I preface this post with stating that this is merely my personal perspective/opinion as a young (age 30) potentially triple-negative ET individual based on my own research having been in the diagnosis process for a couple months now.
I've seen triple-negative ET described in this forum many times as the "most benign form" of ET. However, to me, this seems somewhat misleading in that it appears to be biased toward the largest portion of the ET population (patients diagnosed at older age) because the "most benign" designation appears to be strictly based on thrombotic risk (the short-term threat) rather than risk of disease progression (the long-term threat).
Most, if not all, studies I have read comparing the long-term progression risk of ET have determined that triple-negative ET, particularly after 20 years, has a significantly higher risk of disease progression to AML compared to ET with JAK2, CALR, or MPL. Additionally, after progression, triple-negative MF/AML have a significantly poorer prognosis compared to those with driver mutations. This is believed to be primarily due to the higher rate of "non-driver mutations". Triple-negatives have a much higher rate of non-driver mutations than those with JAK2, CALR, and MPL. My understanding is that the driver mutations are more influential in causing the disease phenotype itself (hematopoesis), and the non-driver mutations are more influential in disease progression (and are involved in many other cancers).
So, for the majority of the ET population (older patients diagnosed when they are already somewhat close to a "normal lifespan"), yes, triple-negative ET may indeed be more benign since the risk of thrombosis is lower, meaning they are perhaps more likely to die of something other than their ET since they would expect to live approximately (or less) than 20 years from diagnosis anyway even if they did not have an MPN. However, for younger patients who still have 30, 40, 50 more years to live to a "normal lifespan", it seems triple-negative ET is actually greater overall risk in the long-term to living a normal lifespan compared to those with a driver mutation due to the increased risk of progression.
Of course, everyone's disease is different, and the prognosis of an individual is very different than looking at large groups of people, but it seems to me that this is what the evidence suggests as a general trend.
Would appreciate anyone's thoughts on this.
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cmc_ufl
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I asked something similar today, because of some articles i read! I am confused and worried like you , but in the link below you will find an article that says:
"After a median duration of follow-up of 7.0 years (range, 1.2–36.8), no case of fibrotic transformation or leukemic evolution was recorded. On the contrary, myelodysplastic syndrome (MDS) was diagnosed in one (2.5%) patient after more than 32 years of follow-up."
"Discussion
In this real-life, single-center cohort study, we investigated the mutational profiles and reviewed the clinical data and BM biopsies of 40 consecutive triple-negative ET patients with a median follow-up of 7 years.
From a strictly clinical point-of-view, we first confirmed that triple-negative ET is a very indolent disease, with a low incidence of vascular events as only two patients suffered from thrombosis. Furthermore, no case of fibrotic progression or leukemic evolution was registered, thus confirming the different behavior of this condition when compared with triple-negative PMF. Interestingly, MDS evolution was diagnosed in one (2.5%) patient after more than 32 years of follow-up, underlying therefore the need of a prompt recognition of different types of disease progression in MPNs"
"Furthermore, it should be highlighted that none of our cases harbored variants (affecting TP53, SRSF2 and/or TET2) previously reported to impact on leukemic evolution of MPNs "
( although it says that 27% have a variant of TET2 mutation. But I can't understand all the perspectives of the study)
Thanks for your reply. The median follow-up in that study was only 7 years, which means half the study population was only followed for up to 7 years. It is the long-term outlook (decades) that is the focus of my post. Studies show triple-negative ET is indolent in the first decade (as is ET with driver mutations), but after that, it has a higher progression rate than other forms of ET.
Hello! I’m triple negative and 37... my mpn expert says triple negative is a great place to be as far as clots, bleeds AND progression.. I believe calr is highest risk of progression and jak2 highest risk of clots.. triple negative seems to be the least for all
Thanks, I appreciate your reply, but it is a little more complicated than that, especially when assessing long-term outlook (many decades), which is the focus of my post.
CALR has the highest progression rate to MF, but when they do progress, it is relatively mild which gives them the longest life expectancy both in post-ET MF and overall. They also have the lowest rate of progression to AML.
JAK2 has the highest risk of thrombosis and an intermediate risk of progression to MF/AML.
