Interferon in polycythemia vera and related

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Perspective

Interferon in polycythemia vera and related neoplasms. Can it become the treatment of choice without a randomized trial? Expert Rev. Hematol. Early online, 1–7 (2015)

Hans Carl Hasselbalch*1 and Richard T Silver2 1 Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark 2 Myeloproliferative Disease Center, Division of Hematology-Oncology, Weill Cornell Medical Center, New York, USA *Author for correspondence: [email protected]

Recently, it was concluded that the optimal therapy for essential thrombocythemia and polycythemia vera, either recombinant interferon alpha (rIFNa) or hydroxyurea can only be determined by the completion of a randomized clinical trial. We present our recommendations for the use of rIFNa for those patients who are not candidates for the randomized trial. We argue for rethinking the approach whether we should continue to wait for the results from a randomized trial before recommending treatment with rIFNa for those unable and unwilling to enter these trials. The interferon story shows that clinical experience may be an alternative path to follow when making treatment decisions and recommendations in orphan diseases. KEYWORDS: clinical experience . essential thrombocythemia . hydroxyurea . interferon . polycythemia vera .

randomized trial

An Editorial/Perspective article recently published in Haematologica concluded that the optimal therapy for essential thrombocythemia (ET) and polycythemia vera (PV), either recombinant interferon alpha (rIFNa) or hydroxyurea (HU), can only be determined by the completion of a randomized clinical trial [1]. On behalf of the many hundreds or thousands of patients worldwide not receiving treatment with rIFNa because their physicians are awaiting the results from this randomized trial, we present our recommendations based on decades of experience for the use of rIFNa for those patients with ET and PV who are not candidates for this randomized trial. This issue is most relevant and timely to discuss now when the use of rIFNa for the treatment of these neoplasms is increasing significantly in several centers in some parts of the world, whereas at other myeloproliferative neoplasms (MPN) centers of excellence it is not recommended as first-line therapy [2,3]. Since the ultimate goal as physicians is to serve our MPN patients according to the most effective and safe therapy available, the unmet need informahealthcare.com

10.1586/17474086.2015.1045409

for a large proportion of MPN patients to access rIFNa is discussed from a patient perspective as well. Discussion

Recombinant IFNa was used efficaciously for the first time in the treatment of PV and ET about 25 years ago [4,5]. Since then, its efficacy and safety have been confirmed in a large number of non-randomized studies [6–18], which have been reviewed recently, highlighting the fact that rIFNa is likely to become the drug of choice for the treatment of patients with ET, PV and hyperproliferative myelofibrosis [19–24]. In this context, it has been argued that when used from the time of diagnosis, when there is ‘minimal disease’ and the tumor burden is at a minimum, interferon treatment may have the best chance of a successful outcome [20–22,24,25] with subsequent normalization of the marrow in a subset of patients with PV [26,27]. In PV, there is, therefore, a steady decrease in high WBC and platelet counts and establishment of a phlebotomy free state within weeks or months.

