Dr Verstovsek on Besremi and Outcomes: targetedonc... - MPN Voice
Dr Verstovsek on Besremi and Outcomes
Nice summary of treatment with Besremi
Nice summary, thanks for the discovery.
He said the study went for 7 years, but the published mean allele results are stuck at 5 years (see the very familiar plot here) . I'm still hoping they publish at least to year 6.
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On a separate aspect:
ashpublications.org/ashclin...
"At six years, 20.7% of patients in the ropeginterferon alfa-2b group (n=19) achieved a JAK2V617F allele burden of less than 1%"
He notes 14% at 5 years has less than 1%AB.
- So from year 5 to 6 it improved from 14-21% having less than 1%AB, a nice trend.
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His reference to 14% having undetectable is for 0.01-1%AB (from a word doc ref I have posted) In the same doc, 5.4% had less than 0.014% AB. So they are calling up to 1% as undetectable, while 0.014% seems more likely to be such a level with modern Jak2 tests. More detail from Dr V here would be good.
In this same doc, as I've posted, the best responses correlated well to CHR.
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He did say over time "if we continue like this, (14% undetectable) and you can apparently with this drug, then more and more patients will have a molecular response" meaning over more time more patients than 14% will have the lowest AB levels. I assume he's using the jump to 21% at 6 years for this statement.
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He implicitly saying that PEG is included in the set of poorly tolerated IFNs. "Usually in clinical studies with prior versions of interferon is only about 3 to 5 years on average duration" I believe we have members doing fine here on PEG well over that period. But my info on Dr. V suggests he's only recently been more enthusiastic about IFN, maybe because of Besremi's approval.
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He said "(MF and AML progressions) which are long term complications not too many people talk about" I'm not sure who are these "people" but among us patients there's not much higher on our list than that. He might mean "we didn't used to talk about it because there was nothing we could do about it"
Here you can see from Dr. Kiladjian's presentation that Pegasys beat Besremi by enabling 30% of patients to achieve complete molecular response (jak2 AB zero or near zero) after 4 years of treatment:
Here you can see from Dr. Kiladjian's presentation that Pegasys beat Besremi by enabling 30% of patients to achieve complete molecular response (jak2 AB zero or near zero) after 4 years of treatment:
But we still don’t know the full clinical implications of a CMR in terms of preventing disease progression, do we?
I've never heard of a CMR achiever progressing to MF if they continued to take a disease maintenance dose of Pegasys interferon (around 22.5 to 45 mcg every 3-4 weeks).
Delighted to hear that. Why are the haematologists so coy, then? I achieved a CHR within a matter of weeks and, 35 weeks in, have platelets well below 400 (322), whilst maintaining haemoglobin (151) and without neutropenia. I’m on 45mcgs a week and would happily continue that for life (I’m 54) if I thought it would prevent post-ET MF.
Sounds like you started Pegasys early in your disease and so 45 mcg has been sufficient to normalize your blood counts and do it quickly (within the first year). You probably have decades of progression free life ahead of you assuming no seriously detrimental secondary mutations ever develop. Interferon seems to inhibit most of them, but not all.
Thank you! Yes, I was diagnosed in Dec ‘20 (JAK2+) and took HU for just over a year before switching to PEG in Jan ‘22. I hope - as we all do - to be progression-free. With a bit of luck, the newest drugs will be even more effective and will be available before progression is more likely.
According to the PEG study I linked here, there was no progression benefit, while the Bes study had a benefit. But with such small numbers,it's hard to be confident in any of these results.
But these continuing vague or incomplete results I believe are a reason Drs are still not all on board.
This looks most interesting, lots to think about see details.
I get from here that:
-PEG has better or faster CMR
-Bes has better progression
-Studies aren't comparable, being of very different eras and limitations
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I think this is the report it comes from:
citeseerx.ist.psu.edu/viewd...
It does look quite compelling, see box plot here. But this report is from 2008, so there may be limitations since Jak2 was still very new at the time and measuring allele was just getting started.
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Consistent with allele measuring limitations of the period, I think this is a more recent follow up on it, not sure:
ncbi.nlm.nih.gov/pmc/articl...
"However, studies have shown...the presence of the JAK2V617F allele at very low levels in more sensitive assays (level of detectability, 0.1%) in patients who achieved a CMR with PEG-IFN-α. " "In addition, because the JAK2 testing was not performed with the most highly sensitive method, patients with CMR may have minimal residual disease that was not detected with our assay."
So this PEG study was not sensitive to even 0.1, while modern studies can use 0.01. The Ropeg study used current methods and broke down to fine sets of 0.01, 0.014, 0.1% etc.
Good PEG result: See next reply for a plot I've posted before on this PEG study, the CMR is very good, subject to the limitations at the time. It's also clear according to this plot that if you don't get CMR by 2 years, it's not going to happen. For Bes it seems more drawn out, for better or worse.
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One downside on this PEG study is it seems they found no difference in progression.
"The rate of transformation to MF/AML did not differ when compared with a cohort of age- and gender-matched historical patients not treated with PEG-IFN-α-2a "
The Ropeg study found a clear benefit on progression, but for all n is not so large so hard to be certain.
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My take is PEG looks better here for CMR and inferior for progression. But PEG & Bes have not been compared in contemporary studies so we can't conclude much with certainty. In contrast, Bes and HU were compared directly in time and cohort (The ropeg study) so we know with good confidence how they compare.
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I do suspect that IFN-alpha-2a (PEG) is better than IFN-alpha-2b (Bes) but I assume Bes maker chose 2b for a good reason. I've actually asked them, but of course no answer.
2nd plot form PEG study. It shows the excellent result for CMR, with the measuring limitations discussed above.
This and a related plot indicate a loss of MR for no-CMR after 5 years. The Ropeg study has not released the plot for after 5 years, I hope they do.
It’s enough to make your head spin! Thanks for being so tenacious. As you’ve said before, PEG is a good place-holder therapy, at least, whilst we’re waiting for better drugs to enter the scene.
My skinny head has a high ratio of spin/inch.
I recently saw a refresher on the idea that IFN has only a mild preference for targeting the mutation over the wild (good) type, hence the slow action. I've known this but it's clear we do need some sort of extra kick to IFN.
It's interesting that IFN for Hep C was normally a combo with Ribavirin. We MPNs have not been offered our combo yet. This would hold our place a little better.
Perhaps Bomedemstat will be one such drug to be used in combo? Statins have also been cited as potential enhancers. Well, I’m on one anyway!
I expect Bomed would be limited to those that don't get CHR. But I've heard about statins also. I was half hoping to need them, but my heart calcium scan came out clean.
I've been reviewing the NAC/IFN studies. A pattern seems to be NAC made no diff for Hepatitis therapy, but had potential effects with liver cancer. So a favorable tilt to a cancer benefit. NF-kB comes up often with MPN and NAC and other relevant things.
Regarding liver cancer: "NAC increased the toxicity of IFN-α through an additive induction of apoptosis and a synergistic decrease of NF-kB expression in HCC cells, pointing to different targets being modulated by IFN-α and NAC."... " These results are in agreement with the poor response observed clinically, in which only around 30% of the patients respond to treatment (on IFN only). These data confirmed that development of alternative compounds to treat HCC, such as NAC tested here, is necessary."
ncbi.nlm.nih.gov/pmc/articl...
There was a small clinical study I recall also.
The current NAC study will not look here since IFN patient are not qualified.
Great discussion. Thank you for the continued conversations and comparisons. It is always interesting to see the advances being made and the hope it creates. Someone will crack the code one day. 🍻
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