Practical Considerations of Polycythemia Vera Treatment
Srdan Verstovsek, MD PhD; Jamile M. Shammo, MD; and Ruben Mesa, MD
Jamile M. Shammo, MD; Srdan Verstovsek, MD, PhD; and Ruben Mesa, MD, discuss the maximum tolerated dose of hydroxyurea for patients with polycythemia vera, as well as factors to consider beyond hematocrit when assessing success of therapy.
Jamile M. Shammo, MD: I think the maximally tolerated dose of Hydrea [hydroxyurea] may be patient-dependent. Some patients are able to tolerate 2 g per day. Some patients aren’t able to take more than 3 tablets a day, because if you push this beyond 1500 mg, they will develop hematological toxicity. So, then, if you truly are trying to identify if your patient is able to tolerate this after 2 g of Hydrea for 3 months, it may not be practically feasible.
So, this may be patient-dependent. But, generally, most of my patients seem to tolerate 1000 mg to 1500 mg. I am, of course, on the lookout for patients who demonstrate myeloproliferation and may require a dose increase or those who, despite adequate dosing and duration of treatment, continue to have uncontrolled blood parameters and symptoms.
Srdan Verstovsek, MD, PhD: Once we classify the patient as high risk for thrombosis, based on the standard prognostic factors, the first question is which cytoreductive therapy to use: hydroxyurea or interferon. Most of the patients in the United States are given hydroxyurea. The goal of therapy these days is, first, to control the hematocrit—that should be below 45% all the time without the use of phlebotomy. It can be achieved in a good proportion of the patients, but we also look at other factors. Apart from normalization of hematocrit below 45%, you should also look at the normal range of the white cells, platelets, symptoms, and spleen. Now, control of hematocrit below 45% cannot be overemphasized, because the prospective randomized study showed that those who did not have good control had a high risk of cardiovascular complications and thromboembolic events. And, a high number of deaths were seen in a group of patients who did not have good control of hematocrit. So, that is a very important factor to really pay attention to—maintaining that hematocrit below 45%.
Ruben Mesa, MD: Determining control of polycythemia vera by current European Leukemia Net criteria involves trying to keep the blood counts as normal as they can be. So, that begins with control of erythrocytosis and hematocrit, but it also, certainly, includes control of the white cells. We really don’t want them to be too high, because that might increase vascular risk, but, by the same token, we really don’t want them to be too low as a sign of toxicity from myelosuppressive therapy or hydroxyurea. So, chronic neutropenia would clearly be unacceptable. But, we really aim to have that neutrophil count be as close to the normal range as possible. The same would be true in terms of platelets. Thrombocytosis can clearly increase the risk of vascular events, but, likewise, we do not wish to have thrombocytopenia from excess myelosuppression, either, as that might clearly increase the risk of hemorrhage, as well.
Jamile M. Shammo, MD: When I start patients on Hydrea, I generally check their blood counts every 1 to 2 weeks, probably a little more stringently. But I have seen people develop certain hematological toxicity that could easily be prevented by dose modification. If they are getting phlebotomy, you obviously want to do this at least twice a week, assuming they are tolerating it. And then, later on—perhaps in the first month or so—you make it less frequent. Generally, the initiation of phlebotomy and cytoreductive therapy is somewhat intense, because you want to get blood parameters periodically to ascertain that the patient is responding appropriately and that you are attaining the appropriate blood parameters later on. And that frequency diminishes as you move on with treatment.
The goal of treating someone with either phlebotomy or Hydrea is to optimize the blood parameters. So, I want their blood counts to be as close to normal as possible. When the hematocrit is below 45%, with a white blood cell count as close to 10,000 as possible and a platelet count below 400,000 or 450,000, that is the definition of a complete hematological response. I can tell you that in practical terms, my interest is mostly on hematocrit. So, if a white blood cell count is 11,000, it’s not normal. But, it would be difficult to justify that, because you also have to weigh risks and benefits when utilizing cytoreductive therapy.
Ruben Mesa, MD: The criteria for determining whether or not a patient is adequately controlled with medical therapy is the same regardless of the therapy that we choose. In the setting of hydroxyurea, which is the most common front-line cytoreductive therapy, those criteria are control of the white blood cell count, less than 10,000; a platelet count of less than 400,000; and to have patients become phlebotomy-independent in parallel with other issues, such as controlling the spleen size, improving symptoms, etc. Now, the criteria are to achieve those target counts while the patient has a tolerable dose of hydroxyurea. This is really the key part. Does it take a dose that they really do not tolerate to achieve those goals, e.g., they develop a mouth ulcer or skin ulcer or have neutropenia? Or, are they on a tolerated dose of hydroxyurea, but they’re not reaching those treatment targets?
Srdan Verstovsek, MD, PhD: Hydroxyurea is traditionally the first choice for oncologists and hematologists in the United States for patients at high risk for thrombosis who have polycythemia vera. It aims to control the red blood cells and to maintain hematocrit below 45%, but also to control white cells, platelets, symptoms, and the spleen. This is called a “complete response.” First, we would like to have a hematological response, but everything together, all 5 factors, is what we look for at this point in time.
Now, this is not possible in every patient. There is a fraction of patients, perhaps 20% to 25%, who do not have a good control of the blood cell counts, symptoms, and spleen, who have polycythemia vera and are treated with hydroxyurea. The dose needs to be optimized to the highest dose that will do the job. Otherwise, you can do the maximum tolerated dose or the maximum safe dose that will provide the benefits. If we cannot provide the benefits using the maximum dose that is tolerable for the patient, then that patient has uncontrolled disease. That is easy to understand. If we cannot use the maximum dose that is tolerated by the patient to control the red blood cells, white cells, platelets, symptoms, and spleen, that patient is not responding very well. And, in fact, that patient is in need of an alternative option, which would, perhaps, be interferon or a JAK [Janus kinase] inhibitor, such as ruxolitinib.