With many of us starting Besremi, there is discussion of what dose we are or will be getting. As noted by member mfh7 the clinical studies for Ropeg (Besremi) used dosings of 500mcg. The study even went to 700.
<<The median dose of ropeginterferon alfa-2b per treatment cycle (4 weeks) in the fifth year was 499 μg, compared with > 700 μg in Years 1 and 2.>>
These are huge numbers for us who are starting on 50 or 100. 500 is the whole fat syringe. It would seem many of us should get decent responses on the lower doses, or does Bes really require these elephant sized shots to work? Or are they quietly admitting we should go high to shoot for the molecular response?
The broad questions I have is: How will we define effectiveness: is it just hematological, or are we (and the profession) going for molecular? I don't have any answers, but I'm sure we will be finding out as our time on Bes continues.
For PEG from reading here it seems, to keep tolerance in range, most go for the minimum dose that gives a good hematological response. With Besremi it might be easier to tolerate a dose that is well over what is needed for an adequate response. If so will we actually want that higher dose?
Any comments very welcome.
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EPguy
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Most haems are still not interested in molecular response. They don’t have reliable figures and the dynamic of ET or PV is still not well understood. Why should they bother about something no one fully understand ? Some like my haem doesn’t agree with that. The INFpeg dose should be as high as tolerated. I’m still having weekly 135mg Pegasys injection although I don't need it. As a 57 y.o. male, my hematocrit is at 38 for a long time, RBC and WBC are low, same for platelets at 168, etc… The only reason to keep a high dose of IFN is to improve the molecular response, in case it proves to be relevant one day.
My QoL is excellent so far. No symptoms. My AB was 84% at diagnosis in Sept 2019, 50% one year later, and 11 % in Sept 2021. It must be now between 5-10% but will now for sure in 6 months time.
That's fabulous. You're dose is at the high end of what we've seen here, and your allele is incredible. So neat to be symptom free. According to the audio in Paul's link from Dr. Kiladjian you could be a candidate for trying to discontinue INF with CHR and allele <10%.
Seems you have determined the high dose gives the allele result, and are safe with low blood counts that follow.
Some studies have shown that 4 factors could lead to a very good molecular response: 1) low platelets, 2)low WBC, 3) weekly injections of INFpeg> 100mcg. 4) absence of other mutations(?).
Shiftzz is a bit in the same situation. Is it worth discontinuing Pegasys at this stage when one could possibly eradicate the mutant clone ? The only decisive factor would be the apparition of some signs of toxicity during the course of the treatment. The idea to temporarily discontinue IFN would then be very attractive.
“%V617F decrease at 12 months was not influenced by age (P = .85), sex (P = .43), Hct (P = .92), hemoglobin (P = .88), initial %V617F (P = .98), and cumulative dose of peg-IFN-α-2a (P = .64), but there was a strong trend for greater %V617F decrease in patients with lower baseline platelets count (P = .06) and lower baseline ANC (P = .05).”sciencedirect.com/science/a...
“In our study, JAK2V617F was still undetectable 6 to 18 months after treatment discontinuation in 5 patients who had received 12 to 24 months of peg-IFN-α-2a and had achieved complete MR. Thus, achieving prolonged complete MR may require sufficient treatment duration, suggesting that peg-IFN-α-2a should not be discontinued as soon as molecular CR has been reached.”
My JAK2 was 55% when dx in 2016, rising to over 80% before starting Pegasys March 2018. It has slowly decreased to c. 10 - 15% for 2021. My peak dosage was 120 mcg weekly but has now been reduced to 40 mcg every two weeks since my bloods went too low.
However now my JAK2 has suddenly spiked, rising from 11.2% on the 1st November 2021 to 20% on 20th December and 30% on 8th February. My BMB JAK2 was 13.9% on 30th November. All other bloods were stable over the last few months.
I’m focused on the molecular response because the latest research indicates that getting JAK2 under 10% for 2 years greatly increases chance of remission. Hence it appears to be prognostically significant and the two highly regarded UK Hems I’ve discussed this with agree. However they believe I must keep my Neutrophils above 1.5.
I have discussed switching to Besremi in case this offers a better molecular (versus haematological overkill) response but the consensus opinion was that Pegasys still working so ‘bird in the hand’. However my TET2 mutation does seem to reduce Pegasus efficacy.
I’d be grateful to hear the reasons why others have switched to Besremi from Pegasys?
As an aside, it’s a strange coincidence that this sudden spike coincides exactly with commencing 2 x 600 mg NAC daily and starting a spoonful of Black Seed oil once a day - again was based on a successful MPN trial. I can’t believe either could actually increase my JAK2 but wondered if Black Seed oil might somehow interfere with the test.
Obviously I have now stopped both and will see what the next JAK2 test brings.
Dx 2016, 67, MPN-U PV, JAK2 (now 30%) TET2 (40%) Pegasys 40 mcg every two weeks, WBC 2.2, NEUTs 1.5, Lymphocytes 0.5.
I switched from Pegasys to Besremi even though I was doing well on Pegasys to treat PV. I did this for several reasons. I do prefer to use a medication that has made it through the FDA approval process for the condition being treated. I am OK with using a medication off-label when there is evidence to support it, but FDA approval is still a good thing. Some of the most recent research on the viability of interferons to treat PV is in fact specifically on Besremi. There are reasons to think that Besremi may be easier to tolerate due to its monopegylated formulation. Given that i may be on Besremi for the rest of my life, this is an important consideration.
Finally, I was interested in being part of the data base of how the switch from Pegasys to Besremi will work. It was not well researched during the clinical trials as that focussed on switching from hydroxyurea. I expect we will have to learn from actual clinical practice how this will work out. Some of us have to be willing to try to generate the data. Since I had other valid reasons for switching, I figure why not be on the cutting edge of change. This is not the right answer for everyone. Someone doing well on Pegasys would have perfectly valid reasons to simply stay on it. I had trouble getting the Besremi approved, which was not the case with Pegasys. Staying on Pegasys could make perfectly good sense for many people making this decision.
Your early allele response fits well the plots for INF we've seen lately. It seems your INF has overcome the TET2 well. Is 40% a common AB for TET2? I've not seen it described as AB before. Your BMB vs blood % also matches differences we've discussed on the Voice.
Was the dose reduction recent where you may expect WBC increases on the 40 mcg?
We've been on the treads about the 10%. You indicate the 10% benefit has been studied with respect to reducing allele through treatment, as opposed to a pre-treatment allele state. I've written about this question, and any info on it would be quite valuable.
I went with Bes since it was approved about when I wanted to switch to INF. Otherwise I would have started PEG. We are seeing some members with tolerance issues on PEG having improved results on Bes in recent threads.
Your spike gets one's attention. I recall you took NAC a couple years ago also. I looked up black seed oil. It seems also to be a powerful anti inflammatory. Dr. Fleischman is running the current NAC trial, but excluding INF bec it theoretically has opposing effects from INF (similar to Rux) But she has patients on both and she told me they are doing well. But I don't know how or whether they are tracking AB. It would be interesting to hear her take on your experience as I think she is the closest there is to an NAC/MPN expert.
Is there a recent MPN trial for either of these supps that points further to good results? I've been taking 500 NAC with Dr approval. If you see a reduction in AB soon, esp if the slope resumes its prior pattern, we will all be well informed of this adverse possibility. Even n=1 matters with so little data to go on.
But could your dose change could be part of it? Is the dose reduction coincident with the AB rise?
I've posted before a plot of 7 year INF results that showed a rise in averages starting at year 6. None of us want that to be real. But you're at year 4 so this would not be a factor. I'm awaiting 6 year data for Bes. It likely exists but is not published.
My TET2 was 50% pre Pegasys so a bit of a reduction.
I have been on low dose Pegasys for over 12 months, for most of last year I was on 40 mcg every three weeks. Increased to every two weeks since early November so prior to the spike. So yes, it’s quite possible/probable that the spike could be the result of insufficient dosing.
However my bloods are stable and I’d have expected a corresponding spike?
Also it is strangely coincidental that the spike coincided exactly with commencing NAC and Black Seed oil!
I think your info has reduced dose for ~1year, with the allele spike occurring about a year after the reduction, is that right? In contrast, the supp change matches within a month the allele spike. The various plots of allele I've seen do not show changes that rapid, so something could be new here. If only it went the other direction we'd have a great therapy to try.
Dr. F's email from jmctrek reply here is the one I used. I think she will be very interested in your story, as are all of us. See also my question below in reply to jmctrek.
In the audio from your link, It's easier to follow text, but I think I got it. Option for stopping INF requires both of 10% AB and CHR. Best odds are if CHR lasts 24 months on INF before stop INF. He says 50% odds of being ok to hold off INF at 10 years of "evolution". Not sure what evo means. Overall survival and event free are same for those remaining off INF, For those in the other 50% that required restarting INF, 80% re-achieved CHR, thus a successful restart.
This report did not directly address progression vs allele. I think some of the other reports we've discussed looked at that, but these I believe looked at the non-treated allele state being below 10% and not specifically whether reducing it helped.
I asked Dr. Fleischman about NAC and interferons during my participation in the NAC study, and as EPguy noted, she said that NAC, as an antioxidant, may work in opposition to Pegasys b/c interferons decreased JAK2 mutated cells through oxidative stress in one research study involving mice. Dr. Fleischman did confirm that she has 2 patients on interferon therapy + NAC, and both are doing well. Her email contact is: agf@uci.edu
If possible, would be good to know how she defines "doing well". Are their allele trends similar to non-NAC patients? Or does she refer to only blood counts? n=3 (including Paul) is not a lot of info but any is interesting. Paul here is holding good bloods even as the allele spiked.
I have been stable for nearly two years on low dose Pegasys so makes spike more likely to be NAC. However clearly could easily be progression breakthrough.
Had my bloods today and all bloods now higher, not a lot but significantly.
I’m increasing dosage and stopped NAC/Black Seed but of course this means I’ll ever know what the cause was.
