The news is GOOD! Josh's PCR test came back with good results. Obviously we are looking for a number of 0. But that is going to take time to achieve if we ever hit it. But until they see zero they are looking for a 3-log reduction as the goal. So I was right in reading Josh's chart for his original PCR test - he had 91.43%. So to lay out the numbers....
91.43 - 0 log reduction (base count)
9.143 - 1 log reduction
.9143 - 2 log reduction
.09143 - 3 log reduction
So this most recent test result came back with a result of 5.19. So you can see we got a 1 log reduction, but we've got quite a ways to go to hit 3 log, if I am figuring this whole thing out correctly. I know people see these results and think that means everything is completely hunky dory, but I just have to keep it in perspective that yes, things got better, but he has a long way to go. I found this transcript of Dr. Druker explaining the meaning of these tests. I thought it might help others cause he explains it really well, so here is the important part (warning, this is long and the formatting copied poorly!)....
How do we monitor CML?
Clearly, we can monitor blood counts. We can also test for the presence of the abnormal chromosome that marks leukemia cells, the Philadelphia chromosome.
We can look for the Philadelphia chromosome either through cytogenetics, it can be done on bone marrow, or we’ll look at 20 dividing cells.
We can also use FISH (fluorescence in situ hybridization), either on blood or bone marrow, where we look at 200 cells, either dividing or non-dividing, or a polymerase chain reaction (PCR) where we can look for traces of leukemia in as many as a million cells.
So, let’s talk about this in a slightly different way, and let’s think about this in terms of numbers of leukemia cells. The ideal would be not to have any leukemia cells.
If you didn’t have any leukemia cells, you don’t have leukemia, and if we can ever get you to that point, we can say that you’re cured.
At diagnosis, most people with CML will have a white count of 50,000 to 500,000. A normal white count should be 5,000 to 10,000.
That’s anywhere between 5 to 50 times the upper limit of normal. In a normal bone marrow, there are 1 trillion cells.
Now that sounds like a big number, but that’s how many normal cells are in a normal bone marrow. If the bone marrow’s been taken over by leukemia, you have as many as 1 trillion leukemia cells. That may sound like a huge number, but that’s how many cells a normal bone marrow has, and now your bone marrow has leukemia.
The first goal of therapy is to get your white count down to normal. If you have a normal white count, we would call that a complete hematologic response. So a complete hematologic response simply means a normal white blood count.
Now the problem with that is that we really don’t know how much lower you’ve gone, how close you are to zero. We’ve only reduced the number of leukemia cells by maybe 10-fold, perhaps down only to 100 billion leukemia cells. So we’ve got to do much more sensitive testing, and this is where cytogenetics comes in.
This looks for the abnormal chromosome. This abnormal chromosome, which marks the leukemia cells, comes about because 2 chromosomes, chromosomes 9 and 22, exchange pieces, and you end up with a short chromosome 22, which is called the Philadelphia chromosome, and a longer chromosome 9.
It’s this short Philadelphia chromosome that we can look for in the bone marrow that marks leukemia cells and is actually what causes leukemia. This is what we look for in cytogenetics. We look for the presence of the Philadelphia chromosome.
As I mentioned, we look at 20 cells. Typically, when someone is diagnosed, all 20 of their bone marrow cells will have the Philadelphia chromosome. So it’ll be 20 out of 20 Philadelphia chromosome positive.
Now when somebody has a normal white blood count, what if they still were 20 out of 20 Philadelphia chromosome positive?
What that tells us is that most of their blood cells are still leukemic despite having a normal white blood count, and our estimates would be that that patient has 100 billion leukemia cells left.
Now, the reality is it’s better to have a normal white count than a white count of 500,000, but you could still be left with a lot of leukemia cells.
So the next goal of therapy would be to try to get somebody down to 0 out of 20 Philadelphia chromosome positive, also called Philadelphia chromosome negative, or a complete cytogenetic response. All those terms mean the same thing. It just means we’ve gotten you to Philadelphia chromosome negative.
In reality, we’ve only looked at 20 cells. A normal bone marrow has a trillion. We’ve just looked at a drop in the bucket. We’ve got to get much more sensitive tests if we’re going to figure out how well controlled somebody’s disease is.
