Haemato-oncology‎ > ‎


  • Myeloproliferative disease that originates from a pluripotent stem cell with the BCR/ABL fusion gene
  • Although the initial major finding in CML is neutrophilic leukocytosis the abnormal fusion gene is found in all myeloid cell lineage

Incidence 1/100,000

15-20% of all leukaemia


20-40% asymptomatic at diagnosis.

Common findings include anaemia, night sweats and splenomegaly


Aetiology unknown

Some cases related to irradiation.



Chronic phase

Blood film

  • WC median 170 – neutrophilia / myelocytes
  • Blasts usually < 2%
  • Absolute basophilia invariably present
  • Platelet count normal or increased (thrombocytopenia is uncommon in CML-CP), some giant platelets (occasional bare megakaryocyte nuclei)
  • Absolute monocytosis is common but rarely exceeds 3
  • Tear drop poikilocytes present when there is extensive fibrosis

Bone marrow

  • Hypercellular (M:E ratio >10:1 – often nearer 25:1)
  • Similar maturation pattern to peripheral blood
  • Paratrabecular cuff of neutrophils thickened from 2-3 to 5-10 cells
  • Blasts usually < 5% (>10% indicates transformation to accelerated phase)
  • Megakaryocytes small with hypolobated nuclei, may be decreased in numbers but micromegakaryocytes (as occur in MDS with one or two small round nuclei) are not usually seen
  • Erythroid precursors usually decreased
  • Increased reticulin (up to 40%)
  • Pseudo-Gaucher cells seen in about 30% - due to increased bone marrow cell turnover and are derived from the neoplastic clone.


Accelerated phase

Characterised by one or more of the following:

  1. Blasts (10-19%) in blood or marrow
  2. Basophils > 20%
  3. Thrombocytopenia (<100) unrelated to treatment
  4. Thrombocytosis (>1000) despite adequate therapy
  5. Increasing WC and spleen unresponsive to therapy


Kantarajan criteria

  1. 15-30% blasts in blood or marrow
  2. >30% blasts and promyelocytes
  3. >20% peripheral basophils
  4. Platelet count <100 unrelated to treatment


Other features include

  • Marked dysplasia in the granulocytic lineage
  • Prominent proliferation of small dysplastic megakaryocytes in large clusters with marked reticulin or collagen fibrosis
  • Any lymphoblasts in blood or marrow are a concern as it may indicate lymphoblastic transformation.


Blast phase

Resembles acute leukaemia – can be made when

  •  >20% blasts in blood or marrow
  • Extramedullary proliferation of blasts
  • Large aggregates or clusters of blasts on the trephine
  • 70% blast lineage is myeloid (neutrophilic, eosinophilic, basophilic, erythroid or megakaryocytic blasts)
  • 20-30% lymphoblasts
  • Rarely there can be simultaneous populations of myeloid and lymphoid blasts.
  • Immunophenotyping essential to delineate the blast lineage



  • Decreased neutrophil alkaline phosphatase
  • Weak CD15 and HLA-DR


Myeloid Blasts

  • Strong / weak / no MPO activity
  • Will have ag associated with
  • Monocytic (CD13, CD14, CD15, CD33 etc)
  • Megakaryocytic (CDw41, CD61)
  • Erythroid (glycophoin, haemoglobin A)
  • Often also express lymphoid antigens as well


Lymphoid blasts

  • Most are precursor B lymphoblasts (CD10, CD19, CD34 and TdT but negative for slg)
  • Precursors of T cell origin also occur (CD3, cCD3, CD7, TdT etc)
  • In many cases also express some myeloid antigens as well.



Philedelphia Chromosome t(9;22)(q34;q11)

  • 90-95% have the characteristic cytogenetic
  • Fuses BCR (chromosome 22) with ABL (chromosome 9)
  • Remainder have variant translocations involving a third or fourth chromosome or a cryptic translocation of 9q34 and 22q11 that can’t be identified with routine cytogenetic analysis.
  • In these cases BCR/ABL can be detected by FISH, RT PCR or Southern blot


Site of the breakpoint may influence the phenotype of the disease:

  • In CML the BCR gene breakpoint is almost always in the:


Major break point cluster (M-BCR, BCR exons 12-16 or b1-b5)

  • Forms fusion protein p210, which has increased tyrosine kinase activity.


Minor breakpoint region (m-BCR, BCR exons 1-2)

  • Shorter fusion protein p190
  • Most frequently associated with Ph positive ALL
  • But small amounts of p190 transcript can be detected in 90% patients with CML
  • Can also rarely be seen in CML which is distinctive with increase numbers of monocytes (and thus resembles CMML)

Other chromosomal abnormalities

  • Significance unclear at diagnosis – probably confer worse prognosis
  • At time of transformation 80% have other abnormalities such as an extra Ph, +8 or I(17q)
  • Genes involved include TP53, RB1, MYC, p16INK4a, RAS, AML1 and EVI-1