Blood changes seem quite small vs the allele changes. Your blood numbers look like you're on less cytoreduction, as you said you are, although the change is small.
To confirm, the INF dose change is not at the same time as the NAC/Black seed start, is that right?
You're right about something to think about, in fact quite distracting. You have unusual opportunity to learn on this since you're getting very frequent allele results. In the literature, I've never seen such rapid changes, if anyone else here has, would be great to know. It's possible you're catching short term changes with your frequent gene counts, and this has happened before but not been visible.
Have you contacted Dr. Fleischman? I'm taking only 500 NAC but may quit doing so with this info. I will discuss with my Dr. Could be the power of the combo you took had this effect, but does point broadly to ani-inflam being incompatible with INF at least for one patient.
Another thought item, in the past Drs looked only at cytoreduction, which you were doing ok while on the supps. Now we also look for allele reduction. I expect allele reduction on INF vs anti inflammatories has no published data anywhere.
Hope to see your alleles revert to the trend. You were on a typical INF path. If it does on your 40 mcg dose the anti inflams will look very guilty. Keep us posted.
I did another JAK2 test on the 22nd of March so this may prove the most illuminating of all since I stopped Black Seed oil/reduced NAC from 2 x 600 mcg to 1 x 600 mcg on 27th February. If my JAK2 is lower than 30 % it increase the likelihood that the Black Seed the culprit, perhaps combined with NAC.
If above 30%, it may imply that my current Pegasys dosage now insufficient.
Future results will be inconclusive since could be either.
Eagerly awaiting the allele data. I'll add it to the plot. Is your insurance ok with these frequent alleles? More frequent tracking would be good for everyone on INF.
Agree a reversal will be indicative, esp of the seed oil. I'd like to stay with my 500-600/day NAC, if it seems low risk.
Not sure if you mentioned, what approx date did you reduce the PEG?
Your data is significant in the realm of MPNs where n values can be quite small in some of the real studies. We're used to uncertainty and skimpy data in much of what the MPN field seeks to do.
See the reply to EP guy below about the NAC study. In sum, the 2 ET patients taking NAC and INF concurrently are both doing well, with reduced allele burdens. I hope your recent JAK2 allele burden result indicates a decreasing trend again.
Got my JAK2 for 22bd March, dropped to 23% from 30%. This coincided with reducing NAC from 2 x 600mcg daily to 1 x 600 daily and stopping Black seed oil.
Next test, in mid May, will be after stopping all NAC but also increasing Pegasys dosage.
Great data. Here is a finer plot with your latest report. Does that look right?
The slope on 1/2 NAC and zero seed (right side green) is steeper than with no supps. (left side green)
It points to the black seed being suspect. Of course this remains limited info, but as I noted above, much of MPN reports we read rely on very small n values as it is.
If NAC is guilty we may expect your next allele on zero NAC to be even steeper green, esp with higher INF.
My personal take (my opinion only) is lay off the seed, while, combined with report from jmctrek re Dr. Fleischman, NAC does not stand out negatively to the same extent as the seed.
This is amazingly detailed data you're getting and is a big asset for us all. It's almost like you're Dr has you in an allele trial.
Now had my blood results from yesterday which show a sharp drop from a month ago. eg for the last 12 months my WBC has averaged 2, last month it spiked to 2.75 and has now dropped to 1.6 after stopping all NAC
I copy an email I’ve sent my Hem
“I know that ***** is sceptical regarding Angela’s claim that reducing oxidative stress by NAC could theoretically reduce Pegasys efficacy. However if there was any truth to this, I would be at the front of the line thanks to my healthy lifestyle - anti inflammatory diet, anti oxidants, probiotics, exercise etc. Hence for me, NAC could have been overkill.
It’s certainly a coincidence that my JAK2 increased in line with NAC and has reduced, from 30% to 23%, since halving NAC dosage. And my bloods have ‘crashed’ over the last four weeks since stopping NAC altogether although this could be solely related to increased Pegasys dosage.
However if we dismiss NAC as a factor, my bloods and JAK2 were increasing over January - March implying that Pegasys no longer working and I required a higher dosage. Latest blood results show that Pegasys still working very well on a haematological level. Dosages below:
I was taking 40 mcg Pegasys every two weeks, last dose 11th March.
In light of rising bloods/JAK2, I increased dosage to 45 mcg and reduced spacing as follows
22nd March (11 days) 45 mcg
29h March (7 days) 45 mcg
9th April (11 days) 45 mcg
Was due another 45 mcg today but clearly I need to now adjust this. How about waiting another three days and then 30 mcg every two weeks? Reevaluate in four weeks. I’m assuming my whites should start recovering about 10 days after my last dose so hopefully I’ve hit the low.”
I did another JAK2 yesterday so will get the result in several weeks. This will not be conclusive since I increased Pegasys over the last month. However thereafter it will be interesting to see how my bloods/JAK2 behave now that I reverted to close to my previous dosing regime.
I’ve been trying to research the relationship between oxidative stress and interferon efficacy but can’t find anything relevant. The only articles I’ve seen indicates that high levels of oxidative stress can inhibit interferon which is what you would expect? I don’t understand the process whereby too low is also bad!
