https://www.cancertherapyadvisor.com/home/cancer-topics/chronic-myeloid-...
“In this update, low-dose dasatinib continued to demonstrate faster and deeper molecular responses in comparison with standard-dose dasatinib and imatinib,” stated the researchers. They also noted the lack of new safety signals during this follow-up and suggested that dasatinib given at 50 mg per day may be an appropriate option for initial CML-CP treatment.
This is great to hear, and super interesting but I’m not quite sure of this trial - the link in that article points to a trial with 50mg dasatinib alongside venetoclax. Are there two arms of the trial?
In any case, the first 70 patients recruited are 50mg dasatinib only and the remainder (83 total?) with venetoclax as well so I think it’s double-armed but I can’t see how the arms compare.
Results seem really positive, but it’s not a massive sample size and there is for sure some selection bias given the centre it’s been run from. I’d love to see this reproduced elsewhere, and I suspect results would be similar.
I had a long chat with my haematologist the other day at clinic about dose reduction. She told me dose reduction is on the radar of many more patients than it was even a year or two ago. Anecdotal, of course, but she also said that after a dose reduction she often sees a small-ish spike in PCR, followed by a regression. She’s not sure why, but said it might be a pattern. Happened in my case - but on 20mg my last result was MR5 (IS). 2 positives from 105,000 assays with a x0.5 IS conversion factor.
David,
Hi David, you mention a x0.5 IS conversion factor. I was looking through some of my old PCR scores and noticed that for about the first year and a half that the lab was reporting the raw score with the IS. I couldn't figure out how the conversion was done. How does the conversion work?
Here are my scores from early treatment:
I.S. result (result without conversion)
118.683% (88.57%)
3.590% (1.438%)
0.914% (0.813%)
0.434% (0.574%)
0.412% (0.611%)
0.360% (0.859%)
Hi Kirk,
So the x0.5 conversion factor I mentioned is specifically for my lab. It is just chance that it happens to be a really simple one to do, just dividing the unadjusted result by 2.
Other labs will have different conversion factors. Page 17 of our primer goes into more detail: https://cmlsupport.org.uk/node/20097
I must say though, your results confuse me. The conversion factor should be constant (it does change as a lab is re-baselined, but this is not a frequent thing - every few years I think) and the ratio of your converted results to non-converted results isn't constant.
Is there any chance that those blood tests were actually two different tests by different labs? Early in my diagnosis I had something sort of similar where my PCR was done at my hospital lab, but also done at another lab (Hammersmith) so the results would diverge.
David.
I'm pretty sure all of the PCR results came from the same lab, but I could be wrong. I assumed it would be a linear relationship. Here's quote from the PCR primer: "This calculation will be invalid if the reproducibility or linearity of the assay is poor, in which case the methodology will need to be optimized." So maybe the lab has to do some extra calculations because their unique procedure isn't linear?
I found something else unexpected when going over the PCR reports. The report from April 2013 says this: "Current quantitative BCR-ABL1 transcript analysis reveals 0.914% p210 transcript on the International Scale. These results indicate the patient has achieved a major molecular response." The next report from July 2013 says this: "Subsequent qRT-PCR analyses, including the current showing 0.434% p210 transcripts on the IS, have continued to show evidence for a steadily decreasing BCR-ABL1 transcript level. However, he has yet to attain a major molecular response (MMR)."
I suppose it's probably just a mistake where it says I had reached MMR in the April report.
Sounds like a clerical error for that 0.914% MMR declaration alright.
The point in the primer relates to PCRs where there are < 100,000 assays. With more than 100,000 you can have confidence in the numbers, with it becoming less and less usable the lower the number. I can't remember offhand, but I think it becomes totally useless at less than a few thousand.
As for linearity of the amplification with the number of cycles ... that's beyond my level of knowledge to be blunt.
It's interesting though, and if you find out more about it I'd love to know.
David.
Kirk,
It is possible that your PCR results were determined using external calibrators as opposed to a laboratory specific conversion factor. Labs back then were either "validating" their local method by a thorough analysis using sample exchange to establish their lab's specific conversion factor (a constant value used to adjust the results from each test to report out an IS value) or they used "validated" external calibrators during each test and thus each test would be adjusted individually to an IS value based off the external calibrator standard curve. This may explain your results.
I think you're right about that. The conversion factors to IS do seem to follow some sort of curve. Here's the fine print from the PCR reports:
Methodology:
Total RNA was isolated from the provided specimen and subjected to reverse transcription-polymerase chain reaction (RT-PCR). Amplification products were monitored by real-time PCR using primers and probes specific for the p210 (b3a2, b2a2) and p190 (e1a2) fusion transcripts. An additional RT-PCR amplification of the ABL1 transcript was performed to control for cDNA quantity and quality. Serial dilutions of RNA isolated from a cell line with a known t(9;22) was utilized for quantification of BCR-ABL1 fusion transcripts relative to the ABL1 control gene. The results are reported as a percentage representing the normalized copy number (NCN) of BCR-ABL1 transcripts expressed per 100 copies of the ABL control gene. The International Standard Result is calculated by multiplying the local (unconverted) BCR-ABL1 result by the International Scale Conversion Factor. The Conversion Factor is determined by the use of a calibrator which is referenced to a secondary reference standard which has been referenced to the primary international standard (CRM/NIBSC). The assay has a limit of detection of 0.0069 BCR-ABL1 NCN (%) with high analytical precision at the MMR level.
This test was developed and its performance characteristics have been determined by Compass Oncology Laboratory Services. It has not been cleared or approved by the US Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.
