chronic myeloid

CHRONIC MYELOID CHRONIC MYELOID LEUKAEMIA.LEUKAEMIA.

CLINICAL FEATURES.CLINICAL FEATURES.

Rare below the age of 20 years, but Rare below the age of 20 years, but occurs in all decades, with a median occurs in all decades, with a median age of onset of 40-50 years.age of onset of 40-50 years.

The incidence is slightly higher in The incidence is slightly higher in males than in females.males than in females.

In most cases there are no In most cases there are no predisposing factors but the predisposing factors but the incidence was increased in survivors incidence was increased in survivors of the atom bomb exposures in of the atom bomb exposures in Japan.Japan.

Clinical features.Clinical features.

The clinical features include:The clinical features include: Symptoms related to hypermetabolism e.g Symptoms related to hypermetabolism e.g

weight loss, lassitude, anorexia or night weight loss, lassitude, anorexia or night sweat.sweat.

Splenomegaly is nearly always present and Splenomegaly is nearly always present and is frequently massive – can be associated is frequently massive – can be associated with considerable discomfort, pain or with considerable discomfort, pain or indigestion.indigestion.

Features of anaemia – pallor, dyspnoea Features of anaemia – pallor, dyspnoea and tachycardia.and tachycardia.

Bruising, epistaxis, menorrhagia or Bruising, epistaxis, menorrhagia or haemorrhage from other sites because of haemorrhage from other sites because of abnormal platelet function.abnormal platelet function.

Clinical features.Clinical features.

Gout or renal impairement caused by Gout or renal impairement caused by hyperuricaemia.hyperuricaemia.

Visual disturbance and priapism.Visual disturbance and priapism. In more advanced disease – bone In more advanced disease – bone

tenderness or signs of infection.tenderness or signs of infection. In established blastic transformation – In established blastic transformation –

spleen is enlarged and may be painful, spleen is enlarged and may be painful, massive hepatomegaly, lymphadenopathy, massive hepatomegaly, lymphadenopathy, fever or very rarely, lytic lesions of bone.fever or very rarely, lytic lesions of bone.

In up to 50% of cases the diagnosis is In up to 50% of cases the diagnosis is made incidentally from a routine bld count.made incidentally from a routine bld count.

Haematological findings.Haematological findings.

Chronic phase.Chronic phase. Early phase, Hb usually normalEarly phase, Hb usually normal Low Hb when the patient develops Low Hb when the patient develops

splenomegaly.splenomegaly. WBC count is increased, usually 50-WBC count is increased, usually 50-

200×10200×109/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 % of eosinophils and basophils are increased.increased.


Chronic phase (cont.)Chronic phase (cont.) Platelet count usually increased Platelet count usually increased

(300-600×10(300-600×109/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.


Chronic phase (cont.)Chronic phase (cont.) Examination of the bone marrow by Examination of the bone marrow by

aspiration or trephine biopsy is not aspiration or trephine biopsy is not necessary to confirm the diagnosis necessary to confirm the diagnosis of CML, but it is carried out to of CML, but it is carried out to assess:assess:

The degree of marrow fibrosisThe degree of marrow fibrosis To perform cytogenetic analysisTo perform cytogenetic analysis To exclude occult transformation.To exclude occult transformation.


Advanced phaseAdvanced phase The haematological findings are very The haematological findings are very

variable.variable. It may differ little from the chronic It may differ little from the chronic

phase, but blast cell numbers may phase, but blast cell numbers may be increased disproportionately.be increased disproportionately.

There may be anaemia in the There may be anaemia in the presence of a normal leucocyte presence of a normal leucocyte count.count.


Advanced phase (cont.)Advanced phase (cont.) Platelet count may be greatly Platelet count may be greatly

increased (>1000×10increased (>1000×109/l) or reduced (< 100×109/l) in a manner not accounted for by treatment.

Marrow shows increased number of blast cells and/or increased fibrosis.


Blast phase.Blast phase. Blastic transformation is defined by the Blastic transformation is defined by the

presence of >30% blast or blast plus presence of >30% blast or blast plus promyelocytes in the blood or marrow.promyelocytes in the blood or marrow.

The morphology of blast cells is very The morphology of blast cells is very variable:variable:

~ 70% of patients have blasts classifiable ~ 70% of patients have blasts classifiable generally as myeloid, which resemble to a generally as myeloid, which resemble to a degree the cells that characterize AML.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 ~10% of patients the blast cell

transformations have mixed myeloid and transformations have mixed myeloid and lymphoid characteristics.lymphoid characteristics.

Biochemical changes.Biochemical changes.

