Tomorrow is the day I start Besremi. I was dx with PV 4/15 (tax day in US) in 2015. Since then I've only had phlebotomies and taken aspirin.
I've had no issues or challenges other than low ferritin which I believe contributed to my fatigue. I immediately upon dx began educating myself on treatment options and possible cures. In 2016, I started following the research that eventually lead to Besremi to be approved by the FDA.
An RN at my HEMO's doctors office is doing an injection training session with my husband and I. I will wait a bit at the HEMO's office to see if I have a reaction which was suggested by others in this community.
I'm started (less than the recommended dose) at 50 mcg to give me body a chance to adjust. (I advocated for that with my doctor again, thanks to this community.)
Special thanks to hunter ETguy, hunter5582 for their massive contributions to this community and their insights which have contributed to my final decision on taking the drug. Also, thank you to Paul123456 and JohnSC for sharing their personal experiences with me which also helped a great deal.
Mindset: I will feel okay and not lose days feeling bad after injection!
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My insurance approved Besremi for PV. (I know not everyone has been able to get it approved and I hope they can.) I know I'm lucky, but to be honest, I'm still on the fence about taking it.
Other than some minor issues that I mostly revolve with supplements, I don't have any symptoms that impact my life with my PV. I control my HCT with PB and aspirin.
I focus on everything I can to stay healthy and strong. Taking a serious medication like this feels like I'm moving away from my idea of who I am. Now, I'm taking something that is not natural and could cause issues for my kidneys and liver, etc.
If I knew for sure it could stop progression I would start in a heartbeat but research isn't there yet to prove that. And the fact that doctors still don't know how Interferon works for MPN's is also concerning.
Just sharing. Not sure what I expect anyone to say or recommenced.
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Elizka
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As you say, there is uncertainty on how INF works. My thought is I'd rather go for the allele response now and learn how useful it is later. I'd regret finding out later that allele really matters and/or INF really works after not starting it. Plenty of experts are convinced it does matter, but many want better evidence.
But you will need to monitor for adverse effects, esp in the early days/months. As you say, everything has a trade off.
What is your Dr's opinion?
This retrospective study on progression and survival suggests INF is quite compelling, but the study has limitations.
You may know whether you respond to INF by its effect on your blood counts before you see any allele changes. Long term PB can cause various problems, so reducing or avoiding it via other therapies may be a good thing. Has you Dr discussed the options in detail?
We already have some serious medication in us in my view, that being the busted bone marrow that shoots out its bad signals.
This community is very fortunate to have your expertise, attention to detail and insights.
I've shared with my family the clever and direct statement you made: "being the busted bone marrow that shoots out its bad signals." Point taken. I can't pretend how "normal" or "healthy" I feel that all is okay inside.
What I didn't convey well in my post is that I have few symptoms or things that impact my life in my PV journey right now. I have some itching off and on, but not enough where it bother me. I get hot, but a chili pad at night solved that issue.
Even my fatigue is gone by eating more protein and working out more often.
I still have migraines but I've had those for 40 plus years.
When you say "My thought is I'd rather go for the allele response now and learn how useful it is later. I'd regret finding out later that allele really matters."
My doctor's feedback and articles I've read don't seem to correlate allele burden to disease progression.
Since you are an avid researcher, is that not true?
You also asked about my hematologist. He is amazing and trained at Stanford. I trust him. That said, he isn't pushing for me to take Besremi. He discusses my treatment plan with me as a partner in my health, he doesn't dictate or tell me what to do. I respect that very much. He says he's not worried about me as much as he is with his other MPN patients because I take very good care of myself. I brought it up with him on last visit that I was diagnosed in April 2015. Probably had PV 2 years before that (based on lab work done for life insurance) so at a minimum I'm at 7 years. How long can I go without something bad happening? No one knows.
If I do start Besremi, I would like to start at a lower dose then they suggest, but I'd need to discuss that with my doctor.
Here are my supplements:
The usual multi's including extra vitamin C, zinc, B's.
That's great to be near symptom free. The many supplements may be part of that. Are these coordinated with your Dr or others? Hunter has described his care team that covers such things.
