Treatment for PV: Moving Beyond Hydroxyurea

Srdan Verstovsek, MD:Once we have a diagnosis of polycythemia vera, we assess the risk of blood clotting. The patients are usually divided in two groups. That would be patients with a low risk for thrombosis and high risk for thrombosis. If the patient has a high risk for thrombosis, then phlebotomy and aspirin are not good enough. For low risk patients, phlebotomy and aspirin are the standard practice. The goal of the phlebotomy usually is to reduce the hematocrit to less than 45%. That has been validated in a prospective randomized study, published in January of 2013, that clearly show that patients with a strict control of hematocrit below 45 have advantage over those patients that do not have such strict control. I’m talking about decrease of cardiovascular events and even mortality related to those complications with the blood clotting and bleeding.

It’s very important to try to maintain and strictly maintain hematocrit below 45 with phlebotomy. Aspirin is added to maintain perhaps easier blood flow to decrease the thickness of the cells, but in the high-risk patients that have a high risk for thrombosis within the PV group, the phlebotomy is not good enough. So, we add hydroxyurea or interferon, which are the generally acceptable guidelines, to maintain the hematocrit all the time, if possible, as a level below 45% and further decrease the risk of blood clotting. Cytoreductive therapy is mandatory in patients that are older than 60 or have a history of blood clotting. Those are two factors that will identify patients with a high risk. And, the goal of therapy traditionally has been hematocrit maintenance below 45%.

In patients that have a high risk of thrombosis and have polycythemia vera, we will introduce cytoreductive therapy. And hydroxyurea is traditionally first choice, particularly here in the United States, with the goal of decreasing and maintaining hematocrit below 45%. That has been proven in a prospective randomized study to be the goal of the therapy. However, we have been cognizant of other issues that people with polycythemia vera may have, not only increased hematocrit. I’m talking about increase in white blood cells, increase in platelets, enlargement of the spleen, and bad quality of life. Even with good control of hematocrit, these other factors can be present. And, experts in the field, in general, community of physicians, are cognizant that we are not only treating the number of red blood cells, we need to look beyond.

So, once we settle on a cytoreductive therapy, hydroxyurea as a first choice, usually, we should be looking beyond the red blood cell control. One would like to have control of all the other factors: control the red blood cells, platelets, white cells, spleen, and symptoms. This is how we would like to assess the response to therapy, and particularly in the development of new drugs to be able to fully comprehend the benefit of the new therapy that we are developing.

The hydroxyurea traditionally has been used over decades to control the red blood cells. And, now, with our understanding of complexity of the disease, sometimes it’s not easy to really say how well hydroxyurea does in controlling these five factors. But, attempts have been made in a retrospective way to assess the utility of hydroxyurea, and it is very active, in fact. In many patients, it can control all these five factors, but in about 20% to 25%, it does not really work at all. About 10% to 12% of the patients will not respond, they’re refractory, and about 10% to 12% would also be intolerant. There will be toxicities to hydroxyurea. It’s interesting to analyze just a little bit what kind of toxicities we are talking about. The first and most common, 90% of the toxicities related to hydroxyurea, are related to the ulcers. Are these skin ulcers or mouth ulcers, particularly skin ulcers on the lower part of the legs around the ankle? Then, you have can have GI upset with diarrhea, low-grade fevers, hair loss, and skin rash. Those are relatively rare. But, about 10% to 12% of the patients do have intolerance to hydroxyurea, and it should be recognized as such.

Case 1:A Patient with Disease Progression on Hydroxyurea