And if this is theoretically true, can we aspire to be too healthy, to excessively anti oxidise, hence not just inhibiting Pegasys but also our naturally generated interferons?
To clarify, Dr. Fleischman did not claim that “reducing oxidative stress by NAC could theoretically reduce Pegasys efficacy”. She read one article that indicated INF may work via oxidative stress in mice and decided to exclude INFs and antioxidants in her study to have a better representation of NAC’s effect on MPN patients. I am curious to see you allele burden results in a few weeks. Thanks for posting your progress.
ThanksThis is the reply I received from Angela. As I said above, if there is any truth in this, then I’m more likely than most to experience it since I’m very focused on anti oxidising/inflammatory etc! You have to be sceptical and I should have a much clearer picture over the next two months…
“Interferon may possibly work by preferentially inducing oxidative stress in jak2 mutant cells. If so, then reducing oxidative stress with nac may dampen the efficacy of inf. The concern is theoretical and I have a few patients on both ifn and nac who haven’t had an increase in their allele burden.
I would probably recommend stopping the nac and the black seed oil and seeing whether your allele burden goes back down.”
Thank you for the clarification. I wanted to be mindful of not providing any misinformation based on my conversation with Dr. Fleischman. Her reply to you does seem to indicate a reason for you to to discontinue NAC. Gives thought to whether any oxidative stress responses our bodies naturally produce against JAK2 mutated cells would be negated by NAC.
For your research, I think you are singly the best data source there is right now on the subject of anti-inflams vs INF allele. Your frequent allele readings are unique, I think even in context of clinical trials.
I note your letter is focused on NAC, while the plot (assuming its timeline is accurate) seems to implicate the black seed. The steep green decline has similar slope as the red increase, and this steep decline occurred while you were still taking NAC, albeit reduced. Only black seed was discontinued. If NAC were the primary culprit I would expect the decline to be shallower.
To confirm, your PEG dosing was relatively constant thru Mar 22, is that correct?
Do you have CBC data during the same period shown in the plot? I could add that. It could show effects of the supps since your PEG was constant during that time. You say your bloods rose before you increased PEG. Is that PLT and/or HCT? Keeping WBC and HCT balanced is a challenge on INF, I'm seeing some of that to a less extent. (I'll post my latest) Did HCT and PLT also crash after Mar 22?
Did you show your Hem the plot? Assuming PEG was constant, it heavily implicates at least one of the supps. (black seed in my opinion)
Regarding INF inflammation, in other posts I've noted reports ascribing both properties to it. It inflames in some ways and is anti-inflam in others. Hence the vague unsatisfying info in this area.
I showed this plot to my Hem yesterday, he was skeptical of the data accuracy. But I noted one of your red points was via BMB and it matches the adjacent trend. I think that landed a bit. He agreed your frequent alleles are unusual bec of the cost of this test.
I was aware of the NAC trial so started 1 x 600 mcg NAC daily during December. I was previously taking 1 x 600 mcg alternate days. Following a disappointing BMB result I upped this to 2 x 600 mcg daily and started one daily teaspoon of Black Seed oil, both at the end of December.
I maintained this until end of February when, following a bad nose bleed, I reduced NAC to 1 x daily and stopped the Black Seed oil. I stopped NAC mid March.
Hi Paul. Hope you are doing well. Have you gotten an updated allele burden test since dropping NAC completely? I read a few studies that suggest antioxidant supplements can protect both normal cells and cancer cells, which led me to think of your posts about NAC and black seed oil. Your results may help shed light on using both supplements with caution in MPN patients.
If you decide to stop NAC and increase Peg at the same time, it may be difficult to distinguish if a change in your allele level in May is due to the increase in Peg dosing, the elimination of NAC, or a combo of both.
I’ll confirm with Dr. Fleischman when I see her in a few weeks, but I recall she mentioned one of her older ET patients being on NAC with a decreasing allele burden trend throughout the years, and then further reduction of allele burden after INF therapy. This is one of the two patients she said was doing well, I will inquire about the second patient at my next visit.
I've seen a report from her noting the possibility of allele reduction on NAC, could be from this patient. (see note to Paul re low n values) So as I understand at least one ET patient had good allele results on NAC and enhanced result when combined with INF.
Her reference to this older ET patient was not to imply that the decrease of allele burden was being enhanced by the NAC and INF combo, but to emphasize that NAC (in this patient’s case) did not interfere with the mechanisms of INF.
Had my last NAC study visit with Dr. Fleischman, and she confirmed that the two ET patients taking NAC and INF concurrently are both doing well with reduced allele burdens. The next phase of the NAC study would involve a 2nd cohort of MPN patients taking a higher dose of NAC (greater than 1200mg/day) to continue to find the therapeutic dose for symptom burden relief without adverse side effects. Based on symptom surveys taken by NAC study participants, she reported that 2 out of 3 patients indicated improved symptom burden from the 1200mg/day dosing. NAC has definitely made a difference in my energy level, but doesn’t seem to consistently normalize my lab values.
