INF vs HU, histological response (fibrosis, celluarity, etc) Surprise Result, and Possible Reasons

[EPguy]

In this recent post "Phase 3, Trial ..." there was an unexpected result that HU was more effective than INF on marrow remission. Many of us, including the authors of the study, were surprised, esp as some of us plan to switch to INF.

healthunlocked.com/mpnvoice...

ashpublications.org/blood/a...

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Looking through studies we've seen before including here in "Long Term..."

healthunlocked.com/mpnvoice...

ashpublications.org/blood/a...

there is a figure I've not noticed before, see here. Like the survival and progression data in the report it's part of, it shows INF to be best, in the long term, with HU also good.

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But quite interesting, in this chart, INF is clearly inferior to HU in the early years (0-2) to (2-8) (500% rise in progression INF vs ~130% HU) but provides remission to years (8-14) (33% remission INF vs 40% progression HU)

** "Phase 3" went only 1 or 2 years so maybe this is the answer to the surprising result; the study caught only this early inferior marrow INF effect. As is familiar, INF needs longer studies to measure properly.

Some other of the discrepancy between "Phase 3 Trial" and "Long Term INF" may be from the different things measured. "Phase 3" measured a broad category of marrow results, (histopathological) while "Long Term" measured only fibrosis. My recent searching indicates that INF has less effect on cellularity than fibrosis. If Long Term INF is relevant, fibrosis is an important survival/progression measure, while celluarity is not addressed here in survival/progression.

In a separate note after 14 years, INF starts to rise faster than HU. Maybe allele on INF rises too after that much time?

[Paul123456]

Had many/any of the INF cohort had prior HU treatment. ie INF was their second line of treatment which would indicate that they had a more aggressive MPN?

I was swayed to INF because Dr Silver has used it as a first line early stage treatment plan for 30 years and he therefore has unrivalled data to support his claim that INF is superior to HU re deferring progression

[EPguy in reply to Paul123456]

I checked the supplementary info for the "Phase 3" trial, it says for inclusion: <<Never treated with cytoreductive drugs except hydroxyurea for up to 3 months maximum >> Prior INF was also not allowed.

So it seems patients were relatively fresh in treatment.

The Phase 3 trial's authors' surprise suggests a bias toward INF, so the contra result may be more solid. But as above there seems a plausible explanation for the surprise.

Agree Dr Silver is a strong supporter of INF, for good reason. I discussed the Long Term Study by Silver's group both with my Dr and one of the study's authors. My Dr is suspect of a retrospective study, while the author said they designed the study carefully and the very strong results compensate for possible remaining bias.

I'm also biased toward INF based on the total info we have and hope to be on Besremi soon. But I have been discovering that HU is not necessarily dead end that I have thought as it is clearly better than PLB-only in both studies, including for long term in one.

[FG251]

Great work, as always - thank you.

[Meatloaf9]

Thank you for posting this, very interesting. Do you know of any literature explaining the role of cellularity in disease progression/transformation. I was only told that cellularity should be about 100 minus your age. Based on that mine should be about 30 but it is 50-60, not sure what that means long term. Maybe a study of a combination of INF and HU (low doses of both) would yield interesting results based on this study?? What do you think?

[EPguy in reply to Meatloaf9]

I'm not very knowledgeable on cellularity.

From pathologyoutlines.com/topic...

<<Cellularity averages 79% at ages 0 - 9 years, 50% at ages 30 - 69 versus 29% at ages 70 - 79 >>

This is consistent with your numbers. My Dx only says "BM showed hypercellular marrow" but no value. I get the idea that cellularity is used for Dx of which MPN but is less relevant to prognosis than fibrosis. Any better info is most welcome. I plan to ask my Dr about it.

I agree about the combo. HU does have some unique features. I don't know of any studies on that. The switch to Besremi does include a dual dose period for HU patients, but it gets phased out.

There has been a Ph 2 study of Rux with low dose INF

haematologica.org/article/v...

I seems mostly relevant for INF resistant or refractory, and I don't see obvious advantage in this report vs regular INF therapy, might be missing something. I asked my specialist, who was involved in Rux research, about it but he won't do it without more data. But I wanted the reverse, low dose Rux to better preserve immune condition.

As I've posted elsewhere, INF plus (something) is likely to be in our future. One could be INF+ATO being amazing for mice with our disease, a quick apparent cure. I posted on it before. Long time if/when we could see this one however.

[Meatloaf9 in reply to EPguy]

Hi again,Several times in the hematologica article cellularity and fibrosis are mentioned together which leads me to believe that the higher the cellularity the higher the risk of fibrosis, I may well be wrong, I hope so.

My specialist told me not to put much stock in mice studies. He said that some leukemias have been cured in mice but not humans, but I guess you have to start somewhere.

Thanks again for posting all this info and for sharing your knowledge.

[Bluetop]

Thank you for all your analysis! With reference to your last sentence '...after 14 years INF start to rise...' which study did this come from? (I intend to be in this for the long-haul!!)

[EPguy in reply to Bluetop]

That is the 38% value at the right of the graph at >14 years. The graph is from the link at the top post, Long Term:

ashpublications.org/blood/a...

Unlike PHL and HU, INF had an undesirable reversal in the fibrosis score. This is another different unexpected result, but still clearly INF remains better than the alternatives after its reversal. Note it is >14, so the average of this group is not exactly 14 years, but something longer.

See Fig. 1c from the same report, I've posted before. This seems the most relevant as it tracks actual MF cases rather than the state of the marrow. But the graph at top was most useful to explain the unexpected result regarding marrow (not MF progression) that started this thread.

As always this stuff is complicated and there are almost as many ways to see it as there are observers.

MFS Long Term

[Bluetop in reply to EPguy]

Ah, got it. Thanks. Yes, very complicated, but the more I look, the more questions I have, which is good. Thank you for your explanation and time.

[pard77]

Thanks so much for posting, this is very interesting! I am a bit of a newbie so please, what is PHL? And MFS? Thank you!

[EPguy in reply to pard77]

Sorry for the abbrevs, so easy to get lazy.

PHL is phlebotomy, MFS is myelofibrosis free survival.