»The variant allele frequency (VAF) of driver mutations (JAK2, CALR) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long-term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%–99%) to 3.5% (0%–98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction >50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis-free, event-free and progression-free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials. »
Clinical impact of mutated JAK2 allele burden re... - MPN Voice
Clinical impact of mutated JAK2 allele burden reduction in polycythemia vera and essential thrombocythemia
this is so very encouraging! Thank you very much for sharing the results, Manouche. It’s a continuing saga of course but it surely shows there is reason to be thankful for research and managing treatment expectations.
It likely is the same study as the link below since n=77 on both and it's the same authors. The top message was/is VAF matters.
One standout here is "At last observation time, JAK2 VAF reduced overall from a median of 68% ... to 3.5%... " This is in the prior report but stated differently. This is a blow out amazing result that seems to conflict with the other limitations reported. IFN is not that good, but I didn't think Rux was either. Must be in the mystery meanings of "median".
healthunlocked.com/mpnvoice...
This abstract mentions CALR, the other report does not. Knowing CALR result would be of great interest to those pts, presuming the full report will expand this.
The study found a strong correlation of molec response and non-progression. IFN has not been prospectively studied directly this way to my knowledge but the same effect seems likely.
"A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR (VAF < 2%) and reduced progression to myelofibrosis"
As discussed in the prior post, the starting VAF is important with Rux, IFN is less sensitive to this. But mean starting was 68%, ending 3.5%, so this limitation feels dissonant.
dear Manouche. I was diagnosed with PRV in June 2016 and tested Jak2 + with an AB of 59%I am currently taking 11/500mg Hydroxycarbamide (same dose for last 7 years) and I have repeatedly asked what my current AB is (as I am keen to know if I have a reduction) and my haematologist has told me it is an expense test and in any event is not important.What is the way forward
Hi cs1941,
« The price of a JAK2 genetic test in the UK is approximately £336. This test typically includes the V617F mutation analysis and is available at over thirty-one private hospitals across the UK. The estimated turnaround time for the results is about 15 working days1. Please note that prices may vary depending on the facility and any additional tests that may be required. It’s always a good idea to contact the testing facility directly for the most accurate and up-to-date pricing information ».
Can you tell us which Hospitals do it privately for that kind of money, I searched the UK last year and only found one clinic in London doing it for approx £750. Some of the hospitals can do it but first needs a consult with a doc , then the cost of the test and then another consult to discuss results.
Hi, I see that you started with a AB of 83.8%, what is your most recent AB. My Ab went from 50 to 19.7 after 30 months of HU. I am approaching 36 months on HU. At age 75 soon, I don't know whether to switch to Besremi or not? My MPN specialist says the decision is mine to make, all my blood counts are normal except for a slightly low RBC (4.09), I have no adverse effects from HU that I know of. Do I switch or not, any advice??
Hi Meatloaf,
My last AB test was done last October and the JAK2 AB was at 2.3 %.
Should you switch to interferon ? I don’t know but why not giving it a try ? You could always go back to HU if it doesn’t work.
That is a great AB result you have achieved. Hope you get to undetectable.
My only concern with trying besremi, is the possibility of some serious side effects especially with the auto immune complications that could possibly be permanent. It also seems that quite a few people have low WBC's, especially lymphs and neutrophils, I don't like that idea, especially in the winter. Just me. Best to you.
to Meatloaf9
This familiar plot shows the results from the Besremi trial. HU typically lowers VAF quickly but the response is less durable. But these are averages, you're already doing much better than this average. If you stay on HU maybe this benefit can continue.
Your autoimmune concerns may be from my stories. It is real and devastating for me but very rare. Do you have any history of autoimmunes? I didn't but having does increase risk. Low Lymphocytes is common and often determines a max dose.
Rux is another option without the autoimmune risk and with benefits seen in this thread. (but as always its specific sides)
It sounds as if you’re doing well on HU and that’s a pretty good reduction in AB at 30 months, the literature seems to imply patients on HU can have a quick reduction in AB initially but then it can start to rise again, maybe worth keeping an eye on that, EP Guy posted the graph in this thread showing that. However you seem to be so far proving the graph wrong a bit with sustaining the reduction at 30months. So who knows you might be different. If you’re feeling good on HU and counts are all in line there is something to be said for that. As Manouche mentioned if you wanted to try Peg or Bes and it didn’t agree with you you are fortunate you can go back to HU.
Thank you for your reply. I was hoping to get a direct answer from 2 different MPN specialists as to whether I should switch. So far the 2 that I have asked are non committal. They say it's up to me. I think that their years of education, training and practice experience should make their opinion more valid than mine. I believe that my age is the overriding factor in them not saying 'Yes, you should switch to besremi" I'll try again next month. I appreciate and agree with everyone's comments and advice.
Thank you for sharing
so does this mean that ruxolitinb for 7 years actually had a disease modifying effect. It reduced the allele burden and produced a complete haematological response (or near enough?). Not thinking very clearly right now, but I’d so like this to be true.
Correct on disease modifying effect, this plot shows the result from the study to over 12 years. Achieving 2% VAF gave 100% MFS, and a partial response (>50% VAF reduction) had a still very beneficial effect. Reduced progression is a specific criteria for disease modification.
I forgot to directly include the referenced prior report that this is an apparent update to:
ashpublications.org/blood/a...
Thanks for posting that paper, I don’t recall seeing it before,very interesting , its a pity it was only 77 patients though
It was in this post:
healthunlocked.com/mpnvoice...
but I also had some work to re-find it. There are now a few reports on Rux that are sort of similar and getting harder to track. But the pattern is a good one.
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