Thanks for update. Reduced allele with ET is by itself interesting since we see often stronger reductions with the higher levels in PV. I've posted a plot below here in this thread.
From your reply here, your blood counts are out of range?
I have discontinued my NAC. I found no consistent symptom benefit, and in fact a correlation to worse at least the start of my course in Feb. I took 600 or 1200, I didn't find obvious differences. Correlation or cause is unknowable for now. It's possible the highest doses will work better and I may restart esp if the study shows dosing values and success.
I did see a possible benefit in my CMP bloods. Liver and Kidney values were trending well, but as my Dr said, there was nothing to fix in my numbers so he's not impressed, but maybe for someone with certain out of range CMP, NAC will help. Another benefit seemed to be less arm/finger tingling.
I have started Curcumin, using the one Hunter has good experience with. So far a correlation to good results after ~5 days. If I can get a few weeks without any really bad days it gets interesting as that has never happened since early '20. As I posted elsewhere, it could be the Curcumin formulas have only recently become enough bio-available to have more desired effect.
I take curcumin in addition to NAC. Dr. Fleischman didn’t think it would interfere with the study, which leads me to think they work differently. I think curcumin is listed as an anti-inflammatory whereas NAC is an antioxidant. Curcumin seems to help with recovery after my runs, and after the addition of NAC, I noticed my running pace was back to my pre-ET days, at least that is what Strava indicates, an objective measure vs my anecdotal account.
My abnormal lab values are platelets in the 600s, with occasional 700s. What I meant was that NAC didn’t help lower or increase my platelet levels consistently.
<<,Both curcumin, a component of the spice turmeric, and N-acetylcysteine (NAC), an antioxidant, inhibit activation of NF-κB by inflammatory stimuli, albeit by different mechanisms.>>
So they act on some similar areas but in different ways. This reminds of many combo therapies with "real" medicines. As I've noted, recent success with Curc may be from the improved formulations.
I found your reply in another thread, you're on only asipirin and the supps. So no cytoreduction. So you and your Dr are ok with PLT 600-700. We do know 600 is an ok limit for some practitioners.
Because my elevated platelet level is the only consistently abnormal lab value at this time, I was informed that there hasn’t been much data on whether decreasing platelet counts alone in ET patients would prevent thrombotic events. It would be absolutely indicated if my lab values trend towards PV, but cytoreduction is not so clear cut in ET patients with my lab parameters, risk factor, and symptomology.
According to Dr. Fleischman, some ET patients can have stable JAK2 allele levels for a long time, even though the JAK2 mutation has been shown to have clonal advantage. I stay optimistic but understand that I will need to decide if I want to be more aggressive in treating my condition. For me, the risks for all ET treatment modalities (except aspirin) outweigh the benefits at the moment, but that may change in a few years or even a few months because the trajectory of MPN is unpredictable.
Agree on the ambiguous data on plt reductions for <600.
I've also read that ET can hold stable alleles for very long time. The converse is from some of the plots I've posted, ET tends to have less dramatic allele reductions on INF; reasonable since it tends to start from a lower value.
At the core this is a treatment philosophy question. Different people have different opinions about a conservative approach where we use the lowest dose possible to get a complete hematologic response vs an aggressive approach where we use the highest dose tolerated to seek the most complete molecular response. While there is some debate about the value of the molecular response, I certainly think that this is a case where less is clearly better.
I have decided to go with the more conservative approach to Interferons based on my treatment goals, risk tolerance, and treatment preference. My primary focus is on quality of life. Length of life is a secondary goal that is dependant on QOL. While I hope to see a molecular response, I do not require one to consider the treatment successful if it controls symptoms and permits me to have an acceptable QOL. I am willing to be patient in attaining a molecular response, preferring to avoid adverse effects of any treatment or from the PV.
My decision is what is right for me. We each have to decide what is right for ourselves. My approach may not be the right approach for someone else. I am at 100mcg of Besremi. It is causing mild lymphopenia and I am having some mild transient rashes and generic itching. These side effects are certainly tolerable and preferable to what I was experiencing with venesections or with hydroxyurea. I would not, however, want for these side effects to get any worse. I am happy with my response at 100mcg and hope to keep my dose at this level permanently.
I agree QoL is way up there in priority. Also this may relate to age, an 80 year old has less concern about decades of results, while the 40 year old cares more about long term issues.
It seems all three INF veterans here are or have been on the max practical dose as defined by some aspect of CBC numbers, and this is well below 500mcg Bes or its PEG hi dose equivalent. At 500mcg Bes equivalent it seems none of the three would do very well if minimum normal blood counts are the measure. It magnifies the original question of how the trial patients in ProudContiPV managed 500+ dosings.
Age could certainly affect how we set our goal priorities. At age 66 I think differently about it than I did 20 years ago. Prioritizing QOL over longevity is something I discuss in detail with all of my providers. As relevant to whatever issue I am dealing with, I always make sure the provider understands what my treatment priorities are.
I have found that some providers are very uncomfortable talking about longevity when it comes up. I have a written commentary i give to them as part of my appointment agenda, but I do not make them discuss it. I have heard from a few that I will apparently outlive Methuselah. It is actually a bit funny, but a needless distraction at times. Provided that doc understands that the goal is to live a high quality life for as long as possible then it is all good.
