Here are my notes on Mesa's Talk for quick summaries:
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Mesa Talk
15 years of slow progress borrowing drugs from other diseases
Two big things:
cml was 1st drug for a targeted small group.
Discovery of Jak2
New therapies:
Ropeg. INF “interferes” with viruses. So it was used for hep c virus.
INF is more active against disease vs HU
Mesa did early trial with PEG but a small study.
PEG is more uncertain than Bes bec Bes is FDA approved. Not sure about PEG long term avail
Side Effects: He has not seen depression a big issue
Rare autoimmune
Most common: is liver function tests, requires dose adjust
Overshoot blood counts
Flu like symptoms, gets better over time (This is good to know)
50% of Cancer drug use is not FDA approved.
Many MPN drugs were not approved, now we’re getting more FDA approved MPN drugs.
If you’re starting INF, skip PEG, go to Bes. If you’re on PEG, maybe leave it alone.
If patient is doing very well on HU maybe no need to change.
Bes For ET/MF? Ongoing clinical trial for 2nd line for hi WBC counts only.
Ropeg should be just as good for ET as it is for PV, using experience of PEG
Ok to use Bes for early MF but not likely to get insurance paid
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MF Jak2 inhibs
There are now 3 FDA therapies. In 1991 there were 0.
All started with Rux, approved 2011. Improve spleen, symptoms, but more than that:. One pt on Rux for 12 years. Should have survived 3 years. Was progressing after 12 years.
Advantage of Rux might include inflammation.
MD adrerson showed longer survival on Rux.
But still no cure
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Fedratinib approved 2019
PLT >50,000
Side effects, more GI vs Rux. Treat GI before starting (incl nausea- if it never starts, you’re better off) Must watch Vit B1 and take it if required.
High risk MF both Rux and Fed approved 1st line. But Fed is usually 2nd line
But unmet needs before Vonjo:
Cytopenic MF, this is usually PMF vs 2ndary. Higher prog risk.
Pancritanib (Vonjo) It works with low PLT, address the other Jak-i’s that cut PLT too much. IRAK1 is inhibited by Pan.
Mesa led one Pan study
Selected dose of 200.
PLT tends to increase on Vonjo, bec bone marrow gets better, and cuts transfusion
Side effects, similar to Fed.
Pan is special, only med for low PLT pts other than SCT. But don’t leave Rux if your PLTs and other is ok, no advantage. But use might change.
Don’t use Pan for ET/PV, unlike Rux which can use for PV.
FDA approval on any condition allows “appropriate” use elsewhere, but Ins is an issue.
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Bomedemstat
LSD-1 HPSC and megakaryocyte fixer.
Lowered PLT for those failed HU.
GI side effects, adjusting dose for this in trials.
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Hepcidens
Rusfertide
Decrease phlbs, symptoms.
Other Hepcidin inhibs under dev.
Sapablursen
Another hepcidin underway, different pathway.
Momelotiniob
Seeking approval
Non- inferior to Rux
Anemia + symp
Compared to danazol
Will see data in June
Why not stay with phlb?
Inconvenience, feel lousy afterward, iron deficient. Old tech, George Washington had them. Uneven blood levels too extreme changes.
Optimize Jak-i
Rux is still best front line for standard MF patient, if PLT counts ok
Fed is best if Rux not stopping proliferation in MF
Vonjo good for low PLT. If you failed the others
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Non Jak – i’s in MF
Stay on a Jak-i, esp Rux, don’t give up, but may add something non-Jaki to it.
More MF trials than ever right now.
Various agents to add to Jak-i.
Start with combos?
Certain other drugs (eg pelabresive, Navidoclax) in trials for combos.
Imetelstat being studied for Rux failures.
Low Risk MF
Ropeg being tested
If you fail Rux then you’re higher risk
Standard Tx is Rux, but ph 3 studies may lead to combos, but extra cost may not be worth, unlikely to be used with all patients.
Blast Phase; get transplant ASAP if it’s an option. If not Rux + targeted therapy (certain mutations eg IDH mutation)
Newer ones start with "M" MIPSS, to add molecular factors. Also there is GIPSS that looks only at genetics.
(these newer ones require NGS gene test)
One patient freaked out after google search.
43% of physician scores were not accurate., tend to underestimate risk
ET: newer scores also use genetics SRSF2, SF3B1, U2AF1, TP53... Over 60, Male, are negative prognostics.
PV: SRSF2, Abnormal karyotype, over 67 years, Leukocytes over 15
Plots here show adding genetics to PV/ET makes for better defined prognosis. (lines are farther apart)
Is BMB, NGS worth it?
-If you're over 60 molec is well worth it (transplant candidate?) Younger low risk less critical, but future therapies make it worth having (I have posted before)
BMB: This provides karyotype, it really helps add info to genetics, and should be done at Dx. She would like to see all patients with base line BMB and it does affect prognosis (high risk may be hidden if only have genetic. ) Esp PreMF vs ET.
Her example patient had medium to high risk depending on score system. She felt ok, but transplant was recommended.
Transplant candidate needs to be in decent overall health. There are many clinical trials to enter if transplant is not avail. This patient could not find a match and her sister did not cooperate. Went to a trial
Inflammation is good when we have infection, but it needs to go away when all is done.
Cytokines (what killed many Covid patients)
Jak2 alleles cause cells to make cytokines. CALR and MPL affect different cell areas but cause the same result.
There are different cytokines in MPN and they cause different symptoms. See image showing which cytokine causes which symptom. (As usual malaise, as opposed to fatigue, is missing. Maybe future therapies can focus on which one we need reduced)
Inflam wears out blood stem cells. MPNs and other blood diseases bad cells become resistant to deletion. Elderly even without MPN usually have some of these mutations.
Aspirin reduces inflammation.
