Myeloproliferative neoplasms (MPN) are blood cancers that appear after acquiring a driver mutation in a hematopoietic stem cell. These hematological malignancies result in the overproduction of mature blood cells and, if not treated, induce a risk of cardiovascular events and thrombosis. Pegylated IFN is commonly used to treat MPN, but no clear guidelines exist concerning the dose prescribed to patients. We applied a model selection procedure and ran a hierarchical Bayesian inference method to decipher how dose variations impact the response to the therapy. We inferred that IFN acts on mutated stem cells by inducing their differentiation into progenitor cells; the higher the dose, the higher the effect. We found that the treatment can induce long-term remission when a sufficient (patient-dependent) dose is reached. We determined this minimal dose for individuals in a cohort of patients and estimated the most suitable starting dose to give to a new patient to increase the chances of being cured.
Below is another link to the article. However, I'll save you some time by telling you it's very long, heavily math and statistic oriented and you will need a math degree to understand it. I usually jump to the conclusion of a research article to bypass the technicality. This article didn't help me do that.
Here are more details about the article titled "Mathematical modelling, selection and hierarchical inference to determine the minimal dose in IFNα therapy against Myeloproliferative Neoplasms"¹:
### Overview
The study focuses on **Myeloproliferative Neoplasms (MPN)**, which are blood cancers caused by mutations in hematopoietic stem cells. These mutations lead to the overproduction of mature blood cells and increase the risk of cardiovascular events and thrombosis if untreated.
### Objectives
The main goal of the research was to determine the minimal effective dose of **pegylated interferon-alpha (IFNα)** for treating MPN. The researchers aimed to understand how different doses of IFNα impact the response to therapy and to establish guidelines for the optimal starting dose for new patients.
### Methodology
The researchers used a combination of **mathematical modelling** and **hierarchical Bayesian inference**. They applied a model selection procedure to analyze how variations in IFNα doses affect the differentiation of mutated stem cells into progenitor cells. The higher the dose, the more significant the effect on cell differentiation.
### Key Findings
1. **Dose-Response Relationship**: IFNα induces the differentiation of mutated stem cells into progenitor cells. The effect increases with higher doses.
2. **Long-term Remission**: A sufficient, patient-specific dose of IFNα can lead to long-term remission of MPN.
3. **Guidelines for Dosing**: The study provides guidelines for determining the minimal effective dose for individual patients and suggests the most suitable starting dose for new patients to increase the chances of remission.
### Conclusion
The study concludes that personalized dosing of IFNα, based on mathematical and statistical models, can significantly improve treatment outcomes for patients with MPN.
Re dose dependent molecular response- the most relevant citation I can find in the report using a real population study has:
"Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs" This is consistent with reports we've seen.
Are there other trial based results for the dose dependency?
Most the other correlations are calculated. But we have seen for both PEG and Bes a strong correlation to CHR (remission) I recall esp for HCT. (The non-correlation to dose was explicit in the Ropeg write up. This area is in various posts I've made over the years and maybe I could assemble some again) Implication is the safest effective dose should be the lowest that provides CHR, and MR will follow.
I care about this min dosing bec it's likely relevant to my life splat experience.
It would be great to see a calculation that predicts MR vs CHR, but I don't think they covered this area.
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A separate subject in the citation above has- "(In CALR) a high dose of IFNα correlates with worse outcomes" This is worth attention. It may be the same CHR relation, and might be reworded- "In CALR not attaining CHR on IFNα correlates with worse outcomes" (this is my extrapolation, not in these reports).
Thanks for the added info. I was hoping to hear more of their conclusions on dosage, as it sounded as if they were recommending a certain minimal dose, and as I'm currently on THE minimal dose, I'd love to know if it is worth it for me to continue this low dose, given that I'm still experiencing some unpleasant side effects and have no intention of raising the dose.
In your case you already know your dose, as it is toxicity limited.
In the detailed report linked by msr6637 there is a guide for recommended starting dose of 70. This is the Fig most on the point. They recommend "We estimated that an initial dose of 45 μg/week, classically used in clinical trials ..., should only induce long-term remission in 86% of the cases, and we advocate instead to start at about 70 μg/week." This is the plot here.
Authors say one should not reduce the dose at any time to below the selected starting dose but increasing dose is expected to get hemotological response. But they note dose can be limited by toxicities. Strangely they cite depression as the main one. We know there are a wide range of other serious events that can occur. " ...physicians also have to consider additional constraints, such as the occurrence of side effects, mainly depression..."
Much of the paper is expressing their development process to create the simulation. They do detail hetero vs homozy mutation. Best I can tell they reproduce what we've discussed here. Homozy tends to higher mutation levels and response better to IFN.
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In general this is an academic exercise. We've learned here that the best dose for most is the smallest one that gets blood remission (CHR) . Don't rush to raise it, and know that molecular response correlates well to getting CHR. I would have been much wiser to insist on this method.
Interesting, I am tolerating it very well ( no side effects other than mild liver irritation ) but I am still on 1 pill of hydroxyurea every other day. Once I cut that out I’ll be on pegasys only and that will be the true test I think.
Interesting point, Dr Gisslinger talked about this at his talk today at the doc to doc conference in NY, his view was as a general point don’t blow it side effect wise (and that can include autoimmune issues) by going too high too fast, he reckoned to take ones time and maintain the long term benefits, he showed a slide of a marathon.
I have a deep interest in this subject since my Dr and I fatefully disagreed on it.
On manouche note- "The higher the dose (if tolerated), the higher the chance to eliminate the clone. Is there new (or old) data on this? Did Dr Gisslinger provide any new info on this area?
I still believe for safety IFN should be dosed at the min required for CHR, in particular, HCT, and MR will likely follow if CHR happens. My Dr disagreed and is not alone there.
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In this post I did long ago I put in several days and studied in detail related issues. It goes into the tight connection of CHR and MR.
"the chance of achieving CR is 15 times higher for patients with a reduced JAK2V617F allele burden" Question remained whether the inverse is true.
In the Bes trial "Dosing level had no apparent impact on the achievement of an allele burden <10% (p=0.9)." p value is weak but mssg is consistent.
"… a clear relationship between allele burden and hematologic responses"
"We did not identify any predictors of clinical response or observe a relationship between the dose of PEG administered and the degree of clinical response"
The chart here is one of many in my old post; this one showing the tight connection MR to CHR for one study.
The flow chart I posted in "Image #2" there was an interesting hybrid of dosing for HR and MR.
and in another post I noted with a plot:
"So the pattern from before persists, having CHR on INF favors lower AB on INF. Also lower starting AB was favorable."
One of the problems with interferon is that you need the observer, the investigator, to live a very long life in order to control the studies. Because you may need to do studies that stretch over 20 or 30 years in order to have definitive answers, and we may not be able to get this. I’ll give you an anecdotal case.
Moshe Talpaz, MD:
I studied it in 1998; it was a long time ago. A patient who I started with essential thrombocythemia but JAK2 positivity. I started to treat her in the late 1980s. And she developed a complete molecular response after 25 years. She is in remission now, after 30 years on therapy. She still gets it on and off ».
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