Again, however, it’s far better to be Philadelphia chromosome negative than Philadelphia chromosome positive. So we need a more sensitive test known as PCR.
PCR testing is, for those of you that follow some of these crime scene dramas, the cops go to the scene of the crime, they scrape a piece of blood and figure out who did it. We can sort of do the same thing with a test tube, a vial of blood.
We can look for a trace of leukemia in that vial of blood. So with PCR testing, we can amplify a signal, and we can see 1 leukemia cell in between 1,000 to 1 million normal cells.
Now this PCR testing can be qualitative. It simply gives you a positive or negative. It tells you if this Philadelphia chromosome abnormality, which we’ll now call BCR-ABL, is present or not present. We can also do a quantitative test where it gives us an estimate of the number of leukemia cells.
So if we put this back on our graph, the reality is that we now can go from 1 trillion cells down to 1 million leukemia cells, but we have to make a couple of points here.
First, if you do an equivalence ratio, 1 in 1 million is equivalent to 1 million in 1 trillion. So PCR undetectable could still mean you have 1 million leukemia cells left. It doesn’t mean cured, and it also means that we can’t do anything more sensitive to look for lower levels of leukemia.
So PCR undetectable or PCR negative doesn’t mean cured. It just means the lowest level we can identify.
The second point is that about 80% of patients treated with imatinib will be between Philadelphia chromosome negative or complete cytogenetic response and PCR undetectable.
Most people will be there. The only way we can monitor patients in this range, where the majority of people are, is through PCR testing.
So let’s look at this graph, looking at PCR values, and here I’ve taken what’s now known, on the left-hand side, something called the International Scale where newly diagnosed patients arbitrarily would have a value of 100, and I’ve done 10-fold reductions, and you can see on the very far right we have a 3-log reduction. That just means 1,000-fold reduction in the number of leukemia cells, and that has some prognostic importance.
We can make a couple of other points.
First, I’ve shown this on a quantitative scale, meaning the quantitative PCR that gives us a number. If we did a qualitative PCRthat just said present or absent, all of these values would be positive. You couldn’t tell the difference between a newly diagnosed patient who would have a value of 100 and a very, very well-controlled patient, who would have a value of 1, which would likely be a complete cytogenetic response, 0.1 or even lower. So the reality is this quantitative PCR gives us a far better insight into how well controlled people’s leukemia is.
Second, clearly quantitative monitoring is preferred. It gives us an indication of where people are. The problem, though, is that different labs will give you different results. If you come to my hospital in Oregon or Dr. Neil Shah’s hospital in San Francisco, we’ll give you different results. We are working on standardization so that you can go anywhere in the world and have the same testing done and the same results done, but unfortunately we don’t yet have a standardized test. Until then, my
recommendation is that you send your samples to the same lab so that you can follow a trend.
For those of you who are interested, Novartis has set up a program called the CML Alliance™ and they currently use 2 labs. If you’re currently not being done at one of these labs, I would urge you to think about working with your physician through the CML Alliance, to have your testing done routinely at a standardized testing laboratory.
A third point about monitoring is that negative results also depend on the quality of the lab and the quality of the sample. The sensitivities vary from lab to lab, from 1 in 1,000 to 1 in 1 million, and so negative at 1 in 1,000 is not as good as negative at 1 in 1 million. Different labs, again, will have different results.
What do I consider a good response?
There’s a 3-log reduction. Any time you get it, it is a great place to be. (That’s me – Harvey)
Six months, 1 year, 2 years, that’s a great place to be.
The risk of relapse is a half percent per year, and it decreases over time. So at a half percent per year, that means that at 10 years, 5% of people in that category would relapse.
With a complete cytogenetic response to Philadelphia chromosome negative, there is a 2% risk of relapse per year, and by year 4 of maintaining that response, it declines to a half percent per year. So my view is that a stable complete cytogenetic response is equal to this 3-log reduction.
So if you are still reading this then I am way impressed. It is pretty sad that I now find all this stuff interesting! It feels good, though, to know what we are up against. We are feeling encouraged with these results! We will keep everyone updated when we get the rest of the results next week. We're still waiting on the cytogenetics to come back, which will tell us about those pesky chromosomes!
