Can Hydrea Resolve (fix) Marrow?

[EPguy]

In a recent thread one report has HU providing a strong benefit to marrow, esp for ET, but some in PV too, discussed here:

healthunlocked.com/mpnvoice...

This is a surprise. So I did a quick search and two further reports come up supporting this idea.

Are we missing important info in our trade offs of benefits? The improvement is fast if it happens, 6-12 months, so finding out would not delay IFN start much if IFN is the ultimate plan. Is it durable? No info on that I can find.

If it's durable, might it be a good idea to start with HU even if IFN is the end goal? Many of us do this anyway. At least having BMBs before and after 1 year of HU seems indicated here.

But it's possible this marrow improvement is most obvious only at the 1st year. This would be similar to the ~ 1 year allele benefit seen with HU.

This all begs for more info.

Have any members had BMBs before and after a year of HU?

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One report, 22 years ago:

pubmed.ncbi.nlm.nih.gov/106...

This is for myelofibrosis in context of CML, so not right on the point of MPN, but should be relevant. It likely used the early non-peg IFN so that would be a negative on the IFN side. But the result was clear at least for CML:

-"monotherapy by IFN exerts a fibrogenic effect" (promoting the development of fibers)

-"HU treatment seems to prevent and even resolves bone marrow fibrosis in CML"

-"changing content of reticulin fibres was usually accompanied by corresponding alterations in the number of CD61+ megakaryocytes" (megas are especially relevant to ET, maybe that's why the report at top has ET with the higher 50% benefit rate.

-Combo with IFN was less effective but also present: "To a lesser degree, these changes were also expressed in the cohort with a combined IFN and HU regimen."

-"Further evaluations revealed that these effects had occurred within the first year, mostly after 6 months of treatment"

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A 2nd report:

cdn.mdedge.com/files/s3fs-p...

This is just a single patient in an informal report, but it's for actual MPN.

Background info in there:

-Anagrelide should not be 1st line therapy: "Many previous studies have linked anagrelide with progression of bone marrow fibrosis in patients with MPNs"

-In one study "4 patients who developed increased bone marrow reticulin on anagrelide showed regression of fibrosis when switched to hydroxyurea."

-"very little information exists regarding hydroxyurea’s effect on BMF"

The results of this study:

-"Despite the absence of JAK2 V617F mutation, our patient had a dramatic response to hydroxyurea as we have described"

This BMB image in there shows obvious improvement to fibrosis. "B" has the dark stringy things (the fibers of high fibrosis grade), In "D" the strings are all gone (fibrosis of 0) after HU therapy. Cellularity also resolved (Figs A and C) but those images are harder to figure for us non-experts.

[Minu68]

So interesting! I have never had a bmb, as I tested positive for JAK2 mutation. would actually love to know whether hydroxy may have improved my bone marrow. Undiagnosed for at least 10 years, am now wondering whether that delay may have caused damage to my bone marrow as the ET was allowed to progress for so long.

I've lost the love I used o have for my surgery, used to think they were great until finding out they could have referred me to check out platelets being above the reference level years ago, but never did. I remember asking about it and being told its not of concern :(. I keep thinking about making a complaint, but also don't like the thought burdening the nhs system as they are so underfunded and overworked. I tell all my friends to check their blood counts when they have a blood test and to always query any levels that show up as high.

[Exeter21 in reply to Minu68]

Yes I had similar. 8 years of risen platelets but even though markers for observation my surgery never mentioned it. Until this was tested this year at my request resulting in confirmation I have ET Jak2 positive I had never seen or had access to my blood results. I now have the NHS app which shows this. I wonder how long or what the outcome had I not pressed for bloods for a shoulder injury not healing . Took a lot of insisting several times to get correct blood tests I asked for . 👍

[EPguy in reply to Minu68]

These days most MPN specialists recommend BMB. This HU mystery is a great example of why: just in case the future gives new info where we'd like to have known. Same idea for getting our allele burden and NGS to look for all the other mutations.

See my new reply here with more info on the result.

I also has raised PLT for years, it took a crisis to get the Dx started.

Complaining to a bureaucracy is probably not very satisfying, NHS does qualify as one. But for all of us, we are our own advocate as Hunter says.

