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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
PROUD-PV
CONTINUATION-PV
PROUD-PV
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 (N = 127) |
Hydroxyurea arm (N = 127) |
Ropeginterferon alpha 2b (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 |
Table 2. Key results from PROUD-PV phase III trial2
|
Ropeginterferon (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
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 |
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.
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