Second-Line Considerations in Post-Hydroxyurea, High-Risk PV

Following the failure of hydroxyurea in patients with high-risk polycythemia vera (PV), there are 2 well-supported treatment options: ropeginterferon alfa-2b (Besremi) and ruxolitinib (Jakafi).

When weighing these options, oncologists focus on both hematologic control and molecular response, in the form of meaningful reduction in JAK2 V617F variant allele frequency (VAF). Molecular response has increasingly become part of the calculus in recent years as reduction in VAF has been shown to correlate with protection against the most severe outcomes in PV, including thrombosis, disease progression, and death.

Kristen M. Pettit, MD, a hematologist-oncologist at the University of Michigan in Ann Arbor, moderated a Case-Based Roundtable event with oncologists in Troy, Michigan, walking through the decision-making process for the case of a high-risk PV patient who could not be adequately controlled on hydroxyurea.

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This is part 2 of a 2-part series. Read part 1.

CASE SUMMARY

• 66-year-old patient with high-risk PV presenting with shortness of breath and occasional sharp chest pain, as well as hypertension and obesity
• Initially treated with hydroxyurea (HU) at 1000 mg daily, cardiovascular risk factor management, and regular monitoring
• Unable to increase HU dose due to oral ulcers, severe skin reactions, and declining platelet counts. The maximum tolerated dose was reached.
• Current labs: hematocrit (HCT) at 47%; white blood cell (WBC) count 12,500; JAK2 V617F mutation VAF of 65%

EVENT RECAP

The discussion started with participants sharing their preferred treatment option for the patient case. The second-line options considered included increasing the dose of HU further, leaving the same dose of HU, stopping HU and starting another option, initiating JAK inhibitor therapy (ruxolitinib), or initiating ropeginterferon therapy. The discussants were split among the final 3 options, with the consensus being it was time to move on from HU.

Pettit noted that both ruxolitinib and ropeginterferon have National Comprehensive Cancer Network recommendations for use in this setting, with ruxolitinib as a preferred second-line option and ropeginterferon as a preferred first- or second-line option.¹

Pettit then reviewed the phase 3 PROUD-PV trial (NCT01949805), along with its extension, the phase 3 CONTINUATION-PV trial (NCT02218047). Both were randomized controlled trials that enrolled patients with high- or low-risk PV who had an indication for cytoreductive therapy. Patients were randomized 1:1 to receive ropeginterferon alfa-2b vs HU for 12 months (PROUD-PV), then followed for up to an additional 4 years in the long-term extension (CONTINUATION-PV).²

At 12 months, complete response rates, defined as hematocrit below 45%, platelet count below 400 × 10⁹/L, WBC below 10 × 10⁹/L, and normal spleen size, were similar between the 2 arms (38.8% ropeginterferon vs 44.8% HU), with comparable molecular response rates (MRRs).² The meaningful divergence emerged over time: at 36 months, hematologic and molecular responses continued to improve in the ropeginterferon arm while plateauing or declining in the HU arm, and at 6 years, hematocrit control below 45% was achieved in 81.4% of ropeginterferon patients vs 60.0% of control patients (P =.005).²

Event-free survival (EFS), comprising death from cardiovascular causes, thrombotic events, or disease progression, also separated significantly over time: risk events occurred in 5 of 95 ropeginterferon patients vs 12 of 74 control patients (P =.04) over at least 6 years of follow-up.²

Seventy-two–month data from the study, stratified by baseline risk, showed a difference in outcomes between low-risk and high-risk PV patients. Among low-risk patients (n = 46), the complete hematologic response (CHR) rate was 73.2% and MRR was 84.4%, with a median JAK2 V617F allele burden of 5.6% and only 1 patient (1.8%) withdrawing due to adverse events. Among high-risk PV patients (n = 49), CHR was 38.3% and MRR was 49.0%, with a median JAK2 V617F allele burden of 17.9% and 13 patients (18.3%) withdrawing due to adverse events.³ Pettit noted the lower response and tolerability rates in the high-risk group, suggesting that earlier intervention before higher disease burden accrues may be 1 reason low-risk patients respond so favorably to ropeginterferon.

The molecular response data were further contextualized by a 2024 analysis from PROUD-PV/CONTINUATION-PV showing time to first risk event by molecular response status. Among patients who achieved a molecular response, virtually no risk events occurred through 90 months of follow-up, whereas those without a molecular response experienced a steady accumulation of events over time.⁴ “I'm becoming more and more convinced that molecular responses, even when we're not getting to chronic myeloid leukemia levels of disease control, may still be making a dent in the disease and improving things for patients,” Pettit commented.

Pettit then reviewed MAJIC-PV (NCT02218047), a phase 2, randomized, multicenter trial that enrolled 180 patients with high-risk PV who had been previously treated with HU and were resistant or intolerant, comparing ruxolitinib 10 mg twice daily (or 5 mg twice daily for baseline platelet counts of 100-200 × 10⁹/L) with best available therapy (BAT), which included hydroxyurea (32%), interferon (15%), or their combination (12%), among other options.⁵ The complete response rate (normalization of WBC, hematocrit, and platelet count) was significantly higher with ruxolitinib at 23.0% vs 8.1% with BAT (P =.003).⁵

EFS separated significantly in favor of ruxolitinib. Patients treated with ruxolitinib who achieved a molecular partial response (defined as at least 50% reduction in JAK2 V617F VAF) had significantly better progression-free survival, EFS, and overall survival than non-responders, regardless of treatment arm.⁵

One participant raised the point that MAJIC-PV enrolled patients in the second-line setting, making a direct efficacy comparison with ropeginterferon, used across lines in PROUD-PV/CONTINUATION-PV, challenging. Pettit agreed, noting that the data cannot be compared head-to-head, and that her clinical choice between the 2 agents comes down to individual patient factors: patients with high symptom burden, splenomegaly, or bone pain may respond more quickly and noticeably to ruxolitinib, whereas younger patients for whom disease modification is a long-term priority may be better suited to ropeginterferon.

A participant distilled the evolving consensus well, noting that the historical framework of measuring success only in blood counts and thrombosis prevention is giving way to a broader view in which molecular burden, disease modification, and patient-reported symptoms all factor into treatment goals. Pettit agreed: "The paradigm is kind of shifting gradually in these disorders away from just a band-aid kind of treatment and prevention of thrombosis to trying to actually get at a deeper level of the disease."

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DISCLOSURES: Pettit has previously reported participating in advisory boards for CTI BioPharma, AbbVie, Protagonist Therapeutics, PharmaEssentia, and Kura Oncology.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms, version 2.2025. Accessed February 12, 2026. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
2. Gisslinger H, Klade C, Giorgio 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 J-J, 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/s41375-021-01475-x
4. Kiladjian J-J, et al. JAK2V617F molecular response and event-free survival in PROUD-PV/CONTINUATION-PV. Presented at: EHA Annual Congress; 2024. Abstract P254. HemaSphere. 2024;8(S1):254-255.
5. Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial. J Clin Oncol. 2023;41(19):3534-3544. doi:10.1200/JCO.22.01935