Highlight
Ropeginterferon alfa‑2b produced a durable modified ELN response at months 9 and 12 in 43% of hydroxyurea‑intolerant or ‑refractory essential thrombocythaemia (ET) patients with leukocytosis, markedly superior to 6% with anagrelide (difference 36.5%, 95% CI 25.4–47.7; p=0.0001). Serious adverse events and grade ≥3 events were numerically lower with ropeginterferon alfa‑2b.
Background and disease burden
Essential thrombocythaemia (ET) is a Philadelphia‑negative myeloproliferative neoplasm characterized by sustained thrombocytosis and increased risk of thrombohemorrhagic complications, with additional morbidity driven by leukocytosis, disease‑related symptoms, and long‑term progression to myelofibrosis or acute leukemia in a minority of patients. First‑line cytoreductive therapy for high‑risk ET has classically been hydroxyurea (HU). However, up to about one third of patients develop intolerance or resistance to HU, creating a clinically important second‑line therapeutic gap. Anagrelide has been widely used as an alternative cytoreductive agent. Ropeginterferon alfa‑2b (ropeg), a mono‑pegylated interferon with a long dosing interval, has established efficacy in polycythaemia vera and offers a potential disease‑modifying mechanism through immune modulation and reduction of clonal hematopoiesis. SURPASS‑ET was designed to compare ropeg with anagrelide as second‑line therapy in HU‑intolerant or HU‑refractory ET patients who also had leukocytosis, a subgroup at increased thrombotic risk and disease activity.
Study design
Overview
SURPASS‑ET is a multicentre, open‑label, randomized, active‑controlled, phase 3 trial conducted across 55 sites in Asia, North America, and Canada. The trial enrolled adults (≥18 years) with high‑risk ET who were intolerant of or refractory to hydroxyurea and had a white blood cell (WBC) count >10 × 10^9/L. High‑risk criteria included age >60 years with JAK2 V617F or prior history of disease‑related thrombosis or hemorrhage.
Interventions and randomization
Participants were randomized 1:1 to receive either ropeginterferon alfa‑2b subcutaneously every two weeks (starting 250 µg, titrated to 350 µg at week 2 and to 500 µg from week 4 onward) or oral anagrelide dosed per US FDA prescribing information. Randomization was stratified by platelet count, symptom score, and country. The primary efficacy analysis population was the intention‑to‑treat (ITT) cohort.
Endpoints
The primary endpoint was the rate of durable response assessed at months 9 and 12, defined using modified European LeukemiaNet (ELN) response criteria (which integrate platelet count control, leukocyte count, and absence of thrombotic events and major bleeding). Safety and tolerability, including grade ≥3 treatment‑emergent adverse events (TEAEs) and serious adverse events (SAEs), were prespecified secondary outcomes. The trial is registered at ClinicalTrials.gov (NCT04285086) and an extension study for long‑term outcomes is ongoing.
Key findings
Participants and follow‑up
Between Aug 25, 2020, and Nov 12, 2024, 174 patients were randomized (91 to ropeg and 83 to anagrelide) from 245 screened. Median follow‑up was 12.5 months (IQR 11.5–12.9). Baseline demographics were balanced: approximately half were female and 96% were Asian (167/174), with seven White participants.
Primary efficacy outcome
The trial met its primary endpoint. Durable modified ELN responses at months 9 and 12 were observed in 39 of 91 patients (43%) receiving ropeginterferon alfa‑2b versus 5 of 83 patients (6%) receiving anagrelide. The absolute difference was 36.5% (95% CI 25.4–47.7), p=0.0001. This is a large and clinically meaningful effect size favoring ropeg in this HU‑intolerant/refractory ET cohort with leukocytosis.
Safety
Overall, ropeg demonstrated a tolerability profile at least comparable to anagrelide and on several measures favorable:
– Grade ≥3 treatment‑emergent adverse events occurred in 21 of 91 (23%) ropeg recipients versus 27 of 80 (34%) anagrelide recipients (note denominator reflects safety population numbers reported).
– The most common grade ≥3 events with ropeg were infections and infestations (8 of 91; 9%), versus 5 of 80 (6%) with anagrelide.
– Anagrelide had more grade ≥3 nervous system disorders (6 of 80; 8%) compared with ropeg (1 of 91; 1%).
– Serious adverse events occurred in 13 of 91 (14%) patients on ropeg versus 24 of 80 (30%) on anagrelide. The most frequent SAE was cerebral infarction, occurring in 4 of 80 (5%) anagrelide patients but in none of the ropeg group.
– There were no treatment‑related deaths in either group.
These safety signals suggest ropeg may be associated with fewer severe complications in this population during the first year, including thrombotic events captured as cerebral infarctions in the anagrelide arm; however, event numbers are small and longer follow‑up is required to confirm durability of these differences.
