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Optimizing the Use of Ruxolitinib for Polycythemia Vera

Panelists: Harry P. Erba, MD, PhD, Duke University; Rami Komrokji, MD, Moffitt Cancer Center; Ruben A. Mesa, MD, FACP, The Mays Cancer Center, the newly named center of UT Health San Antonio MD Anderson Cancer Center; Jamile M. Shammo, MD, FASCP, FACP, Rush University Medical Center; Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center; Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center
Published: Monday, Aug 06, 2018



Transcript: 

Harry P. Erba, MD, PhD: Jamile, how do you dose ruxolitinib in this indication and what are some of the side effects that you have to manage?

Jamile M. Shammo, MD, FASCP, FACP: I like to evaluate my patients before I start ruxolitinib in terms of kidney and liver function tests. I see this a lot of times, where people go with the 10-mg twice-a-day dose, which is the dose that was utilized in the pivotal trial. But if you have someone who has chronic kidney disease, I think it’s very important to alter the dose accordingly because the drug is excreted around 75% through the urine.

That point always gets missed somehow. It’s very important to monitor the kidney and perform a liver function test, and then somebody can start with 10 mg BID dosing baring those points. That’s how I start. It’s also about expectation. I think it’s very important to sit down with the patient and explain to them what it is that you try to do. Obviously, the drug has myelosuppressive effects and you want to monitor hemoglobin. You want to monitor the neutrophil count and adjust the dose accordingly, also with the platelet account. I tend to monitor the patients very closely, perhaps every 1 to 2 weeks, and do dose adjustments. I try to explain to them that stopping the drug abruptly may not be something that I like to do; hence, monitoring them very closely to adjust the dose accordingly is a very good idea.

I haven’t run into any issues in terms of long-term tolerability, and I think I’m comforted by looking at the results of long-term ruxolitinib use in PV and in MF, so that had not been an issue for me.  As far as other toxicities, most of the toxicities—hematologic in particular—tend to happen at the beginning of therapy. I think this is an intense period where people need to cooperate with their MD and get the labs as needed so that we can anticipate and change the dose accordingly. That’s what I do.

Harry P. Erba, MD, PhD: Srdan?

Srdan Verstovsek, MD, PhD: I fully agree because we do start 10 mg twice a day with everybody in PV. Unlike myelofibrosis, it’s 1 dose for everybody. It is because of the safety. We don’t want to cause too much myelosuppression. This is the benefit, but still we can occasionally cause some myelosuppression even with 10 mg twice a day. During the first 3 or 4 months, about 60% of patients will need dose adjustments to increase it, right? They go to 15 mg twice a day, 20 mg twice a day, and occasionally 25 mg twice a day. This is the area where you have to see, it like it was described, patients more often during the first 3 or 4 months.

In terms of a tolerability, I have a question for the panel because we know that atypical infections can happen. This is not very common. We don’t even talk about percentages except for herpes, which is about 5% to 6% in the study so far. And now, we have a new vaccine from about 6 months ago that was approved in the United States, which we actually can use. That’s my question to you, should we use it in patients who are about to receive ruxolitinib as preventative method?

Ruben A. Mesa, MD, FACP: I certainly have raised that point with my patients. Shingrix is the trade name for the vaccine. I certainly have raised that point with them. The risk of herpes shingles is real; it’s 5% to 6%, but I certainly have had several patients who have developed it. The prior vaccine that was a live vaccine. That was a risk that was difficult to know. It was contraindicated in patients with advanced hemomalignancies. Does a polycythemia vera patient really meet those criteria of sufficient immunosuppression to be at risk for the vaccine? It’s probably a stretch, but still it was technically contraindicated. But with the new vaccine, I have had several patients who received it. I share with them that we don’t know for certain, but all things being equal, it’s not an unreasonable choice.

Harry P. Erba, MD, PhD: Let me ask this. You’re focusing on the risk in the patient because of immunosuppression, but on the other hand, ruxolitinib itself is a JAK1 inhibitor, can block cytokines, and may have some effect on the response to the vaccine. Do you have a certain time period between the vaccine and starting ruxolitinib in terms of allowing for a better response? Do we have to do that, or are you just starting them at the same time? Am I worried about nothing?

Srdan Verstovsek, MD, PhD: No, I think it’s a good point. I have not really used it. I like to discuss it and see how other people like you feel about it. Should we use it and should we recommend it, particularly in myelofibrosis patients? How do we give it? This is a good point.

Rami Komrokji, MD: Yes, you’d think that you should give it a few weeks before, not like what we do with other treatments. You might use it at least 2 weeks in advance of something like that. But on the point that myelofibrosis patients with an immune system could be compromised—are they going to mount a response to the vaccine? Does it really protect them from that? That’s also very difficult to prove.