I've often read that supplements, although being OTC and not formally "medicine" can be strong medicine in their own right. Either way if it's working safely it's good medicine.
I also find exercise can help on a bad day.
The retro study I referenced above strongly points to progression and survival benefit of INF. My Dr was not too impressed by a retrospective study. I contacted one of the authors and he acknowledged limitations of such, but said they did their best to keep it real and the large effect seen compensates for some possible biases.
You're likely familiar with the Richard T Silver MPN center. They have a long experience with INF and consider it beneficial. They consistently say it's best to start early, and ContiPV found a benefit to start younger.
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Below is a bunch of info in my day's search. In my opinion based on these and other info I've read, INF does more than just cut allele, there are weakly understood complex effects that are of separate benefit. But allele reduction could be a proxy for these benefits (I have no explicit info stating this)
Some clear results should come in the far future with MITHRIDATE for which our favorite forum is a collaborator.
This prospective study is old by standards of MPN (2010) and things are not that simple anymore. But I've not seen this one before. Their claim is a current allele is correlated but not whether reducing it will help, as it predates most studies that looked at allele reduction.
<<We state that mutant allele burden is a risk factor for disease progression into post-PV MF...The risk of developing AML was not significantly related to the mutant allele burden>>
<<Studies in PV patients will clarify whether a reduction of the allele burden by treatment may prevent evolution into MF.>>
<<IFNa has regained interest as a potential tool to interfere with the disease course>>
But there is this conflicting statement:
<<To date, therapeutic options are capable of reducing symptom burden (and partially even induce molecular remission), but not of effectively modulating the disease course in the majority of patients.>>
<<A rise in allele burden has been correlated with progression to myelofibrosis in mouse models [33] and is consistent with observations of higher allele burden in MF patients compared to PV and ET>> Suggests stopping the rise is a good thing.
<<homozygous mutations are associated with a greater risk of progression to myelofibrosis>>---I don't know whether I have homozy or heterozy but the former responds better to INF based on recent info from ContiPV. If you have known homozy it is a further reason to consider INF.
<< Treatment with IFNα stimulates both JAK2V617F-positive and WT quiescent stem cells into cycle but leads to a preferential depletion of JAK2V617F LT-HSCs in mice and inability to develop MPN with serial transplantation with JAK2V617F mutant cells subsequent to IFNα treatment>> -----This is new info to me. Putting bad cells in an INF treated mouse does not lead to mouse MPN. I've seen this for an experimental ATO-INF therapy, but not INF alone. This suggests INF causes something more than simply allele reduction.
Regarding MF INF gives <<a strong correlation between overall survival and longer duration of IFNα therapy >> This is unusually definitive for one of the MPNs.
<<Concomitant TET2 or DNMT3A mutations are associated with molecular resistance to interferon>> So if you have these, INF may be less effective, although Hunter is doing well on PEG with TET.
This study also has many details on non-driver mutations.
Wow. I'm reading all the studies and exploring links now; you must be a researcher in your "real life"? Or someone in science? Not to get personal.
Yes, Richard T Silver has decades of research with IF and MPN's. When I was first diagnosed, I remember I found some of his medical presentations on YouTube. In one, he was sharing transformations of BMB's without mentioning which drug he was using. My husband and I watched to the end, and Dr. Silver said, "Interferon." I remember being so disappointed that that was the drug he was advocating. And here I am now considering taking one!
Regarding supplements: I research them myself and look out for conflicts. My GP and HEMO don't have much knowledge on supplementation or focus on learning more. In fact, I discovered that urolithin has antiproliferative capacity, so I started taking Metopure. I did notice my HCT took longer to increase.
Most doctors don't focus on that with patients.
I did have a functional medicine doctor, but she knew very little about PV, and I didn't feel she was providing any value. I want to find another doctor who is up-to-date on new supplements available and PV.
I don't belong to any other social network but I get pleasure putting my information gathering skills to work for my self and others here. Good inventing requires approaching info with minimal bias, but I have formed some bias in favor of INF here as I learned about it.
