Questions about AEs on Interferons w.r.t. liver enzymes

[LongETinUS]

I have seen erratic liver enzyme levels while attempting to transition from hydroxyurea to Pegasys. I'm not convinced that the Peg is the cause of the issue but my Dr has stopped the Peg and I’m back to 2g of HU with platelets at about 1400 and increasing at a good pace. It is not good. Other than a slightly liver elevated enzymes, the Peg at 45 and 90 Mcg was great for me.

The MPN Voice drug document for interferons has a table in which hepatic/liver adverse events are given a frequency of 0.01 - 0.1 %. I’m curious as to the origin of this number because I have seen other papers (see below for example) that indicate it is higher more like 10%. Am I misunderstanding the MPN document.

My own Dr says he sees much higher rates of liver AEs than 0.1% with interferons.

I’ve also seen general comments that Besremi is “better tolerated” than Pegasys but does “better tolerated” include fewer AEs of the liver enzymes?

For Peg and Besremi, are elevated liver enzymes one of those symptoms that tend to revert to normal over time as patients get used to the Peg? If so what would be reasonable time line?

Thanks

“Pegylated interferon alpha – 2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial”, Leukeamia Research 54 (2017) 73-77, coauthored by Rueben Mesa:

For the cohort of 75 patients there was “transaminitis at grade 1 in 6 patients (8%) and grade 2 in 3 patients (4%)”. Unfortunately, the paper is not freely downloadable for public viewing from pubmed (pubmed.ncbi.nlm.nih.gov/281...

[EPguy]

There are members here who have had increased liver numbers, but where it got better after time. Here is some clear info for Besremi that might be a guide for PEG. Note they apparently consider up to 3X of normal to be ok and that 20% had elevated livers.

--

accessdata.fda.gov/drugsatf...

<<5.11 Hepatotoxicity

Hepatotoxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include increases in serum ALT, AST, GGT and bilirubin. BESREMi is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Contraindications (4)].

Increases in serum ALT ≥3 times the upper limit of normal (ULN), AST ≥3 times the ULN, GGT ≥3 times the ULN,and bilirubin >2 times the ULN have been observed in patients treated with BESREMi.In the clinical development program of BESREMi, 36 patients (20%) experienced liver enzyme elevations, 33 of whom had elevations of 1.25-5x ULN. Patients were able to resume BESREMi upon resolution of liver enzymeelevations. Liver enzyme elevations have also been reported in patients after long-term BESREMi therapy.

Monitor liver enzymes and hepatic function at baseline and during BESREMi treatment. Reduce BESREMi dosageby 50 mcg for increased AST/ALT/GGT then monitor AST/ALT/GGT weekly until the values return to baseline or grade 1 (ALT and AST < 3 x ULN if baseline was normal; 1.5 - 3 x baseline if baseline was abnormal, and GGT <2.5 x ULN if baseline was normal; 2 - 2.5 x baseline if baseline was abnormal) [see Dosage and Administration (2.3)].If toxicity does not improve, continue decreasing the BESREMi dose at biweekly intervals until recovery to grade 1.

Hold if AST/ALT/GGT > 20 x ULN and consider permanent discontinuation if increased liver enzyme levels persist after four dose-reductions. Discontinue BESREMi in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage) during

treatment [see Use in Specific Populations (8.7)].>>

[Mymble in reply to EPguy]

Hello -my AST levels rose when I first started taking Peg around three years ago. At one point my AST was as high as 145. My recollection is that this was a not an unexpected response and we kept going with the Peg, upping the dose gradually from 45 to 90 weekly until my platelets normalised. My dr reassured me that with no other signs of liver damage it was safe to persevere with Peg and keep monitoring the enzymes. (I was more worried than he was) His expectation was that my AST would normalise over time and this was proved right. I think he would have been happy to recommend continuing with Peg long term even with slightly elevated AST ( not at the level of 145, though!) but maybe not - we didn’t have to cross that bridge. I have now been able to reduce my dose to 45 fortnightly so would expect my AST to continue to be within normal limits.

[EPguy in reply to Mymble]

Good reassurance that your Dr is agreeable with these guidelines. You were near that 3X level, and normalizing is good news. Did you also check ALT?

[LongETinUS in reply to EPguy]

Thanks for the link and the idea of using the Besremi protocols for Pegasus. I'll bring that up when I discuss my treatment with my Dr.

[Wyebird]

I have no idea regarding my liver function since being on Peg thanks I need to question how it’s doing. Could a low does of Peg combined with hu be considered ? I know it’s an option. Good luck

[EPguy in reply to Wyebird]

Your Dr should be ordering CMP tests, esp as you start INF.

