CML Flashcards
Give a general overview of CML
CML is an expansion of mature myeloid cells. It is caused by the mutation BCR-ABL1 in 95% of cases. It typically occurs in elderly people but has a good prognosis
What is the clinical presentation of CML
B Symptoms Splenomegaly Bruising Bleeding Gout It is a triphasic disease: Chronic phase, accelerated and blast crisis( >20% blasts myeloid or lymphoid )
What are the cytogenetics of CML?
> 95% have BCR- ABL1 abnormalitiy due to t(9;22) fusion gene
this is the philadelphia chromosome
ABL1 is a physiological tyrosie kinase, the BCR-ABL1 gene leads to constitutive activity
Where are the breakpoints found in the BCR-ABL1 mutation?
In the ABL1 gene breakpoints are between exon 1 and 2
On the BCR gene its between 12 and 13 or 13 and 14
Why is knowing where the breakpoint is importnat?
Important for management of MRD monitoring less important clinically
Lucas et al in 2009 showed pts with e14a2 transcript were more likely to achieve a complete cytogenetic response compared to those with the e13a2 transcript. Also allows us to tailor treatment.
What tests are used in diagnosis of CML?
Peripheral smear - leukocytosis with varying maturation and left shift in cellularity
BM Aspirate/trephine biopsy showing prominant leucocytosis with domination of myeloid cells i.e. lack of other lineages
FBC: Sometimes anaemia, high WCC, high or low platelets
FISH: dual colour for BCR-ABL1 fusion is best
What is the treatment for CML?
Tyrosine Kinase Inhibitor - Imatinib
TKIs prevent phosphorylation of target proteins for cell cycle
Which was the trial that demonstrated TKIs ability?
IRIS trial
Demonstrated efficacy of Imatinib. The trial compared efficacy of Imatinib vs current combo therapy (Interferon and Low-Dose Cytarabine) in newly diagnosed chronic CML patients. Findings: Imatinib superior to combo therapy (by 12 months, estimated rate of major cytogenetic response was 84.4% in Imatinib group compared to 30.3% in combo group)
What are the problems with TKI use over time?
There is TKI resistance
This is down to kinase domain mutations which means TKI can’t bind to BCR-ABL1 and inhibit it
What is a particularly troubling mutant?
T315I - confers resistance against all TKI except Ponatinib (cortes et al, Ponatinib caused MMR in 58% of t315I pts)
What are the 2nd generation TKIs?
Nilotinib and Dasatinib
Name an important Nilotinib trial
ENESTnd trial compared low and high dose Nilotinib to Imatinib and found that the number of pts under both doses of Nilotinib that achieved a MMR was significantly higher compared to Imatinib. Also found fewer Nilotinib pts progressed to blast crisis, compared to Imatinib pts.
Name an important Dasatinib trial
DASISION trial compared Dasatinib to Imatinib. Found a 1.5-fold higher likelihood of achieving MMR with dasatinib
What was a 3rd generation TKI?
Bosutinib and Ponatinib - still in clinical trials
What was the phase 3 trial for Ponatinib?
Phase 3 trial by Lipton et al 2014 compared Ponatinib to Imatinib. Results suggested that Ponatinib had improved efficacy with better molecular response rates for all response measures at all time points. But also found Ponatinib to have a higher adverse event rate, particularly vaso-occlusive events