On supplements I have posted this chart before from :
<< Symptom burden was significantly lower among individuals using amino acid supplements (2.8 vs 3.4, P=0.02) and N-Acetylcysteine (2.4 vs 3.4, P=0.02) and significantly higher in individuals taking Bach flowers (5.2 vs 3.4, P=0.008).>>
Those P values under .03 normally mean it is statistically significant. N-AC is a type of amino acid so this category is interesting with a combined frequency of use in this survey = 4.6% . You can compare other supps here too. Of course this is not the last word.
N-AC has shown promise in pre-clinical studies, I and others have posted this link before:
In mice: << Treatment with the anti-oxidant N-acetylcysteine (NAC) substantially restored blood parameters and reduced damages to DNA. Furthermore, NAC induced a marked decrease in splenomegaly with reduction in the frequency of the Jak2V617F-positive hematopoietic progenitors in BM and spleen>>
-It would be very interesting to hear the opinion of your Hematologist on N-AC.
I had an engineer vibe from you. 😀 Two of my daughters and my son-in-law are software engineers. Inventor? Very cool.
I will ask my doctor about NAC. I actually forgot to list it on my supplement rundown. I actually do take it and started doing so when pandemic first hit given its potential impact on reducing lung complications with COVID.
I'll look into upping my dose given what you've share above.
I'm sure you've seen the following interview with Dr. Silver. I saved it in Evernote awhile back and re-reading it today made me feel better about Besremi.
My fav parts:
1: Anyway, there is evidence that interferon will certainly affect significant parameters of the disease.
2: It interferes with cell development and marrow fibrosis by interfering with PDGF and VEGF; it also affects JAK signaling.
As I said, interferon is a drug for which there is a meaningful use—it is not a nonspecific myelosuppressive.
Interview:
Despite the rise of newer, effective therapies since the inception of interferon 30 years ago, there is still a biologic basis for its use in the treatment of patients with myeloproliferative neoplasms (MPNs), according to Richard T. Silver, MD.
In polycythemia vera (PV), for example, patients typically develop symptomatic iron deficiency and thrombotic events. Interferon, which inhibits PDGF, TGFβ, and other critical pathways, reduces the risk of these events, explained Silver, who is a professor of medicine at Weill Cornell Medical College/NewYork-Presbyterian.
“There is evidence that interferon will also reduce the cellularity of the bone marrow, which is responsible for producing the number of white and red blood cells and platelets that we see in PV,” added Silver.
The phase III PROUD-PV study, which compared ropeginterferon alfa-2b with hydroxyurea in patients with PV, further established the role for interferon in the treatment paradigm. Results showed that ropeginterferon alfa-2b was noninferior to hydroxyurea, with a 12-month complete hematologic remission rate of 43.1% versus 45.6%, respectively. The need for phlebotomy for patients treated with interferon dropped from 86% to 6%, and 37% of patients achieved a JAK2 molecular response
with the therapy.
In an interview with OncLive, Silver provided the history of interferon and shared insight on why the drug still holds its place in the treatment of patients with MPNs.
OncLive: How has interferon been used traditionally for the treatment of patients with MPNs?
Silver: The use of interferon was first reported by me in 1988. Since that time, we have developed extensive experience using it at Weill Cornell Medicine. We use it preferentially to any other agent because there is a biologic basis for its use. In comparison with the most commonly used drug—hydroxyurea, which is a nonspecific cell poison—there is a biologic basis for its use. It interferes with cell development and marrow fibrosis by interfering with PDGF and VEGF; it also affects JAK signaling.
As I said, interferon is a drug for which there is a meaningful use—it is not a nonspecific myelosuppressive.
In our clinic, we don't believe in the "watch and wait" approach that is recommended by some [physicians] because it develops iron deficiency in patients; this has been getting a lot more attention now both in men and women. Most women become iron deficient because of menstruation. Phlebotomy will obviously add to that in men, irrespective of the fact that they don't menstruate. The average patient with PV we see requires about 8 phlebotomies. The maintenance thereof should not be phlebotomy only, even in so-called good-risk patients. This is because the phlebotomy rate is higher in those patients than in the normal population and because it doesn't suppress disease. It is sort of like treating a diabetic and letting their blood sugar rise while the patient has blood in the urine. You can't just treat their symptoms without giving them insulin.
