Updated Numbers Based on Recent Appointment

[Luthorville]

Hi,

I'm about 10 months in to starting Besremi and just had a phlebotomy. RBC had gotten to 47 after only 2 months from my prior phlebotomy, which I wasn't happy about. I keep hoping that will stabilize soon, although it took me a while to ramp up to my current Besremi dose. But I did have some questions about some of my other scores from the blood test:

Some other numbers:

I've been on a steady dose of 350 mcg of Besremi for the past couple of months. I briefly was as high as 425, but my liver numbers got worse, but since my dose was reduced, the liver functions have all improved to within range.

My platelets have gone from over 1,000 down to a much better 200-400 for the past 6 months, a direct result of the Besremi.

NEUT between 2.6-4.88

Lymph# 1.16 is this too low?

EOS has been below 0.05 for a while, is this a concern?

Gran% hovered around 75 which is persistently elevated. Is this also a concern?

Lymph% hovered 16.50 to 21

EOS% low at .22 to .38

I'm still low on iron which should continue as long as the phlebotomies continue.

Thanks!

[EPguy]

My Dr is not concerned with the % values. He looks to the absolute, like your 1.16 Lymph. My Dr is ok down to 1.0, and that was what (thankfully for me) limited my dose. There are now several members here reporting sub-optimal HCT on Bes, with low Lymph limiting higher dosing. This HCT result does not match the trend of the trials so it we will be interesting how this evolves. But you may see improvements with more time as you've noted.

If it's a pattern, Rusfertide, if approved, may be a handy add-on.

For gran, you mean immature granulocytes, correct? Is that 75%, 0.75%? My provider has 0-5% in range.

[Luthorville in reply to EPguy]

I'm not really sure how helpful Rusfertide is for disease modification though. From the trials, it seems to help a lot pretty rapidly with HCT control, but has no benefit for platelets. I have not seen any studies on the impact on Rusfertide on allele burden. For now, it is unclear to me if Rusfertide provides anything except relief from the need for phlebotomies.

My Gran# had been very elevated until I began Besremi. It then fell back into a normal range within just a month or two and it has remained 4-5 ever since with normal being 2.5-8.0.

In terms of controlling my HCT, the next 6-8 months will be very telling. While I am 10 months in, my first 2 doses were both only 50 mcg and I was paused again at 150 because my platelets were falling so quickly they wanted to make sure they didn't fall too low.

I have been trying to find good data from the studies that shows the timeline for HCT control relative to weeks on Besremi (and dose). I think the image that I posted has been posted here before, but it is the only one that I found and there were so few participants, it was hard to extrapolate anything from it.

HCT and Platelet levels on Besremi

[Luthorville in reply to Luthorville]

Also, in case others want to see, this is my platelet count relative to my Besremi dose. The impact was rapid.

Platelet count

[EPguy in reply to Luthorville]

Your PLT vs time is very similar to mine, seen here. I was also at ~600 a few years prior. (time scales are different) This was with HU. When I switched to Bes it stayed the same, likewise after switch to Rux, tending to the upper ranges.

HCT is a better one to be high if there must be one since there are familiar ways to fix it.

PLT vs HU

[EPguy in reply to Luthorville]

You're right on "unclear to me if Rusfertide provides anything except relief from the need for phlebotomies". With the trial design this specific limited action is exactly what they are seeking.

As in a recent post, it's being trialed more as an add-on than a mono therapy, specifically as a way to reduce phelbs. They aren't checking VAF or disease mod far as I know, likely because its action is not expected to benefit there. It does not act deeply as IFN and Rux do.

In your context Rusf would be (if/when approved) to get the HCT in line if time on IFN doesn't. .

--

i found this plot of time vs CHR for Bes. It suggests stabilization of pts with CHR after ~ the 1styear. It seems to match the bar chart you found in timing although they measure different things. (CHR vs HCT)

mpninfo.org/wp-content/uplo...

--

There is this recent report of the Bes trials I just found that has some updates:

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

One part may be relevant to the sub-optimal HCT response various members are reporting:

"In a new recent re-evaluation after overall 5 years of treatment, 53/95 patients (55.8%) in the ropeg-IFN arm and 33/75 (44.0%) in the HC arm confirmed CHR."

This is much lower than the plot I found here and means nearly half Bes pts did not hold CHR to year 5. (and more than half of HU). There is no reference for the "re-evaulated" values, which makes it suspect. But it implies whoever did the re-evaluating doesn't agree with the original results.

bes chr

[hunter5582]

I just had to have a phlebotomy today. It is only the second in several years being on IFNs. My current Besremi dose is 175mcg. The dose limiting factor is leukopenia which is what you are referencing on your concern. I have been mildly lymphopenic while on the IFNs. Neutrophils have been borderline, occasionally dropping below reference range until recently, NEUT = 0.99. Mild levels of lymphopenia and neutropenia are considered acceptable providing they do not go too low. The immune system can still respond. the levels we set as acceptable are LYMPH>0.50 and NEUT>1.00. It was not until my last CBC that the NEUT dropped below target. Since HCT=47.3% and I could not increase the Besremi doise, I opted for a phlebotomy. I will get a follow up CBC in a few days and see where the numbers are at.

On the whole, your numbers look acceptable per the guidelines my MPN care team recommends. As EPguy notes, it is the absolute numbers are what is used to monitor. the % figures are relative statements about leukocytes and are not useful for our purposes.

