Intolerant to IFN? Rux/IFN combo might help

[EPguy]

Member monarch5000 posted this report in another thread. I figured it's worth a new post with more notes since the title message is worth a fresh look. I posted on an earlier version of the study, link here, but missed this simple conclusion. (See end for context of this plot)

healthunlocked.com/mpnvoice...

--

--

** A key message I get is if you couldn't tolerate IFN before, the combo could do the trick, but if IFN didn't work before it's only somewhat more likely to with the combo.

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

--

Misc notes:

Reduced dosage of both drugs may lead to fewer side-effects compared with monotherapies, hence the top message above.

--

Intolerant get a 2nd chance: "Of 36 patients previously intolerant of PEG-IFNα2, 31 (86%) completed the study" That opens up IFN to a large group to rechallenge with IFN. These pts had good MR (mutation reductions) while pts refractory (it didn't work before) to IFN had less MR. They don't connect being refractory to blood count response, (CHR) but less MR connects to less CHR, see plot and notes on it.

--

Rux dosing criteria: Rux dosage was 5-20 mg BID orally depending on platelet count. Interesting they chose PLT to drive the dose. They do say it was not a dose finding study.

--

MF patients were in an early stage of disease vs RuxoPeg study that had later stage MF.

--

CALR mutation, one had a decrease in allele burden during treatment, two had an increase. So the combo was not so good in this small CALR sample.

--

25% of PV pts discontinued IFN, stayed on Rux, 3% discon Rux. Broadly ~20% quit IFN from adverse events. But conversely it means ~80% stayed on IFN even as a large set were previously intolerant.

--

(22%) patients had mood alterations, including depressive symptoms, agitation, anxiety, and memory impairment. They don't say whether they had to quit IFN nor whether it was reversible, two essential issues.

--

Sjogrens: This one is sort of buried and missing from the AE table, a huge omission. "one patient was diagnosed with Sjögren syndrome. All the drug-related adverse events are known toxicities of either ruxolitinib or PEG-IFNa2". This works out to 2% with Sjo albeit small n limits the meaning. But it seems about what we see in the forum. So the combo did not reduce this dire risk of IFN and thus Sjo is not a tolerance condition to which the title applies. See my post "Last Dose" why this is such a big deal. It further nixes any hope for me and other Sjogies to rechallenege with IFN. No other auto immune (A-I) occurred, another implication of IFN's peculiar association with this normally irreversible and untreatable severe A-I.

--

Big benefit for marrow improvement: (BMHR) in a short time, esp for MF: "19% of PV patients and 33% of MF patients fulfilled the criteria for BMHR" A minority but BM improvement for anyone is great. They say "Long-term treatment with ruxolitinib in patients with MF seems to decrease bone marrow fibrosis in only a small subset of patients" but their citation for this shows a benefit at least equal to the combo therapy, while they caution its reliability either way. See Fig 2 of:

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

Implication of all this is Rux alone or together may be effective for marrow. The combo had BMHR faster than with IFN alone.

--

On MR (molecular response) vs CHR: "We found an association between MR and both remission and PBCR" (Complete Blood count response) They use "remission" vaguely to cover various improvements. See plot here, Fig. 3C. The red lines are pts who got PBCR (we know this better as CHR). Much better allele reductions when blood counts respond. They note this matches many prior studies, and has been subject of many posts here. But it's always "association", does one cause the other? (CHR-MR, MR-CHR) Which one? No clear answers.

--

This study was a small n with corresp limitations, and went only two years. But it included PV rather than just MF.

[william-Indo]

Thank you for this sharing.

I am PV on this combo for 2 yrs now.

Start from Jak 20mg BID + Pegasys 135mcg weekly, reduce to 5mg BID+ 135mcg each 8 weeks.

Yes, the result is amazing.

Live like normal person.

No more phlebotomy, no dizziness, exhaust.

Once a month, still got pruritus, but manage with zyrtex

Cheers

[EPguy in reply to william-Indo]

I recall you didn't do well with the IFN alone. Great to feel good, I can't remember what that is like.

[william-Indo in reply to EPguy]

I am not well with Jakafi alone.Even with doses 20mg BID, I still need phlebotomy every month.

VAF was 91% and fibrosis grade 2.

I am very lucky to meet a very good MPN specialist at Kuala Lumpur and he gave this combo to me.

Last month my VAF down to 53% and the meds doses has reduce lots.

(Thanks to Hunter for his MPN list worldwide).

For everyone who cant control their blood with single med, it is worth to consider this combo.

Wishes you all the best.

