Dr Prithviraj Bose reviews treatment options in the setting of hydroxyurea failure in patients with polycythemia vera.
Ruben Mesa, MD: Why don’t you tell us a bit more how this patient did?
Prithviraj Bose, MD: The patient was started on Hydrea 500 mg twice a day and titrated to 2 g a day, in addition to phlebotomy and the baby aspirin. He came back 5 months later complaining of fever, extreme fatigue, and worsening itching, both in terms of severity and the area of skin affected. His spleen is now 3 cm, blood pressure is still good, white blood cell count is about unchanged at 22.3 per mm3, platelets are about the same 780 per mm3, and hematocrit is much worse at this point at 60%. The ferritin is 7 µg/L, and EPO [erythropoietin] is still less than 3 mU/mL.
Ruben Mesa, MD: This is clearly a very aggressive case of polycythemia vera. There’s splenomegaly clearly even on Hydrea, significant erythrocytosis, and difficult symptoms. Stephen, do you think this represents formally hydroxyurea resistance?
Stephen Oh, MD, PhD: I think it does. I don’t know if it’s specified how long the patient had been on hydroxyurea at the 2-g dose, but let’s say it’s been at least a few months. That does meet the criteria of hydroxyurea resistance. Obviously, this patient’s counts all remain high or even worse despite this very high hydroxyurea dose. That alone would indicate that the patient does meet criteria for hydroxyurea resistance.
Ruben Mesa, MD: I definitely agree. Although I would say that more patients tend to fail Hydrea because of intolerance, hydroxyurea resistance is out there as well. At a very solid dose, this individual is clearly not meeting the goals. Jamile, what might be the treatment options for this individual?
Jamile M. Shammo, MD: I agree with you, Ruben. I was going to say that assuming compliance—assuming he’s taking the 2 g that he’s been prescribed—he’s obviously not responding well. The counts are high, he’s still unoptimized, and everything is low. Even if you phlebotomize him more, he still has high white blood cell counts. You have to move on to the only other available therapeutic action at this point for patients who have met either Hydrea resistance or intolerance. I would be discussing ruxolitinib in this patient.
Ruben Mesa, MD: That’s an important consideration and a great segue. I share with my colleagues that 1 of the unmet needs in polycythemia vera is that there is frequently reluctance to begin individuals on cytoreduction early enough. Prithviraj took us through those NCCN [National Comprehensive Cancer Network] Guidelines. People are typically a little too slow getting them on cytoreduction, and then sometimes a little too slow recognizing that the initial cytoreduction was suboptimal and then moving them on to second-line therapy with ruxolitinib. Prithviraj, why don’t you take us through a bit of the data regarding Hydrea resistance and what we know about the treatment options?
Prithviraj Bose, MD: Sure. I will quickly go over the formal ELN [European LeukemiaNet] criteria for hydroxyurea resistance and intolerance to serve as a framework for our discussion. As was being discussed, you’re resistant when you’ve done a good dose for a decent duration, which is defined as 2 g a day or as much as the patient can tolerate for at least 3 months. When you’ve done that and you’re still needing phlebotomy or platelets and the white blood cell counts are still high, the spleen has not shrunk enough, and the spleen symptoms are still there, that’s resistance.
Intolerance is a bit more intuitive and, as Ruben pointed out, common. There you can see nonhematologic toxicities like leg ulcers, mouth ulcers, etc. You can also see cytopenias at the lowest dose that you need to get that hematocrit under control. If you are causing other cytopenias, that’s a problem. Why is this important? Hydroxyurea resistance actually correlates with worse survival and higher risk of leukemia transformation. Ruben, as you showed several years ago, it also correlates with symptoms. In a large study with 1334 patients, it was consistently seen that symptoms were worse in the patients on hydroxyurea, suggesting this burden as a whole is higher in those patients.
This transcript has been edited for clarity.