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Determining the Potential of Ropeginterferon Alfa-2b in 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 27, 2018



Transcript: 

Harry P. Erba, MD, PhD: In terms of the last emerging agent that we have time to discuss today, I want to turn our attention to a new formation of interferon, ropeginterferon alfa-2b. There have been a couple of studies looking at this agent recently, but 1 in particular was the CONTI-PV study. Do you want to tell us about that, Ruben?

Ruben A. Mesa, MD, FACP: Without question, interferons are very active in myeloproliferative neoplasia [MPNs]. We certainly know interferons were active in chronic myeloid leukemia. They’ve been superseded, of course, by the TKI [tyrosine kinase inhibitor] therapy, but they were active. Interferons in the Ph-negative MPNs have become an important part of therapy. In some countries, they are actively supported as frontline therapy. There are both short-acting and long-acting interferons with different pegylations. There are 2 formulations there, pegylated interferon alfa-2a and this, which is pegylated interferon alfa-2b.

This compound coming out of Taiwan and codeveloped in Austria is ropegylated interferon alfa-2b. It’s given every 2 weeks, and it’s a fairly clean drug with pretty much 1 main isomer represented. The groups in Austria, Heinz Gisslinger and other colleagues, have done the leading work regarding showing its activity in polycythemia vera [PV], both in initial studies and then a phase III study. Well, they first demonstrated that through 12 months of time with a group of high-risk of patients with PV randomized between hydroxyurea and ropegylated interferon, the agents were relatively equivalent. This showed in a randomized way that it was at least as good as hydroxyurea for decreasing risk of thrombotic events, for tolerability, and for controlling the counts.

The extenuation of that study, the CONTI-PV trial, was looking further in time. Indeed, the long hypothesis has been that interferons may be more disease altering over the long haul. Maybe it leads to more remissions, maybe it helps to better control the genetic burden, maybe it decreases the allele burden, or maybe it achieves the ultimate goal we have of decreasing the likelihood of progressing toward myelofibrosis. The CONTI-PV data show that at 2 years, the interferon is likely already superior to hydroxyurea in achieving complete hematologic response, as well as controlling the allele burden. I think longer-term data will be of great interest to really see how those 2 differentiate.

Our current guidelines in the United States have interferons and hydroxyurea as dealer’s choice for clinicians to choose. If we have an agent that becomes formally indicated in the United States for polycythemia vera, there will be that increasing discussion of which patients should be considered. But certainly, the CONTI-PV data are an important milestone of superiority from a randomized study that may inform that decision.

Harry P. Erba, MD, PhD: I’m not sure I’m remembering the correct study, but was this a study where they reported earlier that there was no difference between the 2?

Ruben A. Mesa, MD, FACP: At 12 months. This is at 24 months.

Harry P. Erba, MD, PhD: So, it shows the importance of long-term therapy with drugs like interferon.

Ruben A. Mesa, MD, FACP: Correct, without question. I relate it, to some degree, to if one was looking at 2 antihypertensive drugs. At 1 year’s time, you are going to be able to read out what the control of the blood pressure was. But as time goes on, you’re going to be able to really read out what the difference was. Were there fewer myocardial infarctions? Were there fewer other secondary events that are relevant? I think over time, it will be very important, because a year is probably not enough time for us to see the differentiation.

Harry P. Erba, MD, PhD: As you say, that would be the same with ruxolitinib in PV and myelofibrosis. In the early reports for myelofibrosis and PV, there’s some decrease in the allele burden, but it’s pretty minimal. But maybe with longer term follow-up, we’ll see something.

Srdan Verstovsek, MD, PhD: I think these are good points to observe over time: tolerability, any adverse effects, new adverse effects we talked about, and biological parameters that are, in our mind, associated with disease activity or disease progression. Bone marrow fibrosis may be decreasing in patients with myelofibrosis on ruxolitinib. JAK2 allele burden might be decreasing in patients with PV on ruxolitinib. Ropeginterferon is certainly a new, exciting medication, where you actually give it every 2 weeks. I call it super long acting. It’s very easy to give every 2 weeks and much better tolerated than the regular interferon. You would expect it to be active for much longer and possibly affect the bone marrow or the biology of the disease. In a true sense, we see less progression, less of thrombotic events. Time will tell.

