More on CHR vs Allele reduction on INF

[EPguy]

I'm working on a discussion of CHR vs molecular response (MR or allele burden, AB) on INF. In a recent post I discussed CHR correlates to MR.

healthunlocked.com/mpnvoice...

Here are results for the best of the reductions in the 5 year Bes trial.

The data here show that the best responses among the good ones also had the best rate of CHR, matching the pattern for the other reports above.

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From Table 5 of the supplement to the 5 year Ropeg report I turned the text into this plot. (I had to think about Log plots, a college flashback)

The red lines are the ranges of AB after 5 years on Bes. Higher is better CHR, left is better MR.

The top left is no Jak2 detected (<0.014%). These started with 14-56%AB. 80% of these had CHR.

The lower right is still good response, 1-10% AB but not as good as the other sets here. It had the lowest CHR rate at 59% with starting AB of 10-84%.

So the pattern from before persists, having CHR on INF favors lower AB on INF. Also lower starting AB was favorable.

Plot using Table 5 from:

static-content.springer.com...

[dbus1417]

Be interested to see this study on CALR ab reduction

[EPguy in reply to dbus1417]

In the study link in the top post here they did not find a strong correlation CHR to AB (VAF) for CALR, although there was some. This image has the CALR portion included, the "post" boxes are not so different from the pre. The Jak2 had a clear difference.

It doesn't mean there cannot be allele response in CALR, only that the CHR correlation is weaker in this study. With a CHR correlation I think titration can follow hematological responses in seeking AB response, but from here, for CALR, CHR seems a less useful guide for dosing regarding AB response at least for the 1st 2 years.

But: note this study was 24 months, I believe some others for CALR went longer and showed better AB responses (and maybe the CHR correlation would hold better too) INF in general needs very long times for its best benefits.

<<In contrast (to Jak2), the mutant CALR VAF did not significantly decline in either those achieving CHR during treatment with IFNα (median, 0.17 to 0.13; P = .078) or in those not achieving CHR(median, 0.21 to 0.17; P = .066)>>

Jak2+CALR INF CHR

[gvibes]

Thank you for sharing your work. An important question.

I'm trying to understand..start with basics. So is CHR a specific number (somehow additive effect on blood cell concentrations) or is it an either/or condition (meeting your blood cell reduction goals)?

Also can allele burden be generated with a relatively simple blood test, at least for v617f? I have exon 12 mutation, which needs the more involved genetic scans, which I am assuming is how you get the allele burden. Its expensive (+-$3000) so I'm pretty sure I can only get this analysis done infrequently. Probably true for other mutations as well.

I am consulting with Weill Cornell - so I am curious if they will ask for another BMB.

[EPguy in reply to gvibes]

CHR is defined here:

ncbi.nlm.nih.gov/pmc/articl...

<<(WBC) <10 × 109/L, hematocrit <45%, platelet <400 × 109/L>>

This matches what we see on the forum, although PLT seems to vary from 400 to 600 depending on the Dr's practice. The "C" part is that all three of these blood counts are met. If any are not met then it's called partial response.

You're right about the exon 12 from what I've seen. They start with the regular Jak2 Exon 14 (v617f) and should "reflex" to Exon 12 if they don't find the regular one. Allele Burden (AB) is normally available by blood or BMB, and I believe this is true for any of the mutations. . They usually are close. I had both with AB 14 in blood and AB 19 in BMB.

Here is a report on non-Jak2 v617f by blood:

hematology.testcatalog.org/...

<<This is a second-order test that should be used when the test for the JAK2B / JAK2 V617F Mutation Detection, Blood test is negative>>

Interesting they say this 2ndary test is less sensitive. Maybe there are better Exon 12 tests?

If your only AB was via BMB then the best comparison could be another BMB. I would ask for a blood AB at least starting with your next visit, or a reason why they require BMB instead.

You're seeing one of the top clinics in the world, so you should feel confident with your care.

[gvibes]

Hi, A little deeper down the rabbit hole. You are great. I had AB (exon 12 mutation) on both blood and bone marrow aspirate but very different numbers. You responded to that a while back - need to ask my expert. I'm going to take some online genetics course to see if I can get deeper into some of this. These specific mutations raise a lot of questions. Pegasys seems to be working for me although after a year of slow action, 90 mcg suddenly really dropped my HCT levels Then when we lowered dose to 45 mcg in one month I was back to the level 3 months ago. So it would seem, the dose is somewhere in between - I am alternating 90/45 weekly. Is pegasys fixing this mutation like it seems to fix v617f (at least for some people)? Because there are so many exon 12 mutation (50 I think), and so few cases of PV, the studies seem to be directed at v617f. The one thing I have seen is that the exon 12 mutations seem to produce higher red cell production but relatively lack of impact on white cells or platelets. I've seen qualitative statements that the exon 12 disease is generally behaving like the v617f disease and can be treated the same

Did I get off track?

Appreciate your research.

[EPguy in reply to gvibes]

Interesting on the wide spread on BMB vs blood alleles. It may be the lower sensitivity of the Exon 12 test noted in the report means results are harder to reproduce. It does suggest it's best to compare the same type of allele test over time.

You're right most Jak2 studies focus on the more common v617f. I have this more generic one.

Your HCT responded quickly to the dose change, we have seen that on the forum, so INF can act slow in general but also can show fast responses to changes. Is there a reason you have 45/90 vs all at 60?

[gvibes in reply to EPguy]

Its what my MPN doc has been asking me to do. I alternated 90/135 for a while as well. I have the same question. Is a constant dose of 67.5 the same as alternating 45/90 doses? If there is non linear response, then it may have a different effect. I thought it might be about keeping dosing to these step numbers so you can compare to the studies and not have a continuum of patients and doses. Certainly my syringe is capable of precise dose of 67.5. Another question that is on my list. So it seemed for me peg wasn't working very well in January, had a phlebotomy and the dose was upped to 135 for a few weeks which seemed to get it going. I had side effects so I wanted to lower it which we did to 135/90 alternating. It started to bring levels down - we lowered to 90 but levels really started down - so lowered to 45 at which point it HC immediately rebounded. I guess it seems like the 4-6 weeks of the high dose got the process going and then you can continue at some lower level (to be determined). So maybe effects are non linear.