Cheers

[jointpain]

You are a marvel EPguy, my lovely wife may well be starting Ruxolitinib in the near future, should she ask for a BMB prior to starting? Her only BMB was around 5 years ago, and a sample from her sternum 6 years ago that reported back with an allele burden of over 70% . If rux might reduce her AB it might be best to know what it is now or would they go by the initial findings?

[EPguy in reply to jointpain]

A BMB is worth having at start of the new therapy if she is ok with the discomfort. But best to clarify what the BMB is mainly for.

-BMB can get allele burden (VAF). But a much more convenient way is via blood draw. Some Drs like to check VAF as often as 6 months, and at least every year or two gives good info. But blood and marrow can give different values as it did for me. So you want to use the same method, and blood is way easier. If she gets BMB now, she should get allele reading by both blood and BMB so you can 1- use BMB to know any change from 5 years ago, 2- compare VAF using only blood in the future.

-BMB is done more to know marrow histology. This is the shape, structure and appearance of the marrow. For example fibrosis level is found this way, a is cellularity (how many blood cell precursors are in the marrow). This allows a check of progression or remission of these areas. She likely has this report. The study above calls it "BMHR" as discussed where the marrow improved for some on the combo, while it also can with Rux or IFN alone.

What MPN does she have? 70% suggests PV or MF.

[jointpain in reply to EPguy]

She has MF, very high platelets when let go, over 2000, very high neutrophils, often over 40 , sometimes 70plus, Hgb often low, but probably due to bleeding, which we blame Anagrelide, was worse when on 3 a day now on 1 a day and Hgb is climbing , and was 116 last week.

[EPguy in reply to jointpain]

Wishing her well on the new Rux therapy.

[ainslie]

thanks for posting this paper again, there is a lot of info in there and it’s possible I missed a few points but my overall view is whether the patients would have got similar results from Rux alone?, hard to say , the trial was done 2014 to 2018 , well before it became clear that Rux can also reduce the AB and appear to change marrow etc.

As you wisely note N was low. Still Quite high drop out rate for those on Peg combo, I read about 30% for PV, also for the record they say typical drop out for Peg alone can be 10-50%, I don’t quite get the 10-50 bit , is it 10 or 50?

I am not sure this paper itself proves that much , what is very interesting though and more clear is what william- info has reported here, ie clear evidence the combo worked really well when Rux alone didn’t, I have heard that from some other patients although usually the other way round ie on 180 or 240 of Peg and not controlling PV counts so added Rux and it worked. Although at all the conferences I have been to and discussing treatments with experts I’ve never heard much about them using combo treatments, I wonder why.

I note that adding Rux helped some of the patients who were previously Peg intolerant to tolerate it. That might be useful if Rux won’t do the job by itself.

I also hear the point that it allows lower dose of each drug hence less side effects, the only thing with that is I rarely hear people having side effects from Rux anyway as solo treatment, I am on 20+20 and have zero sides.

I think what the writers of this paper concluded was wise, ie this combo treatment is worth a try where patients have run out of other options.

[EPguy in reply to ainslie]

I agree it seems more relevant to IFN tolerance than any new info on Rux. This part gets to the key message I found: " ~80% stayed on IFN even as a large set were previously intolerant."

The Sjo finding is also notable and consistent, supporting the need for close vigilance.

The upper end (50%) discon rate for IFN likely comes from the well known Daliah trial (link here) where Peg IFN had discon rate of 65%. (another report had 53%) The Ropeg (Besremi) trial was toward the lower end so they must be proximating these extremes.

ashpublications.org/blood/a...

Further "Treatment discontinuation was higher with pegIFNα-2 (vs HU) treatment, despite a low-dose approach." and "... a higher percentage of patients treated with pegIFNα-2 experienced a worsening of fibrosis "

mpn-hub.com/medical-informa...

Still not sure why the Daliah trial is a negative outlier for intolerance, I thought it was bec of high dosing, but the "low dose" note above suggests not. Dose was (45–135 µg/week) of PEG, typical of current practice.

--

My current sides on Rux (+,-) are a fuller head of hair and minor wt gain. My sides on IFN (+,-) are long term real vision improvement, but malaise and permanent Sjo.

[ainslie in reply to EPguy]

Congrats on the extra hair on Rux, that’s one side I would be delighted to have 😀

[EPguy in reply to ainslie]

Agree pleasant side dish along with the main meal. Another such, my vision has long term improvement from my 11 months on IFN, seen in my numbers at eye Dr test and my own perception. I had extreme light sensitivity the first few days on Bes, maybe that has something to do with it, or maybe that foreshadowed something bad, who knows.