MPL has an elevated risk of progression to MF, somewhere between CALR and JAK2, and an intermediate risk of thrombosis.
Triple negative has the lowest thrombosis/bleed risk, but they have the highest rate of progression to AML over time because they have the most aggressive post-ET MF, with most progressing to AML within 1-3 years after progressing to post-ET MF. Triple negatives, by far, have the worst prognosis upon disease progression, which is the greater threat to long-term outlook of young patients.
Is there a chance that you think triple negative MF is the continuum of triple negative ET? Can you please find some of these studies cause i am interested in?
My MPN specialist told me that, generally, PMF and post-ET MF are the same disease and generally carry the same course and prognosis based on mutation. So triple-negative post-ET MF has a comparable prognosis to triple-negative PMF, including high transformation rate to AML.
I think the biggest issue we face as a younger generation is a distinct lack of research and data. I remember looking for this when I was newly diagnosed and was disappointed to see very little, there are so many variable with this condition.
I was diagnosed 23 years ago. Blood tests and a bi-annual bmb were the way of monitoring. No google, no MPN Voice, no access to international websites, no blogs. Looking back I am amazed and grateful for the ongoing research and for the chances to learn much more. Long may it continue.
This is the answer of Prof Harrison (through Maz) to my post for triple negative ET and possible increased rate of ML:"Hello Aneliv9, I asked Prof Harrison and she replied: UK data suggests this is not the case.Best wishes, Maz"
That answer from Dr. Harrison not address the question you are asking. In that post, she compared triple-negative ET to triple-negative primary MF The question you are asking is “does triple-negative post ET-MF have the same prognosis as triple-negative primary MF”. My understanding, based on specific conversations about this with my MPN specialist, is that PMF and post-ET MF are generally the same disease and generally carry the same course and prognosis based on mutation. So triple-negative post-ET MF has a comparable prognosis to triple-negative PMF.
Dr Harrison does not answer questions albeit very Briefly ... I’m so sorry for anyone who has heard great things about her ( as did I ) and has great expectations but she dismisses much more than she answers ... also she told me there is no connection between mpn and inflammation..it was only this site that explained to me why I was suffering inflammation... imagine the top people at guys & Thomas London ...not knowing Mpn & inflammation are closely connected...don’t really have much information regarding mpn at all ... I’ve learned the hard way .... waiting and hoping for support & guidance will not come from the so called professionals ... I have found much more support on this site and through Macmillan ..,they have answered all the questions I have had since being diagnosed...I did not expect vip treatment from London Hospital, but I did expect someone to at least tell me what mpn is ...how it would affect my life etc ... that has never happened... so I have gone elsewhere...had enough of being treated like a number ... things are looking much brighter with New Heamo & Macmillan Nurse ...love to all of us that need information ...support & prayers for us all to find it ...but for me as ( I can only speak for me ) the lot I have dealt with have been so disappointing to say the least ... so wish your experience will be better than mine ... Lainie xxxx
Sorry to hear you had a bad experience. I can’t comment on that since I am not a patient of hers (I am in the USA). I know the research that comes out of her lab is top-quality and that most people here speak highly of her, but that is the extent of my knowledge.
That answer from Dr. Harrison not address the question you are asking. In that post, she compared triple-negative ET to triple-negative MF The question you are asking is “does triple-negative post ET-MF have the same prognosis as triple-negative primary MF.”
I asked my specialist this question. He told me triple-negative post-ET MF and triple-negative MF have the same prognosis. This is the reason for my post about long-term outlook.
Please do not be stressed. My intention with this post was not to scare anyone. Was just trying to have an open discussion about the discrepancy I found between the data and what I’ve heard on this forum regarding triple-negative ET.
For the general ET population, correct, there is little difference in transformation rates since most of the ET population is diagnosed at older age. But after 20 years, triple-negative ET has the highest AML transformation rate.
Yes. The reason triple-negative ET has the highest transformation rate to AML is because triple-negatives do not stay in post-ET MF for long. They typically progress from post-ET MF to AML within 1-3 years. This is different from those with driver mutations, who can stay in post ET-MF for 5-15 years depending on the mutation. That is why triple-negatives have the most poor prognosis when they transform, because their post-ET MF is the most aggressive and transforms to AML the fastest.
