Ropeginterferon Alfa-2b Demonstrates Durable Activity in Polycythemia Vera

Heinz Gisslinger, MD

Heinz Gisslinger, MD

Two-year findings from the follow-up phase III CONTI-PV randomized trial showed that ropeginterferon alfa-2b, a novel pegylated formulation of interferon alfa-2b, reached a significantly higher rate of complete hematologic response (CHR) versus hydroxyurea (Hydrea) in patients with polycythemia vera (PV).1

At 24 months’ follow-up, the ropeginterferon alfa-2b cohort had a CHR rate of 70.5% versus 49.3% for the hydroxyurea group (P = .0101), according to findings presented at the 2017 ASH Annual Meeting. Ropeginterferon alfa-2a achieved the composite endpoint of CHR and improved disease burden in 49.5% of patients versus 36.6% for hydroxyurea, a difference that was not statistically significant (P = .1183). The investigational agent also achieved partial molecular response almost twice as often as hydroxyurea.

“Ropeginterferon alfa-2b appears more efficacious than hydroxyurea in the long run, showing high and durable hematological responses and symptom improvement,” lead author Heinz Gisslinger, MD, professor of hematology at the Medical University of Vienna in Austria, said at ASH. “The safety and tolerability of ropeginterferon alfa-2b remain excellent beyond the second year of treatment.”

“The unique disease modification capability of interferon and its potential to improve progression-free survival are suggested by the observed effects on mutant JAK2 and other molecular markers,” added Gisslinger.

Interferons have been used since the 1980s to treat PV, consistently achieving high rates of hematologic response and improving other clinical outcomes. Ropeginterferon alfa-2b is a monopegylated formulation of interferon alfa-2b administered every 14 days initially and then once monthly during long-term maintenance treatment. The phase II PEGINVERA study demonstrated the feasibility, efficacy, and tolerability of long-term maintenance therapy with ropeginterferon alfa-2b for PV.

At ASH, Gisslinger presented findings from a continuation phase of the randomized phase III PROUD-PV trial, which compared outcomes after 12 months of treatment with ropeginterferon alfa-2b and hydroxyurea. Patients in the control arm were also able to switch to best available therapy instead of hydroxyurea at the investigators discretion.

Ropeginterferon alfa-2b demonstrated noninferiority to hyaluronic acid at the 12-month landmark, achieving a CHR rate of 43.1% as compared with 45.6% for the control arm. As reported at the 2016 ASH Annual Meeting, ropeginterferon alfa-2b had a better safety profile, reflected in an adverse event (AE) rate of 59.6% versus 75.6% among patients randomized to hyaluronic acid.2

There were 257 patients in PROUD-PV, of whom 171 entered the continuation trial (CONTI-PV)—95 were originally randomized to ropeginterferon alfa-2b and 76 to hyaluronic acid. Follow-up will continue for as long as 3.6 years. Gisslinger reported results after 24 months of follow-up.

Three key efficacy endpoints were established for the 24-month evaluation: CHR, defined as hematocrit <45% without phlebotomy, platelet count <400 x 109/L, and white blood cell count <10 x 109/L; CHR and improvement in disease burden, defined as improvement in disease-related signs and symptoms; and partial molecular response (reflecting the effect on mutant JAK2 allele burden).

According to the updated results, the noninferiority for CHR had changed to a 42% superiority for ropeginterferon alfa-2b. The 13% absolute difference in the composite endpoint of CHR and improvement in disease burden represented a 34% improvement in favor of ropeginterferon alfa-2b. The rate of partial molecular response was 68.1% with ropeginterferon alfa-2b and 34.7% with hyaluronic acid, an 85% difference in relative risk (P = .0002).

Almost 90% of patients in both groups experienced AEs. The incidence of treatment-related AEs was 70.1% with ropeginterferon alfa-2b and 77.2% with hyaluronic acid. Grade ≥3 AEs occurred in 27.6% in the ropeginterferon alfa-2b group and in 26.0% of patients in the hyaluronic group.

Adverse events that were most frequently reported included thrombocytopenia (19.7% with ropeginterferon alfa-2b, 26.8% of the control group), leukopenia (18.9%, 22.0%), anemia (9.4%, 22.0%), and elevated gamma-glutamyl transferase (11.0%, 0%). Interferon-associated AEs occurred more often with ropeginterferon alfa-2b: endocrine disorders (3.9%, 0.8%); psychiatric disorders (2.4L%, 0.8%); cardiac/vascular disorders (10.2%, 5.5%); and tissue disorders (1.6%, 0%). Five malignancies occurred in the control group and 3 in the ropeginterferon alfa-2b group.

The reduction in JAK2 allele burden increased over time with ropeginterferon alfa-2b, whereas hyaluronic acid achieved greater reductions early in the course of treatment and the effect declined over time.

References

1. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b induces high rates of clinical, hematological and molecular responses in polycythemia vera: two-year results from the first prospective randomized controlled trial. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 320.
2. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 475.