EPO levels in ET and prognostics

[EPguy]

We’ve seen some discussion of EPO levels and PV Dx. I am one of the members who has an unspecific mix of ET/PV and curious about EPO. I found a related report.

Quick summary of the report:

-Low EPO is not unusual in ET

-Low EPO ET has lower MF transformation

-Low EPO ET has higher PV progression

-Low EPO has higher thrombotic risk

For reference the 2016 WHO PV Dx criteria are shown at the end of this post. EPO is a minor part.

In this report “Serum erythropoietin levels in essential thrombocythemia: phenotypic and prognostic correlates” there is various new info to me on some prognostic items. As always this is just one report, we’d need multiple such reports to have more certainty. Other references/comments are welcome

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

They studied patients without any cytoreduction and I think they did not receive any during the evaluation period. EPO levels were low in 62 of 177 confirmed ET patients. So low EPO does not preclude ET, consistent with EPO being a minor criteria for PV.

WBC median was normal-high in these ET patients with upper ranges being in the 20’s, well over normal, so WBC can also be abnormal in ET.

PLT was high, not a surprise.

-Is BMB required? ->According to the WHO, for PV you can skip the BMB if you are Jak2, your Epo is low and H/H is constantly very high (18.5/55.5% Male, 16.5/49.5% Female) So EPO matters here for PV Dx. But per WHO if your H/H is just a bit high you need BMB to be sure of PV Dx.

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Implications of low EPO in ET: See plots for events vs Epo levels.

-Most striking is low EPO was correlated to MF free survival, zero transformations for low EPO.

-PV transformation was equally extreme but opposite, being zero for high EPO.

-Thrombotic risk was higher for low EPO.

-Survival was similar for each, but this P value (statistical significance) was not good at 0.41, so the MF and PV events are more reliable results.

-Leukemic transformations were low and similar, but as above P value is also not good. Low P values are likely because there were too few such events.

My thought is if these pts had cytoreduction (HU, INF) at least the thrombotic risk would be much less as we’ve seen in other discussions.

By the WHO criteria and in context of this report, my amateur opinion has me with ET, but I won’t argue with Dr’s Dx.

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Major WHO criteria requires the presence of either all three major criteria or the first two major criteria and the minor criterion

1. Hemoglobin >16.5 g/dL in men and >16 g/dL in women, or hematocrit >49% in men and >48% in women, or red cell mass >25% above mean normal predicted value

2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)

3. Presence of JAK2V617F or JAK2 exon 12 mutation

The minor WHO criterion is as follows:

· Serum erythropoietin level below the reference range for normal

Criterion 2 (bone marrow biopsy) may not be required in patients who have sustained absolute erythrocytosis (in men, hemoglobin/hematocrit of >18.5 g/dL/55.5% or in women, >16.5 g/dL/49.5%) if major criterion 3 and the minor criterion are present

[Hopetohelp]

Thanks for info. I don’t seem to have any EPO results from my blood tests. Does it go under a different name?

[EPguy in reply to Hopetohelp]

The full word is Erythropoietin. It' was a special separate test for me, Dr needs to order it.

[Hopetohelp in reply to EPguy]

Thank you

[Bluetop]

Thanks. Interesting. It was I test I had at diagnosis, but hadn't really investigated.

[gvibes]

Hi EP Guy,Interesting stuff. I thought the bone marrow characteristics were diagnostic for each disease, PV and ET. So if you get a BMB, its pretty clear. Or is it more subjective than that? My BMB results (I'm PV dx, exon 12) seemed to be very different than PV 617f.

I find reading your summaries very helpful and appreciate your work.

[EPguy in reply to gvibes]

I think sometimes Dx is by elimination, if it's none of these then it is that. In my case there is some disconnect between BMB and Dr's holistic Dx.

Our Dx is ultimately up to our Drs, and I think they add their own expertise to WHO guidelines. But what's new to me here is by following the WHO "algorithm" as they wrote it, if you have EPO data, the need for BMB in the Dx can be known.

[Solyesh]

EPguy - thank you for this. A blood test right prior to diagnosis (BMB and Jak2+) indicated I had extremely low EPO (they had to run the test three times to make sure they were getting the correct readings). In fact one of the reasons my MPN specialist wanted me to get a BMB was to rule out masked PV given the EPO score - although given that only my platelets (and WBC) were elevated he was fairly sure we were dealing with either ET or masked MF (pre-MF ET).The study, although only one, does have some very interesting information. Almost all (95%) of the low EPO ET participants were Jak2+. Much higher than the overall incidence of Jak2+ in ET patients.

My personal case lines up fairly consistently with the study in that my WBC, Hemoglobin and LDH are significantly higher than the ET cohort with normal EPO levels. The more information we have the better off we are...this might indicate that cytoreductive therapy for this subset of ET patients (even when low risk (which I was for years)) makes sense to lower thrombotic risk.

Thanks for posting!

[EPguy in reply to Solyesh]

By the letter of the WHO criteria, you're missing #1 so it does point to ET. Is masked PV where H/H are normal? I don't think WHO intended the list to be without adding in Dr judgement, but it is interesting for us.

Agree on the disproportionate rate of Jak2 ET in the low EPO.

Same here on the LDH, I fit in the low EPO group as I was over the max range of the normal EPO group. HU (now Bes) fixed LDH for me. My Dr says LDH level is not medically important for me.

Also agree on cytoreduction, I think standard practice these days is to control the important counts for everybody.

[Solyesh in reply to EPguy]

My specialist had pointed to a few studies where maskedPV can mimic ET. The key determinant seems to be endogenous erythroid colony formation (EEC) and red blood cell measurement (RCM). He wanted to make sure that we were dealing with ET as the aspirin and monitor approach is correct for low risk ET but not for maskedPV (which would benefit most likely from cytoreductive or other therapies).

I was able to find this study ncbi.nlm.nih.gov/pmc/articl...

that details some of what he had mentioned.

The table below shows just how similar some of the key criteria for the different MPNs are (PV, maskedPV and ET).

Characteristics of ET, maskedPV and overtPV

[EPguy in reply to Solyesh]

Interesting on the EEC. Looking up the term, it appears mostly in older reports, suggesting it's not a current focus; this for sure doesn't mean it's not relevant.

Similar on RCM, I think it is no longer common and is expensive. Did you get these two data points? I have not.

But note the title of the report I linked here:

"Time for revival of the red blood cell count and red cell mass in the differential diagnosis between essential thrombocythemia and polycythemia vera?"

This report has a lot of discussion on these points, and is a hard read with lots of info.

One stand out to me is that RBC is important, and this is easily avail in our CBCs:

<<RBC count is the most valuable parameter and is better than Hb-concentration and hematocrit>> where HCT= RBC count x MCV. (my CBC requires MCV/10 to get HCT)

And they say if MCV is low it can throw off the HCT and a patient that should get phleb might not get it. Other implications are that RBC is a decent proxy for RCM.

They also argue that there is no such thing as "masked PV <<mPV patients are only “masked” as long as RCM is not being estimated.>>

As usual there are no 100% conclusions.

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