by Dr. C.H. Weaver M.D. updated 5/2019
Hydroxyurea is currently an initial treatment of choice for individuals with high risk essential thrombocythemia (ET) and polycythemia vera (PV) who require treatment. Pegylated interferon (PEG) is widely used outside the United States and is advocated as an alternate option due to its “success” in Europe and its proposed potential to modify the disease course in PV patients.
Interferon belongs to a group of agents called cytokines that produce their anti-cancer effects by stimulating the immune system to help fight the cancer. Interferon is not a precision cancer medicine but works in a very general manner and is thus associated with several systemic side effects including fatigue, weakness, fever, chills, muscle pain, headache, and irritability.
In order to evaluate peg-interferon the MPN–RC 112 clinical trial was designed and conducted by the Myeloproliferative Neoplasms Research Consortium to compare hydroxyurea to pegylated interferon in patients with high-risk ET/PV. The primary end point being of the study was to compare the complete remission (CR) rate at 12 months. (1)
The final analysis of the MPN–RC 112 trial has now been reported and the CR rates in patients with high-risk ET/PV at 12 and 24 months were found to be similar for peg-interferon and hydroxyurea. Furthermore, pegylated interferon was associated with a higher rate of significant side effects when compared to hydroxyurea.
These trial results are in contrast to other reports and the results of the PROUD-PV study conducted in Europe. (2,5)
Interferon-alfa (IFN-alfa) has been reported to be more effective treatment than hydroxyurea for some patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) in a large review trial by Dr Mondello and colleagues from the Weill Cornell Medical College, New York who have conducted the largest real-life analysis comparing hydroxyurea and IFN-alfa. (2)
Data from 63 patients diagnosed with Philadelphia-negative MPNs who prospectively received hydroxyurea or IFN-α between 2000 and 2016 were collected and included in the study. The study authors reported that 97% of patients treated with IFN-alfa achieved a hematologic response compared with 78% who received hydroxyurea and molecular responses were limited to only those individuals treated with IFN-alfa.
Hydroxyurea was associated with more toxic side effects and leukemic transformation was more likely. The average duration of survival without leukemic progression was 5 years with IFN-α compared to 3 years with hydroxyurea and the overall survival duration was 7.8 years versus 5.8 years.
The comparative PROUD-PV trial demonstrated the superiority of PEG interferon when compared to hydroxyurea in patients with PV. After 24 months of treatment there was a 77.6% CR rate for PEG compared to 55.9% for hydroxyurea. (2)
The reasons for the different results are not immediately apparent but it may be be that longer follow-up is needed to demonstrate superiority of interferon to hydroxyurea in the MPN–RC 112 trial.
Currently in the United States, hydroxyurea is readily available, very inexpensive and ~ 70% of patients who receive hydroxyurea will not need any additional therapy. Interferon is associated with some challenges because it is not FDA-approved for PV and is more expensive. Acquiring it through insurance may takes multiple attempts and is it not always approved for use.
Interferon advocates however believe it is a more valid therapeutic option owing to its more profound hematologic responses, durable molecular remissions, long-term disease control, and reduced risk of leukemic transformation.
Other Ongoing Trials Evaluating Interferon
Daliah Phase 3 clinical trial failed to demonstrated superiority of IFN or HU but reported that the reduction in JAK2V617F allele burden was greater with IFN therapy.(3)
PROUD and CONTI-PV studies of Ropgeinteferon revealed that Ropeginteferon provided durable hematologic responses and symptom control, was well tolerate and 66% of patients achieved a molecular remission for JAK2 as well as a reduction in other disease associated genes such as TET2.(4)
PEG is effective for the treatment of PV or essential ET refractory to or intolerant of hydroxyurea.
Doctors from the University of Kansas Cancer Center evaluated the outcomes of PEG therapy in 65 patients with ET and 50 patients with PV who were previously treated with hydroxyurea to further define the role of recombinant interferon-alpha. Patients were treated on the phase 2 Myeloproliferative Disorders Research Consortium (MPD-RC)-111 clinical trial
The overall response to treatment assessed at 12 months from initiation of PEG therapy was 69% in patients with ET and 60% in patients with PV. Response to treatment was higher among patients with ET who harbored a CALR mutation compared with those without a CALR mutation.
PEG therapy was associated with side effects in 90.4% of patients. Significant side effects occurred in 44% of patients, and 14% of patients requited discontinuation of PEG therapy
In the past several years, consensus opinion has shifted to a risk-stratification syndrome where patients with ET who are CALR-positive are less likely to require cytoreductive therapy because of a lower vascular complication risk rate. While the data on patients who are CALR-positive responding favorably to the interferon is fascinating, it’s not clear that this is enough information for us to say anything definitive about the timing of interferon in this subgroup. It’s possible that in established treatment paradigms these patients might not require therapy. (6)
- Mascarenhas J, Kosiorek HE, Prchal J, et al. Results of the Myeloproliferative Neoplasms - Research Consortium (MPN-RC) 112 randomized trial of pegylated interferon alfa-2a (peg) versus hydroxyurea (hu) therapy for the treatment of high risk polycythemia vera (PV) and high risk essential thrombocythemia (ET). Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 577.
- Clinical Lymphoma, Myeloma, & Leukemia (2019 Apr 1. Epub ahead of print).
- Gisslinger H. et. al. COMPARISON OF LONG-TERM EFFICACY AND SAFETY OF ROPEGINTERFERON ALFA-2B VS. HU IN POLYCYTHEMIA VERA PATIENTS AGED BELOW OR ABOVE 60 YEARS: TWO-YEAR ANALYSIS FROM THE PROUD/CONTINUATION PHASE III TRIALS. Jun 15, 2018; 214443.
- Knudsen T, Hansen D, Ocias L, et al. Long-Term Efficacy and Safety of Recombinant Interferon Alpha-2 Vs. Hydroxyurea in Polycythemia Vera: Preliminary Results from the Three-Year Analysis of the Daliah Trial - a Randomized Controlled Phase III Clinical Trial. Abstract 580. Presented at the 2018 Annual Meeting of the American Society of Hematology. December 3rd. San Diego, CA.
- Gisslinger H, Klade C, Georgiev P, et al. Evidence for Superior Efficacy and Disease Modification after Three Years of Prospective Randomized Controlled Treatment of Polycythemia Vera Patients with Ropeginterferon Alfa-2b Vs. HU/BAT. Abstract 579.Presented at the 2018 Annual Meeting of the American Society of Hematology. December 3rd. San Diego, CA.
- Yacoub A, Mascarenhas J, Kosiorek H, et al. Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood (2019;134:1498-1509).