Effective INF Dose Part 2, more considerations, research, and Dr vs patient wishes

[EPguy]

My last two doses of Bes were 70-80 mcg. In my recent Hem visit Dr was most displeased that I had cut it from 100 (actually 110) prior to that without his approval. He had seemed looser on dose when we discussed before.

The 1st lowered dose was in hope I might feel ok during my one week driving trip (not successful as I posted) 2nd reduced dose was my self test whether I could hold CHR with such a small dose over a month. (successful) All my doses ex one since early Feb have been well below 100 and I've held CHR so far. In fact WBC is headed very low. Next will be 100, 100, and 120 per his order. But this was my only opportunity to test short term CHR vs low dose. Dr wants to keep going up till I can't take it, which is one known titration method.

Below is info I've put together from my best effort to figure the latest dosing ideas. It's dense, long, but lots of info. I plan to discuss with Dr.

I've spent several days on this effort.

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Basic summary is:

-CHR (complete blood count response) is clearly associated with allele (AB) reductions. Three separate studies (below) found this result. If PR (partial response) or none, allele reductions are signif less likely.

-For Jak 2 homozygous type mutation, AB reductions occur with low doses and don't improve with more. Heterozygous Jak 2 requires higher doses to get AB reductions. Homozy is likely for alleles over 50%. My basic understanding Homozy is both parts of DNA pair carry the mutation, heterozy has only one of the pair mutated. We are not normally tested for this, but based on this result it seems anyone with homozy really needs to discuss INF.

-CALR type 2 responds better to INF than type 1 in one report, but this result is not as consistent as the other findings here.

Marrow improvements are possible in INF, but response duration may be limited.

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Details:

Several images are posted, see "replies" where I added more images after the one here.

From

ncbi.nlm.nih.gov/pmc/articl...

See image here.

<<Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001)>>

See Fig. A here for Jak2, the short, low blue box vs the higher red one is a strong signal that CHR matters. The No-CHR boxes, green and purple, are more scattered and with less effect.

<<We found that patients with JAK2-UPD (Homozygous) treated with IFNα had a greater decrease in JAK2 VAF than JAK2-mutated patients without JAK2-UPD (heterozygous) >> See discussion above.

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Dose Escalation, see next image in reply 1.

I like this method that balances blood response and molecular response to decide dose increases. But I'm lame with flow charts.

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Another study also shows better AB reduction with CHR, with a box plot similar to the 1st one above, suggesting a pattern.

ashpublications.org/blood/a...

It goes to 4 years end of study. See image #3 in reply below. In Fig. A note the same squashed box in the right side CR (blood response) plot at 4 years vs the starting CR box far left. The PR and NR do not show much AB benefit, same as above report.

A separate finding has <<patients with CR had a significantly lower VAF at baseline compared with those who achieved NR >>

Fig. B is visually compelling, good AB reductions trend strongly blue (CR) consistent with the box plots. <<...the chance of achieving CR is 15 times higher for patients with a reduced JAK2V617F allele burden>> It seems reasonable that the reverse is true, having CR on INF is a sign that AB reduction is happening. (any statistics people here to figure that one?)

Notable quote <<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.>> So feedback to dosing titration is critical vs just go for max.

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5 year follow Up ContiPV (Besremi trial)

nature.com/articles/s41375-...

and

Supplement:

static-content.springer.com...

<< in patients treated with ropeginterferon alfa-2b for ≥5 years showed a clear relationship between allele burden and hematologic responses>>

<<Dosing increased until blood counts normalized.>>

<<… a clear relationship between allele burden and hematologic responses>>

The equivalent dosing we take is 1/2 that shown below since we are taking Bes per 2 weeks, so the data below for us is a range of 125 to 250.

This statement needs more background but see the table here, where no dose level shows clear advantage for enabling <10%. << Dosing level (derived 4-weekly dose of <250 µg, 250-500 µg or >500 µg) had no apparent impact on the achievement of an allele burden <10% (p=0.9).>>

Table:

Dose------------<10%AB----->10%AB

<250 µg---------2 (5.4%)------2 (6.9%)

250-500 µg----11 (29.7%)--7 (24.1%)

>500 µg---------24 (64.9%)--20 (69.0%)

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ncbi.nlm.nih.gov/pmc/articl...

A deeper consideration for INF dose adjusting. This is from the INF experts Weill Cornell Medicine, but is 2016 vintage with a small sample n.

<<At our institution, we encourage annual marrow examinations of our PV patients to assess cellularity and degree of fibrosis as one of the parameters we use for maintaining or changing the dose of interferon therapy.>>

<<In all patients with CMR, we observed progressive or persistent hypercellularity or fibrosis by marrow examination>> This is different from the results in the next reference below.

