Targeting JAK2 in Myeloproliferative Neoplasms - Episode 7

Targeted Therapies for Polycythemia Vera

Efficacy and safety profiles of therapies for PV are discussed, along with results of the RESPONSE and RESPONSE-2 studies.

Srdan Verstovsek, MD: Let’s move on to the actual therapy for, for example, polycythemia vera [PV], and the development of the JAKinhibitor ruxolitinib in the treatment of polycythemia vera. We all have, and it is written in the guidelines, hydroxyurea at our disposal. It has been around for 60 years, and people are using it to control the blood cell count, but it seems that the control is rather nonspecific when you ask the doctors, “What does this mean?” With the development of the response criteria, perhaps to be applied more in clinical studies, but now considering the extension of those into the clinical practice, the question is, how successful are we with hydroxyurea in the treatment of polycythemia vera?

I remind everybody what the goals are, as stated in the official guidelines. It says that you should normalize the hematocrit to below 45% without the need for phlebotomy, and normalize the white blood cells, the platelets, the spleen, and the symptoms. We have 5 factors to worry about or look at, if you like, so it is not satisfactory to have a patient with, let’s say, controlled hematocrit but a very high white cell count.

I saw a case yesterday, this is why I am saying that, of a patient with a 52,000 white blood cell count with a normal hematocrit on Hydrea. That is not good, right? I think we need to broaden our spectrum of what the goal should be. If we are looking carefully at the efficacy of hydroxyurea, therefore, there is a large group of people who are underserved or suboptimally treated. I see this is as a major problem.

Andrew Kuykendall, MD: Yes; I think it is tough because we just do not have great answers to some of the questions we would like to have answers to. We know we have certain benchmarks we need to hit. We know it is important to keep the hematocrit at less than 45%. We know we need to improve patients’ disease-related symptoms such as a large spleen and constitutional symptoms. We know that a high white blood cell count seems to be more associated with thrombosis and disease transformation. Even for things like the white blood cell and platelet count, we prefer to see them at a normal level, but at the same time we are not sure that if we pharmacologically reduce those numbers that it that makes a huge difference.

I think we would like for that to happen, but at the same time, sometimes achieving those ends causes worsening of other blood counts or treatment-related toxicity. In the case of hydroxyurea, you can go up to pretty high doses of it to normalize the white blood cell count, but it may come with the expensive mouth ulcers, hair changes, and taste changes. If you are not sure that is going to provide a benefit to patients, is it worth the risk? I think that is one of the challenges in managing these diseases.

Srdan Verstovsek, MD: I agree with you that Hydrea has been around for so long that people are just relaxed and now say, “Oh yeah, I am going to give Hydrea and it is going to do the job.” They do not really pay attention to, is this optimally delivered? Then, if you try to push the dose, like you said, there might be toxicities that prevent you from optimally treating patients. There is, therefore, a need to treat a good number of patients with polycythemia vera with the medications beyond hydroxyurea. Here we have, therefore, a development of ruxolitinib in a second-line setting for the patients who are not responding very well, which appears to be at least 20% to 25% of patients who are absolutely not controlled very well. The studies that led to its approval include the RESPONSE studies. I think that is something good to study, how the design was projected, because it is not only about control of the red blood cells, right?

Andrew Kuykendall, MD: Yes, the design looked at these composite end points of both the control of the red blood cells, lacking the need for phlebotomy, but also spleen control, both of which in the population enrolled, which is obviously a group of patients requiring phlebotomies and had big spleens, were very clinically relevant. And the ability to control both of those with ruxolitinib, around 20% to 21% of patients were able to achieve both of those goals together. When you compare that to patients who were not on ruxolitinib, it was virtually 0%, or 0.9%. It really does something that was not able to be done otherwise. Then you can look at those things individually, and a remarkable number of patients were able to have hematocrit control and spleen control individually. This is really an active drug on multiple different aspects of the disease.