Severity scoring

  • Sokal score
    1. Age
    2. Spleen size
    3. Blast percentage (1000 cell count)
    4. Platelet count
  • High sokal score 68% probability of achieving CCyR cf. 84 and 91% for intermediate and low in IRIS
  • Euro / Hasford score modification to incorporate eosinophil and basophil counts




Chronic Phase

1.      Leukophoresis

  • Treatment of hyperviscosity symptoms
  • May be useful to perform stem cell harvest at this stage


2.      Imatinib

  • Standard starting dose 400mg
  • Side effects
    • Bone pain
    • Fluid retention
    • Anorexia
    • Depression
    • Weight gain
  • 93% free of accelerated / blast phase at 5 years
  • 75% continue to be in CCyR at 5 years
  • Rate of therapeutic failure peaks at 2 years
  • Patients who maintain a CCyR for 4 years had a )% risk of progression


3.      Monitoring of imatinib treatment

  • Baseline data - qualitative PCR not routinely recommened, but some do as p190 transcripts not detectable and therefore without baseline data, follow-up results likely to be misleading.
    • FBC weekly until stabilized
  • Once complete haematological remission, bone marrow karyotyping at 6, 12 and 18 months or until CCyR achieved (others recommend 3 monthly)
    • Some do FISH on PB, but this may miss new mutations, not as standardised and not used in IRIS
  • Possibly yearly thereafter to look for other clonal abnormalities in Ph negative cells
  • Once complete cytogenetic remission, RT-PCR for BCR-ABL transcripts
  • Should be measured every 3 months
    • Expressed as a percentage compared to a control gene (often ABL itself)
    • <1% regarded as a 2 log reduction and is consistent with CCyR (usually achieved by 6 months)
    • 0.1% = 3 log reduction = major molecular response
    • Complete metabolic response predicts a very low risk of relapse but is not equivalent to disease eradication


Complete haematological remission

1.      Normal blood counts

2.      Resolution of splenomegaly

3.      Loss of marrow hypercellularity

IRIS study at 12 months

Minimal cytogenetic response

66-95% Ph positive by FISH

32% failed to achieve CCyR

Minor cytogenetic response

36-65% Ph positive by FISH

Partial cytogenetic response

1-35% Ph positive by FISH

Complete cytogenetic response

Absence of Ph-positive metaphases – consistent with 2 log reduction ie <1%

30% CCyR

Major molecular response

PCR <0.1 %

40% MMolR

Complete molecular response

Transcripts not detectable by PCR



Primary resistance

  • Failure to achieve a certain response at a given time after initiating therapy
  • 3 months of starting the drug 2-4 fail to achieve a haematological response
  • 6 months 20% fail to get a cytogenetic response
  • Insufficient BCR-ABL inhibition (low plasma levels / drug pumps – OCT1)


Secondary resistance

  • Increase in leukaemia load at any time during therapy
  • More common in patients who start on the drug later in the disease
  • Earlier the patients start therapy the more likely they are to achieve a deep cytogenetic response as well as failure free survival
  • Out growth of one or more clones harbouring an imatinib resistant clone (currently can only detect 20% of mutations)
  • Overproduction of BCR-ABL
  • BCR-ABL independent mechanisms


Phase at commencing imatinib

% relapse as 42-48 months

Chronic phase


Chronic phase – IFN failure


Accelerated phase


Blast crisis




Failure of imatinib therapy

  • BCR-ABL rising result should be repeated
  • If the repeat test confirms a rise by a factor of 5 or 10 then should perform
  • Ascertain patients adherence, consider measuring imatinib concentrations
  • Mutation analysis – can help guide which TKI to choose
  • Ascertain whether patient progressed beyond chronic phase, if so 2nd line inhibitors unlikely to last and need to consider allogeneic transplant with dasatinib or nilotinib as a bridge


Time (mths)


Sub optimal







No haem response





No cytogenetic response


Partial CyR


No PCyR (Ph >35%)


Complete CyR


No CCyR (Ph >1%)

No MMolR

Major molecular response

Any time

Loss of CHR or CCyR

Mutation eg T315I

ACA in Ph + cells

Loss of MMolR




Different options

1)     Increase dose of imatinib to 600 or 800mg

2)     Try nilotinibdasatinib or bosutinib unless T315I mutation

All more potent than imatinib

  • Dasatinib 2006
    • Current dose 100mg od (less toxicity 6% and better progression free survival compared to 70mg bd)
    • Able to achieve CCyR in patients who are resistant or intolerant of imatinib
  • Nilotinib licensed 2007
    • Less toxic than dasatinib
    • May have higher CCyR rates if used first line than Imatinib – may be close to 100% response rates cf 70% in imatinib

3)     MK0457 if T315I

4)     Allogenic stem cell transplant (possibly RIC)

5)     Autologous SCT (with cells collected at diagnosis or during CCyR)

6)     Classical chemotherapy – hydroxyurea, cytaribine, busulphan, homoharringtonine or interferon alpha

7)     Experimental agents (downstream signal transduction inhibitors)


Advanced disease

  • May be treated with imatinib 600/800mg daily but the duration of response may be short.
  • Should have conventional chemotherapy immediately afterwards with or without allogeneic transplantation.