Prof Claire Harrison on significance of VAF monitoring

[Paul123456]

youtu.be/WifYlSTmWn4(Not working as expected?)

[bruddery]

hi Paul, thanks for putting this up. Interesting piece. Janice

[Cja1956]

Thanks, Paul. Research has really come a long way. Thanks for sharing.

[Meatloaf9]

Thanks for posting this. Something I think we have all believed but have not heard a well known MPN specialist come right out and say. I think I have a very good specialist but when I asked him this question he says the data is not there yet about lowering the AB. Good to have this as another tool to advocate to lower the AB. I currently take HU for PV, maybe it is time to switch to an interferon??

[ainslie]

yes great post, and GREAT trial ,it showed after 5 yrs on Rux 50 had 50% or more reduction in AB, I asked Dr V about his view on this a few days ago and he reckoned that with each year of treatment it should continue to decline. The only question mark I have on this trial is it doesn’t say what BAT was. And there lies the question, in this trial it shows Rux was better that BAT. BUT, in the trials with Besremi and peg they showed that their results were superior in AB reduction to BAT. So what does really mean? The BAT in the Rux trial should perhaps according to Peg/Bes fans be Bes or Peg?

Anyway as a Rux user it’s good to hear it’s not just that feel good drug that many have described it as. We look forward to more data.

Does anyone know what was the BAT used in this Rux trial?

[Manouche in reply to ainslie]

As far as I know, the BAT is still hydroxyurea

[ainslie in reply to Manouche]

just watched a vid by Mary Mcmullin on the trial Clair H is talking about in this vid, it gave a bit more detail. Mary says It was Hydroxy as BAT, her explanation was that there aren’t really any alternatives?. I wonder why Bes or Peg wasn’t considered as or at least part of BAT.?, was it a tolerance issue?, does anyone have any inside on this or can find out.?

[Manouche in reply to ainslie]

Until last year, interferon was given as an off-label treatment. Scientifically speaking, off-label medications can’t be considered BAT.

[hunter5582 in reply to Manouche]

What is odd is that HU is also off label for MPNs in the USA. Perhaps it has a MPN indication in the UK or EU.

[Manouche in reply to hunter5582]

Hi Hunter,

ChatGPT says:

“No, hydroxyurea is not an off-label treatment for polycythemia vera in the USA. Hydroxyurea is an FDA-approved treatment for polycythemia vera, a rare blood disorder characterized by an overproduction of red blood cells. It works by reducing the number of blood cells produced by the bone marrow, which can help prevent complications associated with the disease. In fact, hydroxyurea is considered one of the standard treatments for polycythemia vera, along with phlebotomy (bloodletting) and aspirin therapy”

[hunter5582 in reply to Manouche]

Thanks for bringing this issue up, as it comes up recurrently. I have heard from several of the MPN Webinars that hydroxyurea does not have a FDA indication for MPNs, but is in common use. It is included as a first-line treatment in the NCCN guidelines and in other protocols as well. It is interesting the failure of HU is an indication for Jakafi in the FDA label. . Thinking about this question of an FDA indication for HU for MPNs got me to go look again.

While ChatGPT is generally pretty good, it does give inaccurate answers sometimes. makeuseof.com/openai-chatgp... This may be because there is mixed information on the Internet.

From Leukemia & Lymphoma Society lls.org/drug/hydroxyurea#:~....

Hydroxyurea is FDA approved to treat people who have chronic myelocytic leukemia and some other blood cancers, including essential thrombocythemia and polycythemia vera.

From WikiDoc wikidoc.org/index.php/Hydro...

FDA-Labeled Indications and Dosage (Adult)

Sickle Cell Anemia

Resistant Chronic Myeloid Leukemia

Head and Neck Squamous Cell Cancer, in Combination With Radiation Therapy

Malignant Melanoma

Off-Label Use and Dosage (Adult)

Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in adult patients.

