Selecting Optimal Frontline Therapy for Patients With Myelofibrosis

Expert Roundtable Part 2

In this expert roundtable series, Firas El Chaer, MD, University of Virginia Comprehensive Cancer Center, Charlottesville, Virginia, leads a roundtable panel discussion on updates in myelofibrosis with Raajit K Rampal, MD, Memorial Sloan Kettering, New York, New York, and Lindsay A M Rein, MD, Duke University Medical Center, Durham, North Carolina.

In part 2 of the roundtable, the experts discuss their strategies and process for selecting best first-line therapy.

Transcript:

Dr El Chaer: After risk notification, now we decide on frontline therapy. Now we have 4 US FDA JAK inhibitors approved in the United States. I think it's a bit becoming a little bit confusing which one to use, when to use it. I just want to get a little bit of guidance. Maybe we can start with Rampal. In your clinic, a patient comes to your clinic, what factors do you look at to decide which JAK inhibitor you're going to use in that particular patient?

Dr Rampal: Well, I think I would broaden my response out by saying it's always a question of what's the problem, right? There are some patients who don't need any therapy, at least in the current era, which is not satisfying to not intervene, but the data may not support it. There are patients who've got spleen symptoms, and these are your JAK inhibitor patients. Then there's some subset of patients who perhaps just have anemia and they don't really have a spleen issue or constitutional symptoms and those are patients who are thinking about ESA [erythropoiesis-stimulating agents]. Maybe something like luspatercept or other drugs may be the right move just because all you're trying to do is help them with their anemia.

Getting to your more specific question on the JAK inhibitors, I mean, we're lucky to have the number of JAK inhibitors we have in the moment that we actually have choices and that these drugs serve different needs, which is also really important. I think that for patients with preserved counts who are highly symptomatic, ruxolitinib is certainly the drug we've used the most and we have the most experience with, and we are really adapted to knowing how to manage its side effects. So that often becomes our first choice, but the problem has always been what do you do with the patients who have come to the point of needing therapy and they are very anemic, meaning that they're symptomatic from it or they need transfusions. That has always been a more challenging patient population.

Of course, the most challenging patient population has been thrombocytopenia, because not that many years ago, somebody with platelets in the 40s to 50s, we would put on a subtherapeutic dose of ruxolitinib and we had to be satisfied because that's all we could really do. In patients who are anemic, the first question is how problematic is that anemia? If you have somebody who's hemoglobin is in the 9s, they have no problem, they're out running on a daily basis. It is probably reasonable to think about first line therapy with ruxolitinib or even fedratinib.

But for somebody who perhaps is a little bit more fragile and is not going to tolerate worsening anemia or who comes in with let's say hemoglobin in the high 7s where it's going to fall further and getting transfusions is going to be difficult for them, and let's be real, there are lots of parts of our country where it's just not going to be accessible.If someone's going to have to drive a couple of hours to get transfused, that has to be taken into account and how we think about managing a patient.

For those patients we do have drugs like momelotinib and pacritinib, which can help us mitigate anemia. With the data with momelotinib, this has been seen more in the upfront setting where at least from even simplify one, we know that you can preserve transfusion independence early on.

For patients with thrombocytopenia, again, it's a relative thing, right? Somebody with platelet counts that are in the high 80s or 90s, you could probably reasonably give them ruxolitinib. There is good data that you can dose escalate up to an effective dose like 10 twice a day in that population. But for somebody who's starting out with platelets of 50 to 60, you're going to run into trouble the minute you start therapy. We know that momelotinib we could use down to a platelet count of 25,000 and pacritinib its unrestricted. In those situations, using one of those drugs may be better in order to maximize dose intensity of the drug that you're using.

Dr El Chaer: Thank you. To summarize, you're looking at, of course, patient, if [they’re] symptomatic or not symptomatic to offer JAK inhibition asnd number 2, you look at thrombocytopenia, the level of thrombocytopenia, not only the absolute, as well as anemia and the level of anemia, whether it's symptomatic or not. Dr Rein, if someone is predominantly, a spleen bothering them versus someone else predominantly symptoms bothering them, do you have a favorite first line treatment for those 2 different patient populations?

Dr Rein: Realistically if I've got somebody who's highly symptomatic, big spleen, lots of constitutional symptoms, a lot of fatigue, that's where I typically go to ruxolitinib if I can get a reasonable dose in. If I can get at least 10 BID or 15 milligrams, BID of ruxolitinib into a patient in general, that's my preference for those highly symptomatic with big spleen type patients. Again, if you've got somebody who perhaps has fewer symptoms or some symptoms and has anemia or that particular component or other cytopenias, that's where I start thinking about use of other agents like the momelotinib or pacritinib. That's kind of the breakpoint for where I start to think about those other agents.

Dr El Chaer: It's important to note, although most of these medications are JAK inhibitors, they can affect JAK1 more than JAK2 and vice versa. As well as they can attack other receptors such as [with] momelotinib and pacritinib. They have ACVR1 inhibition, which of course adds to their anemia improvement that we benefit from those drugs. It's a good thing to have that.

We have 4 drugs that we can choose from, and this makes a little bit things more interesting when your patient disease, unfortunately these are non-curative drugs for our patients, the allogeneic stem cell transplantation is the only cure, and at some point the disease will progress whether you call it refractory or resistant or relapsed disease.

