Allele Burden -- Polycythemia Vera

[Hilary777]

Can someone please explain what is the Allele Burden ? Should I be having a regular measurement, by means of a blood test ,to monitor the progress of the disease? What would be the normal range?

I was diagnosed with PV in May 2024 had two venesections then a platelet crash ( down to 7) after 10 days on Hydroxurea and needed a platelet infusion.

Back home , on Aspirin only, and awaiting a follow up appt with the Haematologist on 14 Aug.

I am aware that my HB was 164 and HCT 0.55 at diagnosis but no doctor has mentioned an Allele Burden figure.

In addition to the PV I have iron deficiency -- currently 3, ferritin 18 . I'm wondering what happens when it falls to zero?

Does anyone in NZ read MPN Voice? With only 30 diagnosed cases year in NZ , it feels lonely out here!

Previously Hunter was very helpful in explaining som of the issues with the Iron deficiency.

[Cat_lady52]

I believe only jAK2 patients get to know, its shows the difference between good and mutant cells.If you are calr postive i was told there is no point in having test,as they can't currently do anything with the info at the moment.

I would ask your consultant on 14th for the test / result and see what they say.

Take care xx

[RoundTheWorld]

Hi Hilary. I’m in the uk but v much value that this forum lets us compare notes and support each other across the globe.

Allele burden is the percentage of mutation (I hadn’t realised until CatLady answered that it may only be JAk2; I had assumed it could also be tested for CalR). I was pleased to have an appt. with an MPN specialist recently - he said he will ask my local haematology team if they are willing to test it yearly so that they can see how the burden reduces in response to interferon treatment (reducing it is molecular response). Not all haematologists routinely monitor it as its significance is not yet fully established and it is a cost. Presumably though the more patient data re. reduction of burden the more the researchers can learn how that affects symptom reduction and/or long term outcomes.

Hope that helps.

[Cat_lady52 in reply to RoundTheWorld]

I believe it can be tested in calr, but as the Dr's can't use the info for treatment, it would purely be informational, so they don't tend to run test on calr patients, I asked, I may ask again when I have another bmb in 4/5 years, it's always worth asking, Things change and different doctors may have a different view. xx

[hunter5582]

Mutant Allele Burden is also referred to as Variant Allele Frequency. VAF in MPNs = the percentage of hematopoietic stem cells that carry a MPN driver mutation (JAK2, CALR, MPL). Note that not all of the cells are mutated. Some are wild type (normal).

There is research on the JAK2 VAF that demonstrate that allele burden is associated with symptom burden and risk of progression; however, it is not a purely linear relationship. There are other factors that also impact how the MPN presents. Generally, people with ET have the lowest VAF, people with MF the highest, and people with PV somewhere in the middle. It is thought that VAF less than 50% is associated with a lower symptom burden and risk of progression.

Note that the significance of VAF in treatment is still in debate. Not everyone in the MPN world agree. Not all hematologists are up to date on the research. There is an emerging consensus that VAF does matter and is something that should be monitored. Personally, I believe that routine monitoring should and will become a standard of MPN care. I believe Dr. Harrison has recently presented on this issue. Perhaps someone has a link to that. Dr. Moliterno and her colleagues wrote on excellent article on this topic. ashpublications.org/blood/a...

It is worth noting that the ability to reduce JAK2 VAF is relatively new. We do not have adequate longitudinal data on the significance yet. I agree with MPN experts like Dr. Kiladjian who asks how could reducing the mutation that causes the cancer not be a good thing. x.com/jjkiladjian/status/12... My MPN care team is in agreement. My MPN Specialist's view is that a reduced VAF is a good thing, we just do not yet know how good it is. I consider it to be a valid biomarker for monitoring the status of my PV. We monitor on an annual basis.

Hope that helps to answer your question.

[Hilary777 in reply to hunter5582]

Thank you for your explanation. I am gradually learning more about this disease and MPN is great source of information

[TTA_]

Hunter gave you a good explanation.

My only addition is that there is a difference between somatic mutations in MPNs, that is, mutations that appeared spontaneously and they are found only in the cells that are affected by this mutation, and germline mutations, which are mutations that are transmitted from parents to children and that are found in the DNA of every cell in one's body.

The somatic mutations are the most frequent in MPNs, and the meaning of allele burden in the case of those mutations is what Hunter explained.

There is also a paradox of very small allele burden with JAK2 that results in more risk for transformation, but newer studies show that is linked to other acquired mutations.

Variant allele frequency can also indicate that a mutation is inherited. That is often the clue for germline mutations. A VAF above 50% with specific mutations is an indicator of that mutation being germline, that is, inherited, and one needs to look at family members and check the medical history of the family, as some other members might harbour the same mutation. The research regarding hereditary thrombocytosis is still in its infancy, but one can only hope it will expand.

So variant allele frequency can mean many things, depending on the mutation and family history of blood cancers, chronic or acute. With the awareness that transformation is more of a function of more factors than just allele burden. It is often due to the acquisition of secondary mutations.

[Hilary777]

Thank you for the information which i gradually helping me to understand this disease

[Bogglefish]

I was diagnosed with ET JAK2 in April this year and have been taking Hydroxycarbamide 500mg a day since. I am in the Waikato in New Zealand and went to a MPN specialist in Hamilton. I see her again in a couple of weeks, so will see what she has to say about my ‘progress’. My JAK2 is 22% which the specialist said was not too bad. I’m guessing that is my allele burden?

Anyway, you are not alone in NZ reading all this really helpful information. Please get in touch if you’d like.

[Minify]

Lots of good answers here. My only addition is that the JAK-2 Allele Burden (VAF) test can be run on either bone marrow sample or peripheral blood. I have never had a BMB, and my docs have agreed to yearly tracking with peripheral blood sample.

[Suenami]

I have ET and have asked my hematologist for the percentage of my Jak2, but he says it’s not important, but from what I’ve been reading of late it seems to be gaining in relevance. Just wondering ET versus PV importance when it comes to percentages of Jak2.

Thx in advance for any replies.

Sue

[EPguy in reply to Suenami]

Drs' practice quite often has a delay in absorbing new info. Conversely we are eager to absorb it all. So what we learn may not match what Drs are practicing.

At this point we can say yes the mutation matters. This has more info re PV than for ET, but common sense says less is better for both. But other details also matter (other mutations, marrow condition...) so as always it's not a single thing.

ET has the added complication that two other mutations (CALR, MPL) or none of these three at all, can drive it. Comparing PV and Jak2 type ET, ET tends to a lower mutation level at Dx, on average. So any reductions on therapy (right now this means IFN or Rux) may look less dramatic with ET.

[Suenami in reply to EPguy]

Thanks. I’m going to make the point it matters at next visit

[EPguy in reply to Suenami]

There was a post ~a month or two ago on a statement from Euro or UK I think that VAF( Mutation burden) is now officially a disease status criteria for that organization. I can't find, maybe another member can provide. This could be helpful for your presentation.

[Suenami in reply to EPguy]

Thx I’ll try to find it.

[EPguy in reply to Suenami]

This is not right on the point, but a good one posted by member manouche (who often finds good new reports)

"Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors (as well as IFN) , suggesting an urgent need to incorporate prospective molecular monitoring into PV trials"

healthunlocked.com/mpnvoice...

The benefit for reducing VAF has been explicitly studied as a trial endpoint only for Rux, but the same benefit from IFN is clear from the whole of the evidence as noted in this report.