Harry Erba, MD, PhD: How do we actually treat these patients? Mary Frances, I’d like you to walk us through that. What are the goals of therapy in PV [polycythemia vera]? How do you select patients for phlebotomy, low-dose aspirin therapy, and those who need cytoreductive therapy?

Mary Frances McMullin, MD: The goal of therapy that everybody would want is cure and removal of the disease or the acquired clone. We don’t have that, and I’m going to talk about it in another context later.

There are 2 things that we’re treating. There are particular blood count levels to which we aim for, and in particular hematocrit less than 0.45 and possibly a reduction of the platelets and white cells with therapy. The other thing we need to think about is symptoms. And the patients, as Robyn has alluded to, have a lot of symptoms, and these are major in some of these patients. At the time we had good therapy, which will actually control or improve the symptoms.

The other thing we would like to think of would be if we could prevent progression to myelofibrosis or leukemia. But again, those are the things we would like to do if we have the funds available. From a practical point of view, when we put patients on therapy. we’re looking at control of the blood counts and hopefully improvement in their symptoms.

Harry Erba, MD, PhD: Well, you brought up a lot of issues to discuss. One of them is anything that might be a disease-modifying agent. Moshe, who’s with us today, did pioneering work with interferon in chronic myeloid leukemia, and John has been involved in some of the studies of interferon in polycythemia vera. One of the reasons why people have been proponents of it is maybe it’s a disease-modifying agent. We’ve seen decrease in JAK to allele burden. John, tell us more about what we know.

John Mascarenhas, MD: As Moshe can tell you, interferon is obviously a therapy that’s been used for quite some time. It’s not novel per se, and we believe it has an anticlonal, antihematopoietic stem cell effect with multiple mechanisms that are probably not well understood. But the reality is interferon in different formulations, but more likely in pegylated formulation—a more tolerable form that’s given less frequently—is a therapy that we employ. And it’s regional. I think it depends where in the world you practice or where in the country you practice.

We’ve done studies evaluating pegylated interferon alfa-2a, which is Pegasys, in patients with treatment-naïve high-risk polycythemia vera and essential thrombocythemia. This was a phase III study done through the MPD-RC [Myeloproliferative Disorders—Research Consortium], which Mary Frances was involved with from the beginning, as well as Robyn and many other investigators throughout the world.

This was randomizing almost 175 patients with high-risk disease to either Pegasys or hydroxyurea. These are treatment-naïve patients who had the disease for less than 5 years.

If you look at the data, one has to really understand the nuances of that. At 1 year the CR [complete response] rate is really not statistically different. The CR rate—meaning normalization of the counts, the spleen, and symptoms—is pretty much the same between hydroxyurea and interferon. It’s really after 2 years or so of therapy. It’s clonic therapy with interferon. We’re using doses of 45 mcg weekly and titrate it up slowly with Pegasys trying to balance the toxicity with the efficacy. It’s really not until 2 or 3 years that you start to see a change in outcomes.

You start to see more responses with Pegasys and perhaps more drop-off with hydroxyurea. That’s probably best demonstrated in the ropeginterferon studies that were run, which is really interferon alfa-2b, and a monopegylated form of the drug called the PROUD-PV, the continuation PV study. It was more of a European study that randomized the patients between this formulation of interferon versus best available therapy, which was basically hydroxyurea.

What they saw was it wasn’t until 2 and 3 years that you saw divergence in the CR curves. You saw reductions in JAK2 V617F allele burden as a surrogate for disease-course modification, although—and I’m the first one to say it—we don’t really have data that confirm that that actually associates with longer survival or less disease progression. It’s sort of intuitive that it would and presumed.

If people embark with interferon, which I think is reasonable for patients who are younger in age, particularly with a longer arching theme of trying to control their disease. It’s a drug that can control white counts, red counts, platelets. You have to balance again some of the symptomatology with the disease and the adverse effects of the drug. It would be a long-term effect in which one can follow serial allele burden for JAK2 or CALR if it’s an ET [essential thrombocythemia] patient.

Moshe Talpaz, MD: One of the problems with interferon is that you need the observer, the investigator, to live a very long life in order to control the studies. Because you may need to do studies that stretch over 20 or 30 years in order to have definitive answers, and we may not be able to get this. I’ll give you an anecdotal case.

Harry Erba, MD, PhD: Well, I’m happy that’s happened for you, Moshe.

Moshe Talpaz, MD: I studied it in 1998; it was a long time ago. A patient who I started with essential thrombocythemia but JAK2 positivity. I started to treat her in the late 1980s. And she developed a complete molecular response after 25 years. She is in remission now, after 30 years on therapy. She still gets it on and off.

In other words, it is a very difficult study to do. There is unique biologic activity to interferon, but to really figure it out and sort it out we need to design studies that stretch over very long periods. Because at least the report for now shows that there is no difference in survival between hydroxyurea and interferon. But that’s not the therapist. The therapist is very long-term follow-up.

Harry Erba, MD, PhD: That brings up an issue about this drug. It’s not FDA approved though for PV.

John Mascarenhas, MD: It is approved for hepatitis. In Europe ropeginterferon is now approved for polycythemia vera based on these data from the continuation PV study and the longer-term follow-up. It is now with the FDA for review.

Harry Erba, MD, PhD: That would be helpful because it is a barrier for some.

John Mascarenhas, MD: Yeah, I think it would give patients access to an old but biologic drug that has activity. I would like to think that as we move into 2020, we’re going to continue to move ahead and progress in terms of translating science into new drugs.

Moshe Talpaz, MD: Let me have 1 point on interferon. To a large extent, I am restricted to patients under 50, although it’s an arbitrary number, I am concerned with the effect on the brain, especially the development of dementia and depression in older age. And I’m avoiding older ages from the use of interferon, unless the patient insists on getting it. And it happens. Overall, I restrict it, and I think it’s a good-to-very-good option for young individuals in their 20s and early 30s.

Mary Frances McMullin, MD: The neuropsychiatric complications that are sometimes underappreciated and underwatched have to really be carefully watched, because patients can develop anxiety, depression, and even almost a dementia syndrome if it’s not monitored carefully.

Transcript Edited for Clarity