HU Resistance/Intolerance Prognostic from Dr Gotlib

[EPguy]

I came across this interview including Dr. Gotlib, Stanford MPN expert. It's regarding MDM Inhibitors for HU resistant/intolerant PV, MF

"Experts Explain MDM2 Inhibition and Clinical Trial for MPN Patients"

patientpower.info/myeloprol...

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It includes this statement from him:

<<we know that patients with hydroxy resistance or intolerance have about a six-fold increased risk of death and a seven-fold increased risk of transformation to myelofibrosis>>

I've heard that a good HU response is broadly positive prognostic but never heard such an extreme effect.

Are any Members familiar with more data on this? Maybe related to non-driver mutations?

This article is related to the subject and implicates TP53 and SF-- mutations:

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

<<We found a particularly high prevalence of TP53 and splicing factor mutations, which was strongly predictive of subsequent disease transformation, and was not mitigated by RUX>>

In the image LMR=low molecular risk (without SF or TP53 mutations) My NGS sequencing looked for these. Another good reason to know your NGS results.

So Rux didn't help but MDM inhibitors could be useful here. No study of INF in this set.

[Meatloaf9]

Thanks for posting this. Wow never heard this before that if you are HU intolerant or resistant that you have a 6 or 7 times greater risk of progression or death. That is really significant. I don't think this article said where that number came from, has that been published somewhere?? Am I reading this correctly?? Did I miss something? First time I heard a definition of HU intolerance or resistance.

[EPguy in reply to Meatloaf9]

I agree, this is a big deal if there is any back up to it.

I think at least one Member here consults with Dr. Gotlib's group. Maybe that person can ask more. I will ask my Dr next visit.

[mhos61]

I had heard of similar with regards to hydrea. Are ‘resistance and ‘intolerance’ the same thing though? I suspect intolerance may not be as detrimental as resistance. Just my opinion!

You may find something relevant to your research in the link below.

It does refer to ‘passenger mutations’ Tet2 and DNMT3A resistance to interferons (p.35). Many other interesting facts too.

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

[FG251 in reply to mhos61]

That would be my non-expert feeling too. Many people have side-effects that count as ‘intolerance,’ however mild, but ‘resistance’ to a medication surely implies a more aggressive disease, does it not?

[mhos61 in reply to FG251]

My thoughts too, glad you agree.

There are many people who have stopped taking hydrea for the associated symptom burden, such as headaches/nausea/fatigue (I believe intolerance).

However, I’m of the opinion that ‘resistance’ to hydrea is a slightly more sinister term and ‘maybe’ suggests more aggressive disease.

Definition/clarification of these two terms would be appreciated for anyone who has stopped hydrea for ‘intolerance’ purposes to alleviate any unnecessary concerns.

[FG251 in reply to mhos61]

Indeed. I’m thinking aloud here and don’t wish to frighten anyone as I’m not qualified, but… perhaps there’s a correlation between the two? The more aggressive non-driver mutations tend to emerge in older age. It might be that higher doses of HU are therefore required to treat the disease, leading to more toxicity, leading to greater discontinuation, etc?

[EPguy in reply to mhos61]

My understanding is: resistance means you can take it without getting trashed but it does not help improve anything of interest. Intolerance is getting bad side effects, even as it might provide some measurable benefit. (but it's hard to stay on the therapy long enough to see this benefit) Hunter I believe had intolerance to HU.

[EPguy in reply to mhos61]

I've heard this correlation in a broad sense, but Dr Gotlib's statement is quite strong. I've sent him an email inquiring, so far no reply.

[EPguy in reply to mhos61]

Looking at the report here:

Fig. 1 clearly shows a large number of PMF with CALR. I've read this correlation before but this is visually easy to see that CALR is over represented in MF.