2015 Informa UK Ltd

ISSN 1747-4086

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Perspective

Hasselbalch & Silver

Similar to the decline in the JAK2V617F-allele burden in patients with PV and ET [10–15,18], treatment with interferon is associated with a decline in the CALR mutation in patients with ET likewise treated [28]. All cancers are characterized by increasing genomic instability, subclone formation, resistance to treatment and ultimately metastasis. Although the evidence for increasing genomic instability from early cancer stage (ET/PV) to the advanced cancer stage – myelofibrosis – has to be definitely established (as assessed by rate of accumulation of new mutations and transformation to acute myeloid leukemia (AML) in a large series of patients from early cancer stage (ET/PV) to advanced cancer stage (myelofibrosis/AML)), it is reasonable to assume that the MPNs do not differ substantially from any other cancer in regard to the biology of an untreated cancer – disease progression due to clonal evolution with increasing genomic instability, subclone evolution through the acquisition of additional driver mutations, resistance to treatment and metastasis. Thus, in MPNs, disease progression and leukemic transformation has been shown to be associated with clonal evolution, subclonal mutations (ASXL1, SRSF2, CBL, IDH1/IDH2, TP53 and SRSF2) being independently associated with leukemic transformation and poor survival. Although the mutation rate is low, it has been shown that the presence of two or more somatic mutations (the presence of at least a subclonal mutation) significantly reduces overall survival and increases the risk for leukemic transformation in patients with MPNs [29]. Since MPNs and AML transformation are associated with elevated biomarkers of chronic inflammation [30–37], we speculate if chronic inflammation with increased oxidative stress in the bone marrow and in the circulation might be involved in MPN pathogenesis and in MPN-associated complications and comorbidities [38–40]. In this regard, chronic inflammation may also have a great impact upon mutagenesis and the mutational load in MPNs [39]. The identification of additional mutations already at the time of diagnosis does not argue against this concept of chronic inflammation as a driving force for mutagenesis, since most recent studies have shown that many patients with MPNs have had their disease for several years before MPN diagnosis [41]. Considering that the JAK2V617F mutation induces accumulation of reactive oxygen species (ROS) [42] and ROS in several other cancers induce genomic instability (DNA damage), there is compelling evidence that chronic inflammation with excessive ROS may be harmful for the stem cell compartment in MPNs. Since interferon – with no alternatives – has been shown in several studies to reduce the JAK2V617F mutation, which is an inductor of ROS accumulation [42], a marker of tumor burden and a risk marker of thrombosis [43], it is reasonable to assume that this beneficial effect may be partly related to disruption of ROS accumulation in the bone marrow although several other mechanisms are likely operative – all to be explored in future studies. Until results from such studies are available, current evidence of a link between chronic inflammation, genomic instability and mutational load doi: 10.1586/17474086.2015.1045409

remains weak, but supported by most recent observations that MPNs are associated with massive deregulation of oxidative stress genes and antioxidative defense genes [44] – likely mediated and driven by chronic inflammation [38,39,44]. Conceptually, it is reasonable to treat the MPNs early, since patients with severe myelofibrosis and marked splenomegaly (considered analogous to the ‘metastatic stage’) do not respond to therapy with rIFNa. The beneficial effects of rIFNa in ET and PV are noteworthy. In PV and ET, the decline in the JAK2-allele burden is physiologically important since the JAK2V617F allele appears to be a thrombosis promoter per se [43] and is perhaps a tumor promoter as well [45]. Furthermore, the JAK2V617F mutation negatively regulates p53 stabilization [46], thereby increasing genomic instability [47] predisposing to additional mutations, subclone formation, resistance to treatment and ultimately leukemic and myelofibrotic transformation. This evolution may depict the biological continuum from early to an advanced ‘cancer stage’ [48], in which chronic inflammation is likely a very important driver of clonal evolution and the development of second cancers as well [36,38,40]. Although rIFNa may induce molecular remissions, it is important to underscore that the molecular heterogeneity of MPN is complex, implying variability of molecular responses to rIFNa. Thus, TET2 clones persist in some patients during treatment with rIFNa [49] and additional clones may impair the response to rIFNa as well [50]. Regarding the differential response to interferon between JAK2V617F-positive ET and PV patients, this may be partly explained by differential interferon signaling and STAT1 phosphorylation observed in vitro in erythroid ET and PV cells [51], implying increased STAT1 activity to be associated with an ET-like phenotype and downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors to be associated with a PV-like phenotype. Accordingly, the consequences of JAK2V617F are determined by the balance between STAT5 and STAT1 activation [51]. For those advocating delayed therapy, a risk stratification system is followed, allowing patients with low-risk ET (10 years [68,69], which might in part explain the lack of evidence for HU as leukemogenic [68,69]. An additional argument for the lack of leukemogenicity of HU is the often-cited observation that no increased risk for leukemia has been observed in sickle cell anemia patients treated with HU [1]. However, sickle cell anemia is not a stem cell disease, whereas MPNs, therefore, are more likely to develop genomic instability, when being exposed to an agent which itself impairs DNA-repair mechanