Promising option for pts not responding to current therapies and more - Methotrexate (MTX)

[EPguy]

Below are some reports and a resulting clinical trial on this exciting possibility. Various studies suggest low cost methotrexate (MTX) can provide benefits to MPN pts, and some authors propose using MTX as a low cost alternative to Rux. If you are not responding or cannot take our current drug options, this seems worth asking your Dr about. Spleen and symptom reductions were a consistent pattern in the reports. I’m considering additional immune suppressants with my Rheum, MTX was not on the list but maybe it will behave well with Rux and even allow a Rux dose reduction.

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The Reports:

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“Methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, … and is comparable to the JAK1/2 inhibitor ruxolitinib”

journals.plos.org/plosone/a...

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Case reports on 11 MPN pts showed signif improvements in symptom burden. Three pts had beneficial effects on blood counts from MTX.

onlinelibrary.wiley.com/doi...

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An in-vitro and mouse study:

“suggesting that MTX may potentially be acting directly as a Type 1 kinase inhibitor in vivo (Rux is a type 1 Jak-i) “ …”Strikingly, and consistent with in vitro results, homozygotes treated with MTX have reduced levels of pSTAT5 and pSTAT3”

Spleen size was reduced equal or more than with Rux. (Homozy only, Heterozy mice had no need for reductions, being with low mutation and normal spleens)

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The most compelling case study:

One ET pt was unable to benefit from HU, ANA, or IFN. IFN led to autoimmune in this pt. The 2nd pt was PV Dx, intol to HU and unable to get phlbs. Some of these aspects can be hard to treat pts.

Plots of the effect of MTX here shown here.

The ET pt had rapid normalization of PLT (Blue) The PV pt had same for both PLT and HTC. These plots resemble successful cyto reduction by our usual meds.

They have this misleading statement “Ruxolitinib does not provide significant and rapid reductions of marrow fibrosis and mutation load; analogously, we did not observe significant reduction of the JAK2V617F allele burden over time.”

We know Rux can and does much improve the mutation for many, while it may not be “rapid”. This benefit might carry over to MTX if they measure a long enough duration, it went only 6 months.

“These case reports—being the first on the therapy of MPNs with low-dose methotrexate—has shown in vivo that this approach is efficacious in controlling hematological parameters, systemic symptoms and splenomegaly without inducing additional toxicity”

In context of the “absence of hematological toxicity” the authors say MTX is in league with Rux if a bit lower: “Methotrexate-induced JAK-STAT inhibition was indeed slightly inferior to that observed with Ruxolitinib”

onlinelibrary.wiley.com/doi...

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Clinical Trial. And finally all these hints of effect have led to a real clinical trial, phase 2 with a respected name, John Mascarenhas, as principle investigator. It tracks everything of interest except the mutation (VAF). The mis-impression of Rux may be why this is missing. It’s 48 weeks on therapy so VAF reductions could happen.

clinicaltrials.gov/study/NC...

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These reports discuss reduction of inflammation being a possible method of action for MTX. Rux is known to benefit from this action, including a possible reason for its VAF reductions. I understand this is one reason they added Jak 1 to Rux’s targets.

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If you want info on MTX this is one excellent source from an MD with Sjogrens. MTX is cheap and not high risk in the relevant low dose formats.

sjogrensadvocate.com/medica...

[Wewo01]

Wow! This is amazing news! I wonder if it would help get my white blood cells and platelets in a normal zone?

Thank you for posting this. Good luck with it if you try it.

[EPguy in reply to Wewo01]

The plots here show no effect on whites, but the reports suggest this is a good thing in context where they are already normal.

For a more knowledgeable opinion the trial has as a primary PV endpoint "a reduction in platelet and white cell count". Implication is they are looking for an improvement from a too high value. With the repeated discussion of MTX anti-inflammatory properties, this might be the means for reducing high WBCs that can be from inflammation.

If your Sjo-like A-I includes joint pain, MTX is Rx'd for that purpose. You could ask your Rheum. For better or worse I have no joint or other pains, so the Rx for my Sjo would be not standard.

[Mieshie]

thank you for sharing this encouraging info about methotrexate. I’m very happy to see another treatment option coming up.

[ainslie]

thanks for posting this, how do we know the trial isn’t tracking VAF, I couldn’t see anything to say that, did I miss it?

[EPguy in reply to ainslie]

On the trial page the "study plan" shows the endpoints they are measuring. Image here is part of this section. I don't find it in the primary or secondary. Strangely HCT is a 2ndary while PLT and WBC are primary.

Sometimes they report incidental findings in the post trial report. VAF might get reported that way since some of the pts likely have these results.

outcome

[ainslie in reply to EPguy]

On most trials they track a zillion other things than the end points, knowing the Haem JM who is instigating the trial he will I suspect track it

[EPguy in reply to ainslie]

I agree on the VAF, the data likely will be easily accessible. The MTX case studies that mention it said there was no increase in mutation over a certain time which could suggest a positive influence.

In Sjogren's trials, where I learned to navigate the trials site, there is usually not much reported that was not on the endpoints. But Sjo is a lot mushier than MPNs, what endpoints should be are still evolving, and there were no successful trials at all till last couple years. MPNs have well defined numbers for the essentials.

But if Drug.com reviews are relevant, some RA pts have a bad experience with MTX, while derm pts do better.

