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.
- 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.
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 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+
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:
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
- 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
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