Targeted Therapies for Essential Thrombocythemia
Response criteria, quality of life issues, and therapeutic options including ruxolitinib, hydroxyurea, and interferon are discussed in the context of ET.
Srdan Verstovsek, MD: Let’s move on to essential thrombocythemia [ET], which is very closely related to polycythemia vera [PV] except that, of course, a patient with ET does not have a high red blood cell count. There may be a high white cell count in some patients—not too many, perhaps 10%, maybe a little more—and in an advanced setting patients may have an enlarged spleen. Of course, there are some symptoms, but it is perhaps not as bad as it is with PV. There are circulatory-related symptoms, like blurred vision, headaches, tingling in the fingers or toes, hypersensitivity of the skin, and perhaps some fatigue. I am listing these because, as we were looking through what the response criteria for therapy in PV are, there are also response criteria for ET. That would be the normalization of the platelets and of the white cells. They may be contributing to the thrombotic risk. I would like to hear your view on that. Also, control of the quality of life, which means control of the spleen. You have 4 factors: the spleen, symptoms, white cells, and platelets. Again, hydroxyurea has been around for so long. Nobody really studied it in the proper way, so there is a large group of people who are suboptimally treated.
Andrew Kuykendall, MD: I think ET is really the challenge. These are patients who we say are on the lower end of the spectrum. They have probably the most benign form of myeloproliferative disease, but certainly many of them are not asymptomatic. The symptoms can be quite annoying and problematic when we talk about ringing in the ears and consistent headaches. As you said, neuropathies, paresthesias—those are challenging, and we may be able to control counts and reduce thrombotic risk with agents like hydroxyurea, and, less commonly, anagrelide. Interferon may have a role here, too, but these are not agents that are specifically associated with symptom improvement. We constantly are treating cytoreductively to reduce the thrombosis risk on one arm, but then we are struggling to control some of these more atypical symptoms on the other.
Srdan Verstovsek, MD: That is a very good point because many patients I see in consultations are put on autopilot, where they come for the blood check, the blood is checked, and then nobody actually looks at the spleen. It’s not very commonly enlarged with ET, that is more common in PV, but they are managed in a similar way. Nobody really talks about the symptoms, and as long as the numbers are OK, they say the thrombotic risk is decreased, but what about the person and the quality of life? The application of the questionnaire perhaps, in advance of a visit, could work. The MPN10 [Myeloproliferative Neoplasm-System Assessment Form, total symptom score] is the questionnaire that is accessible to anybody, and aligns with NCCN [National Comprehensive Cancer Network] guidelines, to use in everyday care of patients who have the most common problems present in MPNs.
That is one way to go about it, but just remember to see the patients, do the physical examination, and ask questions about quality of life. That would be a complete assessment of the person, and then that would lead to optimal care, where you look at the numbers, you look at the quality of life, and everybody will be satisfied. If you do that, then again, there is a good number of patients with ET in the advanced phase, after living with the disease for 10 or 20 years, who may need different therapy. Anagrelide, as you mentioned, is the one that controls the platelets but nothing else. Not too many people are satisfied with anagrelide because of the limitations of what it does, and [adverse] effects—palpitations and headaches in particular. I think there is a role, biologically and clinically, for JAK inhibition, and ruxolitinib had some experience in that regard. Do you remember those studies? I think they are valuable to explain to the public because it does work to a degree.
Andrew Kuykendall, MD: I think the MAJIC trial that looked at ET was disappointing as far as results go, but the takeaways from it are that this is an active drug for controlling the platelet count for patients with ET, and it really does help with symptoms, which is something we struggle with. I think we have such high expectations for ruxolitinib trials, given its success in the treatment of polycythemia vera and myelofibrosis. But it should not be surprising that in the form of this disease that activates the JAK-STAT pathway the least that the benefit was not as clearly demonstrated. But that doesn’t mean it is not beneficial.
I think that is one of the things we have to look at; you have to look beyond the data in some sense and say, “What am I really trying to do?” If I’m trying to help a patient, then we need to think about these symptoms and what agents we have out there that could help with them. I definitely have a significant proportion of patients with ET who struggle with disease-related symptoms that have been markedly improved with the treatment of ruxolitinib after trying to get them under control with hydroxyurea, anagrelide, interferon, whatever we have available to us. They are true disease-related symptoms.
Srdan Verstovsek, MD: That distinction between the trial design, the response criteria, and achieving those vs the clinical benefit in the everyday care of the patients need to be, clearly, separated from each other, because we too often go by the percentage of response rate from this drug in that study because of this response criteria. When it is applied to common practice, there are many patients who have a benefit that perhaps cannot be objectivized properly, or cannot be put in a box of response criteria for the study, but it is useful. That is one of the situations here, where patients with advanced ET who are not doing well on hydroxyurea, some may have a big spleen and many may have symptoms, we see that, they would be good candidates to try JAK inhibition. Ruxolitinib might be useful in that situation.
Transcript edited for clarity.
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