A Trial of Ropeg, high starting dose

[EPguy]

There are trials of this sort going on, some members are in one. Not sure if this one has been posted. It's from China n = 44 for the full period of 2 years.

"The patients received ropeg at an initiating dose of 250 μg at week 0, followed by 350 μg at week 2, and subsequently 500 μg from week 4 thereafter, if tolerated."

They discuss this plot wherein CHR is being lost but VAF still goes down hence "decoupled" and the title "Molecular remission uncoupled with complete haematological response in polycythaemia vera treatment with ropeginterferon alfa‐2b"

The pts were all HU intolerant. They don't specify whether resistant, which is the higher risk category.

A very good VAF reduction at 2 years, much better than the original Ropeg trial. It's still not clear how these pts widely tolerate such high doses, we see here many members would not, and my tragic outcome likely was from excess dosing. But if the other ongoing high dose trials reproduce this, it is compelling. One missing detail is the non-driver status of the cohort, this could influence the result.

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

[Grapefruitlohoff]

I read somewhere that over 60 percent of the patients were pre-treated by other interferons before the trial.

[EPguy in reply to Grapefruitlohoff]

They do leave room for prior IFN:

"patients were either not previously treated with IFN or were negative for anti‐ropeg‐binding antibodies at screening."

meaning non-ropeg antibodies (ie PEG) could be present. So if the one you reference is the same, that could suggest a head start for most of the pts here.

[Grapefruitlohoff in reply to EPguy]

I found it. 61.2% of patients were treated by other IFN.

“More than half of the patients (61.2%) received prior IFN therapy. Patients with prior IFN treatment needed to have a wash-out time of at least 14 days and were negative for ropeginterferon alfa-2b binding antibodies”

ehoonline.biomedcentral.com...

[EPguy in reply to Grapefruitlohoff]

I see that is the 24 week report and the 1st one is the 24 month follow up report.

A 14 day wash out is not enough for pegylated IFN, and its influence could persist for many months. But they must had trouble recruiting never-IFN pts. Maybe there is a breakout of the never-IFNs from this study in a separate report.

They say all but one achieved 500mcg. We don't see that in this forum, there is a disconnect that maybe has an easy answer somewhere. Maybe the very high dose start conditions the body for better tolerance.

[Grapefruitlohoff in reply to EPguy]

Yeah that’s quite curious. I also noticed that adverse events seem more prevalent in the Chinese trial. I believe dr. Gisslinger discussed the undesirability of using high dose upfront sometime this year, maybe on the MPN congress or on the ASH.

[ainslie in reply to Grapefruitlohoff]

Yes Gisslinger did say that

[Grapefruitlohoff in reply to ainslie]

Thanks. Do you now where and when did he say that? I can't remember the exact occasion.

[ainslie in reply to Grapefruitlohoff]

The New York doc to doc conference 0ct 24

[Grapefruitlohoff in reply to ainslie]

Thanks, will take a look.

[EPguy in reply to Grapefruitlohoff]

I can attest to the risk of not going with low and slow so I fully agree with Dr. Gisslinger. 100mcg was enough to do it to me. But in these reports the AE's don't look that bad, mostly low grade liver or blood counts. One, myasthenia gravis, they call not treatment related. But any A-I disease emergent with IFN is worth attention. Are there more comparisons you have?

[Grapefruitlohoff in reply to EPguy]

I found this slide from the Gisslinger presentation ainsile mentioned. Spent me some time to figure out how to get the on-demand access to it.

Gisslinger presentation slide

[EPguy in reply to Grapefruitlohoff]

That is a great comparison and find. The liver numbers stand out a lot. The guidelines allow for about 3X above normal limits for livers, so if using that there is a some margin. But clearly there is an elevated risk. Lower WBC can be a good thing for some PV pts, but details matter. Lymphocytes are a dose limiting factor for some (it's why my Dr didn't keep raising the dose)

That Mg case also should not be dismissed so easily as they did. They should explain why it was called not Tx related. This antique report is a 2-pt case study. It was likely non-pegged ifn at high doses, but the article is paywalled so can't know the details.

"Myasthenia gravis during interferon alfa therapy"

neurology.org/doi/10.1212/W...

[Grapefruitlohoff in reply to EPguy]

he also mentioned hair losses appeared unusually frequent in another trial using high dose. But that’s a PMF study if I remember it correctly.

[Grapefruitlohoff]

by the way, it is also curious to see some recently emerged suggestions (not from doctors) that with more serious symptoms or a more advanced state of disease, one would need higher dosage of interferon to bring the numbers down. Don’t know where does that come from but don’t see much evidence for it and it’s quite different from what I have heart from the fellow patients. I thought treatment dose was different from person to person.

[EPguy in reply to Grapefruitlohoff]

From what we see on the forum, the required dose is all over the place. I did a survey early on of members and made a plot. The ones with early CHR required lower doses. But this was a while ago and likely would look different now.

One correlation that keeps showing in reports is the presence of certain non-drivers can lead to some resistance. Could be these certain non-drivers correlate to more advanced disease (or alternately blood control resistance) and thus more aggressive treatment, but I'm not aware of a study that looked at this specifically for a point in time.

[light]

Thank you for posting the information. Wishing you well.

[DiveGoddess]

EPguy, thank you for post. Happy New Year!

[SouthSideA]

Thanks for sharing this, and for the helpful back-and-forth in the chat. Am I correct that the basic take-away from this study is that higher doses of ropeg-IFN helped patients achieve greater and more rapid CHR and molecular response. For someone like me, who is tolerating well a full dose of 500 mcg of Besremi every two weeks, this study would suggest that keeping the high dose as long as I tolerate it is a wise decision. Do you agree that this the bottom-line take-away from this study?

[EPguy in reply to SouthSideA]

I agree if all is well this study shows the benefit of that aggressive dosing. But that autoimmune (A-I) case they found is a worry in my opinion. An unanswered question is whether the high doses get a better response or just a faster response. If the Chinese trial goes to 3 and preferably 5 years it would match the reporting points of the Proud and Conti-PV trials. Then we could compare the CHR and VAF values to know whether high dosing ends up better over time.

[SouthSideA]

All important questions. Thank you again for sharing these findings.