Hello. I understand that as (currently) incurable disorders PV and ET require long term management via venesection, anti-platelet and cytoreductive drugs. Does this mean constant cytroreductive treatment or can there be breaks if a patient’s bloods respond sufficiently, with a return to the drugs when counts rise (so a more stop start approach) ? I suspect it depends on the patient’s specific needs / experience but wondering which is more typical. Thank you
hydroxy/ interferon treatment questions - MPN Voice
hydroxy/ interferon treatment questions
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RoundTheWorld
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I am not there yet as awful side effects from ET JAK2+ common drugs HU and anagrelide caused delays in treatment. Restarted treatment at 1.35m, now at 800k. My expectation, however, is that once platelets do get down to an acceptable level under 600k based on my situation that a maintenance/lower dose taken less frequently than current weekly will be appropriate to keep platelets at the target level. I consider that reaching an acceptable state of remission. That could change if I get PV or MP over time--that changes the rules.
Thanks Mishie14. Hope you have an easier time re. side effects this time.
That is a somewhat complicated question that needs a case-specific answer to ensure accuracy. The short answer is that there are times when a medication holiday are appropriate, but the need to manage the condition remains constant.
With PV, the most important thing to control is the erythrocytosis. This clearly correlates with risk of thrombosis. The goal is to have HCT<45% (males) or HCT<42/43% (females - not all make the gender distinction). Achieving the treatment goal can be done using therapeutic phlebotomy, cytoreductive medications, or both. While thrombocytosis can be part of the PV it is a secondary issue. There is no linear relationship between PLT level and risk of thrombosis. There is no particular "safe" number. Different doctors use different targets.
The primary goal with ET is to reduce risk of thrombosis; however, there is no particular PLT level goal that applies to all patients. It varies by each case. There is no particular value to PLT<450 for all people with ET. Some docs use 600 as the target. Others consider the delta (degree of change) to be more important. There is a linear relationship to hemorrhage risk at higher PLT levels, including risk of Acquired von Willebrand Disease at very high levels. I found that I experienced increased bleeding/bruising whenever my PLT got near or above 800. For those with ET, It is important to discuss your individual goals with a MPN Specialist, understanding the rationale for the goal as well as the risk/benefit analysis for your treatment choice.
There is more to managing MPNs than the numbers. With both ET and PV there is an important issue about how the blood cells behave. There is more to the symptoms than the absolute numbers of the blood cells. There is evidence that the JAK2 mutation can make the blood cells "extra-sticky" which affects how they interact inside your body. There is also the issue of the increased production of inflammatory cytokines caused by the JAK2 mutation. This is thought to be responsible for many of the constitutional/secondary symptoms we experience. While this is not an issue directly related to the number of blood cells, some do find reduced symptoms correlates with the reduction in blood cell numbers. The cytoreductive treatment can have secondary benefits.
Generally speaking, we will be managing ET/PV across our lifespan. We never stop managing it. We may change strategy, dose, and complementary treatments over time. There are times we need to temporarily suspend treatment. In the absence if immediate risk issues, it is most helpful to think about MPN treatment as a marathon, not a sprint. We can afford to be patient while pursuing our treatment goals. It is also important to include quality of life as a central treatment goal. The MPN and the treatment can have negative impact on quality of life. Improving quality of life though treatment choice, while minimizing the negative impact that the treatments can have is essential in the MPN marathon.
Wishing you all the best on your journey,
We must also include Leukocytosis as a risk factor for thrombosis, in particular for ET and arterial thrombosis:
In conclusion, a 60% expected increase of thrombosis risk in the presence of leukocytosis is a consistent estimate with non-negligible clinical relevance that should be taken into account in classifying the thrombotic risk of these patients for arterial events and in ET cases.
Source: ncbi.nlm.nih.gov/pmc/articl...
In contrast, this article stated:
Leukocytes contribute to deep vein thrombosis (DVT)
Clinical studies have described evidence of activated leukocytes associated with venous, arterial, and microvascular thrombosis. Elevated levels of circulating markers of NETs and neutrophil activation,85,86 as well as increased monocyte TF,87,88 have been observed in patients with DVTs compared with control subjects. In addition to releasing disseminated procoagulant factors into the blood, it is increasingly recognized that leukocytes also assemble at the site of vascular injury, and are actively incorporated into forming thrombi. Studies evaluating the composition of venous thrombi from humans demonstrated the presence of TF-expressing leukocytes and NETs.89,90 These processes increase the localized concentration of leukocyte-derived procoagulant activity and potentially forms the nidus upon which the thrombus develops.
Source: ashpublications.org/blood/a...
Thanks once again Hunter. That’s all very helpful.
