Harry P. Erba, MD, PhD: I want to turn the attention of the panel to maybe the 2 most important and most frequent questions I get about testing in PV [polycythemia vera]. The first is if the JAK2 allelic burden at the time of diagnosis is important. The second is about reports of splice site variance: Are those artifacts, or are those clinically important? I’m going to turn it back to Srdan to start on that. The JAK2 allele burden; how about if it was really low? Could this just be CHIP [clonal hematopoiesis of indeterminate potential]?
Srdan Verstovsek, MD, PhD: The testing is usually done in the clinical setting, where you are suspicious of polycythemia vera. We are not randomly testing people to see whether they have a low level of the JAK2 mutation, which can then be achieved. We are testing in the setting of suspicion of polycythemia vera, where there would be a high-normal or above-normal red blood cell count. You would also look for high white blood cells, high platelets, iron deficiency, and erythropoietin level, and in that setting, you would also test for the JAK2 mutation.
The presence of mutations on its own is not in the diagnostic criteria for any of the MPNs [myeloproliferative neoplasms] because they might have the CHIP. If you have the mutation in the context of all these other tests, Dr Shammo has articulated that very well; on borderline cases for mass PV, you would do this testing and account for all these factors to make sure that you don’t miss PV because the therapeutic approach must be different than if there is no PV; phlebotomy is mandatory.
On the other hand, it may be important, but we are not routinely doing that testing to follow. There is good literature on high allelic burden being prognostic in terms of progression to myelofibrosis or exposing people to high-risk of thrombosis itself.
Harry P. Erba, MD, PhD: If the allele burden at the time of diagnosis is less than 10% or less than 5%, could that be consistent with PV?
Srdan Verstovsek, MD, PhD: It can be, in the context of hyperproliferative bone marrow, high red blood cell count, low erythropoietin, and iron deficiency. However, that would be unusual because the median allelic burden in PV is about 45%. It would be an unusual case.
Harry P. Erba, MD, PhD: Ruben, what do we do with these reports of exon splice site variance where exons are dropped out? Is that just an artifact of the assay, or are they clinically important?
Ruben A. Mesa, MD, FACP: We don’t fully know yet. As we continue to get more genetic information, it is a very rapidly moving target. What is an activating mutation and what really is genetic artifact? The annotation of our genetic reports is a very active process that is not fully baked. I’ll try to look them up as they arise, as well as whether they have the potential to alter our understanding of what we should be doing for those patients.
In terms of our decision support as hematologists moving forward, trying to keep track of all these things is quite difficult because there’s such a river of information as it relates to different types of mutations, allelic burden, and other sorts of pieces. As we get supported over time, that will be an important part as we’re trying to digest what the mutual impact of half a dozen or a dozen mutations is, some of which are in nontraditional splice sites. It becomes more and more difficult to interpret that information.
Harry P. Erba, MD, PhD: Srdan, did you want to add?
Srdan Verstovsek, MD, PhD: I fully agree with Ruben. This is the area of research, but specifically on the JAK2 gene variance, what is done in a community setting is you have a hot spot test that you do: a JAK2 V617F. We don’t look for the whole gene; only if you have a negative result do you then do the JAK2 exon 12. In some academic centers they analyze the whole gene.
In some cases, you will then find the variance in addition to the hot spot mutation that you are looking for. It seems that the presence of variance or other genetic abnormalities within those genes make a difference for the outcome for the aggressiveness, but it’s completely new area of research.
Transcript Edited for Clarity