I agree about combo therapies in general for appropriate situations. My Dr is not a fan of that idea.

[Wyebird]

Yes I had various tests before starting Peg but not recently just full blood counts

[EPguy in reply to Wyebird]

The CMP is standard before, after, and for a while after, starting. But you've been on PEG for a while so you're past the initial risk period. Still you may ask Dr why you did not get this procedure, we might learn something too.

If liver/kidney get in trouble there are other ways you and Dr can know, but CMP can get better advance info before you notice any troubles.

[Solyesh]

I have experienced elevated liver enzymes (ALT and AST) on Peg (other liver marks have remained in normal ranges). We definitely know it is the Peg as I had never before seen elevated levels (was on HU for months before switching to Peg). The first few months the liver readings were fine and all other counts were within normal range (first time in years) but after a couple of months at 180mg/2 week my AST shot up to 94 (just shy of 3x normal) and my ALT to 163 (form averaging around 30 for years).

We stopped the Peg for a month after which time my readings fell back to normal for AST (30) and only slightly elevated for ALT (57). As expected all my other counts, especially platelets and WBC jumped to above normal immediately. We decided to go back on Peg at half the dose (so 90mcg/2 week) to see if my liver would stabilize - it seemed to more or less calm down - the readings are still slightly elevated but well within a range my MPN specialist and I feel comfortable. His basic take was the Peg works for me with few AEs (really except for slight fatigue day after shot not much of anything), so we can live with somewhat elevated enzymes (some minor liver damage long term) - what we could not do is trade good blood counts for more serious liver damage.

We continue to monitor levels once a month. My last read was an AST of 41 so just outside upper normal (reference high of 37) and an ALT of 65 so almost 2x top of reference range (37 as well). We are OK at these levels and hope that given more time the liver will learn to adapt and be OK. Interestingly enough this past month I had tow get two full panels done a few days apart (different doctors) and the only difference between the two was my Peg injection one day after one reading and two days before the second reading. The Peg effect was noticeable - in particular on my RBC readings (RBC, Hemoglobin, HCT) all just under the low end of reference range (which never happens - on these three readings I have consistently been at the lower end of the ranges but within normal limits); the Platelets which still higher than reference but down from previous reading 3 days prior; WBCs which remained in normal limits (a good thing for me as prior to cytoreduction I had consistent leukocytosis) but lower than previous reading and my LIVER enzymes which were more or less stable for AST but showed a slight increase in ALT (from 65 to 80).

Have another reading in a week which will be a week after my last Peg shot so it will be interesting to see how the body reacts a week out vs a few days out....

Hopefully the liver numbers calm down for both of us over time!

My MPN specialist says he has seen a number closer to 5-10% of patients in INF (Peg and Besremi) with liver sensitivity/toxicity and he has only had to permanently stop the INF for this particular reason in 2 patients (out of more than 50).

[Meatloaf9 in reply to Solyesh]

Thank you for sharing your experience, very helpful. Best to all.

[LongETinUS in reply to Solyesh]

Thanks for the details.

I think I am going through a similar learning process and working out what trade offs to make to deal with my high platelets (Et-CalR). I only had one injection at 45 Mcg before my Dr had me go to 90. My liver enzymes were in normal range after the 45. After 3 injections at 90 they were still less than 2x the upper limit of normal (ULN) but my Dr wanted me to cut the peg back to 45. The enzymes went down again to near normal but then one of them was about 3X ULN. My Dr said that could be due to factors other than the Peg but to be safe and had me stop the Peg altogether.

From the comments of other members here, my own reading, and the details from the Besremi document that EP guy sent, I think we just did not stay on the starting dose of 45 for long enough to establish how that dose would affect me before progressing to the 90 dose. Also my Dr, not an MPN specialist, may not be as willing to make the trade off for the liver as someone more familiar with familiar with this balancing act.

It is a work in progress.

[EPguy in reply to Solyesh]

Neat detailed numbers. You have various needles to thread on INF dose, H/H level too low, liver and PLT too high. It's good you're ok on WBC, many including me see these go low.

Also good evidence of quick INF action, it's more known for slow effects, but we see here plenty with fast effects.

Your Dr sees 5-10% with high liver, that is better than the 20% in the Bes guidelines above. But the numbers do suggest a high portion with liver issues needed to quit using the worst case 5% and 50 pts.

One way to know your liver is tweaked is when you have grey color poop. It's a sign of liver failure. Both husband and I had that for a while with long covid, luckily ok now. I'd guess liver numbers are way high when it gets that bad. I had no blood tests at that time, but if one sees that on INF I think you would want a CMP right away.

