Interferon in Low-risk Polycythemia Vera: Does Better Tolerability Allow for Earlier Intervention?

Benefit/Risk Profile of AOP2014 in Low-risk Patients With PV (Low-PV)

NCT03003325

Italian multicenter study under the leadership of Professor Tiziano Barbui, Fondazione per la Ricerca Ospedale Maggiore di Bergamo (FROM)

150 as of February 2, 2017

Low-PV is a multicenter, randomized phase II trial in a low-risk population of patients with polycythemia vera (PV; e.g., patients < 60 years of age and without previous thromboembolic complications). Patients receive either pegylated proline interferon (IFN) alfa-2b once every two weeks at a single dose of 100 µg versus the comparator of standard therapy (phlebotomy and low-dose acetylsalicylic acid [ASA] 100 mg daily). The primary goal is to compare the number of patients that maintain the recommended hematocrit level of less than 45 percent over 12 months in each arm. Several secondary endpoints include phlebotomy use, hematologic and molecular responses, splenomegaly, thromboembolic and hemorrhagic events, and quality of life (QoL). Eligibility of patients is defined by diagnosis of PV according to the 2016 World Health Organization criteria, age 18 to 60 years, and hematocrit level less than 45 percent at study entry. Exclusion criteria include history of previous thromboembolic or cardiovascular events, prior exposure to cytoreductive drugs including IFNs, infections, significant comorbidities, and pregnancies. The study is sponsored by FROM and AOP Orphan Pharmaceuticals.

Phlebotomy remains a key intervention in patients with low-risk PV; however, its therapeutic limitations and the use of alternative therapies are debated. As there is no consensus definition of phlebotomy resistance, continuing frequent phlebotomies to avoid pharmacologic cytoreduction may result in symptomatic iron deficiency. Fine tuning the frequency of phlebotomies to achieve iron deficient erythropoiesis but avoid severe iron deficiency is challenging.

IFN therapy is a recommended approach for younger patients with high-risk PV. Early studies described efficacy of IFN at doses of 3 million IU, three times per week.¹  Similar efficacy results can be obtained with pegylated IFN (PEG-IFN).^2,3  Both PEG-IFN alfa-2a and PEG-IFN alfa-2b have been recommended as an alternative to hydroxycarbamide by several society guidelines in Europe and the United States. Pegylation of IFN prolongs serum half-time, thus enabling weekly drug administration. PEG-IFN results in complete hematologic responses in up to 95 percent of patients, together with reduction of JAK2-V617F allelic burden and induction of hematologic remissions.^2,4,5  Furthermore, all patients became phlebotomy-free, and this was durable. Unfortunately, about 90 percent of patients experienced IFN-associated adverse effects, including neuropsychiatric, musculoskeletal, and gastrointestinal events, with a high discontinuation rate owing to adverse effects; even higher incidences of IFN therapy discontinuation were reported in other studies. A randomized phase III trial is currently being conducted in the United States to compare PEG-IFN alfa-2a plus low-dose ASA (81-100 mg daily) versus hydroxyurea (HU) plus low-dose ASA in patients with high-risk PV. In this trial, PEG-IFN alfa-2a is applied initially at 45 μg per week and will be gradually increased to 180 μg per week, whereas HU is administered in a dose of 500 mg twice daily (NCT01259856).

Recently, a novel IFN alfa-2b, ropeginterferon alfa-2b, with an ultralong elimination half-life has been developed for the treatment of high-risk PV. Promising results could be obtained in a phase I/II open-label trial of 51 patients.⁶  Both the efficacy (overall response rate, 90%; complete molecular response, 21%) and safety of the compound in this study supported the development of the drug in a randomized phase III trial (PROUD-PV). The PROUD-PV study (n=254) tested twice-weekly subcutaneous injection of ropeginterferon alfa-2b compared with daily HU or best available therapy. The three-year results of this randomized trial of untreated or HU pretreated patients with high-risk PV showed superiority of the IFN compound versus the comparator with regard to the rate of complete hematologic remissions and reduction of allelic burden.⁷  These results resulted in ropeginterferon alfa-2b becoming the only approved drug for high-risk PV in the EU.

To assess the efficacy and tolerability of ropeginterferon alfa 2b in low-risk PV, this definitive study is needed to inform physicians about its efficacy and toxicity profile compared to the standard treatment of phlebotomies in combination with low-dose ASA.

The Low-PV trial started enrollment in February 2017 with an expected number of 150 participants. Enrollment is expected to finish by the end of 2019. This trial is significant because it will provide the first evidence of whether treatment with pegylated IFN in low-risk PV might be comparable or superior to repeated phlebotomies to maintain the recommended hematocrit level (< 45%), as well as for tolerability and symptom control. Additionally, by targeting patients with low-risk disease, it theoretically provides the best opportunity for pegylated IFN to have disease modifying activity. We believe that this trial may inform the future clinical management of patients with low-risk PV.