Considerations in the First-Line Setting in Polycythemia Vera

After years of hydroxyurea serving as the standard backbone of cytoreductive therapy in high-risk polycythemia vera (PV), ropeginterferon alfa-2b (Besremi) emerged as a promising new option. Unlike hydroxyurea, which controls blood counts without addressing the underlying disease, ropeginterferon can reduce and in some patients eliminate the JAK2 mutation driving polycythemia vera.

Initial evidence from the phase 1/2 PEGINVERA trial (NCT01193699) established ropeginterferon’s safety and efficacy signals, paving the way for a head-to-head evaluation against the standard of care.¹ That came in the form of PROUD-PV (NCT01949805) and its long-term extension, CONTINUATION-PV (NCT02218047)—the first and largest randomized phase 3 program to compare an interferon-based regimen directly against hydroxyurea in frontline PV.^2,3,4

The long-term data for ropeginterferon showed complete hematological response (CHR) rates were significantly higher with ropeginterferon than with hydroxyurea at 36 months, a difference that widened meaningfully as follow-up matured. Molecular responses deepened over time as well, with ropeginterferon demonstrating a sustained and progressive reduction in JAK2 allele burden that hydroxyurea could not replicate.

During a Community Case Forum^TM event in Miami, Firas El Chaer, MD, MSHCM, chief of leukemia and medical director of infusion services at Miami Cancer Institute at Baptist Health South Florida, shared his expert insight on the key findings from PROUD-PV and CONTINUATION-PV and what these data mean for clinical practice.

This is the second of 2 parts. Read part 1.

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Targeted Oncology: Please describe the study design and primary end points of PROUD-PV and CONTINUATION-PV.

Firas El Chaer, MD: The study started as PROUD-PV for 12 months, and then some of these patients went on to CONTINUATION-PV, which was a study that enrolled patients above the age of 18 with PV who were cytoreductive naive—although they allowed patients who were pretreated with hydroxyurea for less than 3 years.

During those first 12 months in PROUD-PV, they received ropeginterferon subcutaneously every 2 weeks or hydroxyurea orally once daily. After 1 year, the patients who went on to participate in the CONTINUATION-PV trial received ropeginterferon or best available therapy for 3 to 5 years. The primary end point for PROUD-PV was composite outcome comprising both CR [defined as hematocrit < 45%, platelets < 400 × 10⁹/L, and WBC <10 × 10⁹/L] and normal spleen size by imaging at month 12. The primary end points for CONTINUATION-PV were the proportion of patients achieving CR and normal spleen size and the proportion of patients achieving CR with improved disease burden.

What were the results of PROUD-PV and CONTINUATION-PV?

The numbers are similar in the 2 arms for the PROUD-PV initial 12-month interval. In the control group 28% of patients achieved a complete hematological response [and normal spleen size] vs 21% of patients in the ropeginterferon arm, with a P value of 0.23. The CHR rate [without the spleen criterion] was 46% vs 43%, respectively [P = .63]. Molecular response was also almost the same in both groups [34% with ropeginterferon and 42% with hydroxyurea; P = .19].

So you would think that PROUD-PV is a failed study, because both arms were the same, but you need to look at the CONTINUATION-PV data for those patients who continued on ropeginterferon. Once we give them enough time, at month 36 or 3 years on the study, we start seeing things diverging. At this point, 53% of the ropeginterferon arm had CHR and improvement in disease burden vs 38% of the hydroxyurea arm. When looking at just complete hematological response, the rates were 71% vs 51%, respectively, and the molecular response rates were 66% vs 27%, respectively.

What do these results indicate about the importance of treatment exposure time to ropeginterferon?

These data tell us that ropeginterferon works better the longer the patient is exposed to it. And actually in the FDA package insert, the median time for complete hematological response was 7.8 months.⁵

With a lot of patients who come to my clinic, they are concerned if at month 3, there hematocrit counts are not all controlled and they still need phlebotomies. I always reassure them from the very beginning of the first visit that if I’m going to start them on ropeginterferon, it might take 7 to 8 months to fully take effect and they should not worry if their disease is not immediately controlled. Before making that switch to another therapy—and we don't have too many therapies—I encourage patients to give enough time for the medication to work.

What did the 72-month data for PROUD-PV and CONTINUATION-PV show?

The PROUD-PV and CONTINUATION-PV 72-month data showed that when they divide the patients between low-risk and high-risk patients, we saw responses in both of these patient populations. In the low-risk patient population, 73.2% had a CHR and 84.4% of the patients had a molecular response. In the high-risk patients, 38.3% had a CHR and 49.0% had a molecular response. The median time to major molecular response was 12 months in in low-risk PV and 18 months in high-risk PV.

And again, when we talk about molecular response and event-free survival, we're repeating the same story—the risk of deaths, thrombotic events, and disease progression is much less with [ropeginterferon than with hydroxyurea].

What did the safety profile for PROUD-PV and CONTINUATION-PV show?

I want to highlight that no new major adverse events emerged with ropeginterferon in PROUD-PV and CONTINUATION-PV compared with the [initial proof-of-concept phase 1/2 PEGINVERA trial (NCT01193699)] of ropeginterferon.

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DISCLOSURES: El Chaer reported that he is a consultant for SPD Oncology, Amgen, CTI BioPharma, AbbVie, MorphoSys, PharmaEssentia, BMS, Geron, Sobi, DAVA Oncology, Taiho Oncology, Daiichi Sankyo, Syndax, Novartis, Merck.

References

1. Gisslinger H, Buxhofer-Ausch V, Thaler J, et al. Long-term efficacy and safety of ropeginterferon alfa-2b in patients with polycythemia vera — final phase I/II Peginvera study results. Blood. 2018;132(suppl 1):3030. doi:10.1182/blood-2018-99-118584

2. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4

3. Kiladjian JJ, Klade C, Georgiev P, et al. Long-term outcomes of polycythemia vera patients treated with ropeginterferon alfa-2b. Leukemia. 2022;36(5):1408-1411. doi:10.1038/s41375-022-01528-x

4. Gisslinger H, Klade C, Georgiev P, et al. Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment. Leukemia. 2023;37(10):2129-2132. doi:10.1038/s41375-023-02008-6

5. PharmaEssentia USA Corporation. Besremi (ropeginterferon alfa-2b-njft) injection, for subcutaneous use: US prescribing information. PharmaEssentia USA Corporation; 2021. Accessed May 26, 2026. https://tinyurl.com/bdyak4mv