CHRONIC MYELOID LEUKAEMIA.

CLINICAL FEATURES. Rare below the age of 20 years, but occurs in all decades, with a median age of onset of years. Rare below the age of 20 years, but occurs in all decades, with a median age of onset of years. The incidence is slightly higher in males than in females. The incidence is slightly higher in males than in females. In most cases there are no predisposing factors but the incidence was increased in survivors of the atom bomb exposures in Japan. In most cases there are no predisposing factors but the incidence was increased in survivors of the atom bomb exposures in Japan.

Clinical features. The clinical features include: The clinical features include: Symptoms related to hypermetabolism e.g weight loss, lassitude, anorexia or night sweat. Symptoms related to hypermetabolism e.g weight loss, lassitude, anorexia or night sweat. Splenomegaly is nearly always present and is frequently massive – can be associated with considerable discomfort, pain or indigestion. Splenomegaly is nearly always present and is frequently massive – can be associated with considerable discomfort, pain or indigestion. Features of anaemia – pallor, dyspnoea and tachycardia. Features of anaemia – pallor, dyspnoea and tachycardia. Bruising, epistaxis, menorrhagia or haemorrhage from other sites because of abnormal platelet function. Bruising, epistaxis, menorrhagia or haemorrhage from other sites because of abnormal platelet function.

Clinical features. Gout or renal impairement caused by hyperuricaemia. Gout or renal impairement caused by hyperuricaemia. Visual disturbance and priapism. Visual disturbance and priapism. In more advanced disease – bone tenderness or signs of infection. In more advanced disease – bone tenderness or signs of infection. In established blastic transformation – spleen is enlarged and may be painful, massive hepatomegaly, lymphadenopathy, fever or very rarely, lytic lesions of bone. In established blastic transformation – spleen is enlarged and may be painful, massive hepatomegaly, lymphadenopathy, fever or very rarely, lytic lesions of bone. In up to 50% of cases the diagnosis is made incidentally from a routine bld count. In up to 50% of cases the diagnosis is made incidentally from a routine bld count.

Haematological findings.  Chronic phase. Early phase, Hb usually normal Early phase, Hb usually normal Low Hb when the patient develops splenomegaly. Low Hb when the patient develops splenomegaly. WBC count is increased, usually ×10 WBC count is increased, usually ×10 9 /l, sometimes upto ×10 9 /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 increased. The % of eosinophils and basophils are increased.

Haematological findings.  Chronic phase (cont.) Platelet count usually increased ( ×10 Platelet count usually increased ( ×10 9 /l) but may be normal 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.  Chronic phase (cont.) Examination of the bone marrow by aspiration or trephine biopsy is not necessary to confirm the diagnosis of CML, but it is carried out to assess: Examination of the bone marrow by aspiration or trephine biopsy is not necessary to confirm the diagnosis of CML, but it is carried out to assess:  The degree of marrow fibrosis  To perform cytogenetic analysis  To exclude occult transformation.

Haematological findings.  Advanced phase The haematological findings are very variable. The haematological findings are very variable. It may differ little from the chronic phase, but blast cell numbers may be increased disproportionately. It may differ little from the chronic phase, but blast cell numbers may be increased disproportionately. There may be anaemia in the presence of a normal leucocyte count. There may be anaemia in the presence of a normal leucocyte count.

Haematological findings.  Advanced phase (cont.) Platelet count may be greatly increased (>1000×10 Platelet count may be greatly increased (>1000×10 9 /l) or reduced (< 100×10 9 /l) in a manner not accounted for by treatment. Marrow shows increased number of blast cells and/or increased fibrosis.

Haematological findings.  Blast phase. Blastic transformation is defined by the presence of >30% blast or blast plus promyelocytes in the blood or marrow. Blastic transformation is defined by the presence of >30% blast or blast plus promyelocytes in the blood or marrow. The morphology of blast cells is very variable: The morphology of blast cells is very variable: ~ 70% of patients have blasts classifiable generally as myeloid, which resemble to a degree the cells that characterize AML. ~ 70% of patients have blasts classifiable generally as myeloid, which resemble to a degree the cells that characterize AML. ~20% of patients have lymphoid blast cells. ~20% of patients have lymphoid blast cells. ~10% of patients the blast cell transformations have mixed myeloid and lymphoid characteristics. ~10% of patients the blast cell transformations have mixed myeloid and lymphoid characteristics.

