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Ropeginterferon alfa 2b shows promise for polycythemia vera
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Ropeginterferon alfa-2b — a next generation, mono-pegylated interferon alfa-2b isoform — administered once every 2 weeks demonstrated safety and efficacy in patients with polycythemia vera, according to the results of a dose escalation study.
The therapy resulted in a reduction in JAK2 allelic burden among treated patients and induced promising partial and complete molecular response rates.
“Polycythemia vera is associated with a risk [for] hemorrhage and thrombosis, and a long-term propensity to develop myelofibrosis and acute leukemia,” Heinz Gisslinger, MD, professor in the department of hematology and blood coagulation at Medical University of Vienna, and colleagues wrote. “Since 1985, observational, nonrandomized studies have provided convincing evidence that interferon alpha treatment of patients with myeloproliferative neoplasms, including polycythemia vera, can effectively normalize blood cell counts and prevent disease-related thromboembolic complications.”
The use of interferon alpha has been limited due to poor tolerance in patients exposed to daily injections of the compound. Ropeginterferon alfa-2b (AOP214, AOP Orphan Pharmaceuticals) has a longer elimination half-life time, which will allow for administration every 2 weeks.
Gisslinger and colleagues conducted a phase 1/2 dose escalation study to determine the maximum tolerated dose of ropeginterferon alfa-2b. They tested a dose range of starting at 50 micrograms and escalating to 540 micrograms (mean adjusted dose, 263 ± 104 μg every 14 days).
Maximum tolerated dose, safety and efficacy served as the primary endpoints.
The study included data from 51 patients (median age, 56 years; 61% men).
Median follow-up was 80 weeks (range, 4-173), and 75% of patients remained on treatment for 50 weeks or greater.
The cumulative overall response rate was 90%. Forty-seven percent of patients achieved a complete response and 43% achieved a partial response.
Among patients with baseline JAK2 V617F allelic burden of at least 20% (n = 43), 27% achieved complete response and 47% achieved partial response, which served as the best individual molecular response.
Eighty-eight percent of patients reported adverse events and 20% of patients discontinued treatment due to adverse events. All drug-related adverse events were known toxicities associated with interferon alpha.
Further, the researchers reported that they did not observe any correlation between dose level and response rate or response duration, which suggested that already low levels of ropeginterferon alfa-2b can sufficiently induce significant hematological and molecular responses.
“Ropeginterferon alfa-2b has been shown to be safe in this study in the administered dose range, and exhibited profound efficacy, observed as normalization of blood parameters and reduction of JAK2 allelic burden,” Gisslinger and colleagues wrote. “Since this enables a more convenient treatment schedule accompanied by low toxicity and high hematological and molecular response rates, this study supports progression to phase 3 trials.” – by Cameron Kelsall
Disclosure: AOP Orphan Pharmaceuticals provided funding for this study. Gisslinger reports advisory and speakers bureau roles with AOP Orphan Pharmaceuticals, Celgene and Novartis. Other researchers report employment with AOP Orphan Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Srdan Verstovsek, MD, PhD
Interferon-alfa along with hydroxyurea, is considered a first-line treatment option for polycythemia vera (PV) patients with high-risk disease (age 60 years or older and/or history of thrombohemorrhagic event). Studies with pegylated interferon-alfa (PEG-IFN-alfa) in particular, have shown that it not only normalizes blood counts but also reduces the JAK2 allele burden in most patients. Complete molecular remission (no detectable JAK2 V617F mutation) has been reported in approximately 20% of patients. The currently available pegylated formulations (PEG-IFN-alfa-2a/PEG-IFN-alfa-2b) require once-weekly administration — rather than three times a week with regular interferon-alfa. This is an important consideration, as less frequent dosing improves tolerance, allowing patients to benefit from the therapy. Gisslinger and colleagues report on a newer longer-acting mono-pegylated formulation of interferon-alfa-2b (ropeginterferon). Ropeginterferon has a longer elimination half-life than conventional PEG-IFN-alfa, requiring administration only once every 2 weeks. Response rates and toxicity profile were similar to those reported for PEG-IFN-alfa. A post-hoc analysis revealed that there was no significant difference in hematologic response rates or duration of response in patients receiving a mean dose of less than 300µg and those receiving a mean dose 300µg or more, suggesting that lower doses may be sufficient. Also of interest is that there was a linear reduction in allele burden over time — time from diagnosis of PV to treatment with interferon was the most significant factor associated with a slower reduction in allele burden. Further, patients previously treated with hydroxyurea were less likely to have a molecular response. Together, the findings suggest that ropeginterferon may be more effective when given at an earlier stage in the disease course and longer-term therapy at lower doses may be more effective. In this regard, less frequent dosing is an important advantage of ropeginterferon.
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