Ruxolitinib Versus Best Available Therapy for Polycythemia Vera posted by Manouche

[EPguy]

Manouche posted the very new Majic-PV trial.

Some thoughts (sorry it's not better organized, I'm not top of my game these days):

Rux is looking similar to IFN for allele reductions (My Dr sort of said "I told you so")

This like most other Rux studies have been handicapped by selecting for HU intolerant/resistant pts.

More than one study now shows Rux can reduce allele quite well and that these reductions are beneficial. Monitoring VAF is recommended. IFN studies have not made this beneficial connection so clearly (doesn't mean there isn't a like one).

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Details:

All pts were intolerant or resistant to HC, same as for the earlier RESPONSE trial. It should follow that any responses on Rux are proportionately more impressive vs pts not selected for HU intolerance. The 2nd option, not so selected, is being studied now in the new RuxoBeat trial which seems to show better hematological results so far at 6 months, but not easily comparable.

The Figures here show:

A-molecular response. Lots of red pointing down; this is good and indicates Rux is doing well to reduce mutations and is not so different from the equivalent IFN plots, as supported by this note for a separate study:

" Data published from (the earlier RESPONSE) study also suggested that molecular responses can occur (with Rux), perhaps to the same extent as with IFN"

ascopubs.org/doi/full/10.12...

The blue lines pointing down, esp the long ones, could be disproportionately the IFN cohort since HU cannot do this past ~ one year.

B- Getting a partial molecular response (MR) improves event free survival. Interesting to compare to the similar plot for the earlier Rux study in-- healthunlocked.com/mpnvoice...

See plot in replies below. They are indeed similar if you look at the 5 year mark in the prior study. So this result has been reproduced and thus has added meaning, ie getting at least some MR is very useful. This connection has not been studied for IFN that I know of but presumably would be similar. Note in the prior Rux study <2% allele has zero transformations at 12+ years. This MAJIC study did not separate the very best responders.

F- Consistent with prior threads, ASXL1 is a clear added risk. I think I've posted somewhere on possible combo therapies being considered for help with ASXL1.

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Dose increased from 10mg:2/day-

Ending median dose is 35, equiv to 20+15. Implication is a large dose is needed to get the molecular response, among others.

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This study is a partial comparison to IFN as BAT, so it's partially Rux vs IFN, but not broken out as such:

In the comparison arm (BAT)

44% had IFN in the mix

10% had Rux in the mix.

But it's a stretch to assume the IFN comparison is suitable with this info as many IFN pts had combos.

[EPguy]

Compare this plot at 5 years to Fig C MAJIC trial of this post, above. Here is from from the earlier RESPONSE trial. Similar results on MR vs bad events. So results are substantially reproduced, a big deal in science and thus a clinical benefit for MR (at least on Rux) is clear.

MR vs risk

[EPguy]

Rux dose increased in the MAJIC study. So the 20 mg I'm on is not likely to do it.

Dose increase

[ainslie]

I haven’t scrutinised this paper yet but having read quite a lot on the subject generally my impression (not necessarily a fact) is that as far as reducing allele burden is concerned Peg/Bes for those that can tolerate it seems to be more effective than Rux. There isn’t that much in the literature comparing so maybe not enough in the data to conclude that for sure.

[EPguy in reply to ainslie]

I agree, same impression for IFN vs Rux, at least till these very recent papers came out. But looking at Fig. A above the waterfall plot could easily be mistaken for the like one on IFN. And the % with extremely low VAF is similar for both therapies. This is new.

I believe Rux has been handicapped by its 1st trials being for MF, where any VAF reduction is great but more challenging. Rux is also not so durable therapy for MF since anemia forces some pts off. (Momelotinib to the rescue here we hope) PV does not have much anemia risk.

Also Rux trials, including this one, have not accepted HU tolerant pts; the Ropeg study conversely accepted only these. This could make Rux benefits a bigger accomplishment for these harder to treat pts.

One thing we don't see for Rux is the VAF vs time plots that is common and easy to read for IFN. Fig A is at the last time point for each pt. But in some ways last time point could be more meaningful in light of apparent loss of VAF reduction on average for IFN starting at year 6. I've posted on this while I was on IFN.

We will learn more on Rux for PV over coming years with the RuxoBeat trial where HU intolerance is not required.

[ainslie in reply to EPguy]

good points, the only thing I would change slightly is that Rux has NO anemia risk for PV patients, I asked Dr V about that before starting and he said all you have to do is reduce the dose which seems logical, all my counts are normal , Hct 41 and Hgb 149, MCV 90 and Ferritin around 60 , would like Ferritin a tad higher but better than 8 pre Rux

[EPguy in reply to ainslie]

That does make sense, as long as the other counts are ok dose should follow RBCs. Sometimes PV needs extra push on PLT, this was my main issue at the start; in this case there might be a trade off for RBCs.