I'm reaching out to share my experience and gather insights from those who've walked this path before. A brief background: I was diagnosed with PV, specifically with the exon 12 mutation. The diagnosis was confirmed via a bone marrow biopsy.
In the span of 2 months, I underwent 10 phlebotomies, but my HCT levels remained persistently above 52. Consequently, I started treatment with Besremi. I'm now five weeks in, having received three doses (100 micrograms for the first dose, and 150 micrograms for the subsequent two). Despite this, my HCT still hovers around 52 with a hemoglobin of about 17. The numbers seem steadfast.
What's noticeable, however, is the dip in my WBC count. It dropped from 8 (within the normal range of 3.5-10) to 2.75. Given this, my haematologist is proposing to decrease my next Besremi dose to 100 micrograms and continue with parallel phlebotomies.
I'm based in North Macedonia, and we face a limitation in MPN specialization here. My questions for this community:
1. Has anyone had a similar experience where Besremi primarily affected the WBC but not the HCT or Hb levels?
2. For those who've been on Besremi, after how long did you notice a significant reduction in erythrocytes and hematocrit?
3. Any recommendations or insights from those with the exon 12 mutation?
Your advice and shared experiences mean the world to me. While we all have unique journeys, the collective wisdom here is invaluable.
Thank you in advance, and sending strength to everyone here.
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skakulec2
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It can take Besremi some time to have its full effect on erythrocytosis. Unfortunately, Besremi does affect the leukocytes too. I experience mild lymphopenia and borderline neutropenia. Overall WBCs are typically showing mild leukopenia.
The targets we set are HCT1.00, LYMPH>0.50. I am staying at target with a 150mcg dose.
I am not aware of any data on a difference in response to Besremi for people who are positive for JAK2 Exon 12. I wonder whether you have any non-driver mutations that may be playing a role.
You have one of the JAK2 Exon 12 mutations. There are more than one. I believe this is a missense mutation. I have not looked into the data on the Exon 12 variants as I have the JAK2v617f variant. Here is a bit of information on your variant.
Do you know what your Mutant Allele Burden (Variant Allele Frequency) is? This may be a part of the picture of what is going on. There is more in the literature than these two articles.
It may also be worth checking on the non-driver mutations like TP53, ASXL1, TET2, etc. These can play a significant role in MPNs. I have one of the non-driver mutations, NF1. This can impact how the MPN presents and the risk of progression. Here are a few resources. There is more in the literature.
Wishing you success in finding more information on the JAK2 Exon 12 variant and how it is impacting you. Please do share what you learn as all can benefit.
No, I do not know what my Mutant Allele Burden (Variant Allele Frequency) is. On the time of official diagnosis I know that it was above 15%, that was condition to be reported. They report only qualitative results not quantitative. I have to find lab abroad that will make that measurement.
Do you have some secret knowledge, how to manage iron deficiency ? After frequent phlebotomies, I feel almost dead. I do not have energy even to get up from bed. Also, I have low blood pressure, 105/75 ... I used to have 125-130 / 80-85. I dont know from where this fatigue comes from, from low iron, low blood pressure, from PV or from Besremi. But I feel it extremely days after phlebotomies, so I suppose it is from low iron and low pressure. I drink min 3L of water, salt, 2 coffee's / day, some how I will increase the blood pressure to 120/80, but again fatigue, that is how I think it is from low Iron, but I was explicitly ordered to eat low iron food and no supplements. I dont know how I am supposed to live like this. My iron level is 4 (on 10-30 range). Or is it getting better and organism is getting use to it. If I increase iron to low range, 10, my Hct is starting to increase immediately (next week test). Until Besremi starts to work, so that I can increase my iron level to feel better, what can be done ?
I am afraid there is no secret knowledge to raising iron levels. Raising iron levels requires consuming more iron, either in food or supplements. Most of the iron your body uses is recycled from red blood cells. That is why venesections are used. Removing RBCs removes iron. Less iron = fewer RBCs. Unfortunately, iron deficiency without anemia can have significant adverse effects. Fatigue is one of them.
Increasing iron levels may make you feel better but will increase your erythrocytosis. It is a balancing act to find the approach that will help you reach your treatment target without unacceptable side effects. I experienced a variety of symptoms due to the iron deficiency that were worse than the PV symptoms. Thee adverse effects included fatigue, loss of concentration/memory, alopecia, and cold-intolerance. I feel much better now with my iron levels closer to normal and in complete hematologic response with Besremi.