In simplified terms there are five treatments commonly used for ET and PV,
- Plhebotomy (phlb) to reduce Hematocrit (HCT)
- Hydroxyurea (HU) to reduce one or all of HCT, white blood cells (WBC) and platelets (PLT)
- Interferon (IFN), to reduce one or all of HCT, WBC, PLT and for many, the mutation.
-Jakafi, with the same benefits as IFN
- Anagrelide. (ANA) to reduce PLT in ET.
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To your question whether these are lifetime, generally yes, at some stabilized dose that may be lower or higher than where it started. For most patients and treatments stopping the treatment leads to fairly rapid rise in blood counts.
-Some exceptions:
-Patients with mild MPN and marginal blood counts that are not too far out of range without treatment.
-Patients on IFN: Dosing can be infrequent, for example just once per month. In the literature discussed in posts here, there are some claims that IFN can be curative, but this not firmly established and rare if so. Similarly there are reports that IFN can be halted for long periods without claims of being curative. In my case, my counts held for three months.
-Phleb can be very infrequent for some, but it, and/or one of the above, are near always lifetime.
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There is cell base therapy in the works that would be "curative", many medical conditions are seeing these efforts. But it is not yet available.
Hi do you know the name of the cell base therapy?
Probably more than you asked but here it is:
CALR should see this first, it's in phase 1 trials. This recent thread (and others) has a discussion of it, including one MF member in the trial:
healthunlocked.com/mpnvoice...
Here is a different thread discussing the less advanced research for Jak2
healthunlocked.com/mpnvoice...
Here is a site discussing in detail their improvement to "cell" therapies to help explain what it is:
crisprtx.com/focus-areas/im...
"Using gene editing, we can engineer immune cells to kill cancer in a robust and specific way while avoiding many toxicities of traditional cancer therapies."
and one of two FDA approved for multiple myloma: "For 78% of participants, there were no signs of the cancer in their bone marrow or blood". Qualified MM pts can get this right now (doesn't help us yet)
cancer.gov/news-events/canc...
and one off subject that I care most about for autoimmunes in ph1-2. This treatment evolved from cancer work, showing how big a deal this tech is across diseases:
"Kyverna is pioneering CAR T-cell therapies for autoimmune disease patients by harnessing the power of T cells to achieve a potentially sustained treatment-free remission by resetting the immune system."
We would all love a "reset" although I think the reset concept is particular to autoimmunes.
You are all so helpful. Thank you - it’s helping me get my head around it all.
Great response, Hunter!
As you may know, these treatments won't cure your MPN. The goal is to manage symptoms and reduce risks of adverse events.
Regardless of your doctor's expertise, only you can assess how treatments impact your quality of life.
My advice: become an expert on your disease. Identify controllable factors like diet, exercise, sleep, fatigue management, and hydration. When starting new treatments, track how you feel and distinguish disease symptoms from treatment side effects.
Advocate for yourself with your medical team.
Best advice 👍👍.
Roughly 20-30% of ET & PV patients taking interferon have been able to take treatment vacations ranging between 3 months to 5 years when their bloods and mutant allele burdens responded sufficiently.
Also, there is multi-decade evidence that interferon slows or stops the progression of ET and PV to secondary myelofibrosis. especially when it is started early in the course of the disease.
Example#1: In a retrospective study of 348 young adults (age < 25) with ET & PV, who were followed for up to 20 years, NONE of those who used interferon as a first line treatment progressed to secondary myelofibrosis whereas 25% of those who used other treatments, including Watch & Wait, did progress. The authors wrote: "Our data demonstrate that interferon specifically compared to other cytoreductive agents yields significantly better myelofibrosis Free Survival compared to other treatments.” ash.confex.com/ash/2023/web...
Example#2 The Silver MPN Center in New York City treated 470 middle to older aged PV patients over a 30 year period and this is how their outcomes differed depending on their treatment: 20 years after diagnosis:
95% of PV patients who had been treated with interferon were still alive and 15% of them had progressed to post PV myelofibrosis
63% of PV patients who had been treated with hydroxyurea were still alive and 41% of them had progressed to post PV myelofibrosis.
57% of PV patients who had been treated with phlebotomy-only were still alive49% of them had progressed to post PV myelofibrosis. Source: tinyurl.com/544sybph
Roughly 20% of interferon users find the drug intolerable for long term use - about the same % that finds that it works so well they can take treatment vacations ranging between 3 months to 5 years. Of the remaining 60%, most find they need to continue treatment indefinitely and a minority find it doesn't work well enough alone on normalizing blood counts unless a second drug is added such as hydroxyurea or Jakafi.
