Chronic Myeloid Leukaemia (CML) (ELN 2013)




  • Part of ABL from 9 moves to the BCR on 22. (and part of 22 moves to 9)

  • Philadelphia (Ph) chromosome = the abnormal 22 that carries the BCR-ABL1 fusion gene

  • BCR-ABL1 fusion gene codes for a protein with excess tyrosine kinase activity

  • Ph chromosome is an acquired abnormality of a haemopoietic stem cell and so found in cells of both myeloid and lymphoid lineages.


Clinical Presentation

  • 50% diagnosed on incidental FBC finding

  • B symptoms, splenomegaly, symptoms of anaemia / thrombocytopenia




Chronic Phase

  • Not accelerated or blastic phase

Accelerated Phase (ELN)

  • 15-29% Blasts in blood or marrow, or >30% blasts + promyelocytes in blood or marrow

  • >20% basophils in blood

  • Persistent thrombocytopenia <100 unrelated to therapy

  • Clonal chromosome abnormalities in Ph+ cells (CCA/Ph+), major route, on treatment

Blastic Phase (ELN)

  • >30% blasts in blood or marrow

  • Extramedullary blast proliferation, apart from spleen


Complete Haematologic Response (CHR)

  • Normal blood counts


Cytogenetic Response (CyR)

  • Assessed by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases. Peripheral blood FISH is an acceptable alternative only when assessing CCyR, defined as <1% BCR-ABL1 positive nuclei of at least 200 cells.


Molecular Response

  • Ratio of BCR-ABL1 transcripts to ABL1 transcripts measured by PCR.

  • It is reported as BCR-ABL1 IS on a log scale, where 10%, 1%, 0.1%, 0.01%, 0.0032% and 0.001% correspond to a decrease of 1,2,3,4,4.5 & 5 logs below the standard baseline.


Major Molecular Response (MMR, MR3.0)

  • <0.1% BCR-ABL1%


Deep Molecular Response (MR)

  • MR4.0 defined as:

    • either i) detectable disease with <0.01% BCR-ABL1 IS

    • or ii) undetectable disease in cDNA with >10,000 transcripts.

  • MR4.5 defined as:

    • either i) detectable disease with <0.0032% BCR-ABL1 IS

    • or ii) undetectable disease in cDNA with >32,000 transcripts.

  • Molecularly undetectable leukaemia

    • undetectable disease (must state number of transcripts analysed)


risk assessment

Risk Assessment Scores devised prior to TKI’s, still of use. 

High risk patients:

  • Sokal Score >1.2

  • Hasford (Euro) Score >1,480

  • EUTOS score >87


Response to Treatment


Optimal response associated with best long-term outcome —> life expectancy the same as that of the general population


Treatment failure can be:

  • Primary – failure to meet expected response at a given time (see table)

  • Secondary – loss of response (at any time: Loss of CHR / CCyR / MMR or CCA/Ph+

cml response.png

N.B. rapidity of decline is also important. Branford (Blood 2014) showed patients with >10% at 3 months that have a transcript halving time of <74 days still have a good prognosis (they probably just started with a higher disease burden. Those with a halving time >74 days is a poor prognosis.


Treatment Recommendations in diagnosis at chronic phase (outside of trial)


1st line

Any of following at standard dose:

  • Imatinib 400mg OD (competes with the ATP binding site of BCR-ABL1 kinase)

  • Nilotinib 300mg BD

  • Dasatinib 100mg OD

HLA type patient and siblings if baseline warnings of high risk, major route CCA/Ph+


2nd line, intolerant to first

Alternative TKI, any of the following at standard or higher dose

  • Imatinib 400mg BD

  • Nilotinib 400mg BD

  • Dasatinib 140mg OD / 70mg BD


2nd line, failure of first

Imatinib, dasatinib, nilotinib, bosutinib or ponatinib

HLA type patient and siblings, unrelated donor search, consider allograft


3rd line, failure or intolerance of first two

Allograft in all eligible patients

Or any of remaining alternative TKI

At any time

If T315I mutation present use Ponatinib 45mg OD and consider allograft.



Hydroxycarbamide can be used briefly whilst awaiting confirmation of diagnosis

Interferon alpha in rare circumstance that TKI cannot be used

Cytotoxic chemotherapy never recommended in chronic phase

Busulfan not recommended



Pregnancy contraindicated during TKI therapy

If optimal response stable for >2 years, consider stopping TKI with very frequent molecular monitoring throughout pregnancy.



Molecular or cytogenetic or both depending on local facilities


  • RQ-PCR required every 3 months until MMR (MR3.0 or better), then every 3-6 mo

  • PCR results can fluctuate up and down.

  • Consider compliance issues if transcript levels increase >5x in a single follow-up


  • CBA of at least 20 marrow metaphases at 3,6 and 12 months until CCyR, then every 12 months. Peripheral blood FISH is acceptable alternative only once CCyR achieved.


Drug details & Side Effects


Patterns of side effects vary with different TKI’s


Three categories

  • Major grade 3/4 effects occurring in first phase of treatment and require temporary cessation of drug and dose reduction. About 10% patients unable to re-start.

  • Minor grade 1/2 effects beginning early in treatment. Chronic but tolerable although negatively affect quality of life.

  • Late ‘off-target’ effects on CVS, heart, lungs, liver, pancreas, immune defense, glucose and secondary malignancies



Less potent than other TKI, but overall survival is no different

Off patent since Nov 2016 – 10x cheaper!

TIDAL2 Sudy – suggests switch to 2nd gen TKI if not <10% at three months

SE: Rash, diarrhea, probably safer than the others


More potent than imatinib, 4-year MMR-rate approx. 75% compared to 60% imatinib

SE: 7-15% cardiac, Arterial pathology in particular


Also more potent than imatinib, 4-year MMR-rate approx. 75% compared to 60% imatinib

SE: 3-5% cardiac, 5% Pleural effusion per year, Pul HTN


Indicated in T315I mutation, which is resistant to most other TKI

SE: 20-30% cardiac,

Stopping TKI Therapy (BJH 2018)


Lots of trial data now supporting discontinuing TKI therapy

  • Generally after 3 years of treatment, with minimum of 1 year in MR4.5

  • Majority of molecular relapses occur rapidly, usually at 6-12 months

  • Loss of deep MR = 51% at 1 year, 54% at 2 years

  • Loss of MMR = 35% ay 1 year, 36% at 2 years

  • Equals a Treatment-Free Remission of 64% at 2 years


Monitoring off treatment

  • 4-6 weekly PCR for first 6 months, then 8 weekly for next 6 months

  • Then every 3-6 months after the first year


Re-start treatment at loss of MMR

  • Re-starting the same TKI at same dose does not prevent patients regaining deep MR.



  • Largest trial so far. 821 patients on 1st line imatinib or after IFN, dasatinib or nilotinib at 1st or more line, excluding patients with prior resistance

  • Minimum 3 years Rx, with minimum 1 year in MR4

    • Trial outcome suggests best prognosis is min. 6 yrs treatment, 3yrs in MR4

  • Definition of molecular relapse was loss of MMR – 45% of patients by 18 months



  • For patients in MR4

  • Reduced dose for 12 months, and then stopped if patient had not lost MMR

  • Conclusions:

    • Reducing dose is safe (may help with SE’s)

    • If you stop after prior dose reduction, better chance of staying in MR4 (vs EUROSKI)


Other trials – STIM, A-STIM, TWISTER, DASFREE and others