<<The progression of clonal haematopoiesis through to the development of disease is principally determined by JAK2V617F mutant allele burden>>

<<homozygous mutations are associated with a greater risk of progression to myelofibrosis>> I posted elsewhere, my understanding is Homozy is where the gene from both parents is mutated, while Hetrozy is only one of the genes is. My gene panel did not look for this and I believe they rarely do. If you have an allele burden in the 90% range you are more likely to have homozy and getting this checked may be worthwhile since homozy responds better to INF (These refs don't have that detail but I've read and posted elsewhere)

Calr PMF

[mhos61]

Yes, that does make a lot of sense.

Like you, I am not medically qualified either, just trying to interpret something I find slightly ambiguous.

Maybe someone with a scientific background can elaborate more.

Thanks for your valuable input!

[mhos61]

The link below is quite helpful. I’ve posted an extract which confirms my thoughts on the definition of the two terms.

I’m just shocked that according to Dr Gotlib’s statement ‘intolerance’ appears to have the same detrimental odds as ‘resistance.’

Extract: ‘10% of the patients do not attain the desired reduction of platelet number with the recommended dose of the drug, thus exhibiting clinical resistance,’ whereas some will develop unacceptable side effects, demonstrating clinical intolerance.’

Interestingly, it goes on to say ‘and different authors have proposed different definitions that were used as either a stopping rule in clinical trials or as management recommendation in clinical practice?’

Is there any wonder interpretation for the lay person is confusing at times?

nature.com/articles/2404473

[EPguy in reply to mhos61]

Agree as above on the respective definitions.

The article in Table 2 has as below:

-Platelet count<600 000/μl after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight>80 kg)

-Platelet count<400 000/μl and WBC less than 2500/μl at any dose of HU

-Platelet count<400 000/μl and Hb less than10 g/dl at any dose of HU

This is strange since getting these blood numbers down is what HU is supposed to do, these show HU being too effective for which a lower dose is obvious solution, but these are clearly not resistant. I must be missing something.

The last two make sense for intolerance:

-Presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU

-HU-related fever

[EPguy in reply to mhos61]

I think the error in table 2 I flagged is a typo the ">" sign is reversed. So it's consistent assuming it has ">".

[mhos61 in reply to EPguy]

That’s what I initially thought, but my reply below is assuming it’s not a typo.

[mhos61]

I agree it’s all very confusing. I’m as baffled as you are!

Table 1 makes sense. With regards to table 2 it states the WG require only 1 of the criteria.

The only explanation I can give and I could be totally wrong is

1) Platelet count<600 after three months on 2g a day hu suggests resistance at a high dose.

2) Platelet count<400 but wbc (2.5) is not desirable

3) Platelet count<400 but hgb (10) is not desirable

Although 2/3 achieve a desired platelet count, it is to the detriment of the wbc/hgb levels.

Whether this is resistance or intolerance would appear to be down to the authors definition....maybe???

[Zeppelin11]

Can you post the article again? I tried to open it and it said the page was no longer available. Thx!

[EPguy in reply to Zeppelin11]

I also found that report is gone. But looking for it brought up this:

onlinelibrary.wiley.com/doi...

"On the whole, the most striking finding of the present study was the poor survival registered in the subgroup of patients qualifying for resistance to HC. Thus, such patients had a six-fold higher risk of death by any cause than the others, and the median subsequent survival from the onset of anaemia, which was always the first factor defining resistance, was only 2·4 years. This increased mortality could be attributed in part, but not exclusively, to the high incidence of myelofibrosis registered in this subgroup. Therefore, the detection of anaemia along with thrombocytosis during treatment should probably be considered a marker of disease progression, unless proved otherwise. Of interest, patients destined to develop resistance to HC had a distinctive clinical profile at ET diagnosis, characterized by marked hyperproliferative features. By contrast, their baseline Hb level was similar to that of the other cases."

It seems anemia while on HC was the main definer of resistance and was a predictor of progression. Anemia in MPN is associated with MF so this seems not so surprising.

But the original statement from Dr Gotlib included intolerance as well I recall. So there should be another report on this risk issue. I have appt with Dr Gotlib in July and will ask.