I have read all the studies as far as triple negative MF!! But like you am not sure if triple negative post-ET MF have the same prognosis. Imetelstat (a new phase 3 trial drug for MF), seems to have the most impressive outcomes in triple negative MF than MF with known driver mutations thought.
I expect the triple negative MPNs are a complex array of similar presenting phenotypes with different genotypes. MPNs in general are no monolithic disorders. Even people with the same drive mutation can present with a wide range of symptoms and prognosis. There is no question that that the non-driver mutations play a significant role in this disparity in MPN presentation. It is likely there is even more to why we see such disparity.
My thought is that triple negative MPNs may be if anything even more diverse that MPNs with a known driver mutation. I also think that the term triple negative should really translate as "driver mutation unknown" since there is something driving the MPN phenotype. There is research underway looking for these additional driver mutations.
The research looking for more effective treatment options for MPNs is very important for all of us. It tend to have more funding and investment since it can lead to profits for pharmaceutical companies. Unfortunately the base science looking at MPN Molecular Biology may not always get the same attention and funding. That is why it is so important to find funding to better understand and treat MPNs.
We had a similar conversation with my partner’s MPN consultant who is a colleague of Prof Harrison.
My partner is in his early 30s too so we were very anxious about progression at diagnosis a couple of years ago.
We have been reassured that although there isn’t a huge amount of data out there for younger patients, what they have found anecdotally is that triple negative ET very very rarely transforms over a longer term.
And perhaps if it does, we will be lucky enough that treatments will have progressed significantly to make this not such a scary prospect.
It’s hard living with uncertainty, but we just have to get on with it with fingers crossed.
Very reassuring and thanks for posting! Mazcd replied exactly the same to me after asking prof Harrison .Of course i can also understand the cmc_ufl's worry about what happens IF transformation occurs... Mpn specialist told him that they have the same prognosis.
I appreciate your reply, but this does not agree with studies on the long-term (decades) outlook.
The general response that “transformation is very rare” is true to an extent, but really only applies up to 20 years post-diagnosis. After that, the odds of transformation to MF, regardless of mutation, typically surpass 15-20%, which I would call “uncommon”, not “rare”. That does not even include AML transformation. The risk continues to increase with time.
A general rule of thumb I was told is that overall transformation risk (between both MF and AML) is cumulative, around 1% per year after diagnosis. Everyone is different, and mutation status adds variability, but this is the general trend that the data shows.
People diagnosed very young have a significantly higher risk of transformation over the course of their life. Year-by-year, no, their risk is the same as anyone else. But since they have many more years to live than someone diagnosed older, their transformation risk over the course of their life is much higher.
This is sensitive stuff and can trigger a huge amount of anxiety for many people.
I appreciate you have read a study that has worried you and it’d be great to see a link (if not already posted).
There simply isn’t the data to be certain for younger ET folk. I would rest assured that specialists are generally very positive on the matter, the science and data is improving and that learning to live with uncertainty is a big part of any chronic illness.
Will be very interesting to see how the data turns out for younger patients.
I myself am not anxious about all this. I was 2 months ago during the “shock” period, but have since come to terms with everything. Was more just hoping to have an open discussion about the discrepancy I was finding.
Important for us all to educate ourselves and live life to the fullest!
I'm a little confused by the debate. I thought your consultant said it was more likely than not you didn't have Et and that he wasn't requesting a BMB? Only if I was diagnosed with a said condition would I research it and look at the prognosis and % of transformation. I wouldn't put myself through all the worry and anxiety of what if's, if its unlikely you have Et. Tina.🤗
I think living with uncertainty, even though no one wants to be in this situation, forces us to appreciate each day more and helps us be better, kinder people with a more selfless perspective. I have found it to be a huge blessing in my life, despite the reality of the situation.