Srdan Verstovsek, MD, PhD: On the other hand, we also don’t certainly have data that shows that starting ruxolitinib stops your ability to respond to a vaccine. It’s a theoretical concern, but I think far from one that we really know.

Rami Komrokji, MD: Yes.

Harry P. Erba, MD, PhD: I think that was a very important point about the patients on the RESPONSE trial, many of them requiring a higher dose. And so we should look for the goals of our therapy along the way, and not only with ruxolitinib, but also what’s great about ruxolitinib coming along is it helps us focus on management of patients with hydroxyurea interferon. Using those drug to their maximal tolerated dose and maximal benefit before thinking about switching. The same thing with ruxolitinib – one dose might not fit all. So, anyone want to volunteer their own clinical experience with this and PV? Do you want to start, Ruben?

Rami Komrokji, MD: Sure. I would say that the clinical experience has really matched the trials very well. One, patients clearly don’t require splenomegaly to have a response. As Srdan said, this is not a spleen drug, just reduction in splenomegaly is a helpful marker of response, but it certainly is not a spleen drug. I think patients really have a significant benefit in terms of the difficult symptoms they can have with PV, which are much more prevalent than I think individuals’ treating physicians often recognize. Two, they frequently can get much better control of their counts along with it. And three, I suspect it does help to further decrease that risk of vascular events, probably because patients are more active, but probably also because of some contribution of the inflammatory state that probably is benefited from ruxolitinib.

Because I found the experience of PV to really be quite beneficial, you know? And certainly there are efforts ongoing looking at trials both domestically and internationally, should we expand the indications for ruxolitinib use in P. Vera in other settings? Should there be a frontline setting that it should be considered for higher risk for other things? A complex economic discussion, which is why that really wasn’t pursued to begin with, but just from an efficacy standpoint, it’s a fair question.

Srdan Verstovsek, MD, PhD: I like the point earlier you made about looking at our own practice with standard medications in Hydrea and interferon, until now, and see whether we actually did a good job or not. And are we not perhaps treating everybody well enough, and maybe those patients needs to be changed to ruxolitinib. And this kind of retrospective analysis is quite information. In fact, we are, including myself, not really good or haven’t been very good in fully, but exploring the potential of a frontline therapies. Or unable to deliver and then we should recognize that as a need for something new.

Harry P. Erba, MD, PhD: I agree, I think there’s been some complacency. These patients didn’t cause us much trouble, especially for a practicing oncologist who’s busy with patients with solid tumors that are active or metastatic. These patients were easier and so maybe didn’t get as much as attention as they deserve, I think with ruxolitinib being available and other drugs being developed in this area, I think it’s really focused attention on a group of patients who have been sometimes neglected, to be quite honest.

Transcript Edited for Clarity 

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Transcript: 

Harry P. Erba, MD, PhD: Jamile, how do you dose ruxolitinib in this indication and what are some of the side effects that you have to manage?

Jamile M. Shammo, MD, FASCP, FACP: I like to evaluate my patients before I start ruxolitinib in terms of kidney and liver function tests. I see this a lot of times, where people go with the 10-mg twice-a-day dose, which is the dose that was utilized in the pivotal trial. But if you have someone who has chronic kidney disease, I think it’s very important to alter the dose accordingly because the drug is excreted around 75% through the urine.

That point always gets missed somehow. It’s very important to monitor the kidney and perform a liver function test, and then somebody can start with 10 mg BID dosing baring those points. That’s how I start. It’s also about expectation. I think it’s very important to sit down with the patient and explain to them what it is that you try to do. Obviously, the drug has myelosuppressive effects and you want to monitor hemoglobin. You want to monitor the neutrophil count and adjust the dose accordingly, also with the platelet account. I tend to monitor the patients very closely, perhaps every 1 to 2 weeks, and do dose adjustments. I try to explain to them that stopping the drug abruptly may not be something that I like to do; hence, monitoring them very closely to adjust the dose accordingly is a very good idea.

I haven’t run into any issues in terms of long-term tolerability, and I think I’m comforted by looking at the results of long-term ruxolitinib use in PV and in MF, so that had not been an issue for me.  As far as other toxicities, most of the toxicities—hematologic in particular—tend to happen at the beginning of therapy. I think this is an intense period where people need to cooperate with their MD and get the labs as needed so that we can anticipate and change the dose accordingly. That’s what I do.

Harry P. Erba, MD, PhD: Srdan?

Srdan Verstovsek, MD, PhD: I fully agree because we do start 10 mg twice a day with everybody in PV. Unlike myelofibrosis, it’s 1 dose for everybody. It is because of the safety. We don’t want to cause too much myelosuppression. This is the benefit, but still we can occasionally cause some myelosuppression even with 10 mg twice a day. During the first 3 or 4 months, about 60% of patients will need dose adjustments to increase it, right? They go to 15 mg twice a day, 20 mg twice a day, and occasionally 25 mg twice a day. This is the area where you have to see, it like it was described, patients more often during the first 3 or 4 months.

