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Is relapse possible after MMR?

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Since my diagnosis with CML, I am trying to learn about this disease and this Forum is my favorite place to find answers, even the ones that my Doctor cannot provide.
I was diagnosed 9 months ago with qPCR = 50.2% IS, I was very happy when 7 month later the qPCR result was 0.013% IS. But I did one test last week and the result is 0.023% IS. I asked my Doctor why it when up, he said it is because I still have active Leukemic cells with the Philadelphia chromosome.
According to many articles, when you achieve CCyR (less than 1% IS) you don’t have any more cells with the Philadelphia chromosome

But how can cells with the BCR-ABL1 gene increase without the Philadelphia chromosome?

Firstly you have not relapsed far far from it.

Secondly on paper I know this is an up 0.013% to 0.023% but really it's the same result. PCR testing isn't perfect and BCR-ABL can and does fluctuate a lot over the course of your disease. Many factors can be involved in the fluctuation of the tests and to be honest I don't think anyone really knows (its a bit like weighing yourself you are never the same each day so many moving parts in our biology). Its hard not to get worried at times so we all get it.

Youre fine and no doubt the next test will be lower.

Al

Thanks Al,
I am still trying to understand CML at a molecular/cell level, if there are no more cells with the Philadelphia chromosome, why is the BCR-ABL1 gene detected by the qPCR ? Where in the cell is this gene located?
Vlacer

Hi vlacer

Your results look really good and aren't cause for concern, in my opinion (but remember that I am not a doctor). I've had ups and downs throughout this CML journey and, after 8 years, it has worked out well for me in the end (touch wood).

I just want to add my understanding to what you posted: CCyR is cytogenetic remission, which means there are no more cells with the Philadelphia chromosome in your bone marrow. However, there are some cells that still carry copies of the BCR-Abl gene in your body. It is this gene that is responsible for CML, and that is what is measured by the qPCR test.

When you are in CCyR, this usually corresponds to a BCR-Abl reading of 1% or lower. In other words, there are no more cells that have the Philadelphia chromosome, but the gene that causes them to occur is still present. It is, however, at such a low level that it doesn't cause health problems and, as long as you keep taking your TKI, it shouldn't cause problems for you in the future.

I hope that makes sense! Good luck with your continued recovery.

Best wishes from South Africa

Martin

Hi Martin,
Thanks for your answer, I apologize, but I still don’t understand. Genes are segments of DNA in the chromosomes, the BCR-ABL1 gene is formed when pieces of chromosomes 9 and 22 break off and trade places and the changed chromosome 22 with the fusion gene on it is called the Philadelphia chromosome.
After achieving CCyR, where in the cell is this BCR-ABL1 gene located if there are no more cells with the Philadelphia chromosome?
Vlacer

Dear vlacer

I will try to explain briefly. CCyR is a clinical (and statistical) threshold in treatment guidelines which is achieved by the patient when there are no cells with the Philadelphia chromosome seen under the microscope by the human eye. The standard is reviewing 20 cells under the microscope (metaphases to be exact) and when there are no cells among the 20 with the Philly (0/20), then this is known as a complete cytogenetic response. This threshold roughly corresponds to 1 % BCR-ABL with a PCR test.

CCyR does not mean that there are no cancer cells anymore. On the contrary, there are a lot of them. A very rough estimate for the average person is that when you reach CCyR, you still have around 1 billion leukemic cells. When you reach MMR, it is roughly 100 million.

The oncogene BCR-ABL and it's mRNA (detected by PCR test) is present in every leukemic cell and since you have them a lot, it is detectable with a PCR.

But don't worry, concerning your health and future outlook, CCyR is a low level and considered to be the most relevant clinical milestone during treatment which translates into near-normal life expectancy and near-zero probability of progression.

Timo

Thanks Timo for the great explanation!
Vlacer