We believe that there are 2 reasons for using interferon. First, there is a biologic basis for its use, and secondly, it avoids the development of iron deficiency. In addition, there is evidence that interferon can reduce thrombotic risk, which is significant for patients who are only treated with phlebotomy. We also have evidence from more than 300 patients with PV that the fibrosis we see in this disease will have a delayed onset of disease when they are treated with interferon; this is because interferon affects PDGF and TGFβ, as well as other cytokines that are responsible for the development of myelofibrosis. This is very exciting, and it is new information; it has never been shown in any population of patients. We presented a poster on this at the 2018 ASH Annual Meeting.
Could you expand on the use of interferon in today’s landscape?
We believe that in the long-term—not the short-term use—that hydroxyurea can cause leukemia in about 8% to 10% of patients. In a 15-year span, this number increases to about 15%. A patient can no longer use the drug if he/she develops secondary leukemia. There has never been a controlled study evaluating hydroxyurea over the long-term compared with phlebotomy because most patients cannot stay on
phlebotomy.
Interferon will significantly reduce the risk of developing secondary leukemia—this is very important. I might say that the reason there has not been a controlled trial for this is because of 1 trial conducted by French [researchers], which compared the use of hydroxyurea with pipobroman. Thank goodness this drug is not available in the United States because it is very leukemogenic in patients with PV, even more so than hydroxyurea. There is evidence that interferon will also reduce the cellularity of the bone marrow, which is responsible for producing the number of white blood cells, red blood cells, and platelets that we see in PV. We reported on that a couple of years ago as well.
We also have evidence that interferon will reduce JAK2, the genetic abnormality that characterizes PV. We are not quite sure what that means, because we can see marrow reduction in patients that don't have significant decreases in JAK2. Anyway, there is evidence that interferon will certainly affect significant parameters of the disease. Lastly, the data from an Austrian group suggest that in a controlled trial, interferon can lead to significant differences in remission rates compared with hydroxyurea [at 1 year]. I would imagine this study will be published relatively soon. Those are the reasons that we believe interferon should have preference over other options in patients with PV.
Thanks for the transcript. It seems to be from several years ago, before the 5 year ContiPV data were available. I've not heard the latest since then on fibrosis that they discussed here, would be interesting.
I think you refer to the "Ropeg/Allele" image. That, and the other ones in the post
"New Plots for Besremi & "Beneficial" are not in any public document I know of. I created them from the text data in the ContiPV report because such plots should have been in the real reports to show the striking effects.
The study you link here is not public, but I had it thru a student friend. I can't find it right now however.
Here is a Voice post discussing it. Note the image discussed in that thread, attached here. A plus for INF vs progression.
Like many of our choices the answer is not black and white. It is more abut which benefits you want to seek and what risks you are willing to take. That includes the risk of not using any medications or the intrinsic risks of phlebotomy and supplements. One of the main reasons I started on Pegasys is that several years of phlebotomy-only had me so iron deficient that the iron deficiency side effects we bothersome. I also have another genetic condition (NF1) that increases my risk of leukemic progression. I think there is sufficient evidence for a decreased risk of progression with PEG. For me the benefits outweigh the risks. We each have to assess this for ourselves based on the unique presentation of our MPN, our treatment goals, risk tolerance, and preferences.
I am very glad that I started on PEG. I am in complete hematologic remission and have had no side effects at 45mcg/week. I know that not everyone is as fortunate.
I know you are not looking for a recommendation, but I will say that you should assess the data and do what you think is right for you. It may be that you would prefer to wat for a bit and see how people react the Besremi as it becomes in wider use. I am sure that you will make the right decision for yourself.
You make a good point about waiting for others to have experience with Bes. There should be plenty of short term info through the Voice in coming months. I hope we both are among them.
Me too. FYI - I contacted PharmaEssentia directly on a number of issues. The medical services folks contacted me. They currently have no idea what to recommend for dosing for people switching from Pegasys to Besremi. Treatment naïve and switching from HU are the only things they researched. They are not going to have lower dose syringes available anytime soon but they are aware of the issue.