[mhos61]

Thanks for the update on methotrexate.

I remember reading the article from the University of Sheffield about 11 patients with MPNs responding favourably to methotrexate, and in conclusion suggested a clinical trial. I never heard anything else so presumed nothing came of it.

I know Steve from Sydney (forum member) used to take methotrexate for PV. Interesting to know if he still does.

From a safety point of view, I can vouch out of all the medications my husband has taken over thirty years for RA that his long term use of methotrexate has had no adverse effect.

Really pleased to hear of the possibility of this drug as a treatment option because we really are quite limited. As an ET patient still responding well to hydrea I do worry about future intolerance and what my options would be. I am extremely cautious of interferon and certainly wouldn’t be happy to take Anagrelide.

Many Thanks

[EPguy in reply to mhos61]

That 11 pts study is one of the reports here. There was enough "smoke" with this multiple set of reports to light the fire of a trial.

The link I provided for Sjogren's Advocate (SA) has real world info on MTX, its bad rep includes liver risk, while noted in SA pts that had such complications were already with unrelated liver risks. The trial seems to take this into account, inclusion requires "AST, ALT <3x upper limit of normal (ULN) and no known history of cirrhosis, Total bilirubin <3mg/dL". Looks familiar from IFN criteria.

I agree a best possibility here is an option for those who have run out of them. With PLT being a primary endpoint in the trial MTX might be a good alternative to ANA, which has its known risks.

[saltmarsh]

Thanks greatly for posting this information. Interesting and encouraging.

[Paul123456]

Another great post, thanks.

Earlier this year I asked a top UK Hem about adding MXT to my Pegasys (which was causing autoimmune issues). Thought too risky as MXT is mutagenic. Another top UK Hem confirmed that it’s no silver bullet so I had to switch to RUXO.

Do you think you are immunosuppressed on Ruxo than Pegasys?

Best PauL

[EPguy in reply to Paul123456]

Did your Dr offer the source for the mutagenic risk? This info is consistent with what I have found:

"It’s also one of the safest arthritis drugs, despite a common misconception among many patients that methotrexate is highly toxic.

Confusion about this medication’s safety seems to exist because it is also used – in much higher doses – for treating some forms of cancer. Most people who use methotrexate to treat their inflammatory arthritis take between 10 mg and 25 mg per week. By contrast, the doses used to treat leukemia and other types of cancer may be hundreds of times larger. "

arthritis.org/health-wellne...

RA dose is usually 7.5mg, while the MPN trial is 15mg.

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We will get a better idea what sort of bullet when the trial reports. But its primary completion is 2027 so we will not know too soon. For now it's mostly those two enticing case reports, and the other supporting info.

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I was on Bes. I have not had any infections on either med so far. But Rux is specifically immune suppressive by design, its Jak1 target has a lot to do with that I believe. IFN can go either way. For us A-I victims I think IFN went the up way, immune over-stimulating.

[Paul123456 in reply to EPguy]

Thanks but no more detail other than mutagenic. It was on a group email between me, the two Hems and my gastroenterologist (I had a 7 cm ulceration in my lower oesophagus which, when combined with bad mouth ulcers, indicated an IFN related autoimmune problem). They were all advocating that I immediately switch to Ruxo and in desperation I asked if MXT might dampen the autoimmune response and allow me to continue with Besremi. When they said no, I didn’t waste anymore of their time.

I suspect the problem may be that MPN’s make us more mutationally unstable so can’t compare our risk with arthritis sufferers?

[EPguy in reply to Paul123456]

Our MPNs makes us a lot of things. These can ovrelap or be additive to our other things. Same the other way around, our A-I's make a lot of things. Mix them together and life gets tough.

I understand your Drs hesitancy on the MTX while IFN was blowing up. There is one drug I think might have helped, Sotyk2 (deucravacitinib ). But only combined with ceasing the IFN. It has IFN as a specific inhibition target, and might have cleansed the long acting IFN more timely. But even if it did work I don't see it getting approved as a rescue therapy.

[EPguy in reply to Paul123456]

Looking on drugs.com it has happy customers but plenty of 1 star reviews for RA. Not specifically for cancer but plenty of other things. It seems folic acid vitamin (oral or injected) is indicated to improve tolerance.

But for dermatology (Psoriasis, Eczema ) the reviews are quite good. Maybe RA has particular risk aspects. Plus or minus this is just a single source on info.

drugs.com/comments/methotre...

So it's like so many drugs with risk/rewards. If the trial goes well we can hope MPN pts tolerance might be closer to the derm set in this reference.

[lizzziep]

Interesting information! Thank you 😊

[Innessant]

Thanks for posting. Drug companies will not like cheap alternatives, but state health services will.

[Looolooo]

This is really interesting.

[Bluetop]

Thank you. My platelets have been high recently and if they are still high at my next appointment I shall discuss this with haem.

[EPguy in reply to Bluetop]

ANA is a default option for non responding PLT, maybe MTX can have a better risk profile. I think as with IFN, regular CMP bloods are indicated on MTX.

[Bluetop in reply to EPguy]

Oh right. Thanks.

[Bikelove]

Thank you for posting this!!! I am very interested in this for my E.T. .

Best...Susan

[JAB6]

Thank you EPguy!