Q: What factors do you consider when determining whether a change in cytoreductive therapy is needed in a patient with PV?

It is important to first establish the goals of cytoreductive therapy in patients with PV. Most patients with PV who do not have additional risk factors will start treatment with aspirin and phlebotomy, with the goals of a hematocrit level of less than 45% and relief of symptoms. Patients aged 60 years and older and those with a prior thrombotic event or severe symptoms may be candidates for initial cytoreduction with hydroxyurea. Whether age or prior thrombosis was the impetus for treatment, we need to consider changing the cytoreductive therapy in patients who are not achieving their goals. The need for frequent phlebotomies to maintain goal hematocrit indicates that dose escalation or a change in the cytoreductive therapy may be needed.

Another factor to consider is symptom control. Hydroxyurea has been the standard of care for many years, but there are issues associated with this therapy. Approximately 15% of patients develop adverse reactions, such as leg ulcers or dermatitis, that will preclude further use of hydroxyurea. At higher doses of hydroxyurea, gastrointestinal tolerance becomes an issue, and we occasionally see patients who develop interstitial pneumonitis. Another subset of patients responds favorably to hydroxyurea initially, but later develops resistance or symptom progression and may require a switch to a different cytoreductive treatment.

The first goal in treating patients with PV is to control the hematocrit (<45%) with minimal need for supplemental phlebotomy. The second goal—and where I think the greatest unmet need exists—is to maintain control of the platelet and leukocyte counts. Maintaining the leukocyte count at less than 10,000/µL and the platelet count at less than 400×10³/µL meets our definition of having adequate cell count control. Our third goal is to control the patient’s splenomegaly, if present. We expect splenomegaly to be reduced and to become nonpalpable with cytoreductive therapy. We also expect adequate control of symptoms related to high cell counts, such as headaches, itching, and night sweats. If patients hit one of their goals but not the others, we consider them to be inadequately treated.

Another indication for changing cytoreductive therapy is intolerance. A patient may have their hematocrit controlled with hydroxyurea, but only at the expense of intolerable neutropenia, gastrointestinal toxicity, cutaneous ulcers, and/or other adverse events. Leg ulcers that are associated with hydroxyurea use range in severity and seem to be dose dependent; they generally heal with hydroxyurea discontinuation but not with dose reduction.

We occasionally encounter patients with PV in whom phlebotomy is controlling the hematocrit, but they are becoming iron deficient with hemoglobin levels less than 10 g/dL and are developing symptoms such as restless legs and impairment of cognition and short-term memory. In these individuals, we discontinue or reduce the frequency of phlebotomy and we consider treatment with cytoreductive therapy such as hydroxyurea. The frequency of phlebotomies is an indirect marker of disease control. Every time a patient undergoes phlebotomy, it means that their hematocrit level is 45% or greater and that they are not as well controlled as we would like. Frequent phlebotomy is often not sustainable in the long-term. The need for more frequent phlebotomies is an indication that the amount of time that the patient is uncontrolled with hematocrit levels of 45% or greater is becoming extended.

Some patients cannot or will not tolerate phlebotomy on a monthly or more frequent basis, and patient preference sometimes determines the need for cytoreductive therapy. The most common side effect that we see with hydroxyurea is leg ulcers, but some individuals develop pruritus, extreme fatigue, or mild depression. Other patients develop significant decreases in their leukocyte and/or platelet counts, but these counts tend to recover over time after reducing the dose or stopping hydroxyurea.