Moving Beyond Hydroxyurea for Polycythemia Vera

Harry Erba, MD, PhD: There have not been criteria for response to hydroxyurea until recently. And, again, a subset of European investigators came up with criteria for defining response, and they very clearly state in their position paper that the criteria had been selected to address the myeloproliferative nature of polycythemia vera. And so, in their criteria, they do not list as a response criterion, the absence of thromboembolic events. After all, that’s a time-dependent variable. It’s affected by multiple other risk factors. Instead, they focused on control of the myeloproliferative neoplasm and the symptoms and signs related to that. Response by the ELN (European Leadership Network) definition has included a hematocrit less than 45% without phlebotomy, normal platelet count, normal white blood cell count, absence of symptomatic splenomegaly, and absence of disease-related symptoms. It’s important to recognize that in this position paper, that the investigators state that those things need to be achieved after at least 3 months of therapy with hydroxyurea with at least 2 g, if not more, of hydroxyurea per day.

And so, of course, the ability to achieve those endpoints will depend on the amount of time on hydroxyurea and the dose that’s used. Often, I see patients referred to me who are put on 500 mg of hydroxyurea once a day, and then just continue phlebotomy. I think it’s important that once hydroxyurea is chosen, that it is pushed to its maximally tolerated dose to achieve those response criteria.

Once you define what response is to hydroxyurea, or response in the disease in general, then it’s possible to define “uncontrolled.” And, uncontrolled polycythemia vera would be absence of those complete and partial remissions. Complete remission includes not only control of hematocrit, the white blood cell count, the platelet count without phlebotomy, control of the spleen and symptoms, but also normalization of the bone marrow morphology. And, a partial response does not require normalization of the bone marrow. In patients who don’t achieve a complete or partial remission, those would be patients that you might consider for alternative therapies.

Intolerance to hydroxyurea is pretty uncommon, and it depends on what type of intolerance we’re talking about. I would divide it, as we divide many adverse events in clinical trials, between hematologic and nonhematologic toxicities. In terms of the hematologic toxicity of the drug, this might be the most important one to consider in looking at the life expectancy of our patients. Hematologic toxicity would be defined as development of a neutrophil count under 1000 or a thrombocytopenia at doses of hydroxyurea that are required to shrink the spleen so it’s not symptomatic, or maintain the hematocrit less than 45% without phlebotomy. What that really says to me is that the hematologic toxicity is, in a spectrum of the disease, related to a bone marrow failure syndrome. There’s less bone marrow reserve to tolerate the toxic effects of hydroxyurea on normal hematopoiesis.

The reason why that’s important is that in a retrospective study by Alvarez-Larrán, from Spain, and his colleagues, looked at 250 patients with polycythemia vera and found that out of 30 patients who were resistant to hydroxyurea, 24 were considered resistant because they could not tolerate a dose of hydroxyurea to maintain the hematocrit and shrink the spleen, without causing cytopenias. What’s important about that is that group of patients with resistance to hydroxyurea had a higher risk of death and transformation to AML, around six to seven times higher than patients who didn’t develop resistance to hydroxyurea.

But, there’s also non-hematologic toxicity, which I believe is less common, the most important of which to recognize are leg ulcerations, typically occurring over the lateral malleolus. They are quite painful, and very difficult to heal. In my experience, they typically only go away if you completely stop hydroxyurea. Often, I’ve used hyperbaric oxygen to help speed the healing process. The other less common toxicities would be GI toxicity. And, then, finally, there are incredibly rare toxicities that I’ve seen. I’ve only seen one case of each in my 25 years of practice. One is a patient who developed fever and alveolitis, a pulmonary toxicity that’s been described with hydroxyurea, quite rare. Another patient, that I had, developed acceleration of multiple cutaneous squamous cell carcinomas, so acceleration of cutaneous non-melanoma skin cancers with hydroxyurea. Those are some of the reasons for intolerance.

A Patient with Disease Progression on Hydroxyurea

Case 1: