JAK2 V617F Allele Burden and Thrombotic Events in Patients w/ JAK2 V617F Positive PCV/ET @ High Risk of Thrombosis

[PhysAssist]

Background: The goal of therapy of polycythemia vera (PV) and essential thrombocythemia (ET) is primarily to prevent vascular events that are the leading cause of morbidity and mortality.

Patients older than 60 years or with a previous history of thrombotic complications are considered at high risk of thrombosis.

Aims: This study aimed to explore the clinical outcomes in high-risk patients with JAK2 V617F positive PV or ET.

Methods: The patients older than 60 years of age or had a history of thrombosis at diagnosis among patients with JAK2 V617F positive PV or ET from Daegu Catholic University Hospital between 2010 and 2021 were included in this retrospective study.

Results: A total of 113 patents, median age 73 years, with JAK2 V617F positive PV (n = 50) or ET (n = 62) were included.

One hundred two patients were over 60 years old and 46 patients had a history of thrombosis or thrombotic event at diagnosis.

At a median follow-up of 62.0 months, thrombosis occurred in 26.0% of PV and 25.8% of ET patients. The cumulative incidence of thrombosis at 7 years was 35.5%.

Arterial thrombosis (93.8%) predominated. Median overall survival was 103.6 months (95% CI 68.8–138.4).

Median thrombosis-free survival was 86 months (95% CI 68.4–103.6).

Age, sex, diagnosis, and presence of vascular risk factors were not associated with thrombosis-free survival, whereas a higher JAK2 V617F allele burden (≥25%) was associated with poor thrombosis-free survival.

Estimated rates of thrombosis-free survival at 7 years were 93.8% in the patients with lower JAK2 V617F allele burden (<25%) and 63.0% in the patients with higher JAK2 V617F allele burden (≥25%).

Conclusion(s): Current therapy remains suboptimal, with ongoing risk for thrombosis and death in high-risk PV and ET patients with higher JAK2 V617F allele burden. A novel approach will be needed in this group

Volume 7 (Suppl. 2) October 2023, 101322

Source: rpthjournal.org/article/S24...

[Turfbeg]

Many thanks for drawing our attention to this article but I wonder why the treatments ( if any) the 113 patients were receiving for their ET/PV?

[PhysAssist in reply to Turfbeg]

Hi Turfbeg,

Many welcomes! 😅

I just like to share what I find...

had similar questions, but given they didn't mention anything about treatment, the only thing I could think of was that either they had no treatment [which would have been highly unethical, and/or criminally negligent] or whatever treatment they had did not affect the results.

I was finally able to locate and pull up the full-text of the article and all it said was: "All patients were treated with cytoreductive drugs."

Best,

PA

[EPguy in reply to PhysAssist]

That is a surprise that "all" got drugs. In the early part of that study, 2010, phlb was a common standard. Implication is all PV pts had excess PLT levels also. Being plural, it would be two or all of ANA, HU, IFN, and Rux.

That is a dramatic correlation to 25% VAF. This study was for high risk pts.

A question unanswered is at which point was the VAF measured? At Dx, or at the median follow up of ~5 years. For example someone with VAF 20% at Dx may be 30%+ with HU at 5 years. This is similar to prior studies that were unclear whether VAF hazard at Dx is affected by reducing it later. We assume so and one Rux study I've posted was explicit there, ie reducing VAF was indeed useful for event free survival.

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On this part "Current therapy remains suboptimal, with ongoing risk for thrombosis and death in high-risk PV and ET patients with higher JAK2 V617F allele burden. A novel approach will be needed in this group"

Implication is Korea is behind in use of IFN and Rux for VAF control, assuming the idea that current VAF level is risk defining.

--

The same authors looked into a larger slice of pts, without the high risk filter. VAF findings were similar for ET similar, while for PV VAF didn't matter:

"allele burden of ≥30%, older age, and a higher hemoglobin level were risk factors for thrombotic events in ET. In patients with PV, older age was the only thrombotic risk factor."

ncbi.nlm.nih.gov/pmc/articl...

--

There is a mismatch, since the 2nd set has an agv age of over 60 hence the strong effect of VAF seen in olders in study #1 should pass thru to the many olders in study 2.

As usual one study adds questions for other studies.

[PhysAssist in reply to EPguy]

Hi EPguy,

I agree with your comments [of course- what is there to refute].

I tried to find contact information for the lead autors to ask them some pointed questions about their methods, and the treatments being used, but didn't have any luck in locating any emails I could use.

Best,

PA

[Ovidess]

Yes, that extract makes one just want to throw in the towel.

[Ovidess]

Seems like this study shortens the average PV/ET Joe's life from the 15 years I've read earlier to 8 and 1/2 years. I protest. Hopefully the "novel approach" they mention includes my reading habit.

[ainslie]

this study was in South Korea , hence I wonder if the treatments and monitoring are the same as we use in the west. It’s also a small study , 100 or so patients, nearly half already had thrombotic issues, median age 73 with 100 or so over 60. I note overall median survival was only 100 months., seems lower than usual. The study may have some value perhaps but I’m not sure how representative it is. Thanks for posting it though

[Jamesxyz in reply to ainslie]

"JAK2 V617F positive PV or ET from Daegu Catholic University Hospital between 2010 and 2021 were included in this retrospective study."

So not a controlled study. They are just plucking data out from past cases.

I would be skeptical.

[PhysAssist in reply to Jamesxyz]

Hi Jamesxyz,

You are correct about the relative reliability of outcomes in retrospective vs prospective studies,

However, it seems that a lot of MPN studies- at least ones that aren't about specific therapeutics [like randomized double-blinded medication trials] end up having to be retrospective in order to find and include enough subjects [patients] to have any kind of validity.

... and even so, this one only had a very small "N" of apprx. 100 patients as Ainslie pointed out.

In addition, as EPguy mentioned, it was a super-selected high-risk group, which definitely made the findings appear more dramatic.

Thanks for your insight and comments,

PA

[EPguy in reply to ainslie]

I agree they may be behind in practice, as my comment above, we of this forum are well versed in the "novel approaches" they seek: (this applies to pts in their later time period since at 2010 most every where was only plb and HU)

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They say: "Current therapy remains suboptimal, with ongoing risk for thrombosis and death in high-risk PV and ET patients with higher JAK2 V617F allele burden. A novel approach will be needed in this group"

Implication is Korea is behind in use of IFN and Rux for VAF control, assuming the idea that current VAF level is risk defining"

[PhysAssist in reply to EPguy]

hi EPguy,

Totally, what I took from it as well.

But I still found their recognition that AB/VAF has an effect on risk and outcomes, which also implies that lowering AB/VAF would decrease risk to be encouraging and more evidence that monitoring/measuring it has merit in our treatment/disease process.

Thanks,

PA

[ainslie]

Also I wonder what Hct level they were keeping the patients below, up to a decade or so ago many thought Hct at 50 was not a issue, it definitely is a issue , I wonder if they were using 45 for men and 43 for women.

[PhysAssist in reply to ainslie]

Hi Ainslie,

Good point- also I wonder what the WBC levels were, and if they were addressed.

I did a quick Google search using the term: "hematologic determinants of thrombotic complications in polycythemia: and found a lot of gris.t for the [thought] mill.

Most of these are not particularly recent, but they were not in my archive of MPN-related articles, so they were new to me, and they all did offer at least some new perspectives regarding the underlying mechanisms of thrombogenesis in MPN's.

mpnconnect.com/polycythemia...

mpnconnect.com/pdf/leukocyt...

sciencedirect.com/science/a...

sciencedirect.com/science/a...

nature.com/articles/s41408-...

ncbi.nlm.nih.gov/pmc/articl...

and finally, a comprehensive review of the role of Hct in thrombogenesis in PV and other disorders with erythrocytosis:

ncbi.nlm.nih.gov/pmc/articl...

Read in good health...

PA

[cs1941]

In 2016 at age of 74 I was diagnosed with PRV and tested Positive Jak2 with AB of 59% and have been on hydroxycarbamide 11/500mgs each week since.I am now 82 years old and have been told that the AB % is not important however it is to me and I would love to know what my current AB is as suspect it is now higher than 59%

[PhysAssist in reply to cs1941]

Hi cs1941,

Congratulations on your 8 years of thrombosis [and leukemia]-free survival!

I was diagnosed with PV in 5/22, with a JAK2 AB/VAF of 48% on BMB, and since reading all of the studies supporting the import of AB level in disease progression, I am going to be asking for mine to assayed as well.

Best regards,

PA