The Expanding Role of Interferons in Myeloproliferative Neoplasms

Richard T. Silver, MD

In the treatment of myeloproliferative neoplasms (MPNs), 1 interferon agent is FDA approved in the United States. Ropeginterferon alfa-2b-njft (Besremi) is indicated for adults with polycythemia vera (PV), but as research continues to support the use of these agents, oncologists have more questions.

To better understand the underlying mechanisms of action associated with interferons, as well as efficacy, safety, and mechanism of resistance, the MPN Research Foundation (MPNRF) launched a 3-year global initiative.

"It is unusual that we have been effectively using interferon for the treatment of MPNs for more than 30 years without fully understanding how it works," said Richard T. Silver, MD, in a press release about the initiative. "That is why the MPNRF's Interferon Initiative is so important. Interferon appears to uniquely affect the MPN stem cells and has other valuable attributes.”

In an interview with Targeted Oncology™, Silver, professor emeritus of Medicine at Weill Cornell Medicine, discussed the role of interferon in the treatment of MPNs as well as the importance of the 3-year global MPN initiative being conducted by the MPNRF.

TARGETED ONCOLOGY™: Can you discuss which patients benefit from recombinant IFN alpha. What agents are showing promise right now?

Silver: Interferon can be effective in a number of hematologic disease but currently, it’s primarily used to treat myeloproliferative neoplasms. It was first used to chronic myeloid leukemia [CML] before we had very specific treatment for it. I happen to be very interested in chronic myeloid leukemia, But now, we have much better therapy than interferon, because of the similar for CML because of the similarities of CML to other disease is of the myeloproliferative group.

In 1988, I had the idea of using it in PV and some investigators in Austria have used interferon to treat essential thrombocytopenia [ET]. So, of the 3 MPNs, interferon is most commonly used in PV because many patients with ET do not require therapy at all, when they do interferon is very effective.

We and others have evaluated interferon in very myelofibrosis and find it to be effective in about 80% of cases. Overall, Interferon is more was effective PV because it's been shown that it affects the PV stem cell leading to its exhaustion.

Resistance and intolerance to interferons has been shown. Can you explain how common this is?

Most patients with PV and ET, develop intolerance rather than resistance to interferons, and mostly, it's in the form of peripheral neuralgia. It can be autoimmune disease, and sometimes people get thinking disorders or depressed on interferon. Sometimes they develop liver abnormalities.

It's not a benign drug. If you look at the total of patients who become intolerant to interferon, it's about 15% to 20%. When the drug is used properly, that is to say we're using low doses of interferon, it's about the same number of patients in our series of 470 patients with PV who have developed intolerance to hydroxyurea, which is a commonly used drug in PV treatment. So, all these drugs have side effects, which must be evaluated very carefully.

Resistance to interferon is a very complex issue. Presumably, there are biologic effects in the stem cells that occur that make the stem cell not responsive to interferon. That is being worked on now in the research setting. But we don't know why some patients develop resistance per se to interferon, but that is not as common as intolerance.

Can you talk about the key goals of the 3-Year Global MPN Interferon Initiative?

The Myeloproliferative Neoplasm Research Foundation that’s very active in raising funds for research around this disease. They organized an initiative to determine how interferon works or what is the mechanism of action accounting for success. It should be noted parenthetically that interferon was first used in viral diseases, and particularly in hepatitis. Its effect rheumatologically and its use in hematologic disease is really a secondary manifestation of its broad physiologic potential.

To determine how interferon works, a combination of laboratory studies were conducted in 4 different laboratories around the world. The goal was to determining the effectiveness and reason why interferon works in hematological disorders. Based on mouse models, they have demonstrated that interferon is effective, because it affects PV stem cell, and probably is most active in affecting the megakaryocytic stem cell, which is sort of the mother cell of all stem cells. There are other proteins that affect this phenomenon, and these were part of the research that was generated by the MPN Research Foundation.

There are many unanswered questions and many detailed questions that need to be answered before we really have a full understanding of how this drug works hematologically. But, I should also note that many drugs have been used therapeutically before we could really understand the basis for its use. The best example is penicillin. You know, the observation that penicillin was an antibacterial agent was made long before the basis for understanding why it was effective. So, this is very encouraging. At Weill Cornell, where I have the privilege of being a professor, we have just completed a retrospective study of 470 patients who have been treated with phlebotomy only or hydroxyurea or interferon. The study has demonstrated that patients treated with interferon have a much better survival than those treated with hydroxyurea and that hydroxyurea is superior to phlebotomy.

What is your key takeaway from the report published around this initiative?

I think the all the laboratory investigators would agree that we have ways to go before we fully understand the mechanism action of interferon and why it works is most effective, as I said, PV and ET. It works in early phases of myelofibrosis. When myelofibrosis for example, becomes advanced in the bone marrow, it becomes very sclerotic or fibrotic, interferon is not effective. So, there are many questions to be answered. This is the beginning and like all research, when you conduct research, it often opens more questions that are answered. And I think this has been true in this MPN Research Foundation. As I said, I think the most important aspect of this has been to focus the effect of interferon on the MPN stem cell and show that is, in fact, very active on that cell.

What interferon research has been most impressive for the treatment of MPNs?

Ropeginterferon alfa-2b is one that has very long action. That is to say that you can give an injection on day 1 and you won’t have to give another injection for another 2 to 4 weeks. This agent has just been FDA approved for the treatment of polycythemia vera in the United States. It was already approved in Europe, so there will be more and more patients being treated with interferon soon.

In your expert opinion, how should interferon be used in the clinical setting? What does the future look like for these agents?

Our goal in using interferon in hematologic malignancies is obviously to keep the patients with a very good quality of life, so they can maintain their professional, social, and family lives with minimal adverse events. That's our goal. And I think we can achieve it with these new forms of interferons. So, I'm very positive.

_Reference:

_{3-Year Global MPN interferon initiative report released by MPN Research Foundation. News release. MPN Research Foundation. November 1,,2021. Accessed November 23, 2021. https://bit.ly/3DLkeW5}