[LongETinUS in reply to EPguy]

My WBCs are borderline OK. They were OK before attempting the transition from HU to Peg. On average over time they went lower, but still OK, as my HU dose went up from an average of 0.75g/day to 1.5g/day. My Dr had me stop the HU when starting the Peg and for that time on just the Peg they were a bit lower but still OK. When the Peg took too long to get the platelets down I went back on HU at 2g/day while continuing the Peg at 90Mcg week. At that point they went down to right at the border of OK. In the time I had to stop the Peg they have remained borderline. I'm not sure how long they take to return to equilibrium following each change in dosing.

I had a look at what a CMP involves. I have had most of these metabolites checked. My B12 was 266 ng/mL which my Dr said amounted to low so I am now on daily pill supplements for that.

For me the real issue is that with my platelets moving up and down in the range 1000 -1500 and prone to rise quickly with any decrease of HU dose or efficacy before some other med can take effect then I have a just couple of weeks to respond and get them under control before they get up to 2000+. There is not much room for trial and error.

I thought about transitioning to anagrelide, which I think only affects the platelets, or using it in comb with the HU to get the platelets to a range where I have more room to work out the appropriate Peg dose. This is something I need to talk over with my Dr. The info I received on living with elevated liver enzymes will be part of that.

I'm living weekly blood test to blood test to see

what the next step should be. It is not ideal but the info from the members here really helps.

[EPguy in reply to LongETinUS]

I see you're now on both HU and PEG, is that right? This largely is to control PLT. And the HU is up to 2g/day. That is a big dose, esp with INF added.

You are correct on Anagrelide, it is directed to PLT. You might get a better response with a relatively lower dose with this better targeted action. No way to know for sure right now of course, we've seen here some with tolerance issues (as with all our meds) I agree it's worth discussing with your Dr.

Here is a recent report on Anag:

<<The rate of achieving a platelet count of <600 × 109/L during anagrelide monotherapy was 83.0%....The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles....The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group>>

onlinelibrary.wiley.com/doi...

So you would need to watch the anemia. This recent thread has at least one Calr member seeing anemia on Anag.

healthunlocked.com/mpnvoice...

With your PLT trouble you might qualify for the Bomedemstat trial. I'm not sure if this came up before. Bomed is esp good for PLT control and the ET trial is looking good so far.

[LongETinUS in reply to EPguy]

I started the Peg at 45 again about a week ago on top of the HU at 2g/day.

When the peg was slow to kick in I needed the 2 g to get the platelets under control. When on both Peg at 90 (about 4 weeks) and 2g/day HU the platelets went back down to under 1000. At which point I went to HU 1.5g/day and the platelets were still going down. When the liver issues (not even twice the normal upper limit) arose I reduced Peg to 45 so for a couple of weeks I was on 1.5g/HU and 45 Peg. The platelets were still below 1000 which for me is the magic number to keep symptoms and worry at bay. The liver was on its way to normal and then one set of high liver tests stopped the Peg. Following that the liver went back to normal in a couple of weeks but by then the platelets were going up. Last week I started the Peg again at 45 but by then the platelets were going about 300/9 days so I went to HU at 2g/day. I'm due to get tested on Saturday to see where to go from there.

This first attempt to make the transition was mismanaged by having me stop the HU before the Peg took effect. Since then I have not been on a stable dose of anything for more than a couple of weeks and thus not able to see where blood or other metabolites would find equilibrium. Even still I thought it was going really good until that one set of high liver enzymes stopped the Peg. The good news is that I know I respond to the Peg. It is just finding the right dosing.

At this stage I'm hoping the 2g/day HU will hold the platelets until the Peg, which will probably continue at 45 for a few weeks, kicks in again.

After that first screw up my Dr has expressed more willingness to work with me. We will see what happens. I now have the Besremi liver info to argue my case.

Thanks

[ritaandscooter1]

Hi, I'm one of those people unfortunately who could not tolerate the standard 45mcg dose of PEG in regards to the ALT liver enzyme. Mine shot up immediately upon the 1st dose and then quadrupled by the 3rd or 4th month. ALT was dangerously high and continuing to rapidly go up with each shot. We cut the dose in half to 22.5mcg and that stabilized the liver back to normal levels but was hardly making a difference in my PLT and other numbers. I decided it was not worth it and discontinued PEG after talking to my MPN specialist who suggested I take 2 aspirin a day and continue getting phlebotomys when needed (about every 4 months) I have had PV for 18 years and have been on 1 aspirin and phlebotomy when needed. I also was not enjoying the frequent brain fog and slight depression that I was experiencing on this very low dose as well. Just did not work out for me. My MPN specialist said the Besremi symptoms would be similar to PEG. Good luck to you.