Richard T. Silver, MD
Despite the rise of newer, effective therapies since the inception of interferon 30 years ago, there is still a biologic basis for its use in the treatment of patients with myeloproliferative neoplasms (MPNs), according to Richard T. Silver, MD.
In polycythemia vera (PV), for example, patients typically develop symptomatic iron deficiency and thrombotic events. Interferon, which inhibits PDGF, TGFβ, and other critical pathways, reduces the risk of these events, explained Silver, who is a professor of medicine at Weill Cornell Medical College/NewYork-Presbyterian.
“There is evidence that interferon will also reduce the cellularity of the bone marrow, which is responsible for producing the number of white and red blood cells and platelets that we see in PV,” added Silver.
The phase III PROUD-PV study, which compared ropeginterferon alfa-2b with hydroxyurea in patients with PV, further established the role for interferon in the treatment paradigm. Results showed that ropeginterferon alfa-2b was noninferior to hydroxyurea, with a 12-month complete hematologic remission rate of 43.1% versus 45.6%, respectively. The need for phlebotomy for patients treated with interferon dropped from 86% to 6%, and 37% of patients achieved a JAK2 molecular response with the therapy.
In an interview with OncLive
, Silver provided the history of interferon and shared insight on why the drug still holds its place in the treatment of patients with MPNs.
OncLive: How has interferon been used traditionally for the treatment of patients with MPNs?
: The use of interferon was first reported by me in 1988. Since that time, we have developed extensive experience using it at Weill Cornell Medicine. We use it preferentially to any other agent because there is a biologic basis for its use. In comparison with the most commonly used drug—hydroxyurea, which is a nonspecific cell poison—there is a biologic basis for its use. It interferes with cell development and marrow fibrosis by interfering with PDGF and VEGF; it also affects JAK signaling. As I said, interferon is a drug for which there is a meaningful use—it is not a nonspecific myelosuppressive.
In our clinic, we don't believe in the "watch and wait" approach that is recommended by some [physicians] because it develops iron deficiency in patients; this has been getting a lot more attention now both in men and women. Most women become iron deficient because of menstruation. Phlebotomy will obviously add to that in men, irrespective of the fact that they don't menstruate. The average patient with PV we see requires about 8 phlebotomies. The maintenance thereof should not be phlebotomy only, even in so-called good-risk patients. This is because the phlebotomy rate is higher in those patients than in the normal population and because it doesn't suppress disease. It is sort of like treating a diabetic and letting their blood sugar rise while the patient has blood in the urine. You can't just treat their symptoms without giving them insulin.
We believe that there are 2 reasons for using interferon. First, there is a biologic basis for its use, and secondly, it avoids the development of iron deficiency. In addition, there is evidence that interferon can reduce thrombotic risk, which is significant for patients who are only treated with phlebotomy. We also have evidence from more than 300 patients with PV that the fibrosis we see in this disease will have a delayed onset of disease when they are treated with interferon; this is because interferon affects PDGF and TGFβ, as well as other cytokines that are responsible for the development of myelofibrosis. This is very exciting, and it is new information; it has never been shown in any population of patients. We presented a poster on this at the 2018 ASH Annual Meeting.
Could you expand on the use of interferon in today’s landscape?
We believe that in the long-term—not the short-term use—that hydroxyurea can cause leukemia in about 8% to 10% of patients. In a 15-year span, this number increases to about 15%. A patient can no longer use the drug if he/she develops secondary leukemia. There has never been a controlled study evaluating hydroxyurea over the long-term compared with phlebotomy because most patients cannot stay on phlebotomy.