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Role of Ruxolitinib in Polycythemia Vera

Insights From: Srdan Verstovsek, MD, PhD, University of Texas MD Anderson Cancer Center; Daniel J. DeAngelo, MD, PhD, Dana-Farber Cancer Institute; Kim-Hien T. Dao, DO, PhD, Oregon Health & Science University
Published Online: Monday, Jan 09, 2017



Transcript:

Srdan Verstovsek, MD, PhD:
Hydroxyurea is a relatively very well tolerated and effective first-line therapy for patients with polycythemia vera. After a quarter of the patients with hydroxyurea therapy developed resistance or intolerance, they need something else. They need a better therapy that would control their symptoms and signs, and this is particularly important for the patients that are really resistant to hydroxyurea. They do have more aggressive disease. They have more symptoms, a bigger spleen. They tend to transform more to myelofibrosis and acute myeloid leukemia, and have a shorter life expectancy.

There are not too many options. Interferon is one of the options, but it does not work in many patients. It does cause many side effects. Even with the advent of new long-acting interferons, the results do not support long-term use of those medications. And, other traditional medications that we have been using in this setting, alkylating agents like busulfan, melphalan, chlorambucil, radioactive phosphorus, are known to be leukemogenic, meaning they increase in the risk of transformation to acute myeloid leukemia. So, there was a clear need for a new therapy that would be developed which is safe and perhaps biologically targeting what is abnormal in PV. And, ruxolitinib has fulfilled that role. It targets the hyperactive JAK/STAT pathway. With that, it does diminish very quickly the number of cells in blood. It does diminish very quickly the spleen that may be enlarged in these patients. And what I see in my patients—I have treated many patients—quality of life markedly improved within couple of weeks in many patients that don’t have good options. So, now we have the complete picture of controlling all blood cell counts, spleen, and symptoms in patients with PV after hydroxyurea. This is where the real role for ruxolitinib is.

Daniel J. DeAngelo, MD, PhD: Most patients with polycythemia vera do well. The goal of therapy is to minimize the risk of thrombosis, reduce the risk of cardiovascular or cerebrovascular disease. There are those patients who continue to have constitutional symptoms. And the patients, at least I find in my clinical practice, that are most troubling to manage are patients who develop and complain of night sweats, fevers, or pruritus. They can be very difficult to manage, specifically pruritus. Hydroxyurea is not really effective in this case, and phlebotomy sometimes makes it worse. So, these are the patients in whom I’ll initiate ruxolitinib therapy. The other patients that I tend to initiate ruxolitinib therapy in are those patients who have clear toxicity or side effects from the hydroxyurea. Two side effects are important. One is lower extremity ulcers, and the second is recurrent squamous cell carcinoma of the skin. Both are known risk factors for hydroxyurea therapy. When these develop, I stop the hydroxyurea and switch to ruxolitinib.

Recently, I took care of a patient with polycythemia vera that was diagnosed 3 to 4 years ago and had a well-controlled hematocrit on phlebotomy and hydroxyurea, with hydroxyurea dosing in the 1000 to 1500 mg/day range, but really good control of her disease counts. However, I started noticing that the patient was complaining of progressive fatigue and insomnia due to horrible pruritus, mostly aquagenic pruritus—that is pruritus exacerbated by water exposure—to the point that she was having difficulty bathing at night and just having the sheets on her was causing troubles, and then horrible night sweats. And so, for this patient, I initiated ruxolitinib. Within 2 to 3 weeks, the night sweats went away, her pruritus resolved, her fatigue improved, she was sleeping better, and it was a transformative event in terms of her quality of life. That’s an example of a patient, although having good control of the hematocrit with best available therapy, where we were losing control of her symptoms. And this was maintained or able to be achieved with initiation of ruxolitinib.

Patients with polycythemia vera who are treated with ruxolitinib can have complications. One of those that has been seen is a rare increase, or low increase, in the risk of zoster, or shingles. Other infections have also been noted to be increased, and those need to be monitored. In general, I find ruxolitinib to be well tolerated. And the only reasons I discontinue therapy with ruxolitinib are when an infection develops in a patient who seems to be losing disease response with a rapidly increasing white cell count, or I’m not able to achieve control of the hematocrit. Having said that, in my experience, that’s a rare development.

The goal of treatment of polycythemia vera is to reduce the risk of thrombosis and cardiovascular toxicity, and that can be done with phlebotomy and low-dose aspirin. It’s unclear where and when the initiation of JAK inhibition, specifically ruxolitinib, should take place. Clearly for patients who cannot tolerate hydroxyurea and clearly for patients for whom the hydroxyurea is ineffective at controlling the hematocrit, those are clear indications to switch therapy. But, what about patients earlier in the disease course? I think that’s a big unknown. The study that’s been done so far was taking patients who were refractory to hydroxyurea in both symptom and disease control. The new studies are going to need to be asking the question, can ruxolitinib be moved earlier in the disease center in terms of a disease-modifying agent? How would that be assessed? A reduction in the risk of thrombosis, cardiovascular toxicity, cerebrovascular toxicity, and maybe decreased risk of transformation to myelofibrosis and/or leukemia. But, this is an unknown at this point.