Suggest that you focus on mitigating the symptoms/adverse effects you are experiencing rather than focussing on higher iron per se. Raising iron levels may be part of the long-term strategy, but you also need to meet your targets for a hematologic response.
My WBCs have dropped as low as 2.43 without it being a concern. We look to maintain Neutrophils > 1.00 and Lymphocytes > 0.50. Suggest you review the targets for your leukocytes with your hematologist. The Neutrophil is the single most important.
Blood pressure of 105/75 is within the normal range. Hypotension = BP < 90/60. If you have reduced your HCT even though it is still higher than your goal, then you have reduced the viscosity of your blood. This would almost certainly decrease your BP. Providing you are not experiencing symptoms of hypotension, which seems unlikely, I would not worry about the BP. Note that 105/75 would be considered good BP, like one might expect with an athlete. Suggest you review this issue with your care team for case-specific feedback.
It sounds like the fatigue is the most bothersome issue. You are correct that it can be from the iron deficiency, the PV, the Besremi, or some combination. Sometimes timing is the only clue about the cause. It sounds like you have concluded that the iron-deficiency is the most likely cause. If this is the case, then your strategy will need to be be to manage the fatigue until the Besremi has time to take effects and you can allow your iron levels to come back up. That is precisely what I did.
Here are some links to managing fatigue. Wishing you success in finding strategies that work.
I read this a lot "It can take Besremi some time to have its full effect on PV/erythrocytosis." Are there any studies, numbers, how the period of its effect is distributed ? If you saw some papers/studies, please share. And in how many % (and what is specific about them) Besremi does not work. Until now I meet only one girl in her 20's with ET, and she got decrease in PLT immediately after the first dose. What about PV/erythrocytosis, and more importantly for my case, PV/erythrocytosis that are JAK2V617F-negative, JAK2 exon 12-positive.
Most of the studies I have looked at only give aggregate data. Perhaps there are some studies that would allow the variability between patients to get teased out. Maybe some other on the forum have seen that data.
At this point, all I could say is that we know there is wide variability in how people with JAK2 positive PV respond to Besremi. I suspect that the reasons for this may be related to factors such as JAK2 allele burden, the degree to which the JAK mutation is homozygous vs heterozygous, and the presence of non-driver mutations. There may be other genetic factors that drive the response to Besremia s well. Note this is all pure conjecture on my part. There is no data to prove any of these theories that I have seen.
I was in a similar situation to yours back in January. My HCT had crept up to 47%. My LFTs were elevated 3x/upper limit of normal. I had mild lymphopenia and borderline neutropenia. I was feeling much better as my iron levels had improved, but the increase the iron was increasing the erythrocytosis. While I would have prefered to increase the 150mcg Besremi dose, we decided not to. Instead, I opted to have the first venesection in several years. I decided on this in the hope that a minimal decrease in iron levels would be sufficient to give the Besremi more time to achieve full benefit. So far, that is exactly what has happened. My HCT remains at target and I am feeling fine. Note that my LFTs are back in range due to a daily dose of Milk Thistle Extract.
Suggest that you review your treatment options with your hematologist. Some of us find we need to combine venesections with a lower dose of Besremi, at least early in treatment. This is a decision you can make with your MPN care team.
According to this relatively old (2011) report, "Compared with JAK2 (V617F)-positive PV patients, those with exon 12 mutations had significantly higher hemoglobin level and lower platelet and leukocyte counts at diagnosis". If this is accurate it might influence your experience even as your WBC started normal. How is your PLT level?
Further Exon 12 pts have " similar incidences of thrombosis, myelofibrosis, leukemia, and death". So no effect on these important areas.
As Hunter notes, there seems no data comparing response on IFN but maybe WBC is extra sensitive with exon 12. As Hunter notes you should ask about NGS(Nex gen sequencing) to check for any other mutations. This is esp useful for future reference.
There is a new therapy that should have approval soon in the US , Rusfertide, that will be good for pts with high HCT as it targets red cell levels specifically and could reduce need for phlebs. But when it will be available for any country is not known.
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I have regular exon 14 and responded well to Besremi. My lymphocytes also went low and that limited my dose, which was too high anyway. But a rare severe adverse reaction forced me off.
I was diagnosed with PV in December 2020 with the exon 12 mutation (mine ends in .....K539delinsL). I presented with very high erythrocytes (hematocrit =67%, hemoglobin=22) and normal platelets and white cells. At diagnosis I had 8 phlebotomies in 2 weeks which brought hematocrit down to 45%. I started pegasys about 4 months later and have been on a varying dose since then. I have had 4 additional phlebotomies since the 8 with the last one in January 2022. I have a local hematologist but also consult with a known MPN center in NYC.
