oa Editorial [Hot Topic: Interferon Alpha2 in the Treatment of Hematological Malignancies. Status and Perspectives (Guest Editor: Hans Carl Hasselbalch)]

About 50 years ago interferon (IFN) was discovered by Isaacs and Lindenmann [1] and described as a cytokine, which was able to interfere with virus replication. The IFN-receptor was identified and shortly after the JAK/STAT-signal transduction pathway being described in several recent reviews [2-6]. Early in this development it was apparent that one of the mechanisms of action of IFN-alpha involved stimulation of immune cells [7, 8]. In the following years, all the other properties of IFN were unravelled, including its antiproliferative, immunomodulatory and antiangiogenic effects, which rapidly elicited great interest in the potential use of IFN in the treatment of several malignancies. The production and purification of human leukocyte IFNs [9] were soon followed by the first clinical study in the late 1970s on the efficacy of IFN-alpha in multiple myeloma (MM) [10]. A few years later IFN-alpha2 was cloned, allowing large amounts of IFNs to be produced for experimental research and clinical trials. Several studies in multiple myeloma and in other hematological malignancies followed including hairy-cell leukemia (HCL), chronic myelogenous leukemia (CML) and the Philadelphia-negative chronic myeloproliferative neoplasms (CMPNs) (essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF)), hypereosinophilic syndromes and systemic mastocytosis (SM). In the following years the outstanding breakthroughs in the treatment of HCL and CML with IFNalpha2 were confirmed in large clinical trials. Many 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 defence towards infections. Likewise, IFN-alpha2 became a historical milestone in the medical treatment of CML, since IFN-alpha2 proved to be the first agent able to induce complete and sustained cytogenetic remissions with disappearance of Philadelphiachromosome 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. Accordingly, IFN-alpha2 was considered the best medical treatment of CML during the past two decades until the targeted treatment with the tyrosine kinase inhibitor imatinib mesylate substituted IFN-alpha2 about 10 years ago. In this theme issue the history, the present and the future for IFN-alpha2 in the treatment of hematological malignancies is described and discussed by experts with many years of clinical experience within the field. Simonsson et al. update on the current knowledge of IFN-alpha2 in the treatment of CML, emphasizing that the mechanisms of action in patients with CML are likely multifactorial. IFN-alpha2 can restore the adhesion of CML primitive progenitor cells to marrow stroma, downregulate the expression of the BCR-ABL1 gene and activate several transcriptional factors that regulate cell proliferation, maturation, and apoptosis. Furthermore, IFN-alpha has very potent immune enhancing capacity, inducing recognition and elimination of CML cells from the immune system [11, 12]. A novel mechanism on hematopoietic stem cells (HSC) has recently been proposed, implying induction of cell cycling in quiescent HSC and early progenitors. Chronic administration of IFN-alpha has been shown to deplete HSC underscoring that “dormant” cancer stem cells may be susceptible to manipulation via an IFN-alpha induced “wake up call” and subsequent proliferation hereby being “visible” targets for the immune system or targeted treatment [13, 14]. The authors describe the potential advantages of combination therapy with imatinib and IFN-alpha in CML, which might be far more efficacious than single agent therapy based upon the fact that the mode of action and biological effects of imatinib and IFN-alpha are quite different. This knowledge has been translated and confirmed in two large randomized studies showing improved outcome if pegylated IFN is added to the treatment with imatinib. Already in 1985 Linkesch et al. from Austria described that IFN-alpha2 was able to control myeloproliferation in myeloproliferative diseases with severe thrombocytosis [15, 16] - only a few years after the first description of the efficacy of human leukocyte IFN to control thrombocytosis in CML [17]. Several studies during the last 25 years have subsequently confirmed that IFN-alpha2 is also able to inhibit myeloproliferation in the Ph-negative CMPNs (ET, PV and PMF) with a reduction or alleviation of the need of phlebotomies in PV, disappearance of pruritus, normalization of leucocyte and platelet counts and a reduction in spleen size [18-25]. Despite all these studies IFN-alpha2 has not been the first drug of choice in the treatment of patients with CMPNs, for many reasons but mainly because of a relatively high drop-out rate (about 20-40 %) due to side effects. With the identification of the JAK2-V617F-mutation in 2005 and reports on the potential of IFN-alpha2 to induce major molecular remissions in patients, the interest in treatment of PV and related neoplasms with IFN-alpha2 has been revived. Accordingly, several studies have shown that long-term treatment with IFN-alpha2 in a subset of patients is accompanied by “complete” molecular remissions [21-25], which may be sustained even after discontinuation of IFN-alpha2 for up to two years [24]. These observations show that immune therapy with IFN-alpha2 is able to induce “minimal residual disease” (“operational cure”?) in subgroups of patients with CMPNs. These aspects are described and discussed in a comprehensive review by Hasselbalch et al. The authors conclude, that induction of “minimal residual disease” by IFN-alpha2 in PV is yet another milestone in the IFN-alpha2-story on the treatment of hematological malignancies, opening a new horizon with potential cure - at least “operational” - if immune therapy with IFN-alpha is initiated at the time of diagnosis, when the “tumor burden” and accordingly, the extent of genome instability and resistance is the least and consequently the possibility of a favorable outcome of IFN-alpha2 is optimal. Such a therapeutic strategy - possibly in the initial disease phase in combination with hydroxyurea or in the future JAK2-inhibitors or histone deacetylase inhibitors, may ultimately inhibit disease progression to the myelofibrotic “burn-out phase of the disease” with massive splenomegaly, bone marrow failure or leukemic transformation - events which are all driven by increasing genetic instability and evolution of resistant subclones during the course of the disease. The challenges in the coming years among others are combined clinical and experimental studies to identify molecular and immunological characteristics of those patients being “good IFN-alpha2 responders” versus “bad IFNalpha2- responders”. By this approach, novel information on the mechanisms of action of IFN-alpha and also on molecular markers identifying those patients who may benefit from IFN-alpha2 treatment may be achieved. In these studies, it is also relevant to investigate whether “bad responders” or patients not tolerating recombinant IFN-alpha2 (IFN-alpha2a - Pegasys - or IFN-alpha2b -PegIntron) may have a better outcome when being treated with human leukocyte-IFN (Multiferon). This agent contains a mixture of several IFN-alpha-subtypes with additive/synergistic immunomodulating properties, which theoretically might further enhance the effects of IFN-alpha in our patients. In particular, it might be efficient in those patients developing neutralizing antibodies during treatment with recombinant IFNs. The role of IFN-alpha2 in the treatment of the hypereosinophilic syndrome and systemic mastocytosis is excellently described and covered by Bjerrum, who concludes, that IFN-alpha definitely has a major place in the treatment of some, but not all patients with hypereosinophilic diseases. It is underscored that controlled and preferably randomized trials of the efficacy of IFN-alpha2 in this patient group are warranted. In addition, Bjerrum concludes, that IFN-alpha -being used for about 25 years in SM - still has a prominent position in first line treatment, but further research in mast cell biology may unravel novel treatment principles, most likely to be used in combination with IFN-alpha2, since the complete response rate for IFN-alpha2 as monotherapy is relatively low. Long-term treatment may be required to induce molecular remissions as assessed by qPCR for the V816 mutation, which is present in the large majority of patients with SM, in whom the “tumor burden” in the future may be monitored by this methodology.......