Triple negative patients can be 1)the driver mutation allele burden is too low to be detected or 2)the driver mutation is not discovered yet or 3)secondary mutation causes the malfunction of bone marrow. Last appointment my doctor said he want to run the genetic test on me every six months. This is the link to the test:mskcc.org/msk-impact
I guess my doctor’s point is it’s either one of the known genes causes my ET or an unknown gene. Regarding the long term prognosis, it varies from different people because TN patients don’t have the same cause.
I agree on all points! Triple-negatives are a very heterogeneous, complicated mixture.
I would add a 4th point to your list: it is now known that there are other mutations in JAK2, CALR and MPL that are not picked up with conventional clinical screening (mutations at unusual locations in the code, different amino acid substitutions, etc.). So many triple-negatives likely actually have a mutation in one of the 3 driver proteins, just in a different form than most of the ET population. There is debate as to whether these can still be called "driver mutations".
There was a paper by Dr. Harrison's group last month that showed that they could re-diagnose >20% of triple-negatives using next generation sequencing (much more sensitive than routine clinical assays), showing they actually did have driver mutations that were not detected upon their initial diagnosis.
Because there is a chance that his allele burden is just too low to detect right now, so testing every 6 months will allow the mutation to be detected once the allele burden goes up past the sensitivity of the assay.
I think because ET is caused by gene mutation, and for me with no known mutation or too low allele burden, the frequent gene tests can help find the answer sooner. Plus the hospital keeps enhancing the gene panel and test sensitivity, that’s another reason for the frequent tests.
“Dr. Deeg: What we do now with patients who do not have any one of those three genes mutated that you just mentioned, JAK2, MPL, and CALR, patients who do not have any of those mutated tend to have a faster progression of the disease. That is, however, most relevant in patients with primary myelofibrosis, and probably much less so in patients such as Mr. Roth, who started out with essential thrombocythemia or with polycythemia and then evolved to secondary myelofibrosis.”
Will ask and will post here when I find out. My specialist told me that post-ET MF and primary MF are the same disease. Once you progress to post-ET MF, you no longer have ET, it is a new disease, so the course of triple-negative post-ET MF is expected to be the same course as triple-negative primary MF.
I’m in my 30s and this is what he told me,. Based on my age, health and being triple negative.. so I’m not young, young (lol) but I’m young for ET ....if that makes sense ...
We are! But, I think it’s becoming more common now in younger groups. Not sure if that’s good or bad. I’m in a few ET Facebook groups and one did a poll in ages and the most common age range was 30-40.. could just be that’s the most popular Facebook age also 🤷🏼♀️
Yes, probably more the average age of FB use. Young people are a minority in the ET population, but I feel for a long time the exact percent of young patients has been underestimated, probably due to lack of diagnosis due to not seeing doctors as frequently. In my case, my platelets have been up for 10 years (since age 20) with no physician saying anything until I switched to a new practice. Most GP’s just aren’t educated on MPNs.
My hemo says it’s very rare and, even though not impossible, not something I should be worried about.. I will try to find the video I took.. I paid out of pocket to speak with an mpn expert (of course not covered by my insurance 🙄), and we did a video conference bc of covid.. I screen recorded tHe whole thing. By the end of the hour and a half long conversation I felt SUCH relief, and very positive for my future.
Very rare hmm???? I hope so! I am a little better now! Please share a caption of the video if you like with pm . Could you ask him next time about long-term (30-40 years) rates of progression or what happens i case it progress?? Is prognosis similar to triple negative MF ? I believe i have ET at least for 20 years.. and just last year diagnosed .I am scared that time is my enemy
I really don’t think it is something we should be worried about, just something we should be aware of.
“Very rare”, in my opinion, applies to the first 10-20 years. After that, every study I’ve seen that focuses on long-term outlook lists progressing risk around 20% for all mutations, increasing every year. I would not call this “very rare”, more “uncommon”, especially for long-term outlook like 30-50 years.
The important message is that, regardless of how long you have it, your odds of not progressing will always be better than the odds of progressing, but after 20 years, it is no longer a “rare” occurrence.
I am sure that you know how to read a study, i just want to make sure that these studies that you talk about are not very old, when a large proportion of pre- PMF patients were included by mistake in the study
For myelofibrosis, yes, there is no doubt that triple-neg has the most unfavorable prognosis.