Transcript Edited for Clarity 

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Transcript: 

Harry P. Erba, MD, PhD: In terms of the last emerging agent that we have time to discuss today, I want to turn our attention to a new formation of interferon, ropeginterferon alfa-2b. There have been a couple of studies looking at this agent recently, but 1 in particular was the CONTI-PV study. Do you want to tell us about that, Ruben?

Ruben A. Mesa, MD, FACP: Without question, interferons are very active in myeloproliferative neoplasia [MPNs]. We certainly know interferons were active in chronic myeloid leukemia. They’ve been superseded, of course, by the TKI [tyrosine kinase inhibitor] therapy, but they were active. Interferons in the Ph-negative MPNs have become an important part of therapy. In some countries, they are actively supported as frontline therapy. There are both short-acting and long-acting interferons with different pegylations. There are 2 formulations there, pegylated interferon alfa-2a and this, which is pegylated interferon alfa-2b.

This compound coming out of Taiwan and codeveloped in Austria is ropegylated interferon alfa-2b. It’s given every 2 weeks, and it’s a fairly clean drug with pretty much 1 main isomer represented. The groups in Austria, Heinz Gisslinger and other colleagues, have done the leading work regarding showing its activity in polycythemia vera [PV], both in initial studies and then a phase III study. Well, they first demonstrated that through 12 months of time with a group of high-risk of patients with PV randomized between hydroxyurea and ropegylated interferon, the agents were relatively equivalent. This showed in a randomized way that it was at least as good as hydroxyurea for decreasing risk of thrombotic events, for tolerability, and for controlling the counts.

The extenuation of that study, the CONTI-PV trial, was looking further in time. Indeed, the long hypothesis has been that interferons may be more disease altering over the long haul. Maybe it leads to more remissions, maybe it helps to better control the genetic burden, maybe it decreases the allele burden, or maybe it achieves the ultimate goal we have of decreasing the likelihood of progressing toward myelofibrosis. The CONTI-PV data show that at 2 years, the interferon is likely already superior to hydroxyurea in achieving complete hematologic response, as well as controlling the allele burden. I think longer-term data will be of great interest to really see how those 2 differentiate.

Our current guidelines in the United States have interferons and hydroxyurea as dealer’s choice for clinicians to choose. If we have an agent that becomes formally indicated in the United States for polycythemia vera, there will be that increasing discussion of which patients should be considered. But certainly, the CONTI-PV data are an important milestone of superiority from a randomized study that may inform that decision.

Harry P. Erba, MD, PhD: I’m not sure I’m remembering the correct study, but was this a study where they reported earlier that there was no difference between the 2?

Ruben A. Mesa, MD, FACP: At 12 months. This is at 24 months.

Harry P. Erba, MD, PhD: So, it shows the importance of long-term therapy with drugs like interferon.

Ruben A. Mesa, MD, FACP: Correct, without question. I relate it, to some degree, to if one was looking at 2 antihypertensive drugs. At 1 year’s time, you are going to be able to read out what the control of the blood pressure was. But as time goes on, you’re going to be able to really read out what the difference was. Were there fewer myocardial infarctions? Were there fewer other secondary events that are relevant? I think over time, it will be very important, because a year is probably not enough time for us to see the differentiation.

Harry P. Erba, MD, PhD: As you say, that would be the same with ruxolitinib in PV and myelofibrosis. In the early reports for myelofibrosis and PV, there’s some decrease in the allele burden, but it’s pretty minimal. But maybe with longer term follow-up, we’ll see something.

Srdan Verstovsek, MD, PhD: I think these are good points to observe over time: tolerability, any adverse effects, new adverse effects we talked about, and biological parameters that are, in our mind, associated with disease activity or disease progression. Bone marrow fibrosis may be decreasing in patients with myelofibrosis on ruxolitinib. JAK2 allele burden might be decreasing in patients with PV on ruxolitinib. Ropeginterferon is certainly a new, exciting medication, where you actually give it every 2 weeks. I call it super long acting. It’s very easy to give every 2 weeks and much better tolerated than the regular interferon. You would expect it to be active for much longer and possibly affect the bone marrow or the biology of the disease. In a true sense, we see less progression, less of thrombotic events. Time will tell.

Transcript Edited for Clarity 
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