For patients with high-risk polycythemia vera (PV) who fail hydroxyurea (HU) therapy, clinical decision-making is shifting toward treatments that offer both hematologic control and molecular response. According to data discussed by Kristen M. Pettit, MD, a hematologist-oncologist at the University of Michigan in Ann Arbor, at a Case-Based Roundtable, oncologists now weigh the benefits of ropeginterferon alfa-2b (Besremi) and ruxolitinib (Jakafi) based on their potential to reduce the JAK2 V617F variant allele frequency (VAF), a marker increasingly linked to protection against thrombosis, disease progression, and death.
Evaluating Second-Line Treatment Options for High-Risk PV
When hydroxyurea fails—often due to intolerance like oral ulcers or declining blood counts—clinicians must select a new path. In a recent roundtable, oncologists considered increasing HU doses, stopping HU, or initiating JAK inhibitor or interferon therapy. Consensus favored moving away from HU entirely. According to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines, ruxolitinib is a preferred second-line option, while ropeginterferon alfa-2b is recommended for both first- and second-line use.
Molecular response, defined as a meaningful reduction in the JAK2 V617F variant allele frequency, is becoming a primary target in PV management because it correlates with protection against the most severe outcomes in PV, including thrombosis, disease progression, and death.
Long-Term Data from PROUD-PV and CONTINUATION-PV
The phase 3 PROUD-PV trial and its extension, CONTINUATION-PV, compared ropeginterferon alfa-2b against HU. While initial complete response rates at 12 months were similar—38.8% for ropeginterferon versus 44.8% for HU—the long-term outcomes diverged significantly. By the 6-year mark, 81.4% of patients on ropeginterferon achieved hematocrit control below 45%, compared with 60.0% in the control arm (P = .005), according to findings published in The Lancet Haematology and subsequent analyses.
Event-free survival (EFS) also favored ropeginterferon. Over at least six years, five of 95 patients on the drug experienced risk events, compared with 12 of 74 in the control group (P = .04). Notably, a 2024 analysis presented at the European Hematology Association (EHA) congress showed that patients achieving a molecular response remained almost entirely free of risk events through 90 months of follow-up.
Comparing Ruxolitinib and Interferon in Clinical Practice
The MAJIC-PV trial provides evidence for ruxolitinib in patients resistant or intolerant to hydroxyurea. Results showed a complete response rate of 23.0% for ruxolitinib compared to 8.1% for best available therapy (P = .003). Furthermore, patients achieving at least a 50% reduction in JAK2 V617F VAF saw significantly improved progression-free and overall survival.
Directly comparing these agents is difficult because trials were conducted in different settings. Pettit notes that the clinical choice often relies on patient-specific factors:
- Ruxolitinib: Often prioritized for patients with high symptom burdens, splenomegaly, or bone pain due to its rapid effect.
- Ropeginterferon: Frequently considered for younger patients where long-term disease modification is a priority.
When assessing a patient’s trajectory, look beyond blood counts. The current paradigm is moving toward deeper disease control, where molecular burden and symptom management are as critical as preventing thrombotic events.
Frequently Asked Questions
Why is JAK2 V617F VAF monitoring important?
Recent analyses suggest that reducing this allele burden correlates with a lower risk of thrombosis, disease progression, and death, providing a more comprehensive view of disease control than blood counts alone.
How do the efficacy profiles of ruxolitinib and ropeginterferon differ?
Ruxolitinib often provides faster relief for symptoms and splenomegaly, while ropeginterferon has shown durable long-term molecular and hematologic responses in clinical trials like PROUD-PV and CONTINUATION-PV.
Does the NCCN recommend these treatments?
Yes. The NCCN Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms list both as preferred options for patients requiring second-line therapy after hydroxyurea failure.
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