I agree with EPguy about the rusfertide being a hopeful adjunct to Besremi since Besremi can take a long time for full efficacy. Hopefully it will make it into clinical practice before too long.

Wishing you all the best.

[Luthorville in reply to hunter5582]

Actually I just found this. Incredibly, it appears to take up to 2.5 or so years from starting Besremi to get to a point where no phlebotomies were needed -and that was true for only 80% even then.

So far my takeaway from this is that you need to stay on this drug for up to a few years to determine its impact on HCT.

Need for phlebotomy on Besremi

[hunter5582 in reply to Luthorville]

In my view treatment with Besremi is a marathon, not a sprint. We do not need to be in a hurry. We need to live good lives while keeping long-term goals in mind. While besremi is certainly a potentially beneficial drug, it is not entirely benign. None of the cytoreductive medications are. We always have to balance the benefits with the risks.

[ainslie in reply to Luthorville]

Good info, nice find

[Jamesxyz in reply to hunter5582]

Hi,

Just curious what guage needle do they use when you get a therapeutic

phlebotomy?

Thanks

[hunter5582 in reply to Jamesxyz]

I believe it is a 16 gauge needle.

[Jamesxyz in reply to hunter5582]

Ouch.

[hunter5582 in reply to Jamesxyz]

It's a bit of an ouch but not too bad. What is interesting is how widely th pain level varies from time to time.

[Jamesxyz in reply to hunter5582]

The reason I bring this up is that some patients have had success in convincing them to use a smaller needle. This results in less trauma,

snd if you hva e to get alot of these less vein damage.

Too many of these with 16 guage can results in a big probelm.

They use 16 guage beacuse that's with comes packaged.

If you insist they may agree to use a smaller needle.

Best

[hunter5582 in reply to Jamesxyz]

Thanks. I would ask for a smaller needle if I was doing them more often. I might try a local anesthetic next time, ut his go round it really did not hurt.

[Luthorville]

It's interesting that your target minimums of NEUT>1.00 and LYMPH>0.50 are different from EPguy whose minimums were set at LYMPH >1.00.

[hunter5582 in reply to Luthorville]

I expect the differences may be more a matter of philosophy than science. Some docs are more comfortable with some compromise to the immune system. We see that same thing with liver function tests, Ultimately, it is up to each of us to decide what risks are acceptable to meet our treatment goals.

[EPguy in reply to Luthorville]

This is the plot from my provider, The listed min is 1.2. The low point is 0.83, which corresponded to my "Overdose" of IFN. The higher values are HU and Rux. My Dr likely was right that I would not have tolerated doses that put Lymph to 0.5. The large variation among practices is interesting.

Lymph

[AnPV]

Hi, i am participating phase 3 of the study of Rusfertide. As you all mentioned the purpose of this medication is to reduce the need for phlebotomies. But according to my doctor, using Rusfertide could also have a good impact on the iron levels (which are very low when one has phlebotomies).

[Luthorville in reply to AnPV]

As I understand, phlebotomies reduce the iron. I am perpetually low on iron as most would be who are getting phlebotomies. This is intentional. On rusfertide, without phlebotomies, iron levels should return to a more normal level.

[ainslie]

10 months isn’t long for the interferons , it can take years to fully control Hct without venisections, you numbers look fine,lymphs over one is good compared to many of us on here

[Luthorville in reply to ainslie]

This does suggest a real purpose for combination of rusfertide and Besremi. At least for some time.

[ainslie in reply to Luthorville]

Maybe but I think it may be some time until docs will be prescribing the combo, in the meantime the odd venisection may not lower ferritin too much

[Luthorville in reply to ainslie]

Agreed. First they need Rusfertide approved, and the launch is only estimated to be by 2026.

[EPguy]

I've found some interesting info on CHR. This report is for low risk pts on Bes. (under 60 no thrombotic events) Might be closer to your situation. I get this plot from their text results. This points to a rapid rise in CHR thru the first two years.

sciencedirect.com/science/a...

Some other possibly new info "males were overrepresented among non-responders (15/23 non-responders [65.2%]"

Another notable: "The most frequent reason for non-response was failure to meet the CHR criterion hematocrit <45% without phlebotomy in the past 3 months"

This may track what we're seeing here and why Rusf may come in handy someday.

--

On the discrepancy I noted earlier regarding lower CHR results from the "new recent re-evaluation" I think the lower CHR may be because they used a different criteria that leaves out the "H" in CHR, I missed that, so it is a stricter requirement: "CH complete response (CR) was: platelet count less than or equal to 400 x 10(9)/L, no disease-related symptoms, normal spleen size, and white blood cell count less than or equal to 10 x 10(9)/L." It's a challenge to compare the various reports that don't all use the same standards.

pubmed.ncbi.nlm.nih.gov/192...

CHR Low Risk Bes

[Luthorville in reply to EPguy]

Yeah, that seems consistent with the other study: "High long-term response rates (80.4% at 24 months; 73.2% at 72 months) were achieved with ropeginterferon alfa-2b treatment in the low-risk PV population when the dose was optimized on an individual basis. " That seems faster by a year than the other study that I posted which may stem from the younger population tested or perhaps because the dose peaked and was maintained at 500 mcg. I'm sure there's also variability from study to study and the statistical sample size is also not all that large in most of these studies, so the confidence interval is likely fairly wide. Thanks for finding this, it was great data.