When it comes to complete hematologic response (CHR) to treat polycythemia vera (PV), ropeginterferon alfa-2b is noninferior to hydroxyurea (HU). In fact, it is safer and more tolerable, according to final results from the phase 3 PROUD-PV study, that showed robust hematologic control with either therapy starting at 12 weeks of treatment, said Heinz Gisslinger, M.D., 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 1 PEGINVERA study, ropeginterferon was associated with a hematologic response rate of 60 percent, an overall response rate of about 80 percent, cumulative complete responses in 45 percent to 50 percent, 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 percent, and transformation to acute myeloid leukemia/myeloproliferative dysplastic syndrome, which occurs in 3 percent to 10 percent 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 percent.
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 less than three 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 less than 45 percent without phlebotomy (at least three months since last phlebotomy), platelet count less than 400 G/L, leukocyte count less than 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 percent) of patients required dose reduction due to adverse events (AEs). The median plateau dose of HU was 1250 mg, and 51.2 percent required dose reduction due to AEs. The 12-month discontinuation rates were 16.5 percent and 12.6 percent in the ropeginterferon and HU arms, respectively.
A CHR on intent-to-treat (ITT) analysis was achieved by 43.1 percent of patients randomized to ropeginterferon and 45.6 percent of patients assigned to HU, which met the criterion for non-inferiority. In the per protocol analysis, CHRs were achieved by 44.3 percent in the ropeginterferon group and 46.5 percent in the HU group.
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 percent for ropeginterferon vs 27.6 percent for HU).
“The safety and tolerability of ropeginterferon showed benefits over HU,” said Gisslinger. Treatment-related AEs occurred in 75.6 percent of HU patients but only 59.6 percent 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 3 program of ropeginterferon, which includes not only the PROUD-PV trial but CONTINUATION-PV as well, which is examining safety and efficacy with three to five years of treatment, no secondary malignancies occurred in the ropeginterferon arm compared with 5 in the HU arm (two acute leukemias, two basal carcinomas and one 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.