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.
50% diagnosed on incidental FBC finding
B symptoms, splenomegaly, symptoms of anaemia / thrombocytopenia
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.
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)
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 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+
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)
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
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
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