Non specific.Non specific. Chronic phase: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 Serum vit. B12 and B12 binding

capacity are increased due to capacity are increased due to increased level of Transcobalamin 1.increased level of Transcobalamin 1.

Biochemical changes.Biochemical changes.

In transformation phase:In transformation phase: Serum uric acid may be raised, Serum uric acid may be raised,

sometimes substantially.sometimes substantially. LFT usually moderately abnormal.LFT usually moderately abnormal. Hypercalcemia is present Hypercalcemia is present

occasionally (usually due to bone occasionally (usually due to bone destruction or very rarely it may be destruction or very rarely it may be attributable to a parathormone-like attributable to a parathormone-like material ectopically produced by the material ectopically produced by the blast cells).blast cells).

Management of CML.Management of CML.

Chronic phase.Chronic phase. Various options of treatment.Various options of treatment. For younger patients, the question of BMT For younger patients, the question of BMT

(allogenic BMT) should be addressed as soon as (allogenic BMT) should be addressed as soon as possible after the diagnosis.possible after the diagnosis.

There is no immediate urgency to start treatment in There is no immediate urgency to start treatment in asymptomatic patients with leucocytes counts < asymptomatic patients with leucocytes counts < 100×10100×1099/l./l.

If the possibility of treatment by BMT is excluded or If the possibility of treatment by BMT is excluded or uncertain, therapy should be initiated with:uncertain, therapy should be initiated with:

Interferon Interferon αα or or Hydroxyurea orHydroxyurea or Tyrosine kinase inhibitorTyrosine kinase inhibitor Busulphan (reserved for special indications).Busulphan (reserved for special indications).

Management.Management.

αα-interferon-interferon Have antiviral and antiproliferative properties.Have antiviral and antiproliferative properties. Active in reducing the leucocytes count and Active in reducing the leucocytes count and

reversing all features of CML in 70-80% of patients.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 It identifies, on the basis of the speed of the

hematological response and degree of cytogenetic hematological response and degree of cytogenetic response, subgroups of patients who will survive response, subgroups of patients who will survive longer than others;longer than others;

It probably prolongs survival by perhaps 1 or 2 It probably prolongs survival by perhaps 1 or 2 years in the majority of patients.years in the majority of patients.


Tyrosine kinase inhibitors Tyrosine kinase inhibitors (Glivec)(Glivec)

Is indicated for the treatment of Is indicated for the treatment of patients with CML in blast crisis, patients with CML in blast crisis, accelerated phase, or in chronic accelerated phase, or in chronic phase after failure of IFN-phase after failure of IFN-αα therapy.therapy.


Glivec (cont.)Glivec (cont.) Acts specifically by blocking the binding site for ATP Acts specifically by blocking the binding site for ATP

in the Abl kinase.in the Abl kinase. This inhibits the ability of Abl to transfer phosphate This inhibits the ability of Abl to transfer phosphate

groups from ATP and phosphorylate tyrosine groups from ATP and phosphorylate tyrosine residues on substrate proteins, which in turn residues on substrate proteins, which in turn prevents the transduction of energy signals prevents the transduction of energy signals necessary for Abl-induced cellular proliferation and necessary for Abl-induced cellular proliferation and apoptosis.apoptosis.

Thus, the specific signal transduction pathway Thus, the specific signal transduction pathway abnormally activated in the leukaemic abnormally activated in the leukaemic transformation process is inactivated by Glivec transformation process is inactivated by Glivec while the normal pathways are unaffected.while the normal pathways are unaffected.


Hydroxyurea.Hydroxyurea. Is a ribonucleotide reductase Is a ribonucleotide reductase

inhibitor, which targets relatively inhibitor, which targets relatively mature myeloid progenitors in mature myeloid progenitors in the proliferative cycle.the proliferative cycle.

It is usually possible to reverse It is usually possible to reverse all the features of CML within 4-all the features of CML within 4-8 weeks of starting treatment.8 weeks of starting treatment.


Busulphan.Busulphan. Is a polyfunctional alkylating Is a polyfunctional alkylating

agent.agent. It is rarely used nowadays and It is rarely used nowadays and

reserved for patients who are reserved for patients who are intolerant of hydroxyurea.intolerant of hydroxyurea.


Advanced phase.Advanced phase. Combination of cytotoxic drugs.Combination of cytotoxic drugs. Glivec.Glivec. Allogenic BMT.Allogenic BMT. Patients in blastic transformation Patients in blastic transformation

may be treated with combinations of may be treated with combinations of cytotoxic drugs in the hope of cytotoxic drugs in the hope of prolonging life, but cure can no prolonging life, but cure can no longer be a realistic objective.longer be a realistic objective.


