Ropeginterferon Provides Improved Hematocrit Control Over Phlebotomy Alone in Low-Risk PV

Tiziano Barbui, MD

Treatment with ropeginterferon alfa-2b led to a larger proportion of patients with low-risk polycythemia vera (PV) maintaining their hematocrit levels at ≤45% for a year as compared with phlebotomy alone, according to the results of an interim analysis from the Low-PV trial.¹

Enrollment in the trial was ended early following the overwhelming efficacy seen in the interim analysis, but follow-up will continue for 2 years, as per protocol.

“This interim analysis demonstrated ropeginterferon in low-risk patients is more efficacious in keeping the hematocrit [at target levels]. In addition, we get a better quality of life and the target was reached with a reduction of phlebotomy needs,” said Tiziano Barbui, MD, a professor of hematology and scientific director of the Research Foundation at Ospedali Riuniti di Bergamo in Italy. Results from the preplanned analysis of the phase 2 investigator-driven, multicenter, randomized trial (NCT03003325) were presented during the virtual 25th Congress of the European Hematology Association (EHA).

Investigators have found that in patients with PV, the risk of cardiovascular issues, including major thrombosis, is increased about 4-fold when hematocrit levels increase 45%.² As such, guidelines now recommend trying to maintain patient hematocrit levels below the target threshold of ≤45% to prevent blood hyperviscosity and cardiovascular complications.

Monthly phlebotomy is the current standard treatment for patients with low-risk PV—defined as age of 60 years or less and no history of thrombosis—to maintain hematocrit at recommended levels. However, the investigators questioned whether phlebotomy alone was adequate to maintain hematocrit levels, as in the investigation of cardiovascular risk association with hematocrit levels, about half of the patients treated with only phlebotomy could maintain target hematocrit levels. As such, the investigators of the Low-PV study questioned if added cytoreductive treatments could help keep the risk of thrombosis at bay.¹

Planned enrollment for Low-PV included 150 adult patients with no history of cardiovascular events who would be randomized equally between the ropeginterferon and phlebotomy-alone arms. At baseline, all patients underwent phlebotomy to achieve hematocrit levels below 45%. In the second year of follow-up, non-responders in each arm were allowed to switch over to the other treatment arm.

The interim analysis presented at EHA included findings from the first 100 patients who were followed for 1 year; the study database was locked at the end of February 2020 for the interim analysis.

In the investigative arm, ropeginterferon was administered at 100 mcg subcutaneously every 2 weeks. Acetylsalicylic acid was allowed in both treatment arms.

The primary composite end point was the percentage of patients who maintained hematocrit ≤45% for 12 months in the absence of progressive disease. In the context of the study, progressive disease was defined as thrombosis, bleeding, progressive leukocytosis, symptomatic or extreme thrombocytosis, symptomatic splenomegaly, or other uncontrolled symptoms. Secondary end points included the number of phlebotomies, molecular responses, bone marrow morphology, thrombohemorrhagic events, quality of life, and safety. The investigators also wanted to assess the impact of treatment on the clonal architecture of non–JAK2 V617F mutations.

Between both arms (n = 50 each), the majority of patients were male, had previously received low-dose aspirin and phlebotomies, and had been diagnosed less than 3 years prior. In the ropeginterferon arm, the median age was 51.4 years (range, 31.9-59.7) and the median hematocrit level was 44.2%. In the control arm, the median age was 48.1 years (range, 23.5-60.8) and the median hematocrit level was 44.6%.

Eighty-four percent of patients in the ropeginterferon arm achieved the primary composite end point compared with 60% in the phlebotomy arm (odds ratio, 3.5; 95% CI, 1.3-10.4; P= .008). In terms of just hematocrit control, 84% of patients maintained target hematocrit levels with ropeginterferon compared with 66% in the control group (P= .038).

Four patients treated with phlebotomy alone had disease progression of platelet count progression or splenic infarction. No patients in the ropeginterferon arm demonstrated signs of disease progression.

Preliminary results for secondary end points showed that the number of phlebotomies needed was higher in the control arm than in the ropeginterferon group (57% vs 43%; P= .024). This started to occur after 5 to 6 months of exposure to ropeginterferon, Barbui noted.

Patients in the ropeginterferon arm showed improvements in symptoms in terms of a mean 21% improvement in 7 out of 10 items from the myeloproliferative neoplasm symptom assessment form. On the other hand, in the phlebotomy arm, patients showed a 10% worsening of symptoms in 5 of the 10 items (P= .033).

Additionally, treatment with ropeginterferon was associated with reduction of splenomegaly and decreased leukocyte and platelet counts.

Significantly more adverse events (AEs) were observed in the investigational arm (78%) versus the control arm (42%) and treatment-related AEs were seen in 48% and 6% of patients, respectively. There was no difference noted in severe AEs between the 2 arms (6% with ropeginterferon vs 8% with phlebotomy). In the ropeginterferon arm, severe AEs included 4 cases of decreased neutrophil counts, and 1 case each of hypertransaminasemia and pruritus. Alternatively, in the control arm, the severe AEs were cutaneous symptoms in 2 patients and knee impingement syndrome, pain, and thrombosis in 1 patient each.

EHA commentator Ruud Delwel, PhD, noted that the interim results of the study already challenge standard practice and this important study will continue to be discussed for years with further follow-up results. Barbui said that these findings require further follow-up and the secondary end points will be assessed following the conclusion of the second year of the trial.

_References

_{1. Barbui T, Vannucchi AM, De Stefano V, et al. Phase II randomized clinical trial comparing ropeginterferon versus phlebotomy in low-risk patients with polycythemia vera. Results of the pre-planned interim analysis. Presented at: EHA25 Virtual; June 11-21, 2020. Abstract LB2602.}

_{2. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500}