[Cja1956]

I did not have this experience. I had a BMB in 2008 which showed ET. Some years later it progressed to MF. I found that out from a second BMB in 2019. In 2021 I had another one to determine whether I was a candidate for a stem cell transplant. I’ve been on Hu the entire time with only a few breaks in between, and my fibrosis has not shown improvement. It may have slowed it down, but I have no proof of that.

[EPguy in reply to Cja1956]

I posted more details of this new info here. I'm not sure how durable the response is as noted, they checked only at 12 months. So even if you did have the benefit it might not last. Same for my 1+ year on HU before starting Bes.

These studies are begging for better research.

How was your SCT candidate result?

[Cja1956 in reply to EPguy]

As of 2021, I was still at Intermediate 1 and I was told I wasn’t ready for one. They like to wait until you’re at int 2. I went for a second opinion and she said it probably wouldn’t change my life expectancy which she said was a median of 9 years from my diagnosis in 2019 at age 63. I’ve also had some setbacks this year with my health when I contracted pneumonia in March and intermittent fevers. So at this time, I’m still not a candidate.

[KLCTJC]

thanks for the information. I recently got diagnosed with MS on top of my PV. So, they are not really wanting me on interferon. So, I may be faced with hydrea. Will see what my labs are doing Thursday. I am hoping that I will still be able to take interferon at some point as MS can also be treated with interferon just a different type. This year will be 2 years since I have found out I have PV. My neurologist said I have had MS for many years and it is what they call benign as I have had no symptoms and still really don’t. But I am ready to do something for my PV. I am scared of it turning into MF. I hope if it does it takes a long time, but I would really like to try besremi if I can convince them to let me. Trying to view HU as temporary until they can determine what to do

[EPguy in reply to KLCTJC]

Interesting on the alternate IFN. I checked it out.

For treating MS IFNβ is "disease-modifying therapy... (and the new) Peginterferon beta-1a has an extended half-life and requires less frequent administration than other available treatments...the efficacy and long-term safety profile of interferons make them an important first-line option for (MS) treatment."

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

So for MS they use "IFNβ" while for MPN (and Hep B in the past) they use "IFNα". And you should benefit from the same new long duration Peg formulas we discuss here for MPN.(PEG/Bes)

Did Dr say why your cannot have or add IFNα (PEG, or Besremi)?

[Bluetop]

An interesting question re hydroxy. to take to my haem. Thanks

[EPguy in reply to Bluetop]

Will be curious to hear Dr's opinion.

[EPguy]

Better details on the original study MPD-RC 112:

Here is what I believe is the study the original post (but not the picture) comes from. This plot shows the marrow result more clearly. The IFN used was PEG. The large green bars at left show HU causing a complete fix to the marrow, with about half of ET pts seeing this best response and a large portion seeing some marrow results. So odds of some improvement were large with ET, but good in PV too.

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They (and we on the forum) did not expect this result. They don't offer a coherent theory for it:

"Because PEG is thought to act at the level of the mutated MPN stem cell, more frequent histological responses in patients treated with HU were unanticipated"

ashpublications.org/blood/a...

The molecular (VAF) responses were familiar, PEG was best for long term; they note Besremi showed this same benefit.

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"The PROUD/CONTINUATION-PV study did not include patients with ET, (nor) bone marrow histopathology,..."

This is a big loss to our knowledge here as it could have resolved this question well with the long term study Conti-PV had.

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This MPD-RC 112 study seems to stop at 12 months for the marrow values. So as I noted it's possible the HU response is not durable past 12 months same as HU molecular responses.

Histological Response

[william-Indo]

Hi EPguy,

I'd read about combo treatment if HU and INF to treat PV and almost 30% of the patients achieve complete remission.

I am now in combo treatment of Pegasys and Jakafi for 4 months and the result is amazing.

HGB, WBC, HCT, PLT are in normal range now.

[EPguy in reply to william-Indo]

That's great progress. That combo has been trialed but i think many Drs are not offering it.

We have 3 broad categories that can seek remission:

1-Blood counts

2-Molecular (mutation %)

3-Histological (marrow improvements, fibrosis, cellularity ...)

IFN is well known now to have ability to improve 1 and 2, but seems less clear or rapid on 3. What's new here is HU offering fast effects on #3 for a surprising % of esp ET. As you say this might also be the combo IFN/HU.