Harry Erba, MD, PhD, provides information on the diagnosis and treatment of patients with polycythemia vera: Case 1 - Episode 5
Harry Erba, MD, PhD:In considering when to treat a patient with polycythemia vera, I believe there are a number of important features that need to be taken into account. For me, the most important continues to be the hemoglobin or hematocrit, and I personally use them interchangeably, even though there’s a lot of discussion about which one is actually measured by our automated machines in the laboratory and which one is calculated. Nevertheless, if the patient has an elevated hematocrit over 45%, I do believe that should be a trigger for beginning therapy. Now, again, when I was training, I was just told that’s what we did. We phlebotomized patients; we treated them with hydroxyurea to get the hematocrit less than 45%. And there were some epidemiologic reasons why that was thought to be the case. There’s some in vitro data showing blood viscosity goes up sharply above a hematocrit of 45%.
But it wasn’t until the publication by Roberto Marchioli and his colleagues, in the New England Journal of Medicine, that we actually had some data that a goal of 45% hematocrit was important. In that study, they randomized patients with polycythemia vera to tight control with hematocrit less than 45%, or less stringent control of between 45% and 50%. The study accrued slowly, maybe because clinicians thought they already knew the answer. In any case, it never completed its full accrual and was stopped by the Data and Safety Monitoring Committee because of poor accrual. However, in that study, where patients were given phlebotomy, hydroxyurea, and low-dose aspirin in both groups to maintain those levels, there was a 4-fold higher incidence of mortality due to thromboembolic events or serious thromboembolic events in patients who had their hematocrits maintained between 45% and 50% instead of less than 45%.
Now, an interesting corollary of that study is that there was one other feature that correlated with a lower risk of thromboembolic events, and that was maintaining the white count lower. And, as you might expect, as you give more hydroxyurea to lower the hemoglobin or hematocrit, you’re also going to lower the white cell count. And that may be very important in preventing thromboembolic events. And so, the primary goal should be looking at preventing thromboembolic events by lowering the hematocrit. However, patients can also have a number of symptoms that are quite debilitating and impair quality of life, and those symptoms that we discussed previously should drive intervention.
The goals of therapy in polycythemia vera are really to prevent thromboembolic events from happening, and when they happen, manage them to reduce the symptom burden in patients. Those are the overlying goals.
In a patient who presents with an elevated hematocrit as their reason for requiring therapy, typically we can start with phlebotomy and low-dose aspirin. In the ECLAP study, it was shown that low-dose aspirin did help prevent the occurrence of thromboembolic events. As I mentioned previously, the Marchioli study performed in Italy showed that maintaining the hematocrit less than 45% with phlebotomy was important. And so, patients can be potentially managed with just phlebotomy and aspirin at the initiation of treatment, which begs the question: what would require cytoreductive therapy with drugs, such as hydroxyurea, interferon, and in the old days, busulfan, which we don’t use anymore? And there are a number of criteria. One would be an intolerance of or poor compliance with phlebotomy. It’s difficult for patients to have large bore IVs placed on a regular basis for phlebotomy. Patients can be symptomatic after a phlebotomy, and often we’ll give them back a half-liter or a liter of fluid to help with the volume loss that acutely occurs during that time. It’s an inconvenience to their life.
But, I think the most devastating consequence of phlebotomy that we need to consider much more closely, as we move forward with cytoreductive therapies in this disease, is iron deficiency. The entire goal of phlebotomy therapy is to make the patient iron-deficient. And we often see this. You’ll see in their hemograms that the red blood cell count may remain elevated, but the hemoglobin and hematocrit are in the normal range because the MCV (mean corpuscular volume) has dropped because of the iron-deficient state. But we have to remember that iron deficiency can cause other symptoms unrelated to anemia, such as dysgeusia, or change in taste; mouth ulcerations; angular cheilitis; restless legs; and even insomnia and short-term memory loss. And so, iron deficiency should be considered when choosing phlebotomy as the primary form of therapy.
If the patient is receiving phlebotomy and develops leukocytosis or thrombocytosis, risk factors for thrombosis and alternatively bleeding, those would be considerations for cytoreductive therapy. Also, if symptomatic splenomegaly is occurring or if the patient is just at high risk for thromboembolic events, many of us will institute the use of hydroxyurea in those patients, as well, so age over 60 and a prior thrombotic event. And then, finally, other symptoms related to polycythemia vera, such as pruritus and night sweats, may not be controlled with just phlebotomy and aspirin.
A Patient with Disease Progression on Hydroxyurea