Interpretation of clinical effect
The magnitude of the treatment effect—an absolute 36.5% higher durable response rate with ropeg—supports a real clinical advantage in achieving hematologic control defined by modified ELN criteria. Given the trial enrolled patients with leukocytosis (WBC >10 × 10^9/L), the data are particularly relevant to treating clinicians who consider leukocytosis an adverse prognostic feature and a treatment target in ET. The open‑label design could introduce bias in subjective endpoints, but the primary endpoint relies substantially on objective laboratory measures and adjudicated events.
Expert commentary and critical appraisal
Strengths
– Randomized, multicenter, active‑controlled phase 3 design directly compares ropeg with anagrelide, the commonly used second‑line agent.
– Clear, clinically relevant primary endpoint (durable modified ELN response) assessed over consecutive timepoints (months 9 and 12).
– Safety data show fewer SAEs and serious thrombotic events with ropeg during the first year.
Limitations and generalizability
– The study population was predominantly Asian (96%), limiting direct generalizability to other racial and ethnic groups; confirmatory data in more diverse cohorts would be valuable.
– Median follow‑up of ~12.5 months is relatively short for MPNs, which are chronic diseases where long‑term outcomes such as thrombosis rates, progression to myelofibrosis or leukemic transformation, and molecular remission matter. The ongoing extension study will be critical to determine whether early hematologic benefits translate into durable clinical and disease‑modifying effects.
– Open‑label conduct is susceptible to bias for subjective measures, though the primary endpoint relies on laboratory values and objective event capture.
– The trial focused on patients with leukocytosis; applicability to HU‑intolerant/refractory ET patients without leukocytosis requires caution.
– The study was funded by PharmaEssentia, a potential conflict of interest that warrants transparency and independent confirmation where possible.
Biologic plausibility and mechanism
Interferons, including ropeg, act via immune modulation and antiproliferative effects on hematopoietic progenitors and have been associated with reductions in mutant allele burden (e.g., JAK2 V617F) in other MPN settings. This biological rationale supports the observed cytoreductive efficacy and raises the possibility of disease‑modifying impact beyond simple platelet lowering, a potential advantage over anagrelide, which primarily reduces platelet production without clear clonal suppression. However, molecular response data were not reported here and should be sought in the extension study or subsequent publications.
Clinical implications and practice considerations
– For clinicians managing HU‑intolerant or HU‑refractory high‑risk ET with leukocytosis, SURPASS‑ET provides randomized evidence that ropeginterferon alfa‑2b achieves higher rates of durable hematologic response than anagrelide and may be associated with fewer serious adverse events during the first year.
– Ropeg’s every‑2‑weeks dosing schedule is convenient compared with conventional interferons and may favor adherence. Clinicians should remain vigilant for interferon‑class adverse effects (flu‑like symptoms, mood disturbances, autoimmune phenomena, and infections), and monitor accordingly.
– Treatment choice should incorporate patient comorbidity, pregnancy potential (interferons have historical use in pregnancy for MPNs), access and cost considerations, and patient preference regarding subcutaneous injection versus oral therapy.
– Regulatory status, reimbursement, and local availability will influence adoption; the sponsor relationship should be considered when interpreting results.
Conclusion and research priorities
SURPASS‑ET demonstrates that ropeginterferon alfa‑2b is superior to anagrelide for achieving durable modified ELN hematologic responses at months 9 and 12 in HU‑intolerant or ‑refractory high‑risk ET patients with leukocytosis, with a favorable short‑term safety profile and fewer serious adverse events. These data support consideration of ropeg as a second‑line option in this specific clinical context. Key unanswered questions include long‑term effects on thrombotic event rates, progression to myelofibrosis or leukemia, molecular responses, and outcomes in more racially diverse populations. Ongoing extension follow‑up and independent real‑world evidence will be important to define ropeg’s role in ET management.
Funding and trial registration
The SURPASS‑ET trial was funded by PharmaEssentia. Registered at ClinicalTrials.gov: NCT04285086.
References
Mesa R, Gill H, Zhang L, Jin J, Kirito K, Komatsu N, Qin A, Xiao Z, Tashi T, Shimoda K, Ohishi K, Chen S, Zuo X, Shirane S, Hu Y, Zhang S, Wang Y, Takenaka K, Ichii M, Xu N, Shih LY, Lim KH, Lee SE, Bae SH, Teo WZY, Maze D, Oh ST, Bose P, Sato T, Zagrijtschuk O, Lin S, Shih WJ, Mascarenhas J, Masarova L; SURPASS‑ET Study Group. Ropeginterferon alfa‑2b in hydroxyurea‑intolerant or hydroxyurea‑refractory essential thrombocythaemia (SURPASS ET): a multicentre, open‑label, randomised, active‑controlled, phase 3 study. Lancet Haematol. 2025 Nov;12(11):e862‑e875. doi: 10.1016/S2352‑3026(25)00264‑9. PMID: 41193116.
ClinicalTrials.gov Identifier: NCT04285086.