Ropeginterferon alfa-2b is noninferior to hydroxyurea in terms of complete hematologic response for the treatment of polycythemia vera, and has the advantage of being a safer and more tolerable therapy.
Heinz Gisslinger, MD
Ropeginterferon alfa-2b is noninferior to hydroxyurea (HU) in terms of complete hematologic response (CHR) for the treatment of polycythemia vera (PV), and has the advantage of being a safer and more tolerable therapy. Final results from the phase III PROUD-PV study showed robust hematologic control with either therapy starting at 12 weeks of treatment,1said Heinz Gisslinger, MD, at the 2016 ASH Annual Meeting.
“Results from this first and largest prospective controlled trial of an interferon in PV confirm previously reported efficacy,” said Gisslinger, for the Medical University of Vienna, Austria. “The observed safety and tolerability profile of ropeginterferon appears to be superior to previously reported data.”
Ropeginterferon alfa-2b is a monopegylated interferon that features every-other-week dosing in the treatment of PV. In the phase II PEGINVERA study,2ropeginterferon was associated with a hematologic response rate of 60%, an overall response rate of about 80%, cumulative complete responses in 45% to 50%, and a reduction in spleen size in most patients.
PV treatment is aimed at managing the long-term risk for disease progression, which approaches 20%, and transformation to acute myeloid leukemia/myeloproliferative dysplastic syndrome, which occurs in 3% to 10% of PV patients, said Gisslinger. Interferons have been used as a treatment for PV since the 1980s, but toxicities such as flu-like symptoms, depression, and autoimmune side effects contribute to discontinuation rates in the neighborhood of 25%.
The PROUD-PV study was a parallel group multicenter trial conducted in 254 patients diagnosed with PV according to the World Health Organization’s 2008 criteria, who were either naïve to cytoreduction or who had already been treated with HU but were neither intolerant nor complete responders following a treatment duration <3 years. The study was performed at 48 sites in 13 countries.
Patients were randomized to treatment with either ropeginterferon or HU, with the primary endpoint being non-inferiority of ropeginterferon compared with HU at 12 months of therapy on the CHR rate, defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelet count <400 G/L, leukocyte count <10 G/L, and a normal spleen size. Thirty-seven percent of patients in each arm were HU pretreated and the median spleen size was about 13 cm in each arm.
The median plateau dose of ropeginterferon was 450 µg. About one-fourth (25.2%) of patients required dose reduction due to adverse events (AEs). The median plateau dose of HU was 1250 mg, and 51.2% required dose reduction due to AEs. The 12-month discontinuation rates were 16.5% and 12.6% in the ropeginterferon and HU arms, respectively.
A CHR on intent-to-treat (ITT) analysis was achieved by 43.1% of patients randomized to ropeginterferon and 45.6% of patients assigned to HU, which met the criterion for non-inferiority (P= .0028). In the per protocol analysis, CHRs were achieved by 44.3% in the ropeginterferon group and 46.5% in the HU group (P= .0036 for non-inferiority).
The inclusion of a return to normal in spleen size in the primary endpoint was a potential confounder, as the median spleen length was close to normal at baseline in both arms. The observed change in median spleen, therefore, in the ITT population in either treatment arm was not clinically relevant (21.3% for ropeginterferon vs 27.6% for HU;P= .2233).
“The safety and tolerability of ropeginterferon showed benefits over HU,” said Gisslinger. Treatment-related AEs occurred in 75.6% of HU patients but only 59.6% of the ropeginterferon group.
AEs of special interest (including endocrine disorders, psychiatric disorders, cardiac/vascular disorders, tissue disorders) were no more frequent in the ropeginterferon group compared with the HU group.
Throughout the phase III program of ropeginterferon, which includes not only the PROUD-PV trial but CONTINUATION-PV as well, which is examining safety and efficacy with 3 to 5 years of treatment), no secondary malignancies occurred in the ropeginterferon arm compared with 5 in the HU arm (2 acute leukemias, 2 basal carcinomas, and 1 melanoma).
“The unique disease modification of interferon and its potential to improve progression-free survival hold promise for long-term patient benefit,” with data currently being gathered in CONTINUATION-PV, Gisslinger concluded.