Interferons (IFN) are cytokines released by host cells to induce innate immune response against viral infections and are characterized by immunomodulatory, antiproliferative, and antiangiogenic effects. Since the discovery of IFN-α in the 1980s, it has been approved for use in a variety of oncologic disorders including hairy cell leukemia, AIDS-related Kaposi sarcoma, hepatitis B and C infections, and follicular lymphoma along with other off-label use for many cancer types including myeloproliferative neoplasms (MPN).
The experience with IFN in the treatment of MPN goes decades back, however, its hard-to-manage side effect profile and no official regulatory approval for its use in MPN have reduced interest over time. Efforts to obtain improved IFN formulations including pegylated forms, with a more manageable safety profile and promising results in reducing burden of driver mutations have redrawn attention to its potential in treating patients with MPN. In this educational theme, the MPN Hub will discuss the role of IFN-α, including its pegylated formulations such as ropeginterferon-α-2b, based on a recent review published in Cancersby Joan How and Gabriela Hobbs. 1
The effects of IFN
IFN-α is a type I IFN, and IFN-α-2 is the main form used therapeutically, including standard IFN-α-2b, pegylated IFN-α-2a and -2b, and ropeginterferon-α-2b. The mechanism of action of IFN involves activation of the IFN-α-receptor chains to activate the Janus kinase (JAK)-STAT pathway signaling. However, its impact on MPN is not clear, and possible mechanisms are detailed below.
- Targeting colony-forming unit megakaryocyte proliferation thereby reducing thrombocytosis
- Suppressing JAK2 substrate phosphorylation and inhibiting thrombopoietin expression
- Forcing differentiation of JAK2V617F-mutated stem cells which may lead to depletion of the mutant clone
- Stimulating the immune system with enhanced activity of T cell, macrophage, and natural killer cells, and increased expression of tumor antigens
- Inducing caspase and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which are known mediators of apoptosis
- Preferably targeting mutated hematopoietic progenitor clones for apoptosis
- Antiangiogenic effects of IFN are not yet clear, however, they may be related to modulation of the tumor microenvironment.
From standard IFN-α to ropeginterferon-α-2b
Standard IFN-α-2b has been associated with hematologic response rates similar to hydroxyurea, and molecular responses in patients with JAK2V617F mutations. It has been shown that patients with high-risk essential thrombocythemia (ET) or polycythemia vera (PV) had lower rate of venous thromboembolism, along with lower rates of paresthesia and erythromelalgia in PV on treatment with IFN. However, there is a lack of evidence for improved survival or preventing progression to a myelofibrotic or leukemic state. Limitations of this IFN form, which is administered three times a week, include a serious toxicity profile with common side effects of flu-like symptoms, fever, nausea, and vomiting reported by up to 35% of patients.
To overcome the tolerability issues, pegylated IFN formulations which can be administered once a week, have been developed. This formulation of IFN has been associated with hematologic remission rates of up to 80%, with no requirement of phlebotomy in more than half of patients with PV. Higher molecular responses have been seen in patients with JAK2or CALRmutations, however, harboring concurrent non-driver mutations has been associated with poorer molecular responses. This finding indicates that genomic characteristics may predict treatment responses to IFN. The MPN Hub has recently reported results on correlating genetic predictors with ropeginterferon-α-2b treatment response, here.
The duration of responses was stable, e.g. the median duration of response in patients with ET was 66 months while in patients with PV was 53 months. However, the disease transformation rate to myelofibrosis (MF) or leukemia was comparable to other therapies used for MPN.
Head-to-head comparison trials with hydroxyurea, in the MPN-RC 112 and DALIAH trials, have shown numerically lower overall response rates for pegylated IFN and hydroxyurea; however, updated results with a longer follow-up period may show further clinical improvements with IFN over time. In addition, pegylated IFN therapy was associated with higher discontinuation rates than hydroxyurea.
With a better safety profile by means of tolerability, and lower rates of treatment discontinuation compared with standard IFN, the most reported adverse events included fatigue, myalgia, nausea, vomiting, and diarrhea. The important rate of neuropsychiatric events including depression, suggests that the evaluation of the neuropsychiatric state may be important before treating patients with IFN. Other adverse events included
- hematologic events, e.g. leukopenia, anemia, thrombocytopenia, elevated liver enzymes
- hypothyroidism, vasculitis, hepatitis
When investigated in a population of patients with high-risk ET and PV who were refractory or intolerant to hydroxyurea (MPD-RC-111 trial), the complete response rates were comparable to other studies, and remission rates were low.
