Ropeginterferon α-2b extends benefit to another rare blood cancer

Topline results of the phase III SURPASS-ET trial show the superior efficacy of ropeginterferon α-2b (ropeg) compared with anagrelide as second-line (2L) treatment for high-risk essential thrombocythaemia (ET), a rare blood cancer that may progress to myelofibrosis or acute myeloid leukaemia.

Ropeg is a novel interferon-based therapy approved for the treatment of polycythaemia vera (PV) globally based on effective cytoreduction and direct anticlonal impact. [Blood 2015;126:1762-1769; Lancet Haematol 2020;7:e196-e208; Br J Haematol 2024;205:2510-2514] This provides the rationale for its evaluation in the treatment of ET and other myeloproliferative neoplasms (MPNs).

In SURPASS-ET, the proportion of patients who achieved durable modified ELN* criteria response rate at months 9 and 12 was sevenfold higher with ropeg vs anagrelide (42.9 percent vs 6 percent; p=0.0001). The criteria components were ≥10-point reduction in MPN-SAF TSS** for at least 12 weeks, normalization of peripheral blood counts for at least 12 weeks, and absence of vascular events and disease progression. [ASCO 2025, abstract 6500]

“To achieve this benefit, the median dose of ropeg over 12 months was around 450 µg. For anagrelide, it was around 2 mg,” noted Dr Ruben Mesa from Wake Forest University School of Medicine, Winston-Salem, North Carolina, US, at ASCO 2025.

Each component of the modified ELN response was met in a statistically significant fashion with ropeg vs anagrelide, he added. These metrics were platelet count response (56 percent vs 21.7 percent), white blood cell (WBC) count response (73.6 percent vs 13.3 percent), peripheral blood count remission (56 percent vs 6 percent), improvement or non-progression of splenomegaly (87.9 percent vs 54.2 percent), symptom response in TSS (71.4 percent vs 33.7 percent), and absence of haemorrhagic or thrombotic events (84.6 percent vs 51.8 percent; p<0.0001 for all).

“Looking at the platelet and WBC counts at 3-month intervals, there were statistically significant differences at each timepoint … The WBC count is important [because it is considered] an additional risk factor for thrombotic events in patients with MPNs,” Mesa pointed out.

Importantly, ropeg treatment led to a significant drop in JAK2^V617F allele burden – a marker of disease activity – from a baseline level of 33.7 percent to 25.3 percent at 12 months (mean change, -8.06 percent). With anagrelide, an increase was seen (from 37.3 percent to 39.7 percent; mean change, 3.21 percent).

Baseline CALR variant allele frequency level dropped from baseline to month 12 with both agents, but the effect was more profound with ropeg than anagrelide (mean change, -5.32 percent vs -1.45 percent).

There were more ropeg vs anagrelide recipients who achieved ≥25-percent (58.4 percent vs 46.5 percent) and ≥50-percent (53.2 percent vs 39.5 percent) symptom improvement.

Safety profile

Compared with anagrelide, ropeg was tied to lower incidences of major ET-related thrombotic (n=1 vs 8) and cardiovascular (n=0 vs 6) events at month 12, as well as cerebral (n=0 vs 6) and cerebellar (n=0 vs 1) infarctions.

Ropeg was also associated with fewer grade ≥3 treatment-emergent adverse events (TEAEs; 23.1 percent vs 33.8 percent), serious TEAEs (14.3 percent vs 30 percent), and TEAEs leading to treatment discontinuation (5.5 percent vs 20 percent) than anagrelide. Three patients on anagrelide had AEs with a fatal outcome; with ropeg, there were none.

The most frequently reported grade ≥3 TEAEs with ropeg were ALT/AST*** increases, pruritus, and weight loss; with anagrelide, the most common were anaemia and dizziness.

Only one approved therapy for ET

Current treatment approaches for ET are very limited, Mesa noted. The only approved therapy is anagrelide, and there have been no new treatments since its approval in the US in 1997. [Am J Hematol 2019;94:5-9; Eur J Haematol 2020;105:335-343] “Hydroxyurea (HU) is also used but is not approved in this space,” he said. Moreover, HU is nonspecific and does not really alter the course of the disease or its progression.

“[In SURPASS-ET,] ropeg showed superior efficacy [and favourable safety] compared with anagrelide. The response rates were higher with ropeg across haematologic parameters, symptom improvement, and spleen size control,” Mesa said.

A total of 174 ET patients (median age 62 years, 52 percent women) with HU resistance or intolerance were randomized 1:1 to SC ropeg Q2W or oral anagrelide for 12 months. Ropeg dose started at 250 µg, titrating to 350 µg at week 2 then to 500 µg from week 4 onwards. About 82 percent of patients had the JAK2^V617F mutation, while 12 percent had the CALR mutation.

All but seven patients were Asian, as participants were recruited from study sites across regions that were mostly in Asia^#.

Key treatment goals

“We have to remember that the goal of treating ET is not to normalize platelet count … Thrombosis is the biggest thing that we are trying to attenuate the risk of,” highlighted discussant Dr Raajit Rampal from the Memorial Sloan Kettering Cancer Center, Manhattan, New York City, US, at ASCO 2025. “The treatment goals in ET are to attenuate the risk of thrombosis, the risk of progression, and, ultimately, the symptom burden that patients face.”

“Ropeg showed a higher response rate as per ELN criteria, but the key things are the reduction in the incidences of thrombotic events and symptom burden. Ropeg is showing efficacy in the things that we should care about when taking care of these patients,” he said.

Considering the dose escalation strategy used for ropeg, Rampal pointed out that it would be worth looking into the potential of a lower dose to deliver the same results with fewer AEs.

Future studies should also aim to address unresolved issues stemming from the study, ie, whether the differences in vascular event rates will persist over time, whether the driver mutation will continue to decline, and whether the findings will translate to an event-free survival benefit in the longer term, he added.