Andrew Schorr: Hello, and welcome to Patient Power. I’m Andrew Schorr, and I’m with a noted MPN specialist and that’s a fellow I’m quite friendly with. That’s Dr. Raajit Rampal, who’s Director of the program for MPNs and rare hematologic malignancies in one of our very top cancer centers, Memorial Sloan Kettering Cancer Center in New York City. Raajit, welcome back to Patient Power.
Dr. Rampal: Andrew, thank you for having me, and a pleasure to be here, as always.
Andrew Schorr: So, Raajit, you do a lot of research and see a lot of patients. People come from all over to see you. Like me, living with myelofibrosis for many years, many people have been on a JAK inhibitor, and fortunately, the JAK inhibitor landscape is growing.
So then the question comes up; at some point, is there an indication that we need to change JAK inhibitors? I want to talk to you about that, what’s involved in the change, what the appropriate expectations are, and any precautions we need to take if we do that. So let’s start with, why change? I understand there’s something called cytopenic myelofibrosis. What does that word mean? What does it mean if you develop that?
Dr. Rampal: Yeah. That’s a great question, right? I think we’re coming to the point where we’re thinking about myelofibrosis now, a little bit differently, and there are a lot of different ways to slice it. But one of the fundamental points that is important for everybody to remember is that myelofibrosis is a spectrum of diseases. It is not one distinct entity, and how it manifests in different patients is different. One way to divide it up is what happens to the blood counts.
Now, there are patients who come in, and they had ET, or they had PV, and they’ve now progressed to myelofibrosis. The tendency in those patients is for their blood counts to be elevated. People who, for example, had polycythemia, may not have any anemia, but they have myelofibrosis.
On the other hand, we have patients who, when they come in and present with the disease, their counts are all low. So their platelets are low; they’re anemic. And those are the patients that we term “cytopenic MF.” So, in other words, patients whose blood counts are lower than normal.
Andrew Schorr: And related to anemia, if I am having more and more problems going up the steps, or even getting out of bed, the same thing.
Dr. Rampal: Exactly, right? Because coming back to the idea that anemia is not a black-and-white issue; it’s grades of anemia. And if the anemia is now getting to the point, as you just said, where it’s affecting your ability to do even simple things during the day, that requires reevaluation.
Andrew Schorr: Okay. Now, anemia – so that’s a problem with the red cells, right? And then thrombocytopenia is a problem with the platelets, and I’ve been blessed with both problems, unfortunately.
Okay. So now, first of all, is it possible that the JAK inhibitor we’ve been on beyond the disease drives those counts down?
Dr. Rampal: You’re exactly correct. There are two ways to think about it. The disease itself can cause these manifestations of having low platelets or low red blood cell count. But the JAK inhibitors, based on the mechanism by which they work, actually all cause some degree of anemia, low red count, or a low platelet count. It varies amongst the different JAK inhibitors, but they all do this to some extent. So there is disease-related and then there is therapy-related. Exactly.
Andrew Schorr: Okay. But now we have an expanding landscape of JAK inhibitors, and more research going on all the time that you’re a part of, and we’re very grateful for that. So would it be an indication then if somebody has these anemia or platelet issues, where you would consider changing to a different JAK inhibitor that maybe has some benefit, may be assessed by the FDA, that might be better in that situation?
Dr. Rampal: Yeah. There are a couple of scenarios that pertain to that. One is that in a patient who’s got low platelets, one of the things, with regard to some of the JAK inhibitors, is that we dose them based on the platelet count, and this is particularly with ruxolitinib (Jakafi) or fedratinib (Inrebic). Meaning that with ruxolitinib, if the platelet count is low, we have to lower the dose of ruxolitinib. But we also know that if you lower the dose of ruxolitinib, the effectiveness of it goes down. And so, you end up in a tough situation where the platelet counts are low. And therefore, you’ve got to reduce the dose of the ruxolitinib that you’re using, and you will end up with less efficacy from that dose. It’s a vicious cycle. But that is now a reason to potentially switch therapies in the landscape of the drugs that we have. So that is a reason, certainly, to think about switching to a JAK inhibitor.
Now, beyond that, we have anemia, right? And so, anemia is not a binary thing. There are degrees of anemia. And for some people, anemia is just a number on paper, and they really don’t feel it. But for other people, they feel it. They get short of breath, and they can’t do what they want to do. And we know the JAK inhibitors can make that worse – ruxolitinib and fedratinib.
But now, we have some newer JAK inhibitors that, at least, in a proportion of patients, because of the way they work, may actually increase the red count. And so for a patient, for example, who is requiring regular red blood cell transfusions, being on the JAK inhibitor, that may be an indication to switch to one of the newer JAK inhibitors that may actually improve the red blood cell count.
Andrew Schorr: Okay. I think you call it a “mechanism of action.” So the mechanism of action is not always the same.
Dr. Rampal: Correct. And I think that it’s an important point, in that all of the JAK inhibitors inhibit JAK2, which is really one of the main drivers, but there is variability in terms of whether or not they inhibit JAK1 or other pathways. And so we have to think about the JAK inhibitors as different branches of the same family tree. They’re not all in the same branch. They’re all slightly different.