Non–Guideline-Supported Use – Essential Thrombocythemia Initial dose: 15 milligrams/kilogram/day. Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3[5]

So two different sources say it is and is not FDA approved for a MPN. Therefor, I went to the FDA Website to look again.

The FDA Website refers to NIH - National Library of Medicine - DailyMed.

From the NIH on hydroxyurea. Note there are many manufacturer labels. dailymed.nlm.nih.gov/dailym...

Hydroxyurea capsules, USP is indicated for the treatment of:

Resistant chronic myeloid leukemia.

Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation.

Two labels with this indication

Significant tumor response to hydroxyurea capsules USP has been demonstrated in melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary.

Hydroxyurea, USP used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

From the NIH on Hydrea. dailymed.nlm.nih.gov/dailym...

HYDREA is indicated for the treatment of:

Resistant chronic myeloid leukemia.

Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation.

From the NIH on Droxia. dailymed.nlm.nih.gov/dailym...

DROXIA is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises.

From the NIH on Siklos. dailymed.nlm.nih.gov/dailym...

SIKLOS® is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises

It took a bit of looking at the FDA labels for the various forms of HU. Not a single one has an indication for MPNs. If anyone can find an actual FDA label with an indication for MPNs, please post it as this is an area of interest. This interest is, however, academic.

I would note that every source of online information about medications such as online.epocrates.com/drugs/... list ET and PV and provide the dosing information. At a certain level it really does not matter whether HU is FDA approved for MPNs since it is in such widespread use. It is recommended as a first-line treatment option nearly everywhere.

Whether HU is the best choice for any one of us is a matter matter of each individual's treatment goals, risk tolerance and actual reaction to the medications. We are each different in how we view our treatment for MPNs and in how we react to the treatment options.

The good news for all of us with MPNs is that treatment options are expanding. This goes beyond the IFNs. There are promising treatments on the horizon, including, LSD1-inhibitors, BET-inhibitors, hepcidin mimetics, new JAK-inhibitors, and more. The days of HU being the only option are over. HU is now just one of several options. There will hopefully soon be even more. This will allow for greater individualized MPN care in the future.

Thanks again Manouche. I always look forward to your posts and your comments. They are very informative.

[ainslie in reply to Manouche]

interesting point, but quite ridiculous in the real world, ie off label meds can’t be used as BAT, especially since for some time now experts tend to prefer Bes or Peg or even Rux over HU

[Paul123456 in reply to ainslie]

I think the big question is whether Pegasys/Besremi is better than Ruxo re slowing down disease progression? Interferons work very differently to Ruxo and there is significant research indicating that they are disease modifying. I’m not yet convinced this applies to Ruxo, at least to the same degree

[hunter5582]

Great presentation. More support for the emerging consensus that allele burden does matter. My MPN Specialist does think that it is a good thing to lower allele burden, but we just do not know how good yet. having lowered my VAF from 38% to 9% in 18 months, my perspective is that a lower allele burden is a whole lot better than a stick in the eye (or a higher allele burden).

[Imkerin]

Thanks for posting this. It is interesting how specialist MPN services in the UK have different understandings. I’m under MPN team at UCLH in London. Middle of last year the senior registrar whose clinic I was in for a few months, was keen to know the impact on the AB of surgery to remove a lung carcinoid tumour and ordered a blood test. By the time of my next appointment he had left. Frustratingly, all the test did was (re) confirm I was JAK2 positive. All docs I have seen since refuse to order a quantative analysis (I think that’s the correct term) as they tell me there is no value in having this information and no evidence to suggest lowering the AB is a helpful therapeutic aim. The initial AB at diagnosis in 2021 was 40%.

[Mirror368]

What is VAF monitoring? Thank you, Eileen

[dbus1417]

it seems self evident that the more malignant mutant cells you have the worse your condition would be..

It would be like saying, we aren’t sure if it matters how big your tumor is..