Perspectives on interferon-alpha in the treatment of polycythemia vera and related myeloproliferative neoplasms: minimal residual disease and cure?

Abstract

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 non-pegylated 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 JAK1-2 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, "triple 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 "triple 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.

Data‐driven analysis of JAK2V617F kinetics during interferon‐alpha2 treatment of patients with polycythemia vera and related neoplasms

“…We and others have argued against the “watch and wait” strategy in low‐risk patients . Our study emphasizes the urgent need to rethink this approach and set new standards for treatment of patients with MPNs, implying normalization of cell counts in all patients using IFN from the time of diagnosis.…”

“…We and others have argued against the "watch and wait" strategy in low-risk patients. 38,40,41,[62][63][64][65][66][67] Our study emphasizes the urgent need to rethink this approach and set new standards for treatment of patients with MPNs, implying normalization of cell counts in all patients using IFN from the time of diagnosis. In addition to the rationales provided by the results in our present study, several others are supportive of the early-IFN-intervention concept.…”

“…Early treatment with IFN has been claimed to be a prerequisite for obtaining remarkable results to prohibit clonal evolution before subclones and additive mutations evolve. 38,40,41,[62][63][64][65][66][67] The present study delivers novel information regarding the JAK2V617F kinetics during IFN-treatment based upon unique serial JAK2V617F measurements from the DALIAH trial. Through this description of the JAK2V617F kinetics, predictions about the development of disease for specific patients can be made.…”

“…Using this “watch and wait” strategy translation of common knowledge on cancer biology to MPNs is neglected, implying progression of any cancer without treatment. Early treatment with IFN has been claimed to be a prerequisite for obtaining remarkable results to prohibit clonal evolution before subclones and additive mutations evolve …”

Anti-cancer immunotherapy: breakthroughs and future strategies

“…The latter is one of the most studied cytokines and is still used in some indications, particularly Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocytosis, polycythemia vera, and myelofibrosis. In the current issue of Seminars in Immunopathology, Hasselbalch and Holmström describe and discuss the effects and perspectives of IFN-α in MPNs [1]. They describe the story of IFN in MPNs from the very beginning in the 1980s until today, and discuss the future perspectives of IFN-α in the treatment of MPNs.…”