Overcoming Treatment Challenges in Polycythemia Vera
Achieving durable cytoreduction and adequate symptom relief in patients with polycythemia vera (PV) is a primary treatment challenge. Individual responses to first-line cytoreductive therapy are difficult to predict, so monitoring for drug resistance and signs of intolerance is crucial.
Q: What are the key challenges related to cytoreductive therapy for PV?
“It is difficult to predict one’s response to hydroxyurea treatment. Some patients develop side effects at hydroxyurea doses of 500 mg per day, while others tolerate doses of 2 to 3 g per day.”
It is important to be mindful of the goals of cytoreductive therapy, which include symptom control and count control with hematocrit levels of less than 45%. Individual patients vary in their response to frontline therapy, so I watch for both tolerability and resistance issues. When I start patients with PV on hydroxyurea, I like to see them more frequently in the beginning because individuals vary in their sensitivity to the treatment. It is difficult to predict one’s response to hydroxyurea treatment. Some patients develop side effects at hydroxyurea doses of 500 mg per day, while others tolerate doses of 2 to 3 g per day. The therapeutic responses and side effects of hydroxyurea are generally dose dependent. Approximately 15% of patients develop side effects such as ulcers or, more rarely, a vasculitis-like reaction, and these side effects preclude further use of hydroxyurea. Gastrointestinal intolerance becomes an issue with higher doses of hydroxyurea and, very rarely, we also see patients who develop interstitial pneumonitis on this treatment. Another group of patients tolerates hydroxyurea without issue but responds suboptimally from the very beginning. Finally, there are others who may do well with hydroxyurea initially but later develop increasing phlebotomy requirements or symptom progression that requires a change in cytoreductive therapy.
Director, Mays Cancer Center at UT Health San Antonio MD Anderson
“Although many practitioners focus almost exclusively on the hematocrit level as the target of their therapy, I think that this approach is inadequate.”
There are both short- and long-term treatment goals in patients with PV. In the short-term, we are trying to adequately control the patient’s hematocrit and symptoms. Over the long-term, we are trying to prevent bleeding, thrombotic complications, and disease progression. And all of these goals must be achieved with the most tolerable therapy, since there is clearly no remission in PV. The cytoreductive therapies are only partially effective; they may control some—but not all—of the counts, or they may have little effect on splenomegaly and/or other symptoms. Additionally, the patient’s hematocrit may be well controlled, but that individual is still at an increased risk of thrombosis or bleeding. The risk of progression to myelofibrosis remains in those with PV who are treated with hydroxyurea. We do not fully understand the biology of why patients progress, but increased understanding may lead to the development of more effective therapies and the identification of factors that may signal an increased risk of progression. Another concern is the long-term safety of hydroxyurea, including toxicities and secondary risks of cancers and other complications. Although many practitioners focus almost exclusively on the hematocrit level as the target of their therapy, I think that this approach is inadequate.
Associate Professor of Clinical Internal Medicine
“Some patients are hesitant to start hydroxyurea therapy because of the side effects. These individuals may benefit from a discussion regarding the rationale for cytoreductive therapy and what to expect from treatment.”
One of the primary treatment challenges in individuals with PV is finding a cytoreductive regimen that is maintainable for patients and allows them to achieve their goals. Once started on cytoreductive therapy, patients may continue to have constitutional and other symptoms such as breakthrough pruritus or splenomegaly, even though their hematocrit has returned to normal. Today, we have ruxolitinib and other agents that we can use in cases when counts are controlled but symptoms are not relieved. Another treatment challenge is the development of iron deficiency that limits the frequency of phlebotomy. Those who develop iron deficiency are often curious about whether iron supplementation would solve the problem, but I explain to them that supplementation would lead to a problematic cycle, causing the hematocrit level to increase, which would lead to the requirement of more phlebotomies. Some patients are hesitant to start hydroxyurea therapy because of the side effects. These individuals may benefit from a discussion regarding the rationale for cytoreductive therapy and what to expect from treatment. Hydroxyurea resistance and intolerance are challenges, and those on this agent require assessments at regular intervals. For example, I see most patients on hydroxyurea approximately every 3 or 6 months, and they have their labs done in between visits. I like to see these patients even more frequently during the beginning of treatment for possible dosage adjustments and to monitor treatment responses and adverse events. The most common adverse events among my patients with PV who are treated with hydroxyurea are skin ulcers, and I also have some patients who experience extreme fatigue. Another potential challenge of cytoreductive therapy occurs when the hematocrit goal is achieved but the dose of hydroxyurea causes too much suppression of the absolute neutrophil count or platelet count to be able to continue.
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