PROUD-PV phase III results on ropeginterferon alpha-2b for polycythemia vera

Interferon alpha (IFN-a) compounds have long been used for the treatment of myeloproliferative neoplasms (MPN), showing a combination of clinical, molecular, and histopathological efficacy.¹ However, in their conventional formulation they have been associated with substantial toxicity, thus limiting their use.¹ This changed with the production of the modified pegylated IFNs, also known as peginterferons, that led to a significant improvement in tolerability and safety.² For the treatment of polycythemia vera (PV), these peginterferons have been used off-label instead of the standard of care, hydroxyurea.² Nevertheless, until recently there were no randomized, controlled, phase III trials comparing these two regimens directly in order to establish a potential superiority.

In January 2020, Heinz Gisslinger and colleagues published the final results of the first randomized, controlled, phase III trial, PROUD-PV, comparing hydroxyurea to the peginterferon alpha compound, ropeginterferon alpha-2b, for the treatment of PV. The authors also included interim data from their five-year planned extension study, CONTINUATION-PV, at 36 months. The results have been published in the Lancet Hematology.²

Study design

PROUD-PV

• Multicenter (48 European clinics), open-label, active-controlled, phase III trial
• Primary endpoint was non-inferiority of ropeginterferon alpha-2b vs hydroxyurea in terms of complete hematological response with normal spleen size at 12 months
• Eligible patients were ≥ 18 years old and had PV diagnosis according to the World Health Organization 2008 criteria, including the Janus kinase 2 (JAK2) V617P mutation
• N = 257 patients were randomly assigned 1:1 for 12 months to either
  • ropeginterferon alfa-2b (rIFN-a; n = 127): starting at 100 mg subcutaneously every two weeks (or 50 mg if patient transitioning from pre-trial hydroxyurea) or
  • hydroxyurea (n = 130): starting at 500 mg per day orally
    • Dosing of both was increased until hematocrit was < 45% without phlebotomy and normalised platelet and leucocyte counts were reached and sustained
• Efficacy assessments every 3 months

CONTINUATION-PV

• N = 171 patients who completed PROUD-PV were enrolled to the extension trial
• Primary endpoints were complete hematological response with normalization of spleen size and with improved disease burden (i.e. splenomegaly, microvascular disturbances, pruritus, and headache)
• Patients previously randomized to rIFN-a continued with the same treatment (n = 95) while those continuing from the hydroxyurea arm (n = 76) received best available treatment (hydroxyurea, IFNa, peginterferon alpha other than rIFN-a, anagrelide, JAK2 inhibitor, phosphorus-32, or busulfan)
• Efficacy assessments every 3 months

Results

PROUD-PV

• Baseline characteristics were similar across arms in both PROUD-PV and CONTINUATION-PV. These are shown below in Table 1

Table 1. Main baseline characteristics of patients in PROUD-PV and CONTINUATION-PV trials²

JAK2, Janus kinase 2; PV, polycythemia vera
PROUD-PV			CONTINUATION-PV
	Ropeginterferon alpha 2b arm (N = 127)	Hydroxyurea arm   (N = 127)	Ropeginterferon alpha 2b arm (N = 95)	Hydroxyurea arm   (N = 76)
Male, %	46	47	49	47
Median age (range), years	60 (30-85)	60 (48-67)	58 (30-85)	59 (32-79)
Hydroxyurea pre-trial treatment, %	35	29	32	26
Median duration of PV, months	10.2 (2.1-21.3)	7.9 (2.7-19.2)	9.5 (2.8-25.1)	8.2 (2.6-23.0)
Positive for JAK2 V617P mutation, %	99	98	99	97
Median hematocrit, %	47.1	48.0	47.7	49.9
Median spleen size, cm	13.1	13.0	13.5	12.8
Presence of splenomegaly, %	9	12	7	11

• The key results from PROUD-PV are shown below in Table 2

Table 2. Key results from PROUD-PV phase III trial²

	Ropeginterferon alpha 2b arm (N = 127)		Hydroxyurea arm    (N = 127)	Difference in response (95% CI)	p value
Median follow-up (range)	182.1 weeks (166.3-201.7)	164.5 weeks (144.4-169.3)
Mean efficacious dose reached at (95% CI)	16.2 weeks (14.8-17.6)	11.4 weeks (10.2-12.6)
Complete hematological response with normal spleen size at 12 months	26/122 (21%)	34/123 (28%)		−6.57 (−17.23-4.09)	0.23
Complete hematological response at 12 months	53/123 (43%)	57/125 (46%)		−3.02 (−15.55-9.52)	0.63
Molecular response at 12 months	42/123 (34%)	52/123 (42%)		−8.07 (−19.99-3.84)	0.19
Discontinued treatment	21/127 (17%)	13/127 (13%)

 

CONTINUATION-PV

• Of the 217 patients who completed PROUD-PV, 171 patients rolled over to the CONTINUATION-PV trial
• Data were analysed up to Month 36
• The key interim results from CONTINUATION-PV are shown in Table 3

Table 3. Key interim results from CONTINUATION-PV trial at Month 36²

Statistically significant p values (p < 0.05) are indicated in bold
	Ropeginterferon alpha 2b arm (N = 95)		Hydroxyurea arm (N = 76)	Rate ratio (95% CI)	p value
Complete hematological response and improvement in disease burden at Month 36	53%	38%		1.42 (1.01-2.00)	0.044
Complete hematological response at Month 36	71%	51%		1.38 (1.07-1.79)	0.012
Molecular response at Month 36	66%	27%		2.31 (1.56-3.42)	< 0.0001

Safety

• The number of reported Grade 3-4 adverse events (AEs) in PROUD-PV and CONTINUATION-PV were similar, with the most frequently reported being
  • rIFN-a arm (n = 127):
    • increased g-glutamyltransferase (8%)
    • increase alanine aminotransferase (4%)
  • hydroxyurea arm (n = 127):
    • leukopenia (5%)
    • thrombocytopenia (4%)
    • hypertension (4%)
• Treatment-emergent AEs (TEAEs) of any grade were reported in 75% of patients in the rIFN-a arm and in 79% of patients in the hydroxyurea arm
• Serious TEAEs of Grade 3-4 were reported in 2% of patients in the rIFN-a arm and in 4% of patients in the hydroxyurea arm
• AEs of special interest
  • rINF-a arm (n = 127): psychiatric TEAEs (2%), musculoskeletal and connective tissue TEAEs (2%), major cardiovascular AEs (10%), major thromboembolic AEs (3%), neoplasms (7%)
  • Hydroxyurea arm (n = 127): psychiatric TEAEs (1%), major cardiovascular AEs (6%), major thromboembolic AEs (3%), neoplasms (8%)
• One treatment-related death occurred in the hydroxyurea arm

Conclusion

The results of the first head-to-head, phase III trial comparing rIFN-a to hydroxyurea for the treatment of PV showed that rIFN-a led to similar responses and efficacy as with hydroxyurea in the first year of treatment. This indicated the non-inferiority of rIFN-a compared to the current standard of care, offering an additional validated treatment option for PV.

Highly intriguing was the observed superiority of rIFN-a vs hydroxyurea in the long term. At 36 months of treatment, rIFN-a led to significantly more complete hematological and molecular responses, with a significant improvement in disease burden. These results indicate that rIFN-a should be considered as early as possible in the treatment of PV and that it should be given over a longer period in order to provide improved durable responses. The authors concluded that rIFN provides a valid alternative to hydroxyurea, with distinct features.