A vote for higher doses but without apparent data to support it:

<<increasing the dose of rIFNα may retard the progression of disease irrespective of marrow fibrosis>>

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A detailed look at marrow responses to INF: (higher n than the Cornell study above with a better marrow result. This report has lots of info only touched here:

ehoonline.biomedcentral.com...

They did not find a correlation between HR, (blood counts) MR (allele %) and BM-CR (marrow complete response) But I see one in line 4 of table 2 where the BM-CR is well weighted with CMR (complete molec resp)

A focus of this post, dosing did not make a difference for BM response. (dosing normally is as required for HR):

<<No differences in median weekly dose of PEG-IFN-α-2a while on therapy or overall treatment duration were found among patients with BM-CR, BM-PR and BM-NR.>>

<<All 13 patients with BM-CR have initially achieved HR>>

BM and HR response could matter:

<<Progression to overt MF and AML occurred in 5 patients (9%; 4 MF and 1 AML), and none of these patients had a BM response…None of the 4 patients were in CHR at the time of progression to MF>>

For discontinued pts<<Only one patient has lost his BM-CR after being off therapy for 24 months, he has also lost his CHR and best MR>>

<<long-term therapy with PEG-IFN-α-2a is not only able to induce CHR and CMR, but could also lead to complete normalization of BM morphology in a subset of patients>>

<<PEG-IFN-α-2a was capable to completely reverse BM fibrosis in up to 22% of patients, which is higher than previously observed by other investigators [23, 26]. BM responses were achieved after median time on therapy of 48 months, confirming the observation that a long treatment duration is necessary to achieve such a response.>>

Correlation between BM and MR:

<<significant reduction in BM cellularity in patients with PV who achieved CMR>>

Repeating this idea: <<none of the patients who had achieved BM-CR progressed to overt MF>>

Most INF data we've seen goes to max ~ 7 years, what happens after that?:

<<PEG-IFN-α-2a is capable of controlling the disease only for a limited time>>

[EPguy]

Image #2

One member pointed out that this image is not in the references here. It's buried in "extra data"

If you want to see the source, check these notes:--

It's a word doc within the reference:

ncbi.nlm.nih.gov/pmc/articl...

it should look like this near the top of the report. (just under "associated data")

On page 14 of the Word Doc.

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Associated Data

Supplementary Materials

advancesADV2021004856-suppl1.docx (1003K)

GUID: D8FAC5F7-A983-43E9-B359-41F9CB8C5C5A

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Dose Escalation idea

[EPguy]

Image #3

2nd study CHR vs AB

[Joetcalr]

Thank you for this, I will come back to it as there's so much here. I've made a note tho to ask whether I'm calr type 1, or type 2, as getting a poor response to inf Alfa 2a.

[EPguy in reply to Joetcalr]

I forgot to detail where this info came from.

<<INF... preferentially targets CALRins5 (type 2) than CALRdel52 (type 1)>>

mpn-hub.com/medical-informa...

This result does not seem as solid as the multiple matching results seen in the Jak2 correlations in the reports.

For the CALR type effect in fact there is a report with a differing conclusion:

ashpublications.org/blood/a...

<<First, we show that peg-IFNα induces high rates of HRs in CALR-mutated patients whatever the type of CALR mutation >>

and an unsatisfying note:

<<whereas %CALR remained stable (in some pts) or even increased despite several years of peg-IFNα in others. No predictive factor for MR could be identified in this study.>>

But either way it seems worth knowing your CALR type for reference. Also you should know which non-driver mutations you have with a NexGen Gene study:

<<we observed a poorer MR rate on CALR mutant clones in patients harboring additional mutations>>

[Paul123456]

My experience with Pegasys has been that important to be patient. My WBC halved from 11 to 6 within a month. My platelets also dropped c. 50% over next two months. However RBC remained stubbornly high so I gradually increased dosage from 45 mcg to 120 mcg about a year later. This did the trick but resulted in haematological overkill. My WBC was under 1.5 and RBC borderline low. It did reduced my JAK2 from 80% (and rising fast!) to under 10%.

Since then I’ve been cutting dosage to try to at least get my WBC up to 2 and RBC c. 4.5. Was on 35 mcg every three weeks until JAK2 and bloods spiked up in January.

Currently on 45 mcg weekly and will update you in a few weeks when more data. However I’m now thinking that doubling up NAC was coincidental with the spike. I think a few months at 30 mcg every few weeks was simply too low to keep a lid on the disease.

I’m trying to regain molecular control without haematological overkill. At least my WBC spiked in tandem so hopefully this gives me a bit of wriggle room.

However balancing JAK2 versus WBC is a tricky Goldilocks act!

What do you think is the timing delay/correlation between WBC and % JAK declining?

[EPguy in reply to Paul123456]

Thanks for the details. You note RBC counts. How is your HCT? This one seems to lag WBC for many on INF.