For ET, generally speaking, triple-negative appears to be more mild, at least for a period of time. That is the subject of this post...how long is it more mild? May not be the case for people diagnosed young since after 20 years, triple-negative seems to have a higher risk of AML transformation.
I started to think that triple negative ET and triple negative MF, should have the same mutations in order to have the same prognosis.... Just a thought...
Again, remember, we aren’t comparing triple-negative ET to triple-negative MF. We are comparing triple-negative post-ET MF to triple-negative primary MF.
I actually addressed the idea of mutations in the post. There will be some variability person-to-person, and some mutations are more aggressive than others, but generally speaking, triple-negatives have a higher rate of “non-driver mutations”, which is what influences progression. This is why triple-negatives have the most aggressive disease if they progress, because of the higher prevalence of non-driver mutations that cause progression to AML.
Ok, I see... but are you sure that the lack of "non driver mutations" influence progression?? Or may be some specific high risk mutations that already exists in triple negative MF and not in triple negative ET??Triple negative MF , seems to be MDS with fibrosis ( from some studies),so there may be more findings in the bone marrow of TN-MF like px dysplasia except from mutations. In general, i see your point (a lot), but you don't provide some evidences and i start to be a little bit tired with the subject without evidences. But otherwise i get your thinking. It seems that we will never know what will happen in this subgroup in the long term. For now i will keep what Prof Harrison wrote to my previous post, that they don't have a great data for the subgroup,cause transformation is very rare. Sorry for my English,i am from Europe
Yes, there are definitely some of the “non-driver” mutations that cause progression more than others, particularly ASXL1 and a few others. Since triple-negatives, in general, have a higher percentage of these mutations, they have a higher proportion of patients with the aggressive non-driver mutations.
I will share some studies I have found on this subject this evening when I am back home at my computer. There are two or three studies specifically talking about triple-negative post-ET MF and triple-negative progression to AML compared to those with driver mutations.
Again, these are things to be aware of, but not to be worried about.
You contradict your self through this whole thing. "This is why triple-negatives have the most aggressive disease if they progress, because of the higher prevalence of non-driver mutations that cause progression to AML." This is what you wrote after saying it was the most benign. If it is aggressive after progression it's aggressive prior. Otherwise it would not have progressed if we're benign.
The focus of this post is how long it stays benign (short vs long-term) and the definition of benign as it applies to different age groups. I’d encourage you to re-read all the content.
My disagreeing with you does not imply I have not read nir do not understand. I simply disagree. I have extensively read up on the genetics. It simply means nothing. They do not understand all of it nor what it all implies. They have even agreed there are more genes they have not found and the effects as well.
I meant re-read the content of the post, not background information on the subject. I believe you have a misunderstanding of the question being asked in this post. If you would like to discuss further, I would ask that you send me a private message. Thank you.
Thank you for sharing. This interview clearly describes triple-negatives as being more prone to disease transformation due to the fact that their disease is often caused by non-driver mutations associated with progression.
Hi cmc_ufl, I find alot of the discussion about mutations & drivers confusing so thanks very much for your synopsis of the interview. In view of the observations raised in the above article I wonder could more detailed tests & investigations be carried out for all triple negative patients in order to identify outlier mutations/drivers? Perhaps, treatment pathways for this specific cohort of MPNs may then be identified which could reduce our symtoms & prevent progression ? 🤔
In my opinion, triple-negative MPN patients should deeply consider getting a genetic panel done. These assays look for “non-driver” mutations that are associated with MPN disease progression (ASXL1, IDH1/IDH2, TET2, etc.). Triple-negatives tend to have a higher rate of these mutations, and it is believed that these mutations are what is contributing to their disease. Below is an example of one of these panels:
Also, it has been shown that a good portion of triple-negatives actually do have mutations in JAK2 and MPL, just non-canonical mutations (mutations in JAK2 other than V617F or exon 12 and mutations in MPL outside exon 10). Only next generation sequencing panels that sequence the entire genes of JAK2 and MPL reveal these mutations. Here is an example study that showed that over 20% of triple-negative ET patients were shown to have non-canonical mutations in driver driver genes after repeating their testing with next generation sequencing:
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