In terms of a tolerability, I have a question for the panel because we know that atypical infections can happen. This is not very common. We don’t even talk about percentages except for herpes, which is about 5% to 6% in the study so far. And now, we have a new vaccine from about 6 months ago that was approved in the United States, which we actually can use. That’s my question to you, should we use it in patients who are about to receive ruxolitinib as preventative method?

Ruben A. Mesa, MD, FACP: I certainly have raised that point with my patients. Shingrix is the trade name for the vaccine. I certainly have raised that point with them. The risk of herpes shingles is real; it’s 5% to 6%, but I certainly have had several patients who have developed it. The prior vaccine that was a live vaccine. That was a risk that was difficult to know. It was contraindicated in patients with advanced hemomalignancies. Does a polycythemia vera patient really meet those criteria of sufficient immunosuppression to be at risk for the vaccine? It’s probably a stretch, but still it was technically contraindicated. But with the new vaccine, I have had several patients who received it. I share with them that we don’t know for certain, but all things being equal, it’s not an unreasonable choice.

Harry P. Erba, MD, PhD: Let me ask this. You’re focusing on the risk in the patient because of immunosuppression, but on the other hand, ruxolitinib itself is a JAK1 inhibitor, can block cytokines, and may have some effect on the response to the vaccine. Do you have a certain time period between the vaccine and starting ruxolitinib in terms of allowing for a better response? Do we have to do that, or are you just starting them at the same time? Am I worried about nothing?

Srdan Verstovsek, MD, PhD: No, I think it’s a good point. I have not really used it. I like to discuss it and see how other people like you feel about it. Should we use it and should we recommend it, particularly in myelofibrosis patients? How do we give it? This is a good point.

Rami Komrokji, MD: Yes, you’d think that you should give it a few weeks before, not like what we do with other treatments. You might use it at least 2 weeks in advance of something like that. But on the point that myelofibrosis patients with an immune system could be compromised—are they going to mount a response to the vaccine? Does it really protect them from that? That’s also very difficult to prove.

Srdan Verstovsek, MD, PhD: On the other hand, we also don’t certainly have data that shows that starting ruxolitinib stops your ability to respond to a vaccine. It’s a theoretical concern, but I think far from one that we really know.

Rami Komrokji, MD: Yes.

Harry P. Erba, MD, PhD: I think that was a very important point about the patients on the RESPONSE trial, many of them requiring a higher dose. And so we should look for the goals of our therapy along the way, and not only with ruxolitinib, but also what’s great about ruxolitinib coming along is it helps us focus on management of patients with hydroxyurea interferon. Using those drug to their maximal tolerated dose and maximal benefit before thinking about switching. The same thing with ruxolitinib – one dose might not fit all. So, anyone want to volunteer their own clinical experience with this and PV? Do you want to start, Ruben?

Rami Komrokji, MD: Sure. I would say that the clinical experience has really matched the trials very well. One, patients clearly don’t require splenomegaly to have a response. As Srdan said, this is not a spleen drug, just reduction in splenomegaly is a helpful marker of response, but it certainly is not a spleen drug. I think patients really have a significant benefit in terms of the difficult symptoms they can have with PV, which are much more prevalent than I think individuals’ treating physicians often recognize. Two, they frequently can get much better control of their counts along with it. And three, I suspect it does help to further decrease that risk of vascular events, probably because patients are more active, but probably also because of some contribution of the inflammatory state that probably is benefited from ruxolitinib.

Because I found the experience of PV to really be quite beneficial, you know? And certainly there are efforts ongoing looking at trials both domestically and internationally, should we expand the indications for ruxolitinib use in P. Vera in other settings? Should there be a frontline setting that it should be considered for higher risk for other things? A complex economic discussion, which is why that really wasn’t pursued to begin with, but just from an efficacy standpoint, it’s a fair question.

Srdan Verstovsek, MD, PhD: I like the point earlier you made about looking at our own practice with standard medications in Hydrea and interferon, until now, and see whether we actually did a good job or not. And are we not perhaps treating everybody well enough, and maybe those patients needs to be changed to ruxolitinib. And this kind of retrospective analysis is quite information. In fact, we are, including myself, not really good or haven’t been very good in fully, but exploring the potential of a frontline therapies. Or unable to deliver and then we should recognize that as a need for something new.

Harry P. Erba, MD, PhD: I agree, I think there’s been some complacency. These patients didn’t cause us much trouble, especially for a practicing oncologist who’s busy with patients with solid tumors that are active or metastatic. These patients were easier and so maybe didn’t get as much as attention as they deserve, I think with ruxolitinib being available and other drugs being developed in this area, I think it’s really focused attention on a group of patients who have been sometimes neglected, to be quite honest.

Transcript Edited for Clarity 
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