Uncontrolled PV: Treating Patients With HU Resistance or Intolerance


Considerations for therapy when patients with polycythemia vera experience hydroxyurea resistance or intolerance.


Prithviraj Bose, MD: One issue we run into, as we saw in this case, is the development of hydroxyurea resistance or intolerance. [This involves] giving the patient a good dose, which has been defined as 2 g, but frankly it’s whatever the patient can tolerate for an adequate period, which has been defined as 3 months. This has all been defined by the ELN [European LeukemiaNet]. If you’ve given them whatever they can tolerate for at least 3 months, and you’re still not controlling their counts—they’re still needing phlebotomy, or their white blood cell count is still elevated—or if you’re achieving what you set out to achieve but they’re getting too cytopenic, for example, then the hematocrit is controlled but the ANC is too low, at less than 1 per mm3, or the platelets are less than 100 per mm3. If you’re making them cytopenic while trying to control their hematocrit, that would be intolerance. Similarly, if they’re getting leg ulcers, fever, and mouth sores, that would be intolerance of a different kind. These are all laid out nicely by the ELN. We can refer to those for a quick reference. They were also used in the trials that got ruxolitinib [Jakafi] approved for second-line use in the setting of hydroxyurea resistance or intolerance. Resistance would be where the myeloproliferation is continuing, despite an optimal dose of hydroxyurea.

In outpatient, not only were their symptoms never controlled, but neither was the hematocrit, in the sense that they kept needing phlebotomies. Certainly, phlebotomies didn’t get eliminated. Also, there was disease progression at 1 year when the spleen started to increase. There could be several ways of addressing this. One is to continue with the same hydroxyurea dose, which was 2000 mg at that point. One would be to increase it further. Another would be stop hydroxyurea and switch to something else. In this case, I would switch to something else because the patient has already been given 2000 mg for a decent period, 3 months, and they’ve never had phlebotomy elimination. They always had symptoms, and now their spleen is growing. It’s time to switch this patient. About 20% of patients could have hydroxyurea resistance or intolerance. In my experience is more intolerance than resistance. This patient is probably a bit of both.

There are a couple of options. Ruxolitinib is FDA approved for hydroxyurea resistance or intolerance, and then there’s interferon. I mentioned earlier that ropeginterferon alpha-2b [Besremi] is now approved for polycythemia vera. This drug is approved across lines of therapy, in the sense that there isn’t a line of therapy specified in the label. The label is for polycythemia vera broadly. There’s pegylated interferon, which was never specifically approved for PV but has been around a long time. It’s certainly quite effective. These are some other options we have for a patient who’s failing hydroxyurea. The NCCN [National Comprehensive Cancer Network] Guidelines were just updated in April 2022 to include ropeginterferon alpha-2b, given its recent FDA approval for low- and high-risk disease. It’s a choice in both settings.

However, what we’re talking about is hydroxyurea resistance and intolerance. This is where ruxolitinib has by far the most robust data. I alluded to this earlier to say that ropeginterferon alpha-2b hasn’t been studied in the setting of hydroxyurea resistance or intolerance in a strict sense. It has been studied in frontline patients and patients who’ve had a short duration of hydroxyurea and are neither failing it nor in complete response to it. That’s where that drug has been studied, but ruxolitinib has been studied very well in patients who have truly failed hydroxyurea by the ELN definition of resistance or intolerance.

Transcript edited for clarity.

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