Results of the phase II trial Low-PV: Ropeginterferon versus phlebotomy for low risk PV

At the 25th European Hematology Association (EHA) Annual Congress, our Steering Committee member Tiziano Barbui presented the preplanned interim results from the phase II trial Low-PV (NCT03003325). This is a randomized study comparing the efficacy of the monopegylated interferon, ropeginterferon alfa-2b, plus phlebotomy versus phlebotomy alone in low-risk patients with polycythemia vera (PV).

Currently, phlebotomy alone is considered the standard of care for patients of ≤ 60 years with PV and no history of thrombosis, who are defined as low risk.¹ However, it is still unclear whether phlebotomy alone is enough to maintain hematocrit (HCT) at < 45% over time, a target that significantly reduces the risk of cardiovascular-related death or major thrombosis events as reported by the CYTO-PV phase III trial.²  Another unanswered question is whether the addition of other cytoreductive agents, like ropeginterferon alfa-2b, can lead to more robust outcomes in this low-risk patient population.¹ To address these questions and evaluate the benefit/risk profile of ropeginterferon alfa-2b versus phlebotomy alone, the Low-PV trial was established.

Study design

• Phase II, multicenter, randomized trial in patients aged 18–60 years without history of thrombosis
• All patients (N = 150) were phlebotomized upon study entry to achieve HCT < 45%, and then randomized 1:1 to either:
  • Phlebotomy plus low dose acetylsalicylic acid (ASA) (n = 75), or
  • Phlebotomy plus ASA plus 100 μg of ropeginterferon alfa-2b every 2 weeks (n = 75)
• The composite primary endpoint was the proportion of patients maintaining a median HCT value of < 45% over 12 months, with no signs of progressive disease, including thrombosis, bleeding, progressive leukocytosis, symptomatic or extreme thrombocytosis, symptomatic splenomegaly, or other uncontrolled symptoms
• Secondary endpoints included the number of phlebotomies, bone marrow morphology, incidence of thrombohemorrhagic events, quality of life, and safety
• Data cut-off for this interim analysis was the end of February 2020 (N = 100)
• Baseline patient characteristics were well balanced between the arms and are shown below in Table 1

Table 1. Baseline patient characteristics from Low-PV¹

ASA, acetylsalicylic acid; CI, confidence interval; JAK2, Janus kinase 2
	Ropeginterferon alfa-2b arm (n = 50)	Standard phlebotomy arm (n = 50)	p value
Male/female patients, %	74/26	62/38	0.198
Median age (range), years	51.4 (31.9–59.7)	48.1 (23.5–60.8)	0.549
Previous ASA/phlebotomies, %	86	94	0.318
Patients with diagnosis, % < 3 years 3–5 years > 5 years	70 16 14	70 20 10	0.757
Median hemoglobin, g/dL (95% CI)	13.55 (11.6–15.6)	13.65 (11.9–15.9)	1.000
Median platelets, x 109/L (95% CI) > 1000 x 109/L, %	645 (278–1127) 14	677 (254–1202) 12	0.549
Median hematocrit, % (95% CI)	44.2 (40.7–47.7)	44.6 (40.3–49.7)	0.549
Median white blood cells, x 109/L (95% CI) > 11 x 109/L, %	10.83 (6.27–21.50) 44	10.89 (6.16–22.64) 46	0.841
Median JAK2 V617F allelic burden, % (range, n = 67)	30.0 (3.0–88.0)	35.9 (0.0–98.0)	0.892
Palpable splenomegaly, %	38	32	0.529
Median bone marrow cellularity, % (range)	80 (35–95)	70 (35–95)	0.132

Results

• The primary endpoint was achieved by 84% of patients in the ropeginterferon alfa-2b arm versus 60% of patients in the standard phlebotomy arm (Odds ratio, 3.5; 95% CI, 1.3–10.4; p = 0.008)
• HCT control was achieved by 84% of patients in the ropeginterferon alfa-2b arm versus 66% of patients in the standard phlebotomy arm
• Disease progression occurred in 0% of patients in the ropeginterferon alfa-2b arm versus 8% in the standard phlebotomy arm (n = 4)
• The number of phlebotomies needed was significantly lower in the ropeginterferon alfa-2b arm versus the standard phlebotomy arm (43% vs 57%; p = 0.024)
• Reduction in symptom severity by 21% occurred in the patients receiving ropeginterferon alfa-2b plus phlebotomy, which was not observed in the standard phlebotomy arm (p = 0.033)

Safety

• The incidence of any adverse event (AE) as well as that of treatment-related adverse events were higher in the ropeginterferon alfa-2b arm than the standard phlebotomy arm. Nevertheless, the incidence of severe Grade 3 AEs was similar between the arms as shown below in Table 2

Table 2. Safety profiles reported in the interim analysis of the Low-PV trial¹

AE, adverse event; TEAEs, treatment-related adverse event Statistical significance is indicated by bold font
	Ropeginterferon alfa-2b arm, % (n = 50)	Standard phlebotomy arm, % (n = 50)	p value
Any AE	78	42	< 0.001
TEAEs	48	6	< 0.001
Severe Grade 3 AEs	6	8	1.000

Conclusion

The above data from the interim analysis of the Low-PV phase II trial indicate that ropeginterferon alfa-2b addition to phlebotomy is more efficacious than the current standard therapy of phlebotomy alone in low risk patients with PV. Patients in the ropeginterferon alfa-2b arm were better able to maintain HCT at target levels for a long duration of time and required a significantly lower number of phlebotomies, when compared to the phlebotomy alone arm. Despite the increased incidence of TEAEs seen in the ropeginterferon alfa-2b arm, the incidence of severe AEs was similar across the arms and quite low. Further secondary endpoints from the trial are planned for evaluation in 2022.

The results of this study have now been published in the Lancet.³