Biochemical changes. Non specific. Non specific.  Chronic phase: Slightly increased serum uric acid. Slightly increased serum uric acid. ALP normal or slightly increased. ALP normal or slightly increased. LDH is high. LDH is high. Spurious hyperkaelemia. Spurious hyperkaelemia. Serum vit. B12 and B12 binding capacity are increased due to increased level of Transcobalamin 1. Serum vit. B12 and B12 binding capacity are increased due to increased level of Transcobalamin 1.

Biochemical changes.  In transformation phase: Serum uric acid may be raised, sometimes substantially. Serum uric acid may be raised, sometimes substantially. LFT usually moderately abnormal. LFT usually moderately abnormal. Hypercalcemia is present occasionally (usually due to bone destruction or very rarely it may be attributable to a parathormone-like material ectopically produced by the blast cells). Hypercalcemia is present occasionally (usually due to bone destruction or very rarely it may be attributable to a parathormone-like material ectopically produced by the blast cells).

Management of CML. Chronic phase. Chronic phase. Various options of treatment. Various options of treatment. For younger patients, the question of BMT (allogenic BMT) should be addressed as soon as possible after the diagnosis. For younger patients, the question of BMT (allogenic BMT) should be addressed as soon as possible after the diagnosis. There is no immediate urgency to start treatment in asymptomatic patients with leucocytes counts < 100×10 9 /l. There is no immediate urgency to start treatment in asymptomatic patients with leucocytes counts < 100×10 9 /l. If the possibility of treatment by BMT is excluded or uncertain, therapy should be initiated with: If the possibility of treatment by BMT is excluded or uncertain, therapy should be initiated with: Interferon α or Interferon α or Hydroxyurea or Hydroxyurea or Tyrosine kinase inhibitor Tyrosine kinase inhibitor Busulphan (reserved for special indications). Busulphan (reserved for special indications).

Management. α-interferon α-interferon Have antiviral and antiproliferative properties. Have antiviral and antiproliferative properties. Active in reducing the leucocytes count and reversing all features of CML in 70-80% of patients. Active in reducing the leucocytes count and reversing all features of CML in 70-80% of patients. Has 2 important effects: Has 2 important effects: It identifies, on the basis of the speed of the hematological response and degree of cytogenetic response, subgroups of patients who will survive longer than others; It identifies, on the basis of the speed of the hematological response and degree of cytogenetic response, subgroups of patients who will survive longer than others; It probably prolongs survival by perhaps 1 or 2 years in the majority of patients. It probably prolongs survival by perhaps 1 or 2 years in the majority of patients.

Management. Tyrosine kinase inhibitors (Glivec) Tyrosine kinase inhibitors (Glivec) Is indicated for the treatment of patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of IFN-α therapy. Is indicated for the treatment of patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of IFN-α therapy.

Management. Glivec (cont.) Glivec (cont.) Acts specifically by blocking the binding site for ATP in the Abl kinase. Acts specifically by blocking the binding site for ATP in the Abl kinase. This inhibits the ability of Abl to transfer phosphate 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. This inhibits the ability of Abl to transfer phosphate 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. Thus, the specific signal transduction pathway abnormally activated in the leukaemic transformation process is inactivated by Glivec while the normal pathways are unaffected. Thus, the specific signal transduction pathway abnormally activated in the leukaemic transformation process is inactivated by Glivec while the normal pathways are unaffected.

Management. Hydroxyurea. Hydroxyurea. Is a ribonucleotide reductase inhibitor, which targets relatively mature myeloid progenitors in the proliferative cycle. Is a ribonucleotide reductase inhibitor, which targets relatively mature myeloid progenitors in the proliferative cycle. It is usually possible to reverse all the features of CML within 4- 8 weeks of starting treatment. It is usually possible to reverse all the features of CML within 4- 8 weeks of starting treatment.

Management. Busulphan. Busulphan. Is a polyfunctional alkylating agent. Is a polyfunctional alkylating agent. It is rarely used nowadays and reserved for patients who are intolerant of hydroxyurea. It is rarely used nowadays and reserved for patients who are intolerant of hydroxyurea.

Management. Advanced phase. Advanced phase.  Combination of cytotoxic drugs.  Glivec.  Allogenic BMT. Patients in blastic transformation may be treated with combinations of cytotoxic drugs in the hope of prolonging life, but cure can no longer be a realistic objective. Patients in blastic transformation may be treated with combinations of cytotoxic drugs in the hope of prolonging life, but cure can no longer be a realistic objective.