Andrew Schorr: Okay. So if you said to me, as my doctor, “Andrew, based on your cytopenia, I think it’s time to change from one JAK inhibitor to another,” it operates a little bit differently. Talk about that transition. How do you make the move? Is it to stop one set of pills one day and start the next? Is there a washout period? Is there a dose reduction? What do you do?
Dr. Rampal: We’re at the point where we have all of these new drugs, but we need to do some thinking about how we do this. Because we haven’t been in a position where this has been a necessity for the majority of patients, but now we have options. Do we have a set way to do this? No, I don’t think we do. And I think, if you talk to enough people, you’ll hear different opinions about how to do this.
The one thing that is certain is this has to be done with an abundance of caution. Meaning that what we have to be careful of is, we know that if you, for example, stop ruxolitinib in patients, they can have a flare of their symptoms that can be quite traumatic. The spleen can increase. A lot of things can happen. So, one wants to think about doing this in a very cautious manner.
Now, there are different approaches that many people in the field use. One is to get the ruxolitinib dose to, maybe, five milligrams twice a day, and then switch the next day to the next JAK inhibitor. A reasonable approach. Some of my colleagues are actually overlapping the JAK inhibitors for a day or two so you’re actually using two different drugs for a day or two. Not that we have any safety data to tell us how safe that is, but at a low enough dose, it’s probably not an issue.
But one thing I think is reasonably certain is that you don’t really need a washout period. The washout periods have been used as part of clinical trials just to try to get a clean reading, but in clinical practice, I see no reason to do a washout. The drugs last in the body for different amounts of time. Pacritinib (Vonjo), for example, lasts longer than ruxolitinib, which has a relatively short half-life. Meaning that it’s out of the body in four to six hours, or half of it’s out of the body in four to six hours.
So I think the major takeaways are that the transition must be done very carefully. That there really isn’t a reason for a washout period. That switching from one drug to another on the next day – so taking the low dose of ruxolitinib on Tuesday and starting the pacritinib on Wednesday is very reasonable, and some people have started overlapping them for a day or two, just out of an abundance of caution.
Andrew Schorr: So what’s a fair shot for a new drug if we switch? And you might have more than one option to switch to. We switched to drug number two from drug number one. How long do you give it to see if that was the right choice, or do we need to go to drug number three?
Dr. Rampal: Most of the data that we have, in terms of the results of the drugs working – when one has switched from one drug to the other – are read out at six months. Now, do we need six months? I don’t think the answer is yes. Because if you look at the benefit of many of these drugs, the maximal benefit will occur around three months. So it’s a bit of a balance between giving the drug an honest try, and not being too quick to switch to another one, versus just saying, let’s continue to wait, and wait, and wait.
So, for most things like spleen and symptoms, I think three months is probably a reasonable trial. For anemia, I think it’s still – we’re not entirely clear. Because we see, sometimes, improvements in anemia occurring later on in four, five, or six months, but it certainly can occur early on. So I think it depends, number one, on what it is that we’re trying to see get better, and that will inform us in terms of when we might expect to see it get better.
Andrew Schorr: Dr. Rampal. So then, if we’ve been taking a JAK inhibitor for years, as I have, and you switch to another – and you said they can be slightly different – then you wonder about different side effects. So, how do you prepare for that? What might be new or different side effects for drug number two?
Dr. Rampal: An important question, and I think that is something that needs to be discussed with a patient before the switch happens. So people need to know what to anticipate and what to watch out for, and everything varies from patient to patient. But we know that some of the JAK inhibitors, for example, fedratinib, and also, pacritinib have a fair amount of gastrointestinal side effects, but the key to managing those is to anticipate them and treat them early on. And I think that’s a really important thing that is, of course, important for the physicians to know, but particularly for the patients. What sometimes happens is that if we know there’s a high incidence of gastrointestinal side effects, we don’t want to wait for things to get out of control. This is like containing a wastebasket fire and not letting it become a forest fire, right? You want to intervene when it is a wastebasket fire.
And so, educating our patients that “Listen, there may be diarrhea with this, but if that occurs you need to take loperamide (Imodium) right away, to reduce that, and it will get better over time. Those are the things that we’ve got to make sure we’re communicating.
Andrew Schorr: Okay. So then we go to the next question. And that is, how do you know if it’s working? You decided to make a switch – the patient and the doctor together – to get some benefit. How quickly does this roll out? Is it “Oh, my God. Tomorrow, it’s going to be different. Is it going to take days or weeks?” How do you know?
Dr. Rampal: Yeah. I think the question is, what are we trying to get? What’s the major benefit we’re trying to get, right? So that could be a couple of different things, and that could be that we want the spleen to get smaller, we want the symptoms to get better, we want the anemia to get better, and the expectation for all of these things is a little bit different. So, with regard to the expectations for spleen size, it could take a couple of months, two to three months, to get our maximal benefit in terms of shrinking the spleen.