I had some of the same questions you had. There are only a couple of studies using patients with the exon 12 mutation - seemingly because they are hard to find. My MPN doctor has stated that the treatment effectiveness for exon 12 people has been approximately the same as v617f mutation patients. EPguy listed some papers above - Linda Scott did some studies.
Pegasys has worked well for me but it took a long time (about a year) to get it working right. Since May 2023 I have been on 45 mcg every other week. My MPN doc has called this hematological remission. My iron levels have recovered to normal. My liver tests have been normal. I had some side effects at the higher doses but have tolerated the drug. My white cells and platelets have been steady, hovering around the low limits and sometimes dipping below but I've been ok. I expected this to be a bigger problem but somehow these levels have remained ok even with the drug injections.
I tried finding others with exon 12 mutation and there was one other person on the board with it - he seemed to be doing ok. So there seem to be three of us.
So as others have said and my doc told me (he told me a year when I started and he was right), you need to be patient with the interferons and somehow keep hematocrit in the MPN range with phlebotomies and dose increases while it gets going. Anecdotally, pegasys seemed to get going once the dose was increased to 135 mcg temporarily - which I didn't tolerate too well - but when the dose was reduced, hematocrit started reducing faster. It seems that you could be a candidate for ruxilitinib (sp?) as it only seems to effect red cells (I believe). I looked into it as a trial but chose pegasys at the recommendation of my doctor.
I wish you the best. If you have any questions, be glad to communicate.
In 2009 I had Hb 20, Hct 58, they did v617f test, I was negative, they did two phlebotomies, in 2 weeks, and I was fine. 14 years I did not know that I have PV, but I hade all the symptoms: Hb and Hct around limit (16-17, 48-52), itching after shower, sometimes blind spots in vision, mild fatigue, rare night sweats, especially in summer, low tolerance of heat.
Now in may 2023, I felt dizziness and fatigue, I made blood test, and again Hb 20, Hct 60. But this time, they made 5 phlebotomies in 2 weeks, and Hct fell only to 56. They did 3-4 more in two weeks, it fell to 54. I was exhausted, i could not make any more phlebotomies.
I started with the first dose 100 mcg Besremi, second one was 150 mcg, third one was also 150 mcg, but now one week after the third dose, my WBC fell below normal range and pruritus was increased, now I have it without showering. They told me that the next dose will be returned to 100 mcg. I dont know how much time Besremi with 100 mcg / biweekly will need to start to have an effect. In the mean time, I need to to phlebotomies once/weeky or once/biweekly, my iron is very low, 4 (on normal range 10-30). I feel exhausted, extreme fatigue, I can not do anything.
I'm sorry to hear of your difficulties. I was lucky enough to not have severe symptoms. It seems to me that phlebotomies would have to eventually knock down your red concentrations and hematocrit. With 500 ml blood removed each one (approximately 1/10 of your total) basically mechanically mining out your red cells and iron. You would think that you cant have a large volume of red cells and high hematocrit without iron. I remember when I was iron deficient after the phlebotomies, that some of the other blood parameters (like MPV, MCH etc) get screwy, with misshapen cells and small cells. There was another measured parameter (Reticulocyte Abs) of the age of the cells and the percentage of immature cells which might be interesting in your case. Another question might be about your diet - Given what is happening I think you would want to restrict iron rich foods (like red meat).
I also got really sick of the phlebotomies and was very glad when we were able to eliminate them.
One other thought - I think I have heard of people taking hydroxyurea and interferon at the same time. My understanding is that hydroxyurea often works faster (seems to be simpler mechanism) and it might be a temporary solution even if a better long term solution is the besremi. Many people effectively take hydroxyurea.
I really think you need an MPN doc to look at this. I have effectively worked with mine remotely with zoom calls. I wish you the best. Please feel free to reach out if I can answer any questions.
While it's routine for interferon to take months to years to lower RBC/HCT/HGB, I've never heard of multiple phlebotomies failing to decrease HCT & HGB. I'n not a doctor, but wonder your the diagnosis of primary PV is correct; i.e. verified via bone marrow biopsy?
There's a non-MPN disorder called secondary polycythemia where only RBC/HCT/HGB are elevated, but Platelets and WBC are normal. The erythropoietin (EPO) blood test result of a patient with secondary polycythemia is usually high normal or above normal, vs below normal or low normal for genuine polycythemia vera.
Yes, it was verified by BM biopsy. Also, the EPO level was extremely low, and mutation in exon 12 on JAK2 gene was found, with prevalence of more than 15%.
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