With a longer half-life, ropeginterferon-α-2b can be given subcutaneously every other week with a maintenance monthly dose. It is available as a pre-filled pen and patients can self-administer the drug at home, which may be translated into improved compliance to treatment. Ropeginterferon-α -2b has been granted approval by the European Medicines Agency (EMA) in early 2019 for the treatment of adult patients with PV without symptomatic splenomegaly as monotherapy. 2This approval was based on the results of the phase III PROUD-PVtrial and its extension CONTINUATION-PVtrials where ropeginterferon-α-2-b has been associated with significantly higher complete hematologic response rates compared with hydroxyurea, and significantly improved molecular responses after 3 years. The U.S. Food and Drug Administration (FDA) has accepted a Biologics License Applicationearlier this year based on positive results of these two studies.
Watch the interviewwith Jean-Jacques Kiladjian about recent findings on ropeginterferon.
The MPN Hub also reported on the phase II Low-PVtrial which evaluated ropeginterferon plus phlebotomy versusphlebotomy alone in low-risk patients with PV, and interim results indicated that significantly more patients (84%) achieve the composite primary endpoint (maintaining a median hematocrit value of < 45% over 12 months with no signs of progressive disease and symptoms) compared with 60% patients who received phlebotomy only, which allowed the trial to stop early due to efficacy. Watch Tiziano Barbui discuss the Low-PV study, here.
Preliminary results from another phase I/II trial, PEGINVERA, investigating the efficacy and safety of ropeginterferon in PV, have shown that almost all patients achieved a hematologic response with complete responses observed in more than half of patients.
Combining IFN with the JAK2 inhibitor ruxolitinib may alleviate inflammation which plays a role in the development of IFN resistance, and thereby ultimately improves IFN signaling. Furthermore, this combination may also allow using lower doses and thereby improves tolerability. The phase II COMBItrial investigated the efficacy and safety of combining ruxolitinib and pegylated IFN in patients with PV or low/intermediate-risk MF, where 31% of patients with PV and 44% of patients with MF had a remission, and symptom scores were reduced. JAK2V617F allele burden was also significantly reduced at 2 years. While 6% of patients with PV discontinued treatment, this rate was 32% for MF.
Use of IFN in MF
In the treatment of MF, IFN as monotherapy led to reductions in bone marrow fibrosis in patients who achieved clinical responses; however, the disease-modifying effect of IFN in MF has not been considered satisfactory, and dose-limiting hematological events led to a higher rate of treatment discontinuation compared with PV and ET. In another study, patients with low-risk or intermediate-1 risk MF achieved an overall response rate of 50%, while reduction in spleen size by ≥ 50% was observed in 40% of patients, and some patients had reduced reticulin fibrosis. Besides this, studies have shown that patients with PV and ET achieved both clinical and molecular responses with IFN treatment, indicating that IFN induces deeper responses in patients with PV and ET compared with those with MF.
Clinical guidelines on IFN use
The clinical efficacy of IFN in treating advanced MF has been limited despite of its ability to reduce bone marrow fibrosis. Studies of patients with lower risk MF have drawn a better picture in terms of clinical outcomes, with significantly better responses in patients with low-risk molecular mutations. The National Comprehensive Cancer Network (NCCN) recommends IFN therapy in symptomatic patients with low-risk or intermediate-risk MF, however, the European Leukemia Net (ELN) recommends first-line treatment with hydroxyurea or ruxolitinib in lower risk MF that requires cytoreduction.
For patients with PV or ET, consensus opinions are as follows:
- In high-risk disease, the NCCN recommends first-line treatment with IFN in young patients or those who are considering pregnancy, while the ELN recommends first-line IFN in case of high-risk PV requiring cytoreduction
- In high-risk disease, a second-line treatment is recommended if patients are refractory or with intolerance to hydroxyurea
In low-risk disease, consensus guidelines recommend IFN if patients are symptomatic and require cytoreduction. In younger patients, or those who defer hydroxyurea, consensus guidelines recommend the use of IFN for first-line treatment due to the potential of IFN in achieving durable responses and its disease-modifying effects.
There is no contraindication for pregnancy in MPN, however, patients with MPN are considered at higher risk for complications associated with pregnancy including thrombosis, hemorrhage, pre-eclampsia, and stillbirth. Studies have shown that IFN was associated with high rate of live births. Therefore, for pregnant patients, or those considering pregnancy and in need of cytoreduction, standard or pegylated IFN is recommended as a first-line treatment in consensus guidelines. IFN is also considered a safe option in lactation.
The long experience with IFN has demonstrated its potential in MPN with reductions in symptom burden, producing durable responses, and achieving both hematologic and molecular responses in patients with MPN. The significant toxicity profile has led to the development of pegylated forms of IFN which have established a more favorable safety profile with the requirement of fewer dosing. In the light of these findings, IFN is recommended as first- or second-line option for patients with PV and ET. However, there is a lack of official approvals by regulatory authorities to support the use of IFN in the treatment of MPN.