In your practice, when are you concerned that your patient is progressing? When do you start thinking about switching therapy? Do you dose escalate first before switching? Maybe we can start with Dr Rein, your approach to identify those patients whose disease is relapsing.

Dr Rein: Million-dollar question. I think this is what we all struggle with. I personally, in my practice, I tend to maximize particular agents before I switch. So when folks come to clinic and I'm talking to patients, I really approach this more of a marathon as opposed to a sprint in a lot of folks, especially the older patients for whom you're not considering stem cell transplant, so if we're going to try and make people feel better for a longer period of time. In terms of how I approach patients, if I've got older patients not heading for transplant, I tend to think of it as a marathon and maximize therapeutic options. If I've got younger patients, somebody that I'm wanting to get to a transplant, I need to shrink the spleen. Those are patients that I'm going to be more aggressive in terms of upfront management.

Then the question becomes, well, how do you decide when people are failing or no longer responding? And I think that's going to be different per patient. There's some obvious things that we obviously look for, so progressive splenomegaly. If you've had a response, say to, ruxolitinib, and now the spleen is growing and patients are developing new symptoms related to splenomegaly; early satiety, worsening constitutional symptoms, that's somebody for whom I would consider switching to an alternative agent. If I'm struggling with progressive cytopenias, increasing transfusion requirements, again, different lab abnormalities like that, that's also a sign for me to switch or consider switching therapies.

Progression of symptoms for patients, and that's a hard one because how do you decide what really is progression from that? But if patients are having more symptoms, more constitutional symptoms, more fatigue, those are scenarios is where when I'll start to think about transitioning to an alternative agent. Again, I do really try to maximize the amount of time I leave patients on agents if they're deriving benefit.

Dr El Chaer: Dr Rampal, I just want to touch base a little bit still on the first line therapy. Do you combine other drugs with JAK inhibitor nucleic in the first line? Particularly I'm talking about ESA, luspatercept, danazol, especially if they have anemia or let's say other drugs, TPO agonists, if they have severe thrombocytopenia, what is your approach in those settings?

Dr Rampal: Yeah, let's just say you start therapy, and somebody's hemoglobin drops a little bit more than you would've expected, you started them on ruxolitinib, which this happens because it is usually not a predictable thing how deep of a drop you're going to get. For those patients, we often will add ESAs if they EPO level is under 200, 250 or so. Luspatercept can also be used in this space. Obviously, this is not FDA approved or MF, it's FDA approved for MDS, but it is in the NCCN guidelines and there's also good phase 2 data behind it. So sometimes we will go to luspatercept and sometimes what helps us make that decision, since these are patients with JAK2 mutations who are prone to clotting, anyone who's had vascular disease or has had a clotting event, we really do try to stay away from ESAs and go to luspatercept.

There is a bit of a difference in terms of thrombotic risk with the 2 agents. We've also added other agents in the past, thalidomide being one, we've done phase 2 studies that we've presented at ASH, and that can be useful for patients who have both anemia and thrombocytopenia as the drugs can be combined safely and it can actually increase the levels of both the hemoglobin and the platelets. In frontline, those tend to be our go-to combinations if needed. We've really shied away from using tpo mimetics and drugs of that class, and the concern being that you're stimulating the megakaryocytes, which could perhaps worsen the fibrosis, so I've not used that generally in practice.

Dr El Chaer: Just to piggyback on progression still, do you use the RR6 model in your clinic when you assess your patients? For our audience, it's a website that you can access that you evaluate the patient's clinical symptom, spleen size as well as the, it's basically for ruxolitinib dose as well as the level of anemia at the zero, month 3, and month 6. Do you apply this in your clinic?

Dr Rampal: Yes and no. Yes and no. Meaning that I don't use the actual RR6 model, I use the principles from it, and there's a couple of key things. One is that if patients don't achieve spleen reduction, and that study I think was by palpation, not by volumetric analysis, those patients are more likely to do worse, but that echoes data that we've known for a while, which is that if you don't get a spleen volume reduction, and this is data from COMFORT I and II, those patients do worse than patients who actually have a volumetric reduction.

In our practice, we get spleen volume assessment by ultrasound at baseline, but I also do it at 6 months and then at 1 year, and I usually do it once a year. That to me is kind of a canary in the coal mine. If you're not getting real spleen reduction or it's starting to increase, to me that's a problem. That's kind of consistent with the RR6 approach.

The second is anemia, right? All of the data to date has suggested early on if somebody develops a transfusion-dependent anemia on ruxolitinib, for example, you can tolerate this. It doesn't seem, it's like it's going to have a long-term impact, but if they persist in having transfusion dependence now 6 months out, this is a problem because it is associated with a worsened outcome. In a patient like that who is let's say, had transfusion dependence to begin with or began to have it with therapy and it's still going on 6 months from the outset of therapy to me that's a problem that this patient is not going to do as well. I need to think about another treatment, adding something to help with anemia, transplanting this patient earlier. To me that's a warning sign. I think the principles of the RR6 definitely I tend to use in guiding whether or not I think the patient is on the right trajectory or not.

Dr El Chaer: Awesome. Dr Rein, do you have anything to add?

Dr Rein: No, I echo the exact same sentiment. I mean, I think we use the principles, I don't know that I pull up the calculator, but certainly the principles hold true.

Dr El Chaer: I'm assuming the same principle applies for the other JAK inhibitors that we have, although the RR6 focus on ruxolitinib, when you decide, let's say to use momelotinib in the very beginning, fedratinib or pacritinib.