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

Apr 20, 2020

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. 1However, in their conventional formulation they have been associated with substantial toxicity, thus limiting their use. 1This changed with the production of the modified pegylated IFNs, also known as peginterferons, that led to a significant improvement in tolerability and safety. 2For the treatment of polycythemia vera (PV), these peginterferons have been used off-label instead of the standard of care, hydroxyurea. 2Nevertheless, 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 Gisslingerand 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 vshydroxyurea 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 trials 2

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 JAK2V617P 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 trial 2

 

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 36 2

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 - 4adverse 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 vshydroxyurea 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.

  1. Kiladjian JJ, Giraudier S, Cassinat B. Interferon-alpha for the therapy of myeloproliferative neoplasms: targeting the malignant clone. Leukemia. 2016;30(4):776-781. DOI:10.1038/leu.2015.326
  2. 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. Lancet Haematol. 2020;7(3):e196-e208. DOI:10.1016/S2352-3026(19)30236-4