Hydroxyurea and thrombocytopenia

[yibberat]

I've been recently diagnosed with PV high risk (age 63 + previous ischemic stroke 4 yrs ago) w JAK2 mutation. It's been a struggle to get the hematocrit down - 9 phlebotomys over the last nine weeks and now three weeks of Hydroxyurea to get from the mid-70's down to 52 (before today's phlebotomy). It seems to be getting close to the 45 target. But with this weeks CBC before the blood draw, I noticed that the platelets have dropped sharply - from 426 before the hydroxyurea to 68 now. Other metrics have clearly responded to the hydroxyurea (RDW, RBC, immature granulocytes, etc), others to the phlebotomies (MCH, etc) I have a phone appointment with the hematology pharmacist in a couple days to help talk over what may need adjusting re the hydroxyurea in the early stages (current 1 500mg twice per day). My questions relate to:

Does hydroxyurea respond differently to different stem cells - maybe suppressing the platelet (megakaryocytes) more than others? Or different stem cell suppression at different times?

There is a side effect (apparently rare - called cyclic thrombocytopenia) where platelets cycle down into thrombocytopenia and up into thrombocytosis. Which then creates a need to adjust dosage of HU - Is this a thing? If it is, I'm only seeing the first down and not the future rise but it would be good to know if there's something to expect

If platelets are jumping up and dropping down, does that change the things I should watch out for - nosebleeds/gums/bruising v clots?

What was the early adjustment period for HU like for you? So far it is clearly responsive which is good - but in weird ways that make me realize why AI (which I am setting up for symptom tracking and treatment assessment in prep for dr consults) will not replace doctors/specialists anytime soon.

[hunter5582]

It sounds like you have a tricky case of PV to manage. Sorry to hear that you are having a significant adverse effect.

HU directly impacts the pluripotent hematopoietic stem cells, which produce all three types of blood cells. HU affects all three blood cell lines. However, there is individual variance in howwe each respond. With your erythrocytosis so high and platelets at 426, it is not surprising that the HU dose needed to effectively reduce HCT would induce thrombocytopenia. You did not mention your leukocyte levels, which I am hoping are still OK.

As you already know, PLT at 68 is far too low. This level of thrombocytopenia puts you at significantly increased risk of bleeding and bruising. This includes the risk of a hemorrhagic stroke. Since you are likely taking aspirin, the risk of hemorrhage is even higher. This is an issue that requires prompt attention. I would not assume that the PLT will bounce back on their own.

Suggest that this situation requires an urgent consultation with your hematologist. A change in dose or consideration of a different medication is indicated. Besremi and Jakafi are both options in this case since you have demonstrated a negative response to HU.

My relapse to HU was also negative. It did not effectively lower HCT, requiring phlebotomies every three weeks . I was not able to tolerate 500mg 1x/day due to the significant adverse effects. I have done much better on Besremi. It has been more effective and much easier to tolerate. Note that we are all different in how we respond to these medications. My response does not predict yours.

Please be sure to see your MPN care team ASAP. Wishing you all the best moving forward.

[yibberat in reply to hunter5582]

Thanks for a very helpful response. You provide so much good info that you've learned about the disease. I've got a similar desire to learn as much as possible - in large part because I've got basically no symptoms. If doctors manage symptoms (as I suspect even MPN specialists do) - and I've got few/none (or maybe ones that don't fit the standard symptoms) - then I'm easy to ignore (including by family/friends - and myself). So instead I have to dig into metrics so that I can ask the docs the right questions.

Your question about leukocytes was very helpful. Yeah they are all still ok and normal and not seemingly affected by hydroxy or the phlebotomies. Except the basos which are high and not being affected by the hydroxy (but maybe by the phlebotomies since they did used to be higher around the time of diagnosis). And which I understand produces a form of heparin. So the immune system's way of thinning the blood to fight venom or other threats. Cool. So on the one side we got aspirin, basos, dropping platelets and on the other hematocrit, ischemic/clotting history, and the standard drop-dead thrombosis risk of PV.

I think I've got some great difficult questions for the docs. And again thank you.

[hunter5582 in reply to yibberat]

Your situation is precisely the type that is best served by a MPN Specialist. While you are relatively free of secondary/constitutional symptoms, an ischemic stroke counts as a major PV symptom. With your erythrocytosis so elevated, I would be not be surprised if your blood pressure was elevated. Other symptoms may be far more subtle but directly related to the proinflammatory state induced by the JAK2 mutation. MPN Spepciats are much more aware of this and the implications for treatment.

Basophilia is a part of the profile for some of us with PV. I also experience that when not on cytoreductive medications. BASOs are involved in fighting parasites, recruiting other leukocytes to fight infections, and are part of allergic response. They contain heparin, histamine, and other inflammatory mediators. They are usually a very small part of the total blood cells. The total percentage of basophils would not be changed by phlebotomies but the absolute numbers might be. Great question to add to the list for the hematologist.

Another question I would consider asking is whether rusfertide would be an option when it becomes available. It is still in a Phase III clinical trial, which unfortunately is no longer recruiting (Phase 3 VERIFY trial NCT05210790). Rusfertide is a hepcidin mimetic which keeps iron in storage so it cannot be used to make RBCs, It would be worth tracking what is happening with this new medication. It is hoped that the application to FDA will happen before the end of 2025. There may be other clinical trials underway that would be worth learning about (e.g., SLN124 AKA divesiran clinicaltrials.gov/study/NC... ). MPN Specialists would be more aware of potential clinical trials that are appropriate for you if that is something you are willing to consider.

Wishing you all the best.

[yibberat in reply to hunter5582]

Thanks again. My blood pressure is pretty good now and the phlebotomies and hydroxy have helped by unclogging the system. The one non-specific symptom that I've been aware of since the stroke was cognitive impairment, executive function stuff or brain fog. That everyone (incl I) blamed on stroke damage or 'aging' but deep down I always knew that was wrong. Didn't understand why it was wrong until the PV diagnosis. A result of a chronic blood problem (which included blood pressure until the phlebotomies) not an acute attack like the stroke. That has hugely improved.

I agree about the MPN specialist too. The local one is part of the research consortium NCCN - nccn.org/home/about - who do the federal funded cancer research and clinical trials for pharma. I told my hematologist (who I like and doesn't seem to have ego problems) - hey I'll be a lab rat. My strategy is to get both my hematologist and the MPN specialist to coordinate care. We'll see.

[hunter5582 in reply to yibberat]

That approach works well. I have a shared care arrangement with a MPN Specialist/Researcher at Johns Hopkins and my wonderful local hematologist. We work as a team and I always get a second opinion on every major decision.