CML (ELN 2013)




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

-       Philadelphia 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, or EUTOS score >87


Response to Treatment


Optimal response associated with best long-term outcome à 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:

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

o   Nilotinib 300mg BD

o   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

o   Imatinib 400mg BD

o   Nilotinib 400mg BD

o   Dasatinib 140mg OD / 70mg BD


2nd line, failure of first

o   Imatinib, dasatinib, nilotinib, bosutinib or ponatinib

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


3rd line, failure or intolerance of first two

o   Allograft in all eligible patients

o   Or any of remaining alternative TKI

At any time

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



-       Hydroxycarbamide can be use 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


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

o   PCR results can fluctuate up and down.

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


o   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

o   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:

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

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


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