The first clinical trials of the safety and efficacy of interferon-alpha2 (IFN-alpha2) were performed about 30 years ago. Since then, several single-arm studies have convincingly demonstrated that IFN-alpha2 is a highly potent anti-cancer agent in several cancer types but unfortunately not being explored sufficiently due to a high toxicity profile when using nonpegylated IFN-alpha2 or high dosages or due to competitive drugs, that for clinicians at first glance might look more attractive. Within the hematological malignancies, IFN-alpha2 has only recently been revived in patients with the Philadelphia-negative myeloproliferative neoplasms—essential thrombocytosis, polycythemia vera, and myelofibrosis (MPNs)—and in patients with chronic myelogenous leukemia (CML) in combination with tyrosine kinase inhibitors. In this review, we tell the IFN story in MPNs from the very beginning in the 1980s up to 2018 and describe the perspectives for IFN-alpha2 treatment of MPNs in the future. The mechanisms of actions are discussed and the impact of chronic inflammation as the driving force for clonal expansion and disease progression in MPNs is discussed in the context of combination therapies with potent anti-inflammatory agents, such as the JAK1–۲ inhibitors (licensed only ruxolitinib) and statins as well. Interferon-alpha2 being the cornerstone treatment in MPNs and having the potential of inducing minimal residual disease (MRD) with normalization of the bone marrow and low-JAK2V617F allele burden, we believe that combination therapy with ruxolitinib may be even more efficacious and hopefully revert disease progression in many more patients to enter the path towards MRD. In patients with advanced and transforming disease towards leukemic transformation or having transformed to acute myeloid leukemia, Btriple therapy^ is proposed as a novel treatment modality to be tested in clinical trials combining IFN-alpha2, DNA-hypomethylator, and ruxolitinib. The rationale for this Btriple therapy^ is given, including the fact that even in AML, IFN-alpha2 as monotherapy may revert disease progression. We envisage a new and bright future with many more patients with MPNs obtaining MRD on the above therapies. From this stage—and even before—vaccination strategies may open a new horizon with cure being the goal for some patients.

Introduction

About 60 years ago, interferon (IFN) was discovered by Isaacs and Lindenmann [1] who described this cytokine to be able to interfere with virus replication. Later, the IFN receptor was identified and shortly after the JAK/STAT-signal transduction pathway as described in several recent reviews [2–۶]. It early became apparent that one of the mechanisms of action of IFNalpha2 involved stimulation of immune cells [7, 8]. Due to all the other properties of IFN, including its antiproliferative, immunomodulatory, and antiangiogenic effects, great interest in the potential use of IFN in the treatment of several malignancies was soon raised. The production and purification of human leukocyte IFNs [9] were followed by the first clinical study in the late 1970s on the efficacy of IFN-alpha2 in multiple myeloma (MM) [10]. Soon after, IFN-alpha2 was cloned, allowing large amounts of IFNs to be produced for experimental research and clinical trials, opening an exciting era of several years, in which the safety and efficacy of IFN was tested in a variety of hematological malignancies. Among these are multiple myeloma, hairy-cell leukemia (HCL), chronic myelogenous leukemia (CML), the classical Philadelphia-negative chronic myeloproliferative neoplasms and essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) (MPNs), the hypereosinophilic syndromes, and systemic mastocytosis (SM). Outstanding breakthroughs in the treatment of HCL and CML with IFN-alpha2 were confirmed in several large clinical trials. Thus, a large proportion of patients with HCL achieved long-lasting complete remissions with normalization of peripheral blood values and the bone marrow in concert with a marked improvement in their immune defense towards infections. Likewise, IFNalpha2 proved to be the first agent with the potential of inducing complete and sustained cytogenetic remissions with disappearance of Philadelphia chromosome in CML and—in addition—in some patients even the induction of major molecular remissions with a significant and sustained reduction of the BCR-ABL transcript in a subset of patients. These results were historical IFN milestones in the treatment of hematological malignancies (HCL and CML), which otherwise had a dismal prognosis with severe and often lethal atypical infections (HCL) or increasing genomic instability with terminal fatal leukemic transformation within a few years from the time of diagnosis in the large majority unless a bone marrow transplantation was an option (CML).