Interferons as the First Choice of Cytoreduction in ET and PV

[Manouche]

 »Interferons are a group of cytokines with immunomodulatory properties and were the first immune therapies used in the treatment of cancers, including hematologic malignancies. Use of standard interferon alfa-2b for MPN treatment has been limited by its difficulty in administration and adverse effect profile. There has been a recent resurgence of interest in interferons for MPNs given the development of pegylated formulations, including pegylated interferon alfa-2a (Pegasys), pegylated interferon alfa-2b (PegIntron), and ropeginterferon alfa-2b (Besremi). The main difference between pegylated interferon alfa-2a and pegylated interferon alfa-2b is the structure of the polyethylene glycol chain, with a branched versus a linear polyethylene glycol chain, respectively, attached to the interferon. This affects the half-life, volume of distribution, and absorption of the 2 drugs, resulting in different dosing schemes. Both pegylated interferon alfa-2a and pegylated interferon alfa-2b have multiple pegylation sites and therefore multiple isomers. In contrast, ropeginterferon is a monopegylated interferon consisting of only one isomer. The pegylated formulations allow for less frequent administration, leading to improved tolerability. Recent data have also shown that interferons have preferential activity against the hematopoietic stem cell clone, with the induction of molecular responses and even remissions in some treated patients. This finding suggests a potential for disease modification that has not yet been shown in any other available treatments, including hydroxyurea and JAK inhibitors »

jnccn.org/view/journals/jnc...

[hunter5582]

This is consistent with the literature we have seen previously. Certainly consistent with the experience with the PEG-IFNs that many of us have had. Thanks for posting.

[Aneliv9]

can interferon cause extra mutations if can't control someone's blood counts?

[hunter5582 in reply to Aneliv9]

I have never heard of the IFNs causing additional mutations. There are other meds that can potentially cause additional mutations. The IFNs are the one treatment option we have with the most support for preventing progression of MPNs. That is not to say that there cannot be any adverse effects. The bottom line is that all medications and supplements can have adverse effects. If something is biologically active enough to help, it can also hurt. We always have to weigh the potential benefits against the potential risks. That is true of every choice, including the choice to not use medication to treat MPNs.

The good news is that we have choices. Treatment options have improved greatly. People with ET (and now with PV) have the potential to live normal lifespans. That is most certainly my plan.

All the best my friend.

[FG251 in reply to hunter5582]

Presumably this is ‘correlation’ not ‘causation’?

If PEG isn’t working, it could indicate the presence of certain non-driver mutations, no?

[hunter5582 in reply to FG251]

Not sure which correlation you are referring to.

I suspect that there are a number of reasons PEG might not work for some. Non-driver mutations would be one possibility. The nature of the driver mutation would be another. There may be additional genetic reasons as well.

[FG251 in reply to hunter5582]

Sorry - yes, non-driver mutations affecting PEG’s effectiveness. As you say, there may be other reasons too.

Whilst I think of it, do you know of any protocols regarding the spacing of doses? I’ve been in CHR for several months, so it would be nice to move to 10/14-day injections instead of weekly. I see a lot of people on this site have wider dosing schedules other than weekly - for PEG, not just for Ropeg…

[hunter5582 in reply to FG251]

The only formal protocol I know of is for Besremi. When hematologic stability is maintained for 1-year, dosing can be reduced per the protocol. I believe you are correct that with Pegasys there are prescribers backing off the weekly dosing sooner than 1-year.

[FG251 in reply to hunter5582]

Thanks, I’ll mention it at my next appointment on Nov 7!

[Manouche in reply to FG251]

Spacing the dose might affect the molecular response. That’s why some haems prefers to play with the dose rather than with the time interval.

[FG251 in reply to Manouche]

Thanks, that’s good to know. I have no problem (yet) tolerating 45mcg, so it was really a matter of wanting to space them for the sake of convenience (travelling, etc)!

[EPguy]

They say that PEG has had a high discontinue rate vs Ropeg (Bes)

"Ropeginterferon seems to be better tolerated than pegylated interferon (incl PEG) , with an 8% discontinuation rate in the PROUD-PV study" while "40% discontinuation rates by 24 months were seen in the DALIAH study" (which did not test Ropeg) and "discontinuation rates with pegylated interferon were high in the MPN-RC 112 and DALIAH trials"

I recall DALIAH was not as positive result as some other IFN studies. But many IFN studies are limited by short duration.

So as we've seen on the forum, if PEG is not working out, Bes is worth at try if it's available. But a few members have actually done better on PEG.

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We've heard about stopping therapy " Unlike with hydroxyurea or JAK inhibitors, there is some evidence that patients can discontinue interferon therapy and still experience a sustained hematologic response"

But some reports are concerned that even with CHR, marrow responses could be affected by stopping.

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This part is of interest to me:

"Patients with high but not low baseline symptom burden saw significant improvements in symptom scores with treatment" I too often fit that high category, so maybe I have something to look fwd to.

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This statement:

"The main difference between pegylated interferon alfa-2a and pegylated interferon alfa-2b is the structure of the polyethylene glycol chain"

I think may be a distraction. Alph-2a differs from 2b only in an amino acid substitution at one location (I found this after much searching, I will edit with these details later) Where the Peg is added is a separate issue, as seen by Ropeg and PegIntron both being 2b, but with very different Peg attachments and effects.

Edit, add details:

"The difference between IFNA2A and IFNA2B is in the amino acid present at position 23."

prospecbio.com/interferon-a...

[Bluetop]

Thanks for this. Interesting to read about the differences between interferons