Advanced phase.Advanced phase. If the patient has a myeloid If the patient has a myeloid

transformation he/she can be transformation he/she can be treated with drugs appropriate to treated with drugs appropriate to the induction of remission in the induction of remission in AML – daunorubicin, cystosine AML – daunorubicin, cystosine arabinoside with or without 6-arabinoside with or without 6-thioguanine, or etoposide.thioguanine, or etoposide.


Advanced phase.Advanced phase. Patients in lymphoid Patients in lymphoid

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


Advanced phase.Advanced phase. Allogeneic BMT using HLA-matched Allogeneic BMT using HLA-matched

sibling donors can be performed in sibling donors can be performed in the accelerated phase; the the accelerated phase; the probability of leukaemic free survival probability of leukaemic free survival at 5 years is 30-50%.at 5 years is 30-50%.

BMT performed in overt blastic BMT performed in overt blastic transformation nearly always transformation nearly always unsuccessful.unsuccessful.


Advanced phase.Advanced phase. The mortality resulting from The mortality resulting from

GVHD is extremely high and the GVHD is extremely high and the probability of relapse in those probability of relapse in those who survive is very who survive is very considerable.considerable.

The probability of survival at 5 The probability of survival at 5 years is consequently 0-10%. years is consequently 0-10%.

Course and prognosis.Course and prognosis.

CML usually shows an excellent CML usually shows an excellent response to chemotherapy in response to chemotherapy in the chronic phase.the chronic phase.

The median survival is 5-6 The median survival is 5-6 years.years.

Death usually occurs from Death usually occurs from terminal acute transformation or terminal acute transformation or from intercurrent haemorrhage from intercurrent haemorrhage or infection.or infection.

Course and prognosis.Course and prognosis.

20% of patient survive 10 years 20% of patient survive 10 years or more.or more.

The patient may be divided into The patient may be divided into prognostic groups according to prognostic groups according to age, spleen size, platelet count, age, spleen size, platelet count, blast cells on presentation and blast cells on presentation and ease of response to therapy; ease of response to therapy; these are only rough guides to these are only rough guides to outcome.outcome.

Variants of CML.Variants of CML.

Ph-negative CML.Ph-negative CML. About 5% of patients with About 5% of patients with

haematologically acceptable CML haematologically acceptable CML lack the Ph chromosome.lack the Ph chromosome.

~1/2 of these patients have a ~1/2 of these patients have a BCR-BCR-ABLABL gene that is molecularly gene that is molecularly identical to the identical to the BCL-ABLBCL-ABL gene of Ph- gene of Ph-positive CML.positive CML.

These patients have a clinical course These patients have a clinical course similar to those with Ph-positive similar to those with Ph-positive CML.CML.


Ph-negative CML (cont)Ph-negative CML (cont) Patients with noPatients with no BCR-ABL BCR-ABL gene gene

frequently have haematological frequently have haematological features that are subtly different from features that are subtly different from Ph-positive disease.Ph-positive disease.

They may lack basophilia, lack blast They may lack basophilia, lack blast and myelocyte peaks in the and myelocyte peaks in the leucocyte differential count or show leucocyte differential count or show dysplastic features.dysplastic features.

Have some degree of monocytosis.Have some degree of monocytosis.


Ph- negative CML (cont.).Ph- negative CML (cont.). They respond poorly to IFN-They respond poorly to IFN-αα or or

to hydroxyurea.to hydroxyurea. Survival is inferior to that of Ph-Survival is inferior to that of Ph-

positive patients.positive patients.


Juvenile CML.Juvenile CML. Rare.Rare. Affecting children <12 year-old.Affecting children <12 year-old. C/F – anaemia, or lymphadenopathy with C/F – anaemia, or lymphadenopathy with

hepatosplenomegaly, skin rashes.hepatosplenomegaly, skin rashes. Lab findings – leucocytosis with variable Lab findings – leucocytosis with variable

numbers of blast in the peripheral blood. numbers of blast in the peripheral blood. Marrow is hypercellular but lacks Marrow is hypercellular but lacks chromosomal abnormalities.chromosomal abnormalities.

Responds poorly to standard cytotoxic Responds poorly to standard cytotoxic drugs.drugs.


Eosinophilic leukaemia.Eosinophilic leukaemia. High number of immature cells High number of immature cells

in the blood and marrow.in the blood and marrow. May progress to blastic May progress to blastic

transformation in a manner transformation in a manner similar to Ph-positive CML.similar to Ph-positive CML.

T.QT.Q

chronic myeloid

Documents

blast phase

chronic phase cont

lymphoid blast cells

blast forms

morphology of blast

advanced phase cont

clinical features

early phase