It would be reassuring if the NAC is not a direct cause of the AB spike. At the least it seems the lower NAC dose is ok, is that right? I've been taking only one NAC/day to be cautious. Also the NAC with 2/day of curcumin have correlated (maybe caused?) improvement in symptoms.

Your note on hem vs molec control is related to the studies here. In fact you note both AB and bloods rose together in January. As I mentioned a while ago, few pts get to measure AB so often so your results are interesting.

The studies here refer to CHR which normally means at least all three of PLT, WBC and HCT being in range. Is there info here or elsewhere on AB correlation to just WBC?

For your decisions on PEG dose changes how closely or in what way do you discuss the changes with your Dr?

[Manouche]

Nice work!..But your haem is right to complain about your change of posology in the absence of medical advise/consent.

[EPguy in reply to Manouche]

You're right, my self test was my science side taking over my patient side. I am happy to have the info I got, but the resulting stress is a downside. But I also don't like to bug him too often.

With the separate info in these study references I think there is a good case for not blindly titrating to 300, which he indicated could be his plan. Rather we should maintain tight feedback to my responses.

[hunter5582]

Thanks for the additional info. We are all working to find the Goldilocks zone for dosing. We can hope it will be more clear as more people have experience with Besremi but I think it will always be an individual thing. Our individual MPN presentation and response to Besremi will always be different.

I agree with why you wanted to try the dose reduction. It was well thought out but I also agree about letting the doc know about dosing variations in advance rather than after the fact. We do not need to ask for permission but do need to let the docs know what we are planning to do. That allows for more nuanced and informed decision making.

In reading what you just reviewed, it sounds like molecular remission may be related to the dose needed for a complete hematologic response rather than a higher dose at some absolute number. Is that how you read the data? Interesting that there may be a difference between the response when the JAK2 mutation is homozygous rather than heterozygous. It is of note since there is some research indicating that the homozygous JAK2 mutation tends to be associated with erythrocytosis and the heterozygous JAK2 mutation tends to be associated with thrombocytosis. The underlying genetics are complex. I suspect the presence of non-driver mutations will also play a significant role in how people respond to Besremi.

Thanks for posting the information.

[EPguy in reply to hunter5582]

Your note "molecular remission may be related to the dose needed for a complete hematologic response" is what I get from these. But it's also the answer I want to see so that makes me hesitant to settle on that answer. If we can simply monitor for CHR and get that correlation to MR it simplifies the goal of INF therapy.

The second part of your note "a higher dose at some absolute number" was my key motivation for doing this research since Mr Dr indicated dose size as our goal. Better to stop at CHR. But a complication we're seeing here for many is the WBC/HCT imbalance where CHR gets messy.

I presented the idea about homozy and heterozy to Dr a while ago. His 1st reaction was this variable does not make sense in a somatic mutation since these are nominally germline features. But I often see this idea:

ncbi.nlm.nih.gov/pmc/articl...

<<Acquired uniparental disomy (aUPD) is a common and recurrent molecular event in human cancers, which leads to homozygosity for tumor suppressor genes as well as oncogenes>>

and recently read that Jak2 often undergoes this change.

[hunter5582 in reply to EPguy]

I think it is pretty well established that the JAK2 gene can present as either heterozygous or homozygous. What exactly it means is still not entirely understood. I suspect it does have significance in MPNs as in other cancers.

There is a fundamental philosophical choice to make with treatment. Do we use the minimum amount of a medication needed to control symptoms and maintain quality of life? Or - do we use the maximum amount we can possibly tolerate seeking the greatest putative benefit despite the greater risk of adverse effects and potential decline in quality of life?

It is not a black-and-white decision. It has to be based on the patient's treatment goals, risk tolerance, and preferences. My approach is to always prioritize quality of life as I define it. Extending or preserving life is always a secondary goal, contingent on the preservation of a high quality of life. These are not usually conflicting goals, but they do shape how I make decisions. I always make sure my care team understands what the priorities are.

It will be interesting to learn more as we all move forward and gain more experience with Besremi.

[Elizka]

Amazing. I'm doing a deep dive now!

[Dan39]

Is this also applied to Primary Myelofibrosis?

[EPguy in reply to Dan39]

The first study looked at all three MPNs, but MF was fewer than ET PV patients (25 PMF vs 161 PV, ET). The other two studies looked at just PV, ET. So implications for MF are less than for PV, ET, while this does not preclude MF relevance.

From other info I've seen, INF has potential benefits for earlier or lower grades of MF, it can stop or reverse fibrosis in some cases. More advanced MF sees less benefit. This is just my recollection.

There is this study that combined INF with Rux for INF resistance patients. It included MF specifically and is interesting, with <<Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions.>> while <<The MF patients were in an early stage of disease,>>

ncbi.nlm.nih.gov/pmc/articl...