Harry P. Erba, MD, PhD: Moving on to our next topic, what are the determinants for patients who are inadequately controlled or intolerant? One of the rare ones that I’ve seen is patients who start hydroxyurea and just have this explosion of squamous cell carcinomas, where the dermatologist is just chasing them. But there are other very specific determinants that we should talk about. Ruben, do you want to tackle that for us?

Ruben A. Mesa, MD, FACP: Without question. Just chiming in on the hydroxyurea piece, I think it’s an important one and largely unrecognized by most treating clinicians. Hydroxyurea is a very helpful therapy, but it’s a particularly tough on the mucocutaneous areas. As we think about resistance or intolerance, there are 2 different groups. Let’s start with the intolerant piece. What is intolerance? Certainly, there is that secondary malignancy, of which skin carcinoma is certainly the most common. Even this week, I was looped in on a case that had metastatic Merkel cell carcinoma with a long history of hydroxyurea use. So, that’s clearly 1 issue.

I think a lot more of the subtle mucocutaneous reasons for intolerance to hydroxyurea are very relevant. Ulcers on the mouth or ulcers on the legs are 1 of those toxicities. If you’re looking for it, it’s very obvious when it occurs. But regarding those who really have a much rarer interaction with hydroxyurea, I’ll see patients who come in with 1 or 2 legs bandaged up with their malleolar ulcers who are having all this extensive vascular workup, and it’s really hydroxyurea related. Other common determinants with hydroxyurea can be fevers, GI side effects, or some alopecia. None of these are common, but they certainly can occur. And there are even individuals who have a very rare cycling of their counts—a strange, almost stem cell type of phenomena where the platelets will rise and fall, and it’s very, very difficult to dose adjust in that case. There are many ways to be really intolerant. I think a separate issue that we can discuss as we go along is just failing to meet the goals of therapy with hydroxyurea. But all of those are areas of intolerance.

Now, what about resistance? Resistance depends on how you define your goals. Our current ELN response criteria for treating polycythemia vera looks at improvement in counts, but it also looks at improvement in symptoms and improvement in splenomegaly. Now, with improvement in counts, it is rare that in the individual you give a high enough dose of hydroxyurea so that their blood counts will not fall. They may not be tolerant of that dose. If we put someone on 6 g of hydroxyurea a day, their counts will fall. They’ll probably become aplastic. They won’t tolerate it. So, I find that the resistance part is less about cytoreduction but more about tolerable cytoreduction. Where I find individuals really fail the efficacy challenge with hydroxyurea is regarding any enlargement of the spleen, difficult symptoms, or, clearly, that tolerability issue.

Rami Komrokji, MD: I also think the dose definition of resistance is based on what you are saying, which is suggested to be if you need more than 3 g. Because in my experience, once we start pushing above that dose is where we run into side effects, mucocutaneous side effects, and the other things that that patients experience—not just the cytopenias but also the other side effects—increase. It’s probably that the resistance is tied to the tolerability of the treatment.

Harry P. Erba, MD, PhD: Remember, in ELN guidelines, it’s not just the dose of hydroxyurea. The maximally tolerated dose is up to 2 g a day, but it’s for 3 months. You can’t just give a patient a prescription and say they’re resistant if they don’t respond the next day.

Ruben A. Mesa, MD, FACP: As I share with patients, it is a chronic disease: ET (essential thrombocytopenia), PV, and myelofibrosis. With myelofibrosis, there clearly are appropriate times that we treat it in a much more acute setting. But polycythemia vera is really about trying to make the disease as invisible in the patient’s life as possible. How do you control the disease in a way that has them feel as normal as possible with the least amount of toxicity? Does it have to be tolerable? I share with patients that hydroxyurea is a long-acting drug. Almost all patients typically fall between 10 and 20 pills of hydroxyurea a week. There are the rare individuals who get by with 1 a day. They’re not common. But as soon as you start going north of 1500 mg of hydroxyurea a day, that’s a pretty rare individual who either requires, needs, or tolerates doses above there. If I see someone who is on 2 g a day for an extended period of time, they’re an outlier.

Harry P. Erba, MD, PhD: And then there’s hematologic intolerance, which is lumped in with resistance sometimes. But it’s really intolerance where, in order to shrink the spleen with Hydrea, you can’t give a dose that doesn’t cause neutropenia or even anemia.

Ruben A. Mesa, MD, FACP: Sure, absolutely.

Harry P. Erba, MD, PhD: So, all of those have to be considered.

Transcript Edited for Clarity