Monarch
Once again the above examples aren’t that useful because the interferon patients were selected low risk patients whereas the non interferon patients were not according to my expert at Mount Sinai as of last Oct
Apparently non-interferon patients were also low risk:
« Overall we included 348 pts (278 ET, 70 PV) with median age 20 yrs at Dx (IQR: 18-23). Median age at Dx for ET was 21 yrs (18-23) and for PV 20 yrs (16-23). 249 pts were female (216 ET, 33 PV). Median follow-up was 9 yrs (4-15). Overall, 237/348 (68%) started a cytoreductive therapy. First treatment was hydroxycarbamide (HU) in 126 pts (100 ET, 26 PV), IFN in 55 pts (33 ET, 22 PV), anagrelide (ANA) in 52 pts (51 ET, 1 PV) and other in 4 pts (1 ET, 3 PV). 111 pts (32 %) did not receive cytoreduction (93 ET, 18 PV) deemed NoCYTO. According to ELN risk group at Dx, 39/43 pts (26 ET, 13 PV) receiving a cytoreductive drug were high-risk and 197/304 pts (159 ET, 38 PV) were low-risk. Reason for treatment initiation was thrombotic event in 32 pts (24 ET, 8 PV), platelets >1000x109/L in 96 pts (87 ET, 9 PV), MPN-related symptoms 12 pts (7 ET, 5 PV), and other/unknown for 97 pts (67 ET, 30 PV). »
This info refers to your first example in post above for young patients, the number of patients is so low eg 13 PV high risk patients were on cyto and overall 2/3 were low risk patients anyway. I also question if the median study time was 9 years bearing in mind these are very young patients , how meaningful is that data considering that even with older patients only 10% or so are likely to convert to MF. It’s also important (and this usually omitted) these are only that patients that were able to tolerate INF , according to Gisslinger and Hasselbalch at a recent conference and from a consult with Hasselbach the INF drop out rate over 5 years is approx 60%, this was also stated by Clair Harrison at a presentation.
In. Addition once again what you posted saying that there is decades of info saying the drug slows or stops progression, what you missed out is that is only a small subset of the 40-50% of patients who stay on it long term.
If you ask most experts apart from Silver etc they never claim it slows or stops progression, they may say it might for a minority. The last time I read the Clair Harrison info on MPN VOICE website re the various drugs it said non of them stop or slow progression.
Pegasys and Bes are likely the best drugs we have from a rather poor selection but why keep re posting inaccurate information claiming it’s better than it is, that is misleading to other patients.
If it was as good as you claim then why are we not all on it and no one progressing.
If was that good every expert would know about it and recommend it, it’s common sense. But the reality is that a lot can’t tolerate it and the reality is a lot on it progress.
It’s definitely worth a try for anyone considering cyto treatment and would be my first choice if I could tolerate it but let’s keep it realistic
« The progression of polycythemia vera (PV) to myelofibrosis (MF) is a known risk, but the use of interferon, specifically recombinant interferon alfa (rIFN-α), has been shown to improve myelofibrosis-free survival (MFS) and overall survival (OS) in patients with PV¹. According to a study published in the journal Blood, patients treated with rIFN-α had a longer MFS and OS compared to those treated with hydroxyurea or phlebotomy-only¹. The study also indicated that rIFN-α is the only disease-modifying treatment shown to reverse marrow fibrosis¹.
In a multivariable analysis, the group treated with rIFN-α had a lower risk of progressing to MF compared to the hydroxyurea group and the phlebotomy-only group¹. It's important to note that while there is a risk of progression from PV to MF, the use of interferon can have a positive impact on delaying or preventing this progression. »
(1) Interferon in Polycythemia Vera (PV) Yields Improved Myelofibrosis-Free .... ashpublications.org/blood/a....
(2) Polycythemia vera: 2024 update on diagnosis, risk‐stratification, and .... onlinelibrary.wiley.com/doi....
(3) When Polycythemia Vera Becomes Myelofibrosis - VoicesOfMPN.com. voicesofmpn.com/mpn-blog/wh....
(4) Polycythemia Vera: Prognosis and Risk for Progression to Myelofibrosis. onclive.com/view/polycythem....
(5) Current treatment algorithm for the management of patients with .... ashpublications.org/hematol....
(6) undefined. doi.org/10.1182/blood-2020-....
Having skimmed these papers I don’t see anything that changes what I have written in previous posts, in fact I’m not sure of the relevance of them.
The second one is by Tefferi who seems to say clearly that none of the drugs in Inf affect progression and that lowering AB should not be interpreted as slowing progression, he also states 55% on Inf had side effects. He also suggest only phlebotomy for low risk patients!
Two of the papers are from the Silver camp and if previous trials reports were misleading , well I will leave others to decide for themselves about those.
The other ones you posted don’t seem to support any of your claims.
