دانلود رایگان مقاله انگلیسی انترفرون آلفا در درمان پلی سیتمی ورا و نئوپلاسم های بیش‌تکثیری مغز استخوان - اشپرینگر 2018

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 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 JAK1–2 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, 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.

Conclusion and perspectives

The MPNs are inflammatory cancers, in which the malignant clone per se generates inflammatory products that in a selfperpetuating vicious circle sustain the inflammatory drive and accordingly disease progression in the biological continuum from the early cancer stages (ET/PV) to the advanced Bburntout^ myelofibrosis stage and imminent leukemic transformation [120–128]. During this evolution, additional mutations, other than the driver mutations, emerge. The MPNs are associated with several Binflammatory^ co-morbidities, including an increased risk of second cancers [105–108], which are likely due to a defective tumor immune surveillance system being partly attributed to the chronic inflammatory state [108]. The cornerstone treatment of MPNs in the future is foreseen to be IFN-alpha2, which as monotherapy in several studies during the last three decades has demonstrated safety and efficacy and as the only agent within MPNs is able to induce MRD and accordingly being disease modifying [30, 31, 33, 41]. Thus, recently, the apparent disease-modifying potential of IFN-alpha2 in PV and ET as evidenced by the progressive reduction of the JAK2V617 tumor burden during prolonged therapy has elicited renewed efforts to evaluate its clinical efficacy as front-line therapy for early stage disease in terms of reducing thrombo-hemorrhagic events, normalization of biochemical, hematologic, and molecular variables, and, ultimately, altering the natural history of these diseases.