5-year results from the PROUD-PV and CONTINUATION-PV studies

Ropeginterferon alfa-2b is a novel pegylated recombinant interferon, approved in the EU as monotherapy for the treatment of adults with polycythemia vera (PV) without symptomatic splenomegaly.

The PROUD-PV study is the first randomized, controlled, phase III study comparing hydroxyurea to ropeginterferon alfa-2b for the treatment of PV. Previously, the MPN Hub covered the final results of the PROUD-PV study, and the interim data from the 5-year planned extension study, CONTINUATION-PV, at 36 months. In addition, a subanalysis of the PROUD-PV trial according to age was reported in a recently published article.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Heinz Gisslinger presented the 60-month interim analysis from the PROUD-PV/CONTINUATION-PV studies; here we report a summary of this talk.  

60-month interim analysis

This analysis included all patients enrolled in the CONTINUATION-PV (NCT02218047) study:

• 89.6% of patients (n = 95) treated with ropeginterferon alfa-2b in the PROUD-PV study entered in the CONTINUATION-PV extension study, and 73.7% of these patients (n = 70) continued their treatment until Month 60
• Similarly, 68.5% of patients (n = 76) treated with hydroxyurea in the PROUD-PV study enrolled in the CONTINUATION-PV extension study to receive best available treatment, where 88% of these were treated with hydroxyurea and 75% (n = 57) were treated up to Month 60

Both hydroxyurea-naïve and pre-treated patients were included, and pre-treated patients constituted 32.3% of the ropeginterferon alfa-2b arm vs 32.9% of the control arm.

The median dose of ropeginterferon alfa-2b per treatment cycle (4 weeks) in the fifth year was 499 μg, compared with > 700 μg in Years 1 and 2. During the first year of treatment, the drug was administered every 2 weeks, but eligible patients were later allowed to switch to administration every 3 or 4 weeks.

Efficacy

Complete hematologic response

Complete hematologic response (CHR, defined as hematocrit [HCT] < 45% and no phlebotomy for at least 3 months, platelets < 400 × 10⁹/L, and white blood cells < 10 × 10⁹/L) is reported in Table 1.

Table 1. CHR up to Month 60¹

CI, confidence interval; CHR, complete hematologic response. Values in bold are statistically significant.
Study month	Ropeginterferon alfa-2b (n = 95) responders/n (%)	Control (n = 76) responders/n (%)	p value	Rate ratio (95% CI)
Month 12	59/95 (62.1)	57/76 (75.0)	0.1303	0.85 (0.70─1.05)
Month 24	67/95 (70.5)	33/67 (49.3)	0.0129	1.41 (1.07─1.84)
Month 36	67/95 (70.5)	38/74 (51.4)	0.0104	1.39 (1.08─1.78)
Month 48	57/94 (60.6)	34/76 (44.7)	0.0275	1.39 (1.04─1.86)
Month 60	53/95 (55.8)	33/75 (44.0)	0.0974	1.30 (0.95─1.77)

At Month 60, the main reasons for not meeting CHR were premature discontinuation (in 25 patients [59.5%] vs 17 [40.5%] for the ropeginterferon alfa-2b arm vs the control arm) and elevated HCT (in 12 patients [28.6%] vs 9 [21.4%] for the ropeginterferon alfa-2b arm vs the control arm). Of the prematurely discontinued patients, the responses at last visit were:

• Ropeginterferon alfa-2b arm (n = 25), 68% CHR vs 32% no CHR
• Control arm (n = 17), 35% CHR vs 65% no CHR

The CHR with last observation carried forward (LOCF) is reported in Table 2. In this case, a statistically significant difference in responses between the ropeginterferon alfa-2b arm and the control arm was observed which deepened over time.

Table 2. CHR with LOCF¹

CI, confidence interval; CHR, complete hematologic recovery; LOCF, last observation carried forward. Values in bold are statistically significant.
Study month	Ropeginterferon alfa-2b (n = 95) n (%)	Control (n = 76) n (%)	p value	Rate ratio (95% CI)
Month 12	59 (62.1)	57 (75.0)	0.1	0.85 (0.70─1.04)
Month 24	70 (73.7)	43 (56.6)	0.04	1.27 (1.02─1.60)
Month 36	73 (76.8)	41 (54.0)	0.003	1.43 (1.13─1.81)
Month 48	68 (71.6)	38 (50.0)	0.004	1.46 (1.13─1.89)
Month 60	69 (72.6)	40 (52.6)	0.004	1.43 (1.12─1.81)

Patients phlebotomy-free at 5 years of treatment reached 81.8% in the ropeginterferon alfa-2b arm and 63.2% in the control arm (p = 0.01).