That is the core of the decision about Besremi dose. I will use the dose I need to achieve hematologic remission and control symptoms, but no more. While I would like to achieve molecular remission, I am not willing to compromise my quality of life to do so. My philosophy is that it is better to live well than to live long. I would, however, like to do both! I do believe that Besremi is the current option most likely to have this outcome.
This is a great conversation about how we each set our treatment goals. Thanks for getting it started.
I agree with Manouche. My haem is primarily concerned with ‘normalising’ blood counts and preventing thromboses. I’m thankfully asymptomatic at the moment, but I assume symptom-relief would also feature in her treatment goals. Molecular responses are, at best, peripheral concerns; she’s not convinced there’s evidence yet of any real clinical benefit from a lowered AB.
The audio report from Dr. Kiladjian (in Paul123456's link) shows a specific benefit to allele lowered via INF, in a decent sample size. I think retrospective. He plans a prospective.
I have never been asymptomatic, so any help would be a big deal as Hunter says.
This is a great question/topic and captures my exact concern as you and I have discussed. As a 55 year old “low risk” PV patient who recently started Besremi at 100mcg for first two doses I am still cautiously wondering why my doc increased my third dose to 200 mcg and fourth to 300 mcg. Had third dose last week. When I asked questions about the purpose of dose increase this early for a low risk patent at my age my doc pointed to the Besremi study you referenced at 500 mcg and goal of amelioration of thrombotic risk ASAP. He is a proponent of management of hct with meds versus phlebotomy even for low risk patients and feels the variation in hct caused by phlebotomies over time may further contribute to thrombotic risk. He said primary goal for Besremi in my case was to normalize labs and he downplayed goals of cellular response when I asked about that topic, seemingly to manage my expectations. He basically said the reduction of allele burden is still to be determined from the studies or at least that was my impression of his comments. That seems consistent with Manouche’a comments. His positive message was that if I can control my labs with Besremi versus phlebotomy he feels I should have a relatively normal life span which I took to mean he was not as worried about progression to MF in my situation as he may be in others. In summary he seems infinitely more concerned in my case with thrombotic risk than progression to MF and feels Besremi is the best option for me to control hct and that any cellular response would be a bonus but there is no guarantee of that. I still wonder if a slower approach to dosing might be the more prudent approach given this is a new drug in the U.S, but at the end of the day we have to trust the experts. The problem is that I’m not sure they even have a handle on this dosing question yet and it seems logical that many patients may respond differently to different doses. As such I intend to continue asking questions of my Doc on dosing and watching posts from others taking Besremi on issues of AEs and dosing.
I think we’re building up a consistent picture of their approach, which is reassuring : managing the biggest threat - namely, thrombotic risk. Meanwhile, we’re all holding out for even more effective, possibly curative, drugs. The future’s bright for us!
I agree we're using what I hope are placeholder therapies. But having INF option to hold our place is nice. As I've said elsewhere, future treatments could be INF combos. We're watching Bomedemstat, but it's not 100% magic either.
Hepatitis C went thru this, (PEG's original Rx) and now they're over INF with curative drugs.
I agree. We know that AB >50% presents greater risk of thrombosis and progression, so I’m really not sure why my haem is reticent to proclaim Interferons’ virtues! After all, I wouldn’t have switched had I thought AB was irrelevant. Perhaps she doesn’t want to get my hopes up (of molecular remission/response)? Or perhaps it’s because AB isn’t the only factor to consider, as far as progression is concerned - particularly leukemic?
We're seeing members' Drs who still say it's not cancer. The profession is conservative sometimes to a fault and we patients are motivated to be otherwise.
It’s true - perhaps they simply don’t want to get our hopes up? Mine recently alluded to some new drug trials taking place. I’ll quiz her more about it at my next appointment and report back. Meanwhile, she was delighted at my response to PEG: coming up to Wk 12 and, so far, still no issues. I’m on 45mcg and it’ll be interesting to see where the numbers are at my next CBC and whether she’ll switch me to fortnightly dosing.
I think you are correct that no one has a complete handle on dosing strategies for Besremi yet. There is just not enough experience with it. You are also correct that we will each respond differently both in terms of efficacy and tolerance.
The MPN expert docs have different philosophies of treatment at times. Some are more conservative than others. I certainly agree with the goal of achieving hematologic remission without needing phlebotomy. That is my goal and the primary reason I started in IFN. I do not believe in using more IFN than is needed to achieve this goal. This is also the recommendation from my doc at Johns Hopkins. He is concerned that the lymphopenia could get worse at a higher dose and the borderline neutrophils could drop lower too. He has seen this happen with Pegasys. Fortunately I was already in CHR while on Pegasys before I switched to Besremi.
If I need a higher dose to stay phlebotomy-free i will increase the dose. I would likely bump it up in 25mcg doses and see how I react. Fortunately I have docs with compatible philosophies who listen to my concerns and respect my decisions. it sounds like you are also able to have informed and collaborative interactions with your MPN Specialist. That is great as is your decision to follow the strategy you are using. This is exactly what we need to have happen. Different strategies for different people and accumulate the experience and knowledge.
