- 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. Morphology 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
- 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: - Blasts (10-19%) in blood or marrow
- Basophils > 20%
- Thrombocytopenia (<100) unrelated to treatment
- Thrombocytosis (>1000) despite adequate therapy
- Increasing WC and spleen unresponsive to therapy
- 15-30% blasts in blood or marrow
- >30% blasts and promyelocytes
- >20% peripheral basophils
- Platelet count <100 unrelated to treatment
- 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
Immunohistochemistry Neutrophils - Decreased neutrophil alkaline phosphatase
- Weak CD15 and HLA-DR
- 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
- 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.
Genetics 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
- Age
- Spleen size
- Blast percentage (1000 cell count)
- 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
Management 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 | 16% | Chronic phase – IFN failure | 26% | Accelerated phase | 73% | Blast crisis | 95% |
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) | Failure | Sub optimal | Optimal | 0 | NA | | | 3 | No haem response | No CHR | CHR | 6 | No CHR No cytogenetic response | No PCyR | Partial CyR | 12 | No PCyR (Ph >35%) | No CCyR | Complete CyR | 18 | 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 Mutation | |
Different options 1) Increase dose of imatinib to 600 or 800mg 2) Try nilotinib, dasatinib 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.
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