With symptoms it varies, and with some of the JAK inhibitors, it could be days to a week, and with others, it’s going to take more than that. It’s going to take several weeks. So I think for each issue that we are trying to address, we need to have some set of expectations in terms of when we may see the benefit. And if we’re not getting there, then we have to think about “Do we need to switch drugs?”
The anemia thing is a little bit different, though. So what we know with pacritinib, which is one of the drugs where we’re seeing some benefits in terms of improving the red blood cell count, that benefit is variable. It could take a few weeks. But in some of the data we’ve seen, it occurs even a couple of months afterward, right? So I think that’s where it gets a little bit trickier, in terms of our expectations, because we’re still learning when we should see those responses. But for things like spleen and symptoms, we have a better idea of when we should start to see responses if they’re going to occur.
Andrew Schorr: So, what about monitoring? If I were your patient, and we were going through this transition, would you ask to see me more often, or have certain tests to see how we’re doing?
Dr. Rampal: Yeah. I think the answer is absolutely yes, but we need to be mindful of a couple of things. What’s the effect on the blood counts? Could it be a worsening of the blood counts? Sure. That’s a possibility. Number two, what are the side effects? As you pointed out, when we’re switching drugs, we may very well encounter new or different side effects. And we need to be cognizant of that and make sure that we are checking more frequently, initially, with the patient on how they’re feeling on the drug and making appropriate adjustments in terms of other medications that can help them.
And then, longer-term, it’s a question of the assessments that we want to do. I’m, at least, a believer that we should be getting ultrasounds, or other images of the spleen, to know where we are when we start any therapy. And where we are, for example, three months later, to really give us some objective data in terms of what we’re accomplishing.
Andrew Schorr: Let’s talk about the emotional side of this for a second. Because, obviously, when somebody’s living with myelofibrosis, there’s a lot of uncertainty. If you have a discussion with your doctor about changing meds, that adds uncertainty and worry. What’s next? Will it work? Side effects. Everything we’ve just talked about.
Tell me if you agree with this. Is – yes, all of that’s true. But in your field, in the field we’re all in together now, isn’t it great that we have these options to even discuss?
Dr. Rampal: The bottom-line answer is yes. But it is an interesting way you’re putting it in the sense that – “security blanket,” maybe, is the wrong term, but people get accustomed to a drug that’s given them benefits, right? In other words, a lot of patients have gone from a point where they were highly symptomatic, they’ve been on this drug, and they have gotten to a level where life is better. And now we’re saying, “We’re going to modify that.” Of course, that’s unnerving. Why wouldn’t it be, right? That certainly can provoke anxiety. There’s no question about that, right?
But I think the way to think about that is, all of the ways the drugs have been approved have been for the same criteria. Meaning they improve symptoms, and they improve the spleen, right? So the expectation should be that those things, hopefully, continue to be controlled with, potentially, an added benefit. Because otherwise, why are you switching the drug if not for an added benefit?
So I think that, maybe, the way for us to think about it with our patients is that we’re transitioning to another thing that is likely to help. And yeah – this is a really great point that you’re making, right? I think that people have been on the drug for years, they become accustomed to it, and what they perceive it to be doing for them. So, no. I think that’s a great point. But that, maybe, is the message: these drugs, all relatively speaking, have the same benefit, but with some differences, in a positive direction.
Andrew Schorr: Right. And I’ll tell you. I was switched, one time, from one JAK inhibitor to another. And I went to the pharmacy, and I had all kinds of new side-effect management medicines. And fortunately, none of them were needed, but I was stocking up, and I didn’t know – and it has been effective. Should I need to change again, would my heart beat a little faster? Sure.
But I think the point for our audience is Dr. Rampal – and there are others around the country who are true MPN experts. Most of them – many of them – have been involved in the research of these drugs that now have been approved, or are coming soon, and so they have a lot of experience with them. So it’s not just “Oh, here’s a newly-approved drug. We’re going to switch you, and we’re on an adventure together.” It’s not that at all. Because you’ve had lots of patients in trials, right, Raajit?
Dr. Rampal: Exactly, correct, right? And I think that – not to go too far off of this message. Going into a clinical trial, of course, that brings trepidation. We’re dealing with something with an unknown efficacy or where there’s limited data. Switching to another JAK inhibitor that’s been FDA-approved means we do have a much more substantial piece of data. Otherwise, it never would have been approved, right?
And so I think that we can have confidence in switching. And going back to something that I said earlier which is, we make the switch for a potential benefit not empirically, and I think that is one of the key messages here, right? Because if it’s an empiric switch, who knows what’s going to happen? If we’re doing it with a specific reason in mind, for a specific benefit, hopefully, that does provide reassurance.
Andrew Schorr: Right. It’s not just because something’s new. Got it.
Well, this has been a very helpful discussion for me, personally, and I’m sure for our audience. As always, I want to thank you for all the work you do in New York, and with your colleagues around the world, in really helping this field advance. And it does give us confidence just to be able to talk to you and hear that you’re feeling positive that we have these options.
So, Dr. Raajit Rampal, from Memorial Sloan Kettering in New York. Thanks for all you do, and thank you for being with us once again on Patient Power.
Dr. Rampal: It’s my privilege and my pleasure.