You said: "most experts never claim it [interferon] slows or stops progression." But at the ASH 2023 meeting, there were 41 authors of this statement including Claire Harrison:
“importantly our data demonstrate that IFN specifically compared to other cytoreductive agents yields significantly better Myelofibrosis Free Survival compared to other treatments. These results support the use of IFN as a currently available disease-modifying agent to improve long-term Myelofibrosis Free Survival and also warrant reconsideration of earlier treatment in patients with ET and PV with IFN to improve Myelofibrosis Free Survival potentially as a primary aim." ash.confex.com/ash/2023/web...
That’s the same paper you posted yesterday with 20 year olds etc where the number of PV patients with high risk on meds was something like 15, posting the same papers over and over again doesn’t change the facts.
If you look at MPN VOICE website for treatments under Interferons and what it’s useful for it doesn’t mention it’s good for slowing or stopping progression at all, in fact there is no mention of it. I suspect if Clair Harrison and Co had firm evidence Inf slowed or stopt progression I suspect it would be on the website, in fact it would be shouted about by all the experts. Similarly on the MPN Voice website it suggests for low risk patents with ET aspirin only and PV low risk aspirin and venisection only, no mention of Interferon. This is same as Tefferi and any expert I follow except the Silver group, I wonder why that is?
Similarly I wonder if the manufacturers of Interferon claim it slows or stops progression would they not include that in their leaflets/ drug inserts/websites. I havnt read a Interferon drug insert recently but I would be very interested to hear if the do include that claim, because if it did do as well as you claim I suspect the drug company would be shouting it at us with adverts etc. If you do find the drug company making those claims perhaps you could post that for us please.
It's a study of young pts and good new info. It had "median age 20 yrs at Dx" with the intent to study young pts under 25. There are young members who need better info like this and a great argument to start IFN for them. Young pts inherently are low risk, being well under the 60 year cutoff, so it's consistent with the largely low risk cohort noted.
For most of us we need to focus on the more common studies of older pts. This is a plot from one, I apologize that I don't have the report it's from, it's in my image files and likely in one of my old posts. Highly likely from the Dr. Silver MPN group. IFN still looks good here and is great therapy but not at the 100% seen in the young pts study here.
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On risk, I think HU resistance should be specified in all trials as it's a very large risk factor as discussed in prior posts. I recall IFN may do well here but don't have any reports handy.
Resistance to HU was associated with higher risk of death (HR, 5.6...) and transformation (HR, 6.8;...)
healthunlocked.com/mpnvoice...
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But missing from all these comparisons is Rux, which is still evolving in its PV results and very limited info in ET.
One surprise from the new report is "suggesting no (thrombosis free survival- TFS) benefit for cytoreduction" with any of the therapies, and a weak signal (p= 0.69) for IFN being inferior for TFS in high risk pts, from fig 1A there. We all care most about MF progression, but TFS is important and seeing that cyto does nothing for it is unfortunate and I think different from other studies.
MFS Long Term
Have ET or PV patients taking Rux by itself ever been able to take treatment vacations ranging between 3 months to 5 years when their bloods and mutant allele burdens responded sufficiently? Or do Platelet, RBC, HGB, etc. counts nearly always start rising soon after treatment discontinuation?
Most of us are familiar with the fact that the elevated LDH levels of ET and PV patients commonly drop down to normal after several months of taking interferon. Do the LDH levels ET or PV patients taking Rux by itself also commonly drop down to normal after several months?
My LDH came down from around 300-500 to 160-200 on Rux.
People on Rux don’t come off, according to expert at Mount Sinai it does the same job as Peg etc but in different ways, hence he could see no benefit from combo treatment, ie Rux +Peg
generally the cyto drugs are for life unless in the case of a minority on Pegasys/Bes/Inf who can after a while sometimes come off the drug for a period.
And of course one can change drugs if desired
Good Morning RoundTheWorld,
I am ET vs PreFibrotic Myelofibrosis. I take Besremi. Saw Specialist couple of days ago. She again said, we are playing the long game. My dose 150mcg every four weeks now. Numbers stable. Never took HU.
Because I have Jak2, Tet2, Doctor wants to follow up in 2 years on Besremi, which will be January 2025, Looking for allele burden. Early in this trial, some people taking much larger doses, up to 500 mcg, then became undetectable. Some came off drug. In September, I will see Dr Komrokji again. I will ask if they were able to remain undectable. I am an aware of venesection for platelets unless requiring surgery.
Hope that helps, best of Luck Christy
Thanks Christy. It’s all helpful.
Does your user name mean you scuba? Have you been given guidance? (I used to; had hoped to again but I had assumed not possible any more).
Yes Scuba has been my favorite thing, my specialist said I may continue. Probably will keep deepest 60 feet. Haven’t been since diagnosed but have a goal to go soon !
Maybe we can plan a MPN snorkel dive trip!
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