Ropeginterferon alfa-2b improved responses overtime in patients with polycythemia vera who presented predominantly without splenomegaly compared with hydroxyurea, according to findings from the phase III PROUD-PV clinical trial and its extension study, CONTINUATION-PV.
Ropeginterferon alfa-2b improved responses overtime in patients with polycythemia vera (PV) who presented predominantly without splenomegaly compared with hydroxyurea, according to findings from the phase III PROUD-PV clinical trial and its extension study, CONTINUATION-PV. However, the primary end point of the study, non-inferiority to hydroxyurea, was not met.
Overall, 257 patients were assigned to either ropeginterferon alfa-2b (n = 127) or hydroxyurea (n = 127). A total of 171 patients also rolled over into the extension study. Median follow-up was 182.1 weeks for the experimental arm (range, 166.3-201.7) versus 164.5 weeks in the standard arm (range, 144.4-169.3).
Twenty-six patients out of 122 in the ropeginterferon alfa-2b arm (21%) met the composite primary end point of complete hematological response with normal spleen size at 12 months compared with 34 patients out of 123 (28%) in the standard arm (95% CI, -17.23-4.09;P=.23). Complete hematological responses were similar without the spleen criterion at 12 months in 53 patients (43%) in the ropeginterferon alfa-2b arm versus 57 patients (46%) in the hydroxyurea arm (95% CI, -15.55-9.52; P=.63).
In the ropeginterferon alfa-2b arm, a complete hematological response was observed in 18 of 46 patients who were pretreated with hydroxyurea (39%) compared with 35 of 77 patients who were not pretreated (46%; odds ratio, 0.57 [0.20-1.42]). In the standard arm, 15 of 47 patients who were previously treated (32%) and 42 of 78 patients who were not (54%) experienced a complete hematological response (odds ratio, 0.43 [0.17-1.02];P=.0666).
The proportion of patients with a complete hematological response in the CONTINUATION-PV study was significantly higher in the experimental arm. Complete hematological response with normalization of spleen size appeared to increase steadily over time in 27 of 91 patients (30%) at month 12 in the ropeginterferon alfa-2b arm compared with 38 of 90 patients (42%) at month 36. Investigators did not find a significant difference between the 2 arms, whereas at month 12, 33 of 76 patients (43%) and at month 36, 23 of 67 (34%) had complete hematological response with normalization of spleen size in the standard arm.
A larger proportion of patients maintained complete hematological response over the 36-month treatment period in the ropeginterferon alfa-2b arm (37 [39%] of 95) versus hydroxyurea arm (11 [15%] of 76;P= .0011). The experimental arm also had a larger proportion of patients who maintained complete hematological response with improved disease burden over the 36-month treatment period (28 [30%] of 95) compared with the standard arm (11 [15%] of 76;P= .025).
Molecular responses did not appear significantly different in the experimental arm (42 [34%] of 123) and the standard arm (52 [42%] of 123;P= 0.19).
Adverse events (AEs) that required dose reductions appeared in 51 of 127 patients (40%) in the ropeginterferon alfa-2b arm compared with 74 of 127 (58%) in the hydroxyurea arm, and dose interruptions were required in 29 of 127 (23%) versus 23 of 127 (18%) respectively. Overall, 11 (8%) patients in the ropeginterferon alfa-2b arm discontinued due to drug-related AEs, which included hypothyroidism (n = 2), dyspnea and pneumonitis, thrombocytopenia, increased aspartate aminotransferase and alanine aminotransferase, microcytic anemia and anemia, anxiety, psoriasis, depression, Sjogren’s syndrome, and rheumatoid arthritis (n =1 each). Five of 127 patients in the standard arm discontinued treatment due to AEs, which included thrombocytopenia and anemia, basal cell carcinoma, pyrexia, skin ulcer, and intolerance to hydroxyurea (n = 1 each).
The most common AEs in the experimental arm, occurring in less than 10% of patients, included thrombocytopenia (22%), leucopenia (20%), increased γ­glutamyltransferase (19%), fatigue (13%), increased alanine aminotransferase (13%), anemia (13%), increased aspartate aminotransferase (10%), headache (12%), arthralgia (12%), and dizziness (11%). In the standard arm, the most common AEs included thrombocytopenia (29%), anemia (25%), leucopenia (23%), fatigue (14%), headache (13%), nausea (12%), diarrhea (11%), and nasopharyngitis (10%).
There were 16 events in 13 of 127 (10%) patients in the experimental arm of major PV-related cardiovascular AEs compared with 25 events in 8 of 127 (6%) of patients in the standard arm. Investigators considered 2 of the events to be related to ropeginterferon alfa-2b, which included atrial fibrillation and intracardiac thrombus. One treatment-related death was observed in the standard arm.
Investigators noted that treatment-related AEs (TRAEs) occurred in 95 of 127 (75%) of patients in the ropeginterferon alfa-2b arm and 100 of 127 (79%) in the hydroxyurea arm. AEs of grade 3 or higher were similar between both treatment arms. Serious TRAEs occurred in 3 of 127 (2%) of patients in the experimental arm versus 5 of 127 (4%) in the standard arm.
In the randomized, controlled, open-label trial conducted in 48 clinics in Europe, patients were randomly assigned 1:1 to receive either ropeginterferon alfa-2b subcutaneously every 2 weeks at a starting dose of 100 μg or oral hydroxyurea starting at 500 mg/day. Patients could enter the extension portion of the study after 1 year.
Based on the durable hematological and molecular response and the tolerability observed with ropeginterferon alfa-2b in the PROUD-PV trial, Gisslinger et al concluded that the agent is a safe for long-term treatment of PV with features distinct fromhydroxyurea.
Gisslinger H, Klade C, Georgiev 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 [Published Online January 31, 2020].Lancet. doi.org/10.1016/S2352-3026(19)30236-4.