Transcript Edited for Clarity
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Transcript:

Srdan Verstovsek, MD, PhD:
Hydroxyurea is a relatively very well tolerated and effective first-line therapy for patients with polycythemia vera. After a quarter of the patients with hydroxyurea therapy developed resistance or intolerance, they need something else. They need a better therapy that would control their symptoms and signs, and this is particularly important for the patients that are really resistant to hydroxyurea. They do have more aggressive disease. They have more symptoms, a bigger spleen. They tend to transform more to myelofibrosis and acute myeloid leukemia, and have a shorter life expectancy.

There are not too many options. Interferon is one of the options, but it does not work in many patients. It does cause many side effects. Even with the advent of new long-acting interferons, the results do not support long-term use of those medications. And, other traditional medications that we have been using in this setting, alkylating agents like busulfan, melphalan, chlorambucil, radioactive phosphorus, are known to be leukemogenic, meaning they increase in the risk of transformation to acute myeloid leukemia. So, there was a clear need for a new therapy that would be developed which is safe and perhaps biologically targeting what is abnormal in PV. And, ruxolitinib has fulfilled that role. It targets the hyperactive JAK/STAT pathway. With that, it does diminish very quickly the number of cells in blood. It does diminish very quickly the spleen that may be enlarged in these patients. And what I see in my patients—I have treated many patients—quality of life markedly improved within couple of weeks in many patients that don’t have good options. So, now we have the complete picture of controlling all blood cell counts, spleen, and symptoms in patients with PV after hydroxyurea. This is where the real role for ruxolitinib is.

Daniel J. DeAngelo, MD, PhD: Most patients with polycythemia vera do well. The goal of therapy is to minimize the risk of thrombosis, reduce the risk of cardiovascular or cerebrovascular disease. There are those patients who continue to have constitutional symptoms. And the patients, at least I find in my clinical practice, that are most troubling to manage are patients who develop and complain of night sweats, fevers, or pruritus. They can be very difficult to manage, specifically pruritus. Hydroxyurea is not really effective in this case, and phlebotomy sometimes makes it worse. So, these are the patients in whom I’ll initiate ruxolitinib therapy. The other patients that I tend to initiate ruxolitinib therapy in are those patients who have clear toxicity or side effects from the hydroxyurea. Two side effects are important. One is lower extremity ulcers, and the second is recurrent squamous cell carcinoma of the skin. Both are known risk factors for hydroxyurea therapy. When these develop, I stop the hydroxyurea and switch to ruxolitinib.

Recently, I took care of a patient with polycythemia vera that was diagnosed 3 to 4 years ago and had a well-controlled hematocrit on phlebotomy and hydroxyurea, with hydroxyurea dosing in the 1000 to 1500 mg/day range, but really good control of her disease counts. However, I started noticing that the patient was complaining of progressive fatigue and insomnia due to horrible pruritus, mostly aquagenic pruritus—that is pruritus exacerbated by water exposure—to the point that she was having difficulty bathing at night and just having the sheets on her was causing troubles, and then horrible night sweats. And so, for this patient, I initiated ruxolitinib. Within 2 to 3 weeks, the night sweats went away, her pruritus resolved, her fatigue improved, she was sleeping better, and it was a transformative event in terms of her quality of life. That’s an example of a patient, although having good control of the hematocrit with best available therapy, where we were losing control of her symptoms. And this was maintained or able to be achieved with initiation of ruxolitinib.

Patients with polycythemia vera who are treated with ruxolitinib can have complications. One of those that has been seen is a rare increase, or low increase, in the risk of zoster, or shingles. Other infections have also been noted to be increased, and those need to be monitored. In general, I find ruxolitinib to be well tolerated. And the only reasons I discontinue therapy with ruxolitinib are when an infection develops in a patient who seems to be losing disease response with a rapidly increasing white cell count, or I’m not able to achieve control of the hematocrit. Having said that, in my experience, that’s a rare development.

The goal of treatment of polycythemia vera is to reduce the risk of thrombosis and cardiovascular toxicity, and that can be done with phlebotomy and low-dose aspirin. It’s unclear where and when the initiation of JAK inhibition, specifically ruxolitinib, should take place. Clearly for patients who cannot tolerate hydroxyurea and clearly for patients for whom the hydroxyurea is ineffective at controlling the hematocrit, those are clear indications to switch therapy. But, what about patients earlier in the disease course? I think that’s a big unknown. The study that’s been done so far was taking patients who were refractory to hydroxyurea in both symptom and disease control. The new studies are going to need to be asking the question, can ruxolitinib be moved earlier in the disease center in terms of a disease-modifying agent? How would that be assessed? A reduction in the risk of thrombosis, cardiovascular toxicity, cerebrovascular toxicity, and maybe decreased risk of transformation to myelofibrosis and/or leukemia. But, this is an unknown at this point.

Transcript Edited for Clarity
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