Published on August 25, 2015
Dr. Stephen Oh from Washington University School of Medicine and Dr. Brady Stein from Northwestern Medicine examine genetic testing as it relates to the prognosis and treatment of myeloproliferative neoplasms (MPNs). Although JAK2 and calreticulin are standard mutations identified in testing, the doctors expand and how these tests may target additional mutations and if extensive testing is beneficial or necessary.
Transcript | Prognosis and Testing for Genetic Mutations in MPNs
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The next question is from Diana. When will genetic mutational status be incorporated into the prognostic scoring systems? Are you already doing that unofficially?
I can start it off. That was kind of teed up for me.
So let’s just so we’re clear on what genetic testing means. So we have the JAK2 mutation. I think, essentially, every patient with an MPN is tested for that. We haven’t talked a whole lot about calreticulin. This is a newer mutation that was discovered or reported about two years ago and is present in the majority of patients with ET and myelofibrosis who lack the JAK2 mutation. So with the exception of some very, very isolated case reports, JAK2 and calreticulin are mutually exclusive. And that has proven to be very helpful for multiple reasons. 1) Diagnosis. So patients, in particular, with the ET elevated platelet count, before we had calreticulin, half of the patients were JAK2 negative.
And we had to be sure they did not have some other cause of elevated platelet count. Now, we have a molecular test that’s pretty definitive in those patients that have a calreticulin mutation. They really, truly do have ET. So that is very helpful. And then second, in terms of prognosis, there’s a whole slew of literature that’s come out since the identification of the calreticulin mutation indicating that those patients who have the calreticulin mutation, in general, have a more indolent course of their disease than patients who lack calreticulin or are JAK2 mutation positive.
Or extending upon that, now we have this sort of triple-negative category. Those are patients who lack JAK2, lack calreticulin and also do not have mutations in MPL, which is found in rare patients with ET and myelofibrosis. So that’s a very small subset in maybe 10 percent of the patients with ET and myelofibrosis. But those patients seem to have, if anything, the worst prognosis compared to those who have any of those mutations. So that part, I would say, at least in academic centers, it’s become pretty standard to test for JAK2, calreticulin for sure and perhaps MPL
Beyond that, and this is more what I was getting at before, there’s a whole slew of other genetic mutations that we know are present in some patients with these diseases.
None of them are more frequent than probably 20 or 30 percent. And some of them are as few as 5 percent or even less. But some of those mutations pretty clearly do affect the prognosis. So I won’t get into all the details about the specific mutations. I’ll just say that the question, which was is this something we’re doing in our practice now, my own practice, I do consider this kind of testing in particular for patients with myelofibrosis in whom the patient and the physician together decide that we want as much detailed information as we can get and how that might be affected by this.
The caveat is that these kinds of tests, which are typically 30 or 40 genes or more in sort of a panel of tests can be quite costly and are not always covered by insurance. So if you were to pay out of pocket, these tests are typically on the order of $5,000.00 or $6,000.00, around that neighborhood. So it really depends, in any particular case, whether the insurance would cover it, what the co-pay will be and, of course, whether that’s feasible for the patient.
And another caveat, this is coming. There are commercial companies that are doing these panels.
And each of the academic institutions [is] developing their own internal panel. One of the key questions, before we send it, is what are we going to do with the information? Is it going to help us make a decision? So that’s what we’re always asking, because another second question is will this be covered by insurance? It’s easier to find out if a CAT scan or another imaging test is covered by insurance. But sometimes, lab tests, it’s harder for us to know in advance. And the last thing we want to know is send a test, the bill comes back at $6,000.00, and we can’t have it covered, and we did nothing with the information.
So that’s one of the critical issues with the genomic testing. This is beyond JAK2, calreticulin and MPL. These are covered tests. These are standard. But what we’re talking about is looking at additional mutations that are infrequently identified in research settings seem to have relevance. But the question is how actionable are they at this point in time?
So that’s an important caveat about the additional tests. Now, they are going to be incorporated I think formally into the prognostic scoring systems. At last year’s American Society of Hematology Meeting, in presentations of large patients from around the world where they did just this. They looked at some of the standard mutations or the additional mutations, and they incorporated it into a scoring system. And they are more precise than what we have now. We have some dynamic clinical variables now. These additions add to precision. And so I think they’re probably coming in the next couple of years.
I think a follow-up question on that would be what about tumor burden? You know that you’re JAK2, or you know that you’ve got one of the other ones. How important is that tumor burden? And how do you use it in practice?
So I think the most data or experience we have with that would be with respect to the JAK2 mutation.
So we know that we can measure quantitatively. We can get a number that’s anywhere from 100 percent to as low as 0.1 percent with some of the sensitive tests that we have available. I guess the summary of the status of this is that it’s very complicated, and we don’t really know exactly what to make of the number. For instance, with PV, if you compare PV to ET or myelofibrosis, the JAK2 percentage tends to be higher in PV. But it’s also we have patients with PV who have very low numbers, 1 percent even.
And they might actually have very similar disease. So it’s very uncertain what to make of that. And then the corollary to that is is this a number that should go down with treatments? With these newer treatments, does it go down? Should we expect it to go down? What we’ve seen with the JAK inhibitors, in general, is that it doesn’t go down dramatically. It doesn’t go down like BCR-ABL does and CML. We talked about Gleevec earlier and imatinib.
It doesn’t go down to 0 or 0.001 like we see with that disease. It might go down a little bit. And it might go down a little bit more over a longer period of time. But what that means is very unclear. So I think we’re faced with this question all the time. And sometimes, it comes into play in terms of insurance coverage. Can you justify sending a test that will measure it that number? And mostly, there’s not a whole lot of practical utility to it.