Patients with polycythemia vera were more likely to achieve durable long-term hematologic response with ropeginterferon alfa-2b than the standard cytoreductive therapy hydroxyurea, according to results from the phase III PROUD-PV trial and its extension study (CONTINUATION-PV). The results, which were published in Lancet Hematology, “suggest that ropeginterferon alfa-2b can be considered as firstline cytoreductive therapy instead of hydroxyurea,” according to lead author Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and colleagues.
PROUD-PV enrolled 306 adult patients with early-stage polycythemia vera, defined as no history of cytoreductive therapy use or less than 3 years of prior hydroxyurea use. After 1 year, patients could choose to enter the extension part of the trial, CONTINUATION-PV.
In PROUD-PV, the primary endpoint was noninferiority of ropeginterferon alfa-2b versus hydroxyurea in terms of achievement of complete hematologic response with normal spleen size (defined as a longitudinal diameter of ≤12 cm in women and ≤13 cm in men) assessed at 12 months.
For CONTINUATION-PV, co-primary endpoints included achievement of complete hematologic response with spleen size normalization, as well as improved disease burden. The latter endpoint was assessed by clinical resolution or improvements in splenomegaly, microvascular disturbances, pruritus, and headache.
A total of 257 patients (median age = 60 years; range = 21-85) in the PROUD-PV trial were randomized (1:1) to receive either:
- subcutaneous ropeginterferon alfa-2b at a starting dose of 100 μg, administered every 2 weeks (n=127)
- oral hydroxyurea 500 mg/day (n=127)
A total of 171 patients chose to enter the CONTINUATION-PV extension trial.
Overall, the median follow-up periods for each treatment were 182.1 weeks (interquartile range [IQR] = 166.3-201.7) in the ropeginterferon alfa-2b group and 164.5 weeks (IQR=144.4-169.3) in the hydroxyurea group.
In PROUD-PV, after 1 year of treatment, approximately 21% of patients treated with ropeginterferon alfa-2b and 28% of patients treated with standard therapy met the primary endpoint of complete hematologic response with normal spleen size. The authors concluded that in the first year, ropeginterferon alfa-2b failed to show noninferiority to hydroxyurea. However, ropeginterferon alfa-2b was better with longer-term use.
“Ropeginterferon alfa-2b was up-titrated cautiously in PROUD-PV,” the authors wrote. The mean efficacious dose in the PROUD-PV study was reached after 3.7 months in the experimental group and after 2.6 months in the standard-therapy group. The median doses at 36 months were 425 μg (IQR=250-500) per administration of ropeginterferon alfa2b and 1,000 mg (IQR=750-1,375) per administration of hydroxyurea, which had remained stable since month 12.
In CONTINUATION-PV trial, a significantly higher proportion of patients treated with ropeginterferon alfa-2b achieved complete hematologic response with improved disease burden at 36 months compared with patients treated with hydroxyurea (53% vs. 38%, respectively; rate ratio = 1.42; 95% CI 1.01-2.00; p=0.044). However, there was no significant difference between the treatment groups in terms of patients who achieved the composite primary endpoint at 12 months.
The investigators observed that the proportion of patients with a response in the ropeginterferon alfa2b arm of the extension trial gradually increased up to 24 months and remained high at 36 months. In contrast, the proportion of responders in the hydroxyurea group was highest at 12 months but subsequently decreased. See the TABLE for a detailed report of the types of responses observed in the CONTINUATION-PV trial.
Responses also appeared to be more durable in the ropeginterferon alfa-2b group: A significantly greater proportion of these patients maintained complete hematologic response (39% vs. 15%, respectively; p=0.0011) and complete response with improved disease burden (30% vs. 15%; p=0.025) over 36 months.
When looking at molecular responses, the researchers noted that, from baseline to 12 months, the reductions in mean JAK2 V617F allele burden were not significantly different between the ropeginterferon alfa2b group (41.9% to 30.7%, respectively) and the hydroxyurea group (42.8% to 25.9%, respectively). However, at 24 months, these values were significantly lower in patients treated with ropeginterferon alfa2b versus hydroxyurea (20.9% vs. 32.1%, respectively; p<0.0001). Similar findings were observed at month 36 (19.7% for ropeginterferon alfa2b vs. 39.3% for hydroxyurea, respectively; p<0.0001). Post hoc analysis revealed that a lower JAK2 V617F allele burden correlated with complete hematologic response at 12, 24, and 36 months.
In the ropeginterferon alfa-2b group, the most frequently reported grade 3 and grade 4 treatment-related adverse events (AEs) included increased gamma-glutamyltransferase (6%) and increased alanine aminotransferase (3%). In patients treated with hydroxyurea, however, the most frequently reported grade 3 and grade 4 AEs were leukopenia (5%) and thrombocytopenia (4%). Overall, the investigators found that the proportion of grade ≥3 treatment-related AEs were similar in both treatment groups, at approximately 2% in the ropeginterferon alfa-2b group and 4% in the hydroxyurea group.
Four deaths were recorded; only one death (in the hydroxyurea group, due to acute leukemia) was considered treatment related.
While these findings appear to corroborate the disease-modifying potential of interferon alfa–based therapy that has been demonstrated in previous trials, the authors noted several potential limitations, including the low number of patients with baseline splenomegaly, the low number of patients who consented to bone marrow assessment for the evaluation of hematologic and clinical efficacy outcomes, the potential of confounding by some patients’ prior use of hydroxyurea for up to 3 years, and the possibility of selection bias in the extension study.
Gisslinger H, Klade C, Georgiev P, et al; PROUD-PV Study Group. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomized, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7:e196-e208.