Srdan Verstovsek, MD: Yes, regarding the hematocrit control in particular, when you look only at that, there was about 60% control of hematocrit. That means complete elimination of the need for phlebotomy. Those who did not respond by the strict rules of engagement in the study had a significant delay to phlebotomy, on average, it was about a year. The benefit in clinical practice is much higher than the official response criteria. One needs to account for that, plus there is the influence on the symptoms, which in treating advanced polycythemia vera, is really valuable. I think that most of my patients are benefitting from that aspect a lot, and they feel so much better. Even if you have the occasional phlebotomy or you are not absolutely controlling the white cells or platelets with ruxolitinib, you do have that quality of life benefit that is so valuable for so many.

The other study, RESPONSE-2, did not require patients to have big spleen. The spleen may be there, maybe not, but it does not really matter. There were other studies focusing on PV that tried to see how the medications would fare for these suboptimal responders and if it would aid in controlling the symptoms. In this setting, it is a mixed bag. One needs to look at an individual approach. Is it needed to control that high white cell count, like my case that I just mentioned? I am not very happy with the lack of control of the white cells. Is the symptomatic control good with hydroxyurea? I think the individual approach when treating patients with a suboptimal response is the way to go.

Andrew Kuykendall, MD: Yes, I think when we looked at other studies beyond RESPONSE and RESPONSE-2, one of the interesting studies was RELIEF, which was looking at patients who are very clinically relevant, the patients on hydroxyurea but still having symptoms. Is it reasonable to switch to ruxolitinib? I think the results of that study are a bit of a challenge to interpret, to be honest. You have, at the end of the day, a group of patients who switched to ruxolitinib after 16 weeks, which is a relatively early end point for symptom improvement.

Nominally, you had an improved symptom control, but it was not statistically significant. About 43% of patients were able to get an improved symptom response compared to the 30% or so who stayed on hydroxyurea. For me, 43% is obviously more than 30%, but it is not statistically significant, and I think it shows that that is a high response rate for hydroxyurea as far as symptom control goes. This maybe suggests we are underappreciating the role that optimally dosing hydroxyurea can have in managing symptoms, but at the same time, I think it again shows that a significant percentage of patients had a drastic response in their symptoms treated with ruxolitinib over a course of 4 months. That is what we see in the clinic as well; beyond its ability to control hematocrit and splenomegaly, ruxolitinib really does help patients with a lot of symptoms.

Srdan Verstovsek, MD: The durability of the benefits was recently looked at in the RESPONSE and RESPONSE-2 trials. It is quite good. As we know—and we’re going to talk about myelofibrosis—the average duration in the clinical studies with ruxolitinib in myelofibrosis is about 3 years. With PV, for these patients in the second-line setting, the majority of them are on therapy for more than 5 years. My expectations are that this is going to last much, much longer, and I do not see a reason to suspect a loss of response or the need for another therapy beyond the second line. We have covered now the population of patients with PV quite well. You have Hydrea, you have interferon in some cases, and now you have a full-fledged label indication for the use of ruxolitinib as a target for the hyperactivity of the JAK-STAT pathway. It does make sense where we have it, considering what it does and how it performs.

Andrew Kuykendall, MD: You bring up a great point there as far as the durability goes, because I have run into a few conversations with folks where there is a concern or some hesitancy to utilize ruxolitinib in the polycythemia vera setting due to concern of using their last gun. “Oh, if I utilize this now, then I do not have anything left to use.” A disease that is usually driven solely by that JAK2 mutation and through the JAK-STAT pathway is remarkably responsive to ruxolitinib, and durably so. Some of the reasons we see patients come off ruxolitinib for myelofibrosis after 3 years really do not apply to our patients with polycythemia vera. It is not something that is worth holding off on for a patient who certainly could benefit from it.

Srdan Verstovsek, MD: Yes. One aspect of the use of ruxolitinib is that the resistance to it does not develop in a sense that you have additional mutations in the JAK2 gene, like you usually think about BCR-ABL inhibitors, and then there are mutations that prevent imatinib from acting and you need another one. That is not the case here. We have not had anything like this so far, and no testing for it is necessary because it does not happen. It is quite unique, actually, the ability to biologically be active for such a long time without having additional genetic abnormalities leading to the loss of response. I think that is an area, still, of research, and we will see what happens in the next few years.

Transcript edited for clarity.