I also gave them a copy of the refusal to pay - excluded drugs I received from my Cigna Medicare Part D Plan. The Med Services rep referred it over to another department. I do not expect them to do anything about it, but hope they will stay aware of Medicare plans that are excluding Besremi.
<<Recommended starting dose: 100 mcg by subcutaneous injection every 2 weeks (50 mcg if receiving hydroxyurea). Increase the dose by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematological parameters are stabilized.>>
So there is an option for a half dose, but no guidance on whether that is useful for PEG.
Interesting item here, if one finds 100 - 150mcg adequate for stabilizing there are 3 to 5 of these doses in one syringe. That would cut the cost, unless storage time limits that. But if it requires the max of 500mcg , then the 1st year cost doubles to $30k/month.
Another item from my Dr, he suggested to start my injections in the office. (if/when we get ins approval) I'm happy to do so.
It is a good idea to do the first dose at the doc's office. Staff can show you how to self-inject and the first time you can be monitored for a reaction.
The plan for most people is to simply waste what is not used in the full dose syringe. The needle would be considered contaminated after the first use, not safe to reuse. Even with the Pegasys vials where I prepare my own syringe, it is not considered safe to use the vial more than once. There is no preservative.
Hopefully a less wasteful strategy for lower dose applications will become available.
If there are extra doses getting dumped it would be like driving a new car over a cliff every few months. A big incentive to have a compounding pharmacy break up the doses. Might be worth exploring if it gets to a dead end.
But as I noted elsewhere, maybe a short term insurance boycott of Bes could get them to a more reasonable place, as just happened with Alduhelm, the Alzheimer's drug.
I would think that PharmaEssentia would realize that they need to compete with Pegasys, not Jakafi. Pegasys is likely just as effective, but only costs 1/3 of what Besremi does. Besremi may well be superior in terms of tolerance and does have the more recent research to support its use. Whether that will justify 3xcost remains to be seen.
I do agree that we need to push the issue both with insurers and with PharmaEssentia. Nothing ever changes when people just tolerate inadequate access to care.
You're right on the compete idea. Neither PEG nor Rux are approved as 1st line for PV. A thought I had is PharmaE (and AOP) just funded a phase 3 trial for a pegylated INF, and PEG is such a thing and thus an indirect beneficiary.
That is correct. My HCT and PLT are within normal limits. I do not need phlebotomies. My iron levels are slowly returning to normal, which is bringing the MCH, MCHC, MCV back towards normal too. The only issue is that the PEG has depressed LYMPH below normal, but not so low as to be a problem. The symptoms of iron deficiency are also resolving as my iron levels return to normal.
That is what my Ferritin got down to for an extended period of time. It caused a variety of issues including fatigue, concentration issues, cold-intolerance, alopecia, etc. I got really fed up with the iron deficiency adverse effects. That had a lot to do with my decision to go on Pegasys. It is all a balancing act of risks and benefits for each of our choices. Sometimes we just have to use our best judgment about what is preferable.
Makes sense, PB does that. In long term it can be a problem as Hunter has noted. It's another trade off to discuss with your Dr vs HU, INF. I have responded well to HU but I consider it a dead end (My opinion) vs INF.
You may be familiar with Rusfertide still in trial. Hunter has discussed it. It likely controls HCT without the iron problem. But INF may do that also as Hunter notes above.
According to Lab Corp re Ferritin <<patients should stop biotin consumption at least 72 hours prior to the collection of a sample>> Maybe you might see a small Ferritin increase, but this report is for a high dose.
Interesting on the MCV, MCH. Those + MPV are the only CBCs I have out of range. My Dr says it's the HU and is not concerned. But normal is better than not I would think. Are you aware of specific risks in these numbers?
Macrocytosis is a normal side effect for HU. Some docs actually use it to monitor compliance. Macrocytosis is the reason the HU has a clinical indication for sickle cell disease. It is not something to be worried about in and of itself.
I've heard that the various forms of interferon list depression as one of the more common side effects. Did this come up during discussions with your doctor?
(Do you know if this is as a direct effect of the medication, or whether this is more likely to be indirect (due to e.g. decreased quality of life that some people might be experiencing, and having to move onto taking interferon as a result of)?)
