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>>