Management. Advanced phase. Advanced phase. If the patient has a myeloid transformation he/she can be treated with drugs appropriate to the induction of remission in AML – daunorubicin, cystosine arabinoside with or without 6- thioguanine, or etoposide. If the patient has a myeloid transformation he/she can be treated with drugs appropriate to the induction of remission in AML – daunorubicin, cystosine arabinoside with or without 6- thioguanine, or etoposide.

Management. Advanced phase. Advanced phase. Patients in lymphoid transformation may be treated with drugs applicable to the management of adult ALL – prednisolone, vincristine and daunorubicin, with or without L- asparaginase. Patients in lymphoid transformation may be treated with drugs applicable to the management of adult ALL – prednisolone, vincristine and daunorubicin, with or without L- asparaginase.

Management. Advanced phase. Advanced phase. Allogeneic BMT using HLA-matched sibling donors can be performed in the accelerated phase; the probability of leukaemic free survival at 5 years is 30-50%. Allogeneic BMT using HLA-matched sibling donors can be performed in the accelerated phase; the probability of leukaemic free survival at 5 years is 30-50%. BMT performed in overt blastic transformation nearly always unsuccessful. BMT performed in overt blastic transformation nearly always unsuccessful.

Management. Advanced phase. Advanced phase. The mortality resulting from GVHD is extremely high and the probability of relapse in those who survive is very considerable. The mortality resulting from GVHD is extremely high and the probability of relapse in those who survive is very considerable. The probability of survival at 5 years is consequently 0-10%. The probability of survival at 5 years is consequently 0-10%.

Course and prognosis. CML usually shows an excellent response to chemotherapy in the chronic phase. CML usually shows an excellent response to chemotherapy in the chronic phase. The median survival is 5-6 years. The median survival is 5-6 years. Death usually occurs from terminal acute transformation or from intercurrent haemorrhage or infection. Death usually occurs from terminal acute transformation or from intercurrent haemorrhage or infection.

Course and prognosis. 20% of patient survive 10 years or more. 20% of patient survive 10 years or more. The patient may be divided into 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. The patient may be divided into 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.

Variants of CML. Ph-negative CML. Ph-negative CML. About 5% of patients with haematologically acceptable CML lack the Ph chromosome. About 5% of patients with haematologically acceptable CML lack the Ph chromosome. ~1/2 of these patients have a BCR- ABL gene that is molecularly identical to the BCL-ABL gene of Ph- positive CML. ~1/2 of these patients have a BCR- ABL gene that is molecularly identical to the BCL-ABL gene of Ph- positive CML. These patients have a clinical course similar to those with Ph-positive CML. These patients have a clinical course similar to those with Ph-positive CML.

Variants of CML. Ph-negative CML (cont) Ph-negative CML (cont) Patients with no BCR-ABL gene frequently have haematological features that are subtly different from Ph-positive disease. Patients with no BCR-ABL gene frequently have haematological features that are subtly different from Ph-positive disease. They may lack basophilia, lack blast and myelocyte peaks in the leucocyte differential count or show dysplastic features. They may lack basophilia, lack blast and myelocyte peaks in the leucocyte differential count or show dysplastic features. Have some degree of monocytosis. Have some degree of monocytosis.

Variants of CML. Ph- negative CML (cont.). Ph- negative CML (cont.). They respond poorly to IFN-α or to hydroxyurea. They respond poorly to IFN-α or to hydroxyurea. Survival is inferior to that of Ph- positive patients. Survival is inferior to that of Ph- positive patients.

Variants of CML. Juvenile CML. Juvenile CML. Rare. Rare. Affecting children <12 year-old. Affecting children <12 year-old. C/F – anaemia, or lymphadenopathy with hepatosplenomegaly, skin rashes. C/F – anaemia, or lymphadenopathy with hepatosplenomegaly, skin rashes. Lab findings – leucocytosis with variable numbers of blast in the peripheral blood. Marrow is hypercellular but lacks chromosomal abnormalities. Lab findings – leucocytosis with variable numbers of blast in the peripheral blood. Marrow is hypercellular but lacks chromosomal abnormalities. Responds poorly to standard cytotoxic drugs. Responds poorly to standard cytotoxic drugs.

Variants of CML. Eosinophilic leukaemia. Eosinophilic leukaemia. High number of immature cells in the blood and marrow. High number of immature cells in the blood and marrow. May progress to blastic transformation in a manner similar to Ph-positive CML. May progress to blastic transformation in a manner similar to Ph-positive CML.

T.Q