I would expect that either of those two mechanisms could occur. It is thought to be more likely if there is a prior history of depression; however, can occur in people with not prior history. I am glad t say that I have experienced no adverse reactions, other than an occasional minor transient rash that I barely notice.
The symptoms of a MPN can reduce quality of life and could be a trigger for depression and anxiety. Certainly a good reason to attend to our own mental wellness.
Thanks. I saw the presentation. The conversion formula is (current weekly dose x 4) x .7 ÷ 2.
45mcg x 4 = 180mcg/month
180mcg x .7 = 126mcg/month
126 ÷ 2 = 63mcg/every other week.
I discussed this with the MPN Specialist. He said the truth is that no one really knows, including PharmaEssentia. There just is not any data on this yet as it was not researched. It is going to be a matter of trail and error and making a best guess.
Another way to look at is is that 1/4 of the max dose of Pegasys is working for me. Perhaps 1/4 of the max dose of Besremi will be the same. Not sure it really works that way though.
I imaging that we will all be finding out together over time. Sharing experiences will be important.
Personally I would focus on statistics. What would be our life expectancy on bloodletting alone compared to interferon ? The difference is statistically quite significant.
Yes, Dr. Silver out of Cornel has some research comparing IF to simply PB and aspirin for treatment in controlled group. It wasn't good for those just using PB and aspirin.
It depends on your profile of your disease. Do you know the number of the blasts, reticulin in you bone marrow, test of NGS, more genes affected and the VAF. To this you have to take in consideration your age. It grows 9% at least a year. If everything is O.K. you have a higher margen. Good luck!
Hi Elizka, I can totally relate! I have ET and am 45 - so "young" in treatment terms and had no symptoms of ET but all of the sudden had blood in my urine and had to start medication. I felt VERY bad about that and had some side effects for about 3-4 weeks. However, now I don't feel it at all and I actually feel safer knowing my blood is controlled. Just a story from someone who felt the same as you Good luck with deciding!
My Besremi prescription was "obstructed" by Caremark/CVS (my pharmacy insurance). My haematologist will appeal for me but I am no longer optimistic because the reply of Caremark is a recommendation to use Jakafi (not Pegasys); mentioning that Besremi is not in its formulary. May I know your pharmacy insurance carrier that approved Besremi, and maybe I could have access to it via my wife's selection of insurance companies from her place of work?
There are only three specialty pharmacies in the USA that will provide Besremi. Biologics, US Bioservices, Onco360.
My hematologist obtained this form that we filled out and submitted to PharmaEssentia. From there it went to the selected specialty pharmacy. The pharmacy submitted to request to my Cigna Medicare Part D Rx plan. The plan denied it and denied the appeal. I had to go to a higher level grievance and got it approved.
Do be ware that the 2022 formulary just rolled out. Things may change in the near future. If not, you need to look into your plan rules for the approval of a non-formulary medication.
Each plan is different both in its formulary and in the procedure for approving non-formulary medications. It often requires at least one appeal. You have to understand the plan rules to successfully challenge a denial.
Hunter, It is very kind of you to provide more detail. UC Davis Health has a specialty pharmacy that is part of their cancer center. I know they worked some magic to get Besremi but I don't know the details. I did fill out the PharmaEssentia form but my health provider didn't need it.
Interesting. They must have gone through one of the three pharmacies carrying ot unless something has changed. Thanks for sharing the info so we can all keep track of accessing Besremi.
There are only three specialty pharmacies in the USA that will provide Besremi. Biologics, US Bioservices, Onco360.
My hematologist obtained this form that we filled out and submitted to PharmaEssentia. From there it went to the selected specialty pharmacy. The pharmacy submitted to request to my Cigna Medicare Part D Rx plan. The plan denied it and denied the appeal. I had to go to a higher level grievance and got it approved.
Do be ware that the 2022 formulary just rolled out. Things may change in the near future. If not, you need to look into your plan rules for the approval of a non-formulary medication. Each plan is different both in its formulary and in the procedure for approving non-formulary medications. It often requires at least one appeal. You have to understand the plan rules to successfully challenge a denial.
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Good luck with deciding!
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