Phase Ⅱ,Open-Label, Multicenter, Single-Arm Study Investigating the Efficacy and Safety of Ropeginterferon Alfa-2b in Chinese Patients with Polycythemia Vera Resistant or Intolerant to Hydroxyurea(HU)

Background: Polycythemia vera (PV) is a common type of BCR-ABL-negative myeloproliferative neoplasms. It often harbors a Janus kinase 2 (JAK2) gene mutation and is associated with elevated blood cell counts, symptoms that can be debilitating over time and risks of thrombosis and hemorrhage, and disease progression to myelofibrosis and acute myeloid leukemia. Ropeginterferon alfa-2b, a novel, site-selective, mono-pegylated proline-interferon alfa-2b, has improved pharmacokinetic properties, allowing dosing every 2 to 4 weeks, with improved tolerability and convenience. The safety and efficacy of ropeginterferon alfa-2b for the treatment of PV has been demonstrated in clinical studies conducted in Europe (PEGINVERA, PROUD-PV, CONTINUATION-PV) and Japan. The approved dosing scheme of ropeginterferon alfa-2b is 100 μg (or 50 μg in patients under another cytoreductive therapy) as a starting dose, with dose increment of 50 μg to the maximum recommended dose of 500 μg. Faster dose escalation may help patients achieve control of hematologic parameters quicker. Aims: The aim of this phase Ⅱ, single-arm study (A20-202) was to assess the safety and efficacy of ropeginterferon alfa-2b in Chinese PV patients utilizing an accelerated dose titration schedule. Methods: Chinese patients 18 years or older with a PV diagnosis according to World Health Organization 2016 criteria and were resistant or intolerant to hydroxyurea (HU) were enrolled. Ropeginterferon alfa-2b was administered subcutaneously every 2 weeks for 52 Weeks at a starting dose of 250 μg, followed by 350 µg at Week 2, and a target dose of 500 μg at Week 4. Patients received the target dose, if tolerated, for the remainder of the 52-week treatment. The primary endpoint was the proportion of patients who reach a complete hematologic response (CHR) at Week 24 (CHR: hematocrit <45% without phlebotomy or erythrocyte apheresis in the preceding 12 weeks, platelet≤400×109/L, leukocyte <10×109/L). Secondary endpoints included changes in hematologic parameters and JAK2V617F allele burden, time to first complete hematologic response, and duration of response. Safety endpoints included the incidence of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Results: As of the data cut-off date of 01 July 2022, a-total of 49 patients, 31 males and 18 females, with a median age of 56 years, were enrolled in this study. Mean baseline values were hematocrit 45.95%, leukocyte count 11.35×109/L, and platelet count 478.5×109/L. All patients had the JAK2V617F mutation (mean allele burden: 58.49%). One patient withdrew consent and discontinued the study. The data of 27 patients were available to evaluate the CHR at Week 24. Fourteen out of the 27 (51.85%) patients achieved a CHR at Week 24 of the treatment. This was comparable to the CHR rate of 43.1% at Week 52 observed in the PROUD-PV study. Hematocrit, leukocyte and platelet levels decreased over time with mean change ± SD from baseline to Week 24: -3.63± 6.14%, -5.77± 12.22×109/L, and -254.0± 177.23×109/L, respectively. JAK2V617F allele burden decreased over time with mean change ± SD from baseline to week 24: -13.95±16.74% (n=26); consistent with an increase in molecular response. The JAK2V617F allele burden in two patients became undetectable after the treatment, as measured by Next-Generation Sequencing with a lower limit of quantitation at 3% by the central laboratory. TEAEs occurred in 47 patients (95.9%). Grade≥3 AEs occurred in 8 of the patients (16.3%) and among them, possibly treatment-related Grade ≥ 3 AEs occurred in five patients (10.2%). Serious adverse events (SAE) occurred in 4 of the patients (8.2%), and possibly treatment-related SAE occurred in two patients (4.1%). The most common TEAEs were alanine aminotransferase increase (38.8%), leukopenia (36.7%) and aspartate aminotransferase increase (36.7%). Preliminary result did not show significant AESIs (e.g., cardiovascular and psychiatric events) in all the patients who received the treatment. Summary/Conclusion: The interim results of our study demonstrate that Ropeginterferon alfa-2b using a 250-350-500 μg dosing scheme was safe, well tolerated, and efficacious in Chinese patients with PV. The data suggest that using an accelerated dosing scheme helps patients achieve a CHR earlier.