Allele burden

The median JAK2 V617F allele burden is reported in Table 3. After Month 24, there was a significant reduction in JAK2 V617F allele burden observed in the ropeginterferon alfa-2b arm in comparison with the control arm. The ropeginterferon alfa-2b-induced suppression of allele burden continued up to Month 60, while allele burden was back to baseline in the control group.

Table 3. JAK2 V617F allele burden (using LOCF)¹

CI, confidence interval; LOCF, last observation carried forward. Values in bold are statistically significant.
Study month	Ropeginterferon alfa-2b (n = 95) Median	Control (n = 76) Median	p value	Rate ratio (95% CI)
Baseline	37.3	38.1	-	-
Month 12	24.4	18.2	0.0244	6.646 (0.86 to 12.43)
Month 24	14.3	25.1	0.0003	–10.745 (–16.50 to –4.98)
Month 36	11.3	40.5	< 0.0001	–18.722 (–24.49 to –12.96)
Month 48	9.2	44.2	< 0.0001	–24.582 (–30.35 to –18.82)
Month 60	8.5	44.4	< 0.0001	–23.959 (–29.72 to –18.20)

Molecular response according to European LeukemiaNet (ELN) criteria

Molecular response rates (Table 4) were significantly higher in the ropeginterferon alfa-2b arm in comparison with the control arm starting from Month 24 up to Month 60.

Table 4. Molecular response (using LOCF) according to ELN criteria¹

CI, confidence interval; ELN, European LeukemiaNet; LOCF, last observation carried forward. Values in bold are statistically significant.
Study month	Ropeginterferon alfa-2b (n = 95) responders/n (%)	Control (n = 76) responders/n (%)	p value	Rate ratio (95% CI)
Month 12	41/94 (43.6)	36/73 (49.3)	0.3744	0.87 (0.63─1.19)
Month 24	64/94 (68.1)	24/74 (32.4)	0.0001	2.00 (1.41─2.84)
Month 36	62/94 (66.0)	20/74 (27.0)	< 0.0001	2.31 (1.56─3.43)
Month 48	63/94 (67.0)	19/74 (25.7)	< 0.0001	2.50 (1.67─3.73)
Month 60	65/94 (69.1)	16/74 (21.6)	< 0.0001	3.04 (1.96─4.71)

Between Month 24 and Month 60, analysis of the combined endpoint of achieving HCT < 45% without phlebotomy and molecular response always showed significantly higher response rates in the ropeginterferon alfa-2b arm vs the control arm:

• Month 24 (LOCF), 55.3% vs 24.3% (rate ratio [RR], 2.26; 95% CI, 1.46─3.50; p = 0.0003)
• Month 36 (LOCF), 57.5% vs 25.7% (RR, 2.17; 95% CI, 1.43─3.29; p = 0.0003)
• Month 48 (LOCF), 57.5% vs 20.3% (RR, 2.79; 95% CI, 1.74─4.46; p < 0.0001)
• Month 60 (LOCF), 58.5% vs 17.3% (RR, 3.26; 95% CI, 1.97─5.42; p < 0.0001)

Safety

For safety, the data lock date was May 29, 2020 (up to 6.3 years of treatment overall).

• The incidence of thromboembolic adverse events (AEs) over the entire treatment period was 1.2% per patient year in both arms
• The incidence of disease progression was 0.2% per patient year in the ropeginterferon alfa-2b arm (myelofibrosis, n = 1) vs 1.0% per patient year in the control arm (total, n = 4; myelofibrosis, n = 2; acute leukemia, n = 2)

An overview of the safety profile is shown in Figure 1.

AE, adverse event; SAE, serious AE.

Treatment related AEs of special interest to interferon therapy in the ropeginterferon alfa-2b arm (n = 127) were seen for: endocrine organs (4.7%), musculoskeletal and connective tissue (1.6%), skin and subcutaneous tissue (1.6%), psychiatric disorders (0.8%), and immune system and blood and lymphatic system (0.8%).

Conclusion

• This long-term analysis showed that ropeginterferon alfa-2b is effective in patients with PV, with deep and durable responses
• Molecular responses continued to improve overtime up to Month 60, while responses in the control arm started to deteriorate at Month 24
• Patients in the ropeginterferon alfa-2b arm were more likely to be phlebotomy-free
• Only one patient progressed during long-term ropeginterferon alfa-2b therapy
• Ropeginterferon alfa-2b was well tolerated over long-time treatment, showing similar rates of treatment-related AEs compared to the control arm