Evolving Role of JAK Inhibitors in Myelofibrosis and Beyond - Episode 7

Management of Toxicities in Patients Treated for MPN

December 24, 2019

Rami Komrokji, MD:You mentioned with ruxolitinib, obviously, that anemia, cytopenia is on target. You briefly mentioned some of the things we do in clinic using ESA [erythropoiesis-stimulating agents], sometimes thalidomide, danazol. Do any investigational agents have promising adjunctive therapy to ruxolitinib to alleviate anemia? I think you’ve led some of the original studies with the sotatercept, so maybe you can tell us about use of TGF-beta inhibitors in conjunction with JAK2 inhibitors.

Prithviraj Bose, MD:This is a very interesting area. This is a novel class of agents, sotatercept and luspatercept. These are activin receptor ligand traps. Basically, they are fusion proteins that bind up and sequester these ligands, which inhibit the terminal stages of erythropoiesis. Basically, by taking the ligands away, they don’t let them bind to the activin receptor, so that pathway is no longer active. Yes, we did an investigator-initiated trial with sotatercept, and we saw activity there, both with ruxolitinib and on its own. I think with ruxolitinib it is more relevant because of what you said, because ruxolitinib causes anemia, and it’s important to counteract that.

Then luspatercept was just approved for beta thalassemia. We had also heard at the 2018 ASH [American Society of Hematology Congress] about the MEDALIST trial, which was positive in lower-risk MDS. There is a trial in myelofibrosis, again looking at it alone or in patients, as well as in patients on ruxolitinib, both transfusion dependent and independent. The first results were at ASH 2019, and there too we are seeing activity. This was not a registration trial, so it remains to be seen what the path forward is in myelofibrosis, but it’s definitely a very exciting drug.

Rami Komrokji, MD:Absolutely. Thank you. Moving from anemia, let’s go to polycythemia. Obviously, polycythemia vera [PV] is another common myeloproliferative disease that we deal with. Can you briefly highlight your approach of risk stratification for patients and evolving new data on other variables that are important, in terms of prognosis for [polycythemia] vera? Then we’ll talk a little more about treatment.

Prithviraj Bose, MD:Sure. PV—I mean, this is 1 of the things that really hasn’t changed in a long time. When we were in training, this is the same that we learned about risk stratification, at least officially, which is that a low-risk patient is somebody who is younger than 60 years of age and has never had a thrombotic event. A high-risk patient is 60 years of age or older or has had a thrombotic event. That is still the same. That has not really changed, although there is increasing recognition that leukocytosis plays into the thrombotic risk—not the platelet counts but the white count. There’s a lot of mounting evidence for this, so perhaps it will get into the formal risk stratification. It hasn’t yet, but it is something I pay attention to in the clinic. If I see, for example, progressive leukocytosis, I’m going to try to change treatment to control that.

Frontline for me, as for most people, is hydroxyurea. There was a study comparing hydroxyurea head-to-head against pegylated interferon, and there was no difference. Follow-up was short, but at least at that follow-up there was no difference. Clinicians are fine using either one. It’s probably a matter of preference. I think interferon can have some difficult adverse effects, which can lead to discontinuation, but it’s certainly an effective drug and can cause molecular remissions as well.

Then we run into the hydroxyurea failure situation. There is a definition for this, and while that’s useful as a framework, people tend to use their own clinical judgment for deciding when a patient is either resistant to hydroxyurea or intolerant to hydroxyurea. Intolerance is intuitively easier to understand, but resistance—again, if your counts are not being controlled, the spleen is not being controlled, symptoms are not being controlled. There are certain definitions for these things. But that will be an indication to change.

Ruxolitinib is approved as a second-line agent, which is usually what I do. Interferon can also be used, but given the RESPONSE trial, which was a trial in these very patients who had hydroxyurea resistance or intolerance, ruxolitinib beat the best available therapy for a number of different end points, like hematocrit control, spleen volume reduction, symptom reduction, complete hematologic response rate. All of those things were superior for ruxolitinib, so that’s what I tend to use in that setting, in the hydroxyurea failure setting.

Rami Komrokji, MD:Absolutely. I think it’s peculiar about the use of ruxolitinib in [polycythemia] vera compared with myelofibrosis. The dosing is different a little. Adverse-effect profile?

Prithviraj Bose, MD:Dosing is different. So, 10 mg twice daily is where we start, and whereas in MF [myelofibrosis], we start based on the platelet count unless they are very anemic, as we discussed. Adverse-effect profile, as I alluded to earlier, my perception is that the shingles reactivation is more in the PV patients. I think that’s what the RESPONSE trial reported as well, if you compare that with the COMFORT trials. Again, anyone on ruxolitinib in my practice gets vaccinated against shingles.

Rami Komrokji, MD:My practice is very similar to what you alluded as well. Obviously, if patients need cytoreductive therapy by virtue of being above the age of 60, because the risk of arterial events increase or if they’ve had event, if they’re high-risk, then I will add cytoreductive therapy in addition to phlebotomies and baby aspirin for those patients. I do also keep an eye on the leukocytosis. Sometimes it’s 1 other variable that will make you decide initiating therapy for patients. Hydroxyurea is still the most probably common standard. In younger patients or those patients who are motivated to achieve a low percentage of molecular remissions, I will discuss with them that pegylated interferon. I think we will hear updates on the ropeginterferon that’s approved in Europe but not in the United States yet. But interesting data about molecular remission. I think patients have to be motivated about the treatment because, as you mentioned also, the toxicity profile with interferon is more, second line, I move to ruxolitinib in those patients. I think we have similar patterns of practice.

Prithviraj Bose, MD:Yes, ropeginterferon is interesting. It is approved in Europe, as you said. It’s given once every 2 weeks, which is an advantage. And it was a frontline trial versus hydroxyurea, where they were initially noninferior but later superior. Because interferon takes longer to achieve those endpoints.

Rami Komrokji, MD:I think all over it’s really exciting time. We have 2 JAK2 inhibitors approved, potentially 2 others, and ropeginterferon approved in Europe. I think our understanding for those diseases has evolved dramatically over the last few years with the next-generation sequencing and the molecular data. Any final remarks or comments you would like to add?

Prithviraj Bose, MD:I think finally after a very long time, this space is really exploding with drug development initiatives. JAK2 was discovered in 2005 and CALR, in 2013. Obviously, it was theJAK2mutation discovery that led to ruxolitinib and the JAK inhibitors that followed. But it’s great to see so many different mechanisms of action being exploited. I’m sure there are many that we didn’t touch on today, but it’s great to see this happening in our field now.

Rami Komrokji, MD:Thank you. Thank you, Dr Bose for this insightful discussion. And thank you to our audience for watching thisTargeted Oncology™ presentation on JAK inhibition in myelofibrosis and beyond.

Transcript edited for clarity.