Mutations Analysis
• Some patients in chronic and advanced phases develop mutations in the BCR-ABL kinase
domain which prevents the Gleevec from properly binding to the oncoprotein. There are
techniques to detect these mutations and the mutations are named according to which point they
are found. Mutational studies show that advanced phase patients and late chronic phase patients
may have low levels of mutations before any therapy but this has not been seen in early chronic
phase patients. 1-20% of patients may have mutations in chronic phase, responding to Gleevec
but they do not consistently persist or proliferate and may not be associated with progression of
the disease.
• Conversely, in clinically resistant disease, 30-50% of patients can express BCR-ABL
mutations.
There are 3 types of mutation analysis of varying sensitivities:
1. direct sequencing of DNA following nested RT-PCR which is capable of detecting
mutations in 10-25% of tumor cells. This technique is the most common used.
2. denaturing high performance liquid chromatography (DHPLC) which has a sensitivity of 5-
10%.
3. fluorescent-based allele specific oligonucleotide (ASO-PCR) which can detect mutations in
0.1%-1% of tumor cells.
Advantages:
• Identifying the T315I mutation early can stop the patient from taking Imatinib, Nilotinib
and Dasatinib, since these cannot overcome this mutation. Such patients can be then referred
early for SCT or exploratory T315I inhibitor drugs. In newly diagnosed patients, the risk of
having a T315I mutation is only 0.1-0.3%.
Recommendations for mutational analysis:
• Mutational studies should be performed when there is cytogenetic or hematologic resistance
or relapse.
• Mutational studies performed when there is a PCR rise must be interpreted with caution
especially if change of therapy based on that is contemplated.
• When a change of therapy is considered, it may be helpful to do a mutations test as there is
differing sensitivities of the new drugs to different mutations. For example, if a T315I mutation is
identified, an allogeneic transplant or a specific T315I inhibitor should be considered.