I feel we're part of a sort of follow up trial, and likely the experts are interested in what we're saying. As I noted above, tolerance limits on INF are being set here by min WBC levels and the like, and seems unlikely any of us so far could do well on 500 if these blood levels are to be safe. The Ropeg trial started 700mcg according to the trial info, that doesn't even fit in the syringe. As more members start Bes we'll find out.
25mcg increments will be tricky, the graduations are so small on the Bes cylinder. But as my Dr says, such precision is not required, averages will be ok.
We are definitely part of the data being collected. biologics calls me about every 10-14 days. They report everything to PharmaEssentia who also calls me about adverse effects.
FYI - I just reached out to PharmaEssentia again about wanting to be able to access Besremi in smaller syringes. I doubt they will do anything in this area if no one is asking about it. Squeaky wheels and all.
Would be good to know why your Dr finds you to be at such high thrombotic risk with your bloods already going the right way. Also if he's quickly upping the dose, he should be ready to cut the dose if your bloods swing to the low ends. Only reason not to would be allele goal.
Hunter is doing well in labs with 100, 1/5 of the trial dosings. So confusing.
I'm in hi risk by the age definition but my Dr is ok with HU gone and still only 50mcg Bes at 3rd dose. My CBC next week will be interesting.
This is a very important and timely question. I have ET Jak2+ diagnosed at 50 but likely have had condition for 7 years prior (as platelet count had been high for a while). Was on aspirin and wait until I had a platelet spike to 1,400 and some bleeding. Started on HU as is common but didn't tolerate well and frankly did not like the thought of being on it for decades. When we decided to switch to Peg, in addition to tolerance issues with HU, one of my key factors was the desire to hopefully minimize risk of progression. Obviously the jury is still officially out on this topic, but my specialist does believe that what we have seen so far is positive for the effectiveness of INFs to possibly achieve molecular responses (more so in PV than ET).
At this point I am worried about QOL AND longevity and am willing to try what I can, safely, to limit potential impact and progression. We are all different, but in my particular case my ET presents with significant leukocytosis and low EPO as well. In fact one of the reasons we did a BMB upon diagnosis was to rule out masked/pre MF. Looking at as much of the literature that was available as well as speaking with two separate MPN specialists, I came to the conclusion that, in my particular case, while not certain, progression is definitely on the table (as it is for many of us to varying degrees).
Given the above and that in general, thankfully, I am in fairly good health overall, we decided to be aggressive with the Peg dosing at the beginning. So my initial dose was 180mg very two weeks. (I believe most on here, and as is general practice, start at lowest possible dose and titrate up if needed). This worked extremely well and brought all of my bloods into normal range almost immediately (within 2 months) with no apparent side effects. Unfortunately, about 4 months in, I received abnormal liver function readings..so the Peg was definitely impacting my liver function (interestingly enough I noticed, before I got the test results back, that I no longer was tolerating my every other day glass of delicious red wine (especially if I had it late at night). Impaired liver function is a known potential serious side effect of pegylated interferons which is why (along with other blood work and thyroid tests) it is important that liver enzymes are monitored while on Peg.
My MPN specialist and I discussed our next course of action which included stopping the Peg outright for 2 months to see if things stabilized. Luckily they did. All liver function went back to normal although predictably both my platelets and my WBC shot back up (WBC actually experienced a larger relative increase than did my platelets). Just proof that; 1) I need the medication and 2) that it works.
Most recently we decided to restart the Peg at half the dose I was receiving previously (so down to 45mg/week). I am very lucky to have an MPN specialist who is top notch and who also wants to work with me to help me achieve my life and disease management goals. His main point was that, in my case, the Peg was working very well and that we would just have to take it slower but hopefully eventually see the molecular benefits of the interferon therapy over time (my initial AB was 40% which is high for ET).
I am OK with the taking it slower approach as long as it is effective over time. He also said that some minor abnormal liver readings might be part of the package, and that would be OK as long as the numbers did not get crazy once again. I have had to moderate (i.e. basically eliminate) my alcohol intake - more as a precaution than anything else - but surprisingly it has also helped reduce overall sugar intake (my only real food vice). So small price to pay if the Peg helps achieve molecular response and delay/halt progression.
Great details. My Dx is similar to yours, including the WBC (~10) , PLT (1000) and EPO. I also likely had it for 7 years prior. But high LDH at start. But my primary Dx is PV, with ET features. See image here, EPO responded to HU. Did your EPO respond to INF?
Are there specific factors that lead you to the progression conclusion?
Your dose reduction on PEG seems not unusual from posts here, and lower doses can work as well as higher for blood counts for many. None of us have figured out Bes dosing yet long term, since it's too new.
Agree 40% allele is on the high end for ET, but well within the known range.
On liver function I've seen posts here that Drs are ok up to 5X out of range on INF. I don't have references for this however. My own experience with NAC supplement suggests it could help, but the result Paul has above points to a risk if using it with INF.
