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Some mutations confer moderate resistance to IM while others confer insensitivity to IM. How to detect these mutations? Can IM be the cause of these mutations? Do they exist before IM therapy? Do they occur with IM therapy? These are all interesting questions that the authors try to answer.
Firstly, they say that RT-PCR can miss mutations when the proportion of mutated cells are less than 30%. Since these mutations have much less percentage occurrence than the Ph chromosome, it is easy to miss detecting them. In patients who have a CHR but no CCR with IM, these mutated cells appear only 20% or less than the BCR-ABL expressing cells. Therefore more sensitive techniques are required to test for mutations and one may easily miss detecting them in pre-IM samples.(before start of IM treatment)
What is the root cause of the mutations? Is it genomic instability? Shah et al did not find additional mutations in other regions of the genome and no evidence of mutations in the kinase domain of c-KIT.
Patients have reported resistance to IM therapy within 1-3 months of starting IM treatment so it is doubtful that IM caused the mutations since they appeared so fast. We are left with pre-existence of these mutations before start of IM therapy at a very low level which escapes detection and then with IM therapy which targets and inhibits BCR-ABL, the mutated clones expand under selective pressure of IM.
They tested out this theory by developing a sensitive detection technique called ASO-PCR which uses allele-specific oligonucleotide assays. 5 patients with mutations were monitored on IM therapy. Rare mutated cells (1/10,000) were detected in pre-treatment samples for all the patients previously treated with IFN providing proof at least in these cases that mutations can exist in the natural course of CML and before IM treatment. 2 patients were late-chronic and 3 were accelerated. The ASO-PCR monitoring proved that the resistant mutated cells expanded over time due to clonal selection conferred by IM.
What was the outcome of these patients? Shah reported that 3 out of 4 chronic phase patients with mutations suffered disease progression within 18 months of detection of the mutated cells. Out
of the 5 patients studied by these authors, 2 went into blast phase within a year of detection of the mutations. The authors say that the patient cohort is too small to conclusively say that all patients
having mutated cells have a poor prognosis (in fact some patients with mutations depending on the type of mutations have benefited from higher IM doses; others have had the mutations disappear when IM was stopped so definitely higher doses would not work in these cases) but suggest that if larger trials support these findings, molecular genotyping using sensitive methods within the 3 previous months of IM refractoriness or relapse may provide information useful for rational therapy management.
This is my understanding of the article as a layman and I apologize for any inaccuracies. Since we talk of Gleevec resistance, higher doses to prevent resistance, mutation analysis, I thought we may want to share our thoughts on a basic understanding for what mutations mean, how they may occur, what is the outcome so that patients who are IM resistant can better discuss with their doctors the next step in therapy.
Anjana
Y253 Mutations
Clinical Decisions in IM Era
CML in IM Era
To Transplant or Not
CML Prisms--Literature for Asian CML Support Group Members
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