Remarkable Molecular Response in Patients with Polycythemia Vera Treated with Ropeginterferon Alfa-2b

Introduction

Polycythemia vera (PV) is a common type of BCR-ABL-negative myeloproliferative neoplasms. It appears that almost all patients with PV carry a mutation in the Janus kinase 2 gene with the JAK2^V617F mutation being identified in more than 95% of the cases. The JAK2^V617F allele burden is associated with thromboembolic events and disease progression. Ropeginterferon alfa-2b (ropeg) represents a novel, mono-polyethylene glycol-conjugated (PEGylated) interferon-based therapy and is approved for the PV treatment. It has been assessed in two different dose titration regimens: a starting dose of 100 μg [50 μg if receiving hydroxyurea (HU)] with 50 μg dose titrations every two weeks to a maximum dose of 500 μg; or alternatively, a starting dose of 250 μg titrating to 350 μg and then 500 μg every two weeks if tolerated. The study assessed the two-year treatment results regarding molecular response, complete hematologic response (CHR) and safety with ropeg therapy at the higher starting dose regimen.

Objective

The aim of the study is to assess the CHR rate, molecular response, and safety of ropeg at a higher starting dose regimen with simpler intra-patient dose titrations in Chinese patients with PV with HU resistance or intolerance.

Methods

Adult patients diagnosed with PV according to WHO 2016 diagnostic criteria from 15 major hospitals in China were enrolled in this single-arm, open-label study. Patients were scheduled to receive ropeg every 2 weeks, starting at a dose of 250 µg at Week 0, increasing to 350 µg at Week 2 and then 500 µg from Week 4 onwards if tolerated. Dose could be adjusted according to tolerability and safety. After 52 weeks, eligible patients without disease progression could continue to receive ropeg treatment for an extension phase.

Results

A total of 49 patients with a median age of 56 years were enrolled in this study. All patients had the JAK2^V617F mutation and HU intolerance. The mean and median allelic burden of JAK2^V617F at baseline was 58.5% and 61.2%, respectively. 46 patients completed the first-year study. A total of 44 patients joined the extension phase since two patients declined consent for personal reasons. One patient discontinued the study due to an adverse event (AE) not related to treatment. After 24 months of treatment, 33/44 patients (75.0%) achieved CHR. Almost all patients except one showed a reduction of JAK2^V617F. The mean and median JAK2^V617F allelic burden at 24 months was 15.6% and 7.8%, respectively. At Month 24, complete molecular response (CMR) was achieved in 11/43 patients (25.6%). Previously, CMR was observed in 18/92 (19.6%) in patients with PV at 5 years (Month 60) of ropeg treatment under the approved, slow dose titration regimen. Notably, JAK2^V617F in one patient decreased from a high allele burden of 83.9% to undetectable at Month 24. Partial molecular response was observed in 25/43 patients (58.1%) and 20/43 patients (46.5%), respectively, according to the 2009 and 2013 ELN criteria. During the extension phase, 37/44 patients (84.1%) experienced treatment-emergent AEs (TEAEs), with the majority being mild or moderate. The most common TEAEs included increased alanine aminotransferase (ALT), decreased WBC count, decreased neutrophil count, and all these AEs could be effectively managed and were reversible. No drug-related serious AEs (SAEs) were reported. There were no thromboembolic events and disease progression to myelofibrosis, acute leukemia and deaths.

Conclusion:

The 24-month data of our study showed that ropeg at the higher starting dose regimen was very effective in inducing molecular remission, and maintaining high levels of CHR. It was generally well-tolerated. Further analysis of the relationship between molecular remission and progression free survival, overall survival will be explored in future.