Is Besremi available to you? It's supposedly milder profile might be useful on the liver issues. Has your Dr commented on it?
Interesting in that I had one or two high LDH readings at the beginning but that settled down even before starting cytoreduction. We went for the BMB at diagnosis as my MPN specialist is a firm believer that all MPNs exist on a spectrum and it is fairly easy/common to have a principal Dx with characteristics from other MPNs. Given that I have never had a hemoglobin or hematocrit result out of range (even near out of range) he was pretty sure it wasn't PV but the consistently elevated WBC (steady state around 10 - 12 with some readings in the 13 range) gave him pause to make sure to check for either pre-MF or masked MF. The BMB was very conclusive that we are dealing (at this stage at least) with ET.
There is no real way to predict who will or won't progress and to where on the continuum just as there is no way to know why the Jak2+ occurred or why it kicked in. My specialist was very adamant that I am more likely to die with ET than from ET - but being somewhat informed (thanks to this site amongst others) - I did push him on the high AB and the consistently high WBC. My non-expert, non-medical thinking was that this could seem to indicate a more aggressive form of ET, which in my mind, could lead to a higher chance of progression. Given that I was low risk (no history of thrombosis; <65; generally healthy and active; no issues with my spleen; etc.) - I was more concerned about progression than the traditional thrombosis (and I tolerate aspirin very well (for now)).
Until the spike in platelets to 1,400 and the bleeding (fairly significant around the gums which I had NEVER had) - I was fine on watch and wait - but once we went the cytoreduction route was always more interested in looking toward a molecular response than just to get my "bloods in line" (although I will take that as well). The Specialist was fine with this thinking as he does not necessarily target platelets <450 (usually about 600 is his target but really dependent on disease burden and symptoms).
Interesting /Good that your EPO responded to HU - mine did not - it did get slightly better on the higher dose of Peg but still lower than reference range. LDH has been fine all the way through except those two elevated early readings.
The go to first line treatment here locally is HU. Peg was fairly easy to get approved for insurance (thankfully). My MPN specialist was the first in the country (Israel) to prescribe Bes for PV (about 18 months ago) but it has not yet been approved for ET. Luckily, save for the liver function set back, I have tolerated the Peg extremely well so am hoping that the lower dose is effective and we will continue on that course. Due to have a NGS panel done in a couple of weeks and then again in a year to see if there has been (hopefully) a meaningful reduction in AB. The specialist has warned me that they have seen more meaningful reductions/molecular response on Peg for PV than ET but that they have seen for ET as well and as each of us presents so uniquely one never knows!
Interesting on the NAC..I actually did ask about it at my last consultation. The Specialist said he was not aware either way but would consult with colleagues..for time being going route of limiting alcohol and increased hydration and "clean" eating (which probably I should be doing anyway to help meet my goals of longevity and QOL)...
We have many parallels in our conditions. My Dr also goes with the continuum and says I have "MPN". Since my Dx is PV I qualify for Bes.
My LDH (and WCB) may have been elevated from long Covid (I actually got covid it before it was fashionable)
WBC went down from 13 to 9.0 (normal) around time of my Dx before starting HU. But PLT down only 100. HCT also was normal, (46-48) but for MPN guy it needs to be at the lower end of that (<45).
For us the victims, molecular is always interesting, Drs don't obsess over it, for presently understandable reasons.
I'm a bit surprised in the EPO too, I've not had a recent count.
Agree the long term data on ET allele shows less effect, minimal in this plot of averages. But n is small for ET. Starting at 40% seems like it should get an easier result. Mine at 14-19 will need a good push to reach the magic 10%, much less the 2%. This chart also shows the PV benefit receding at 6 years. I'm eager for 6 year data on Bes.
Thanks for all the good info! Will definitely report back any and everything I hear on NAC/INF. Hopefully INF does bring the longer term molecular benefits..I figure any reduction in disease burden (symptoms or AB) is an important benefit as well. Getting blood work done now every 6 weeks so will continue to plot and share if anything interesting pops up. Interested also in my next EPO reading to see if INF has had any ongoing effect.
What a great post! I shared it with my HEM it is that good. The engagement and conversations are also helpful.
I'm now at 100 mcg. My HEM wants me to stay at 100 mcg for a month. His thinking is see what the impact of 100mcg is before making any increases. Like other doctors mentioned in this thread, he isn't focused on reducing the allele per se, he wants to see if we can get my counts to normal. His concern is toxicity long term.
Thanks EPguy for bringing this question/observation/ to the forefront.
Thanks for the kind words, I agree this has been a good start to our lessons with so many adding their experiences. I expect we'll have some more solid answers to the conflicting info we're getting only after some time.
Only 9 weeks in with Besremi and I'm seeing my WBC and PLT's dropping. But the HCT drops then comes back up. Like others have shared, my HEM is focused only on normalizing counts and QOL. He wants me to stay at 100 mcg so "see" how things balance out. I agree, but I want to go for the molecular response. What I see so far is that my HCT will need more dosing to keep it under control, but at what impact to my WBC's?
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