT usually moderately abnormal. Hypercalcemia is present Hypercalcemia occasionally (usually due to bone destruction or very rarely it may be attributable to a parathormone-like material ectopically produced by the blast cells). blast Management of CML. Management Chronic phase. Various options of treatment. For younger patients, the question of BMT For (allogenic BMT) should be addressed as soon as possible after the diagnosis. possible There is no immediate urgency to start treatment in There asymptomatic patients with leucocytes counts < 100×109/l. 100×10 If the possibility of treatment by BMT is excluded or If uncertain, therapy should be initiated with: uncertain, Interferon α or Interferon Hydroxyurea or Tyrosine kinase inhibitor Busulphan (reserved for special indications). Management. Management. α-interferon Have antiviral and antiproliferative properties. Active in reducing the leucocytes count and Active reversing all features of CML in 70-80% of patients. reversing Has 2 important effects: It identifies, on the basis of the speed of the It hematological response and degree of cytogenetic response, subgroups of patients who will survive longer than others; longer It probably prolongs survival by perhaps 1 or 2 It years in the majority of patients. years Management. Management. Tyrosine kinase inhibitors Tyrosine (Glivec) (Glivec) Is indicated for the treatment of Is patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of IFN-α phase therapy. therapy. Management. Management. Glivec (cont.) Acts specifically by blocking the binding site for ATP Acts in the Abl kinase. in This inhibits the ability of Abl to transfer phosphate This groups from ATP and phosphorylate tyrosine residues on substrate proteins, which in turn prevents the transduction of energy signals necessary for Abl-induced cellular proliferation and apoptosis. apoptosis. Thus, the specific signal transduction pathway Thus, abnormally activated in the leukaemic transformation process is inactivated by Glivec while the normal pathways are unaffected. while Management. Management. Hydroxyurea. Is a ribonucleotide reductase Is inhibitor, which targets relatively mature myeloid progenitors in the proliferative cycle. the It is usually possible to reverse It all the features of CML within 4all 8 weeks of starting treatment. Management. Management. Busulphan. Is a polyfunctional alkylating Is agent. agent. It is rarely used nowadays and It reserved for patients who are intolerant of hydroxyurea. intolerant Management. Management. Advanced phase. Combination of cytotoxic drugs. Glivec. Allogenic BMT. Patients in blastic transformation Patients may be treated with combinations of cytotoxic drugs in the hope of prolonging life, but cure can no longer be a realistic objective. longer Management. Management. Advanced phase. If the patient has a myeloid If transformation he/she can be treated with drugs appropriate to the induction of remission in AML – daunorubicin, cystosine arabinoside with or without 6arabinoside thioguanine, or etoposide. Management. Management. Advanced phase. Patients in lymphoid Patients transformation may be treated with drugs applicable to the management of adult ALL – prednisolone, vincristine and daunorubicin, with or without Ldaunorubicin, asparaginase. Management. Management. Advanced phase. Allogeneic BMT using HLA-matched Allogeneic sibling donors can be performed in the accelerated phase; the probability of leukaemic free survival at 5 years is 30-50%. at BMT performed in overt blastic BMT transformation nearly always unsuccessful. unsuccessful. Management. Management. Advanced phase. The mortality resulting from The GVHD is extremely high and the probability of relapse in those who survive is very considerable. considerable. The probability of survival at 5 The years is consequently 0-10%. Course and prognosis. Course CML usually shows an excellent CML response to chemotherapy in the chronic phase. the The median survival is 5-6 The years. years. Death usually occurs from Death terminal acute transformation or from intercurrent haemorrhage or infection. or Course and prognosis. Course 20% of patient survive 10 years 20% or more. or The patient may be divided into The prognostic groups according to age, spleen size, platelet count, blast cells on presentation and ease of response to therapy; these are only rough guides to outcome. outcome. Variants of CML. Variants Ph-negative CML. About 5% of patients with About haematologically acceptable CML lack the Ph chromosome. lack ~1/2 of these patients have a BCR~1/2 BCRABL gene that is molecularly identical to the BCL-ABL gene of PhBCL-ABL positive CML. These patients have a clinical course These similar to those with Ph-positive CML. CML. Variants of CML. Variants Ph-negative CML (cont) Patients with no BCR-ABL gene frequently have haematological features that are subtly different from Ph-positive disease. Ph-positive They may lack basophilia, lack blast They and myelocyte peaks in the leucocyte differential count or show dysplastic features. dysplastic Have some degree of monocytosis. Variants of CML. Variants Ph- negative CML (cont.). They respond poorly to IFN-α or to hydroxyurea. to Survival is inferior to that of Phpositive patients. Variants of CML. Variants Juvenile CML. Rare. Affecting children <12 year-old. C/F – anaemia, or lymphadenopathy with C/F hepatosplenomegaly, skin rashes. hepatosplenomegaly, Lab findings – leucocytosis with variable Lab numbers of blast in the peripheral blood. Marrow is hypercellular but lacks chromosomal abnormalities. chromosomal Responds poorly to standard cytotoxic Responds drugs. drugs. Variants of CML. Variants Eosinophilic leukaemia. High number of immature cells High in the blood and marrow. in May progress to blastic May transformation in a manner similar to Ph-positive CML. similar T.Q T.Q ...
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