MAZCD posted a good broadcast on "updates and latest research from the ASH annual meeting." I took some notes and figured it's worth a fresh post.
healthunlocked.com/mpnvoice...
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Some items I found notable:
Claire
HC resistance /intolerance >5x increase of death.
this was noted re Dr Gotlib in- healthunlocked.com/mpnvoice...
Still no source for this, it's a concern. Hope someday we can know what this is and whether the alternate therapies can overcome this issue.
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For Rux:
CHR is important to event free survival, a new finding.
Allele (VAF) reduction of at least 50% associated with superior survival/progression, same benefit as getting CHR. HU did not have this correlation.
See link here for more on Rux and VAF reductions:
healthunlocked.com/mpnvoice...
Durability of MR (VAF reduction) correlates to event free survival and overall survival.
Extra mutations reduce MR
Rux increased skin cancers but no other cancers.
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Bomedemstat:
100% pts had PLT control. This is a big deal if it holds.
Improved fatigue
Some members here in the trial didn't tolerate it however.
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Besremi+ Rux for MF:
Very good spleen and allele reductions. But added mutations reduced allele response.
Better tolerance of IFN high doses
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Pelabresib + Rux
Good allele reductions.
Megakaryocytes were normalized.
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Navoticlax + Rux had good allele and spleen. Less sensitive to added mutations.
One study of Jak-is showed that improved marrow did not help other criteria.
Momelotinib helps anemia by acting on Hepcidin. (same target as Rusfertide)
Adam
MPN starts with one single mutated stem cell. Clones are the copies of this one single cell. Additional mutations work the same. This is a clear definition of "clone" we've discussed a while ago, with the single cell source being clarified. But brings the question, if our VAF reduction is other than every single mutated cell, might that one remaining cell start a new clone line?
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INCA033989 is the new CALR antibody for immunotherapy.
CALR is exposed on the exterior cell surface, an opportunity to attack it via immunotherapy. Doesn't work on Jak2. Fixes everything in CALR mice, blood counts, marrow.
Phase 1 starting this year in UK. It's for real now.
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For MF anti-Gal-1 antibody is near clinical trials.
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Navitoclax + Rux has fast MR in some MF pts. This study showed > 20% allele reduction had 100% survival at 36 months. Similar to the Rux study of MR vs benefit.
He says MR will soon be a normal clinical goal. Most of us are ready for this.
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Q&A
Can the current immune therapy work on Jak2? No. But there is research to address Jak2, including looking for any effect on the cell exterior from the Jak2 inside it. I recall some work to pre-treat in some way to force the Jak2 alleles to reveal themselves.
Claire said Rux ability to reduce Jak2 is important new data, but other mutations are less responsive.
Why not monitor VAF routinely? If on HC, there may be no point. But Adam says it is becoming a thing, implication is do it for therapies that might affect it. He suggests 1 test/year. No added cost to report VAF since it's already in the tests. Not sure what this means.
If you stop HC, blood counts will go back up. In contrast IFN can have prolonged response.
See my own partial experiment on this:
healthunlocked.com/mpnvoice...
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HC will not reduce VAF in a durable way.
Full genetic (NexGen) should be limited to Dx to set the risk. May repeat it if there is a large change. Some pts don't want to know so they don't get NexGen.
ASXL1: correlates to increased progression risk, but requires context to know this.
There is now a clear list of which mutations are risky for progression. (not provided)