Jak-i's (Rux etc) block the stat path, are anti inflams. INF is the opposite, an inflammatory cytokine.
Jak inhibitors do not get rid of Jak, but Interferons, while being a "Jak activator" actually do rid Jak cells. (Other posts have discussed, my understanding is INF can activate Jak alleles to make them visible to immune system, normal Jaks also become more visible to the immune system but bad ones are eliminated faster)
Keep a good weight, healthy lifestyle, low stress.
"Symptom Burden has a major Impact on the quality of Life of MPN patients" (Many of us know this too well)
Mediterranean diet- Fiber, Resveratrol, Good Fats (Resv supps need care in use)
Med diet reduced symptoms more than USDA diet, but any diet improvement helps.
Blood Cytokines in diet study had no signif differences vs type of improved diet.
Gut Microbiome: MF was different vs PV/ET but no diff MPN (I assume except MF) vs normal controls. MF has less biome diversity.
**Some items of note: ET risk no longer includes PLT counts, Rux time on therapy relates to specific mutations, there is increased promise for treating blast phase MF and AML.
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Jak2, CALR, MPL are all lesions in different parts of the same pathway so can have similar if varied effects. A same mutation can cause very different effects
Elderly get MPN type mutations often. See image here. Note Jak2 is in here. (DNMT3A is discussed in detail in another post)
Jak2 can occur decades before MPN. , example 25-40 years.
More advanced disease has more types of mutations.
Jak2 mutated cells can reside in different locations of blood cell production process, could explain differences in disease details..
TET2 does not affect disease directly. But getting it before Jak2 leads more to ET, after leads more to PV.
P53 affects MPN behavior. Most common in any cancer. Must lose both P53s to get bad outcomes.
**New ET risk ratings: PLT counts are no longer in there. Used to be >150000, now not even listed. Jak2 status is now important.
Same as above data from Ellen Ritchie: progression risk (This seems to be the very latest risk sets)
-PV high risk has SRSF2, Karyotype, >67 age, Leuk >15.
-ET is only by mutation, SRSF2, SF3B1, U2AF1, TP53
Number of patients n is small so all data is with qualifiers.
CALR has best progression prognosis in MF.
Sloan Kettering now sequences 600 genes (I had only 54) This number increases every year.
Risk models don't have the latest genes.
How long can Rux keep working: ASXL1, EZH2, DNMT3 reduce time of use for Rux.
Need more patients in studies, big study starting by MPN Research n = 25,000 (huge in MPN research)
Leukemic progression risk: SRSF2, EZH2, ASXL1, IDH1/2. IDH is big in Leuk xforming.
Mouse model of IDH, confirms IDH + Jak2 is bad for Leuk transformation.
There is a pill for this: "Idhifa" approved 2017 for AML, 30-40% remission, way better than chemo.
Mouse study, Rux + IDHIFA worked well. Now in clinical trial, for IDHIFA mutation with AmL or MF with blasts. The 1st trial based on genetics.
There was a lot packed into the Genetics and Biology of MPNs presentation. It could have been an all-day seminar all by itself if more detail was included. The issue that absolute platelet numbers not being linked to risk of thrombosis in Et/thrombocytosis came up more than once. (Note that it is linked to risk of hemorrhage).
As I recall Dr. Mesa also addressed this quring the Q&A session. There is thinking that the value in cytoreduction for thrombocytosis is not in the absolute number, but in the delta (overall change in value). One of the docs also noted that the cytoreduction platelet target may need to be different for different patients. Some need a lower level than others based on actual symptoms that occur.
Good context, Q&A is missing here. I just posted a new thread on this PLT info since it seems a big change, but also added your extra context.
It is surprising that Rampal has PLT count entirely eliminated from thrombosis. Seems he should have qualified that. In the Q&A it's more grey, as usual.
Maybe tracking the PLT change is a way to track whether the therapy is working for other things also? ie PLT counts are not obsolete. The Bomedemstat trial uses change in PLT as an endpoint for example.
I would agree with the notion that are shades of grey and different interpretations of the "facts." The MPN experts do not agree about everything. That is actually a good thing as it encourages debate that advances understanding.
Unfortunately Dr. Rampal was moving very quickly to get through a lot of material. His presentation could easily have taken all day if we had enough time. I expect he could have given a more nuanced answer with more time.
I think you are correct about using a change in PLT as a tracking mechanism. It is cheap and easy to measure. It does indicate risk of hemorrhage. It also indicates that something is altering the activity of hemopoietic stem cells. There simply is no particular value in PLT<400 in terms of risk of thrombosis. For some people it could be PLT<600. For others it could be PLT<300 (if they still have thrombosis at 400).
We have heard here on the forum that some people simply feel better when their platelets are at a particular level, That actually matters more than the putative risk of thrombosis to many of us. As we move forward, it will be important for researchers to use patient-informed endpoints to measure the success of treatment. There are initiatives underway in this regard. mpnresearchfoundation.org/p...
Good posts, guys! This reminds me very much of my reading around cholesterol levels following my MI. The target for lipid-lowering with high intensity statins is <4mmol/L (I think) or 40% FROM BASELINE (my emphasis). This suggests, presumably, that the absolute number may be less important than the percentage reduction following a cardiovascular event. Would you agree? If so, the fact that my haem wants my platelet count to be <400 may well be consistent with your statement. I had an MI with platelets between 600-700, so a lower count in my case would represent a decent percentage drop. As they were 347 at last CBC, that would represent a reduction of roughly 50%.
I do think that using the delta for a cytoreduction goal rather than an absolute number makes sense based on what we know at this point. It is also abut how the blood cells behave, not just the number of platelets we have present. The issue is certainly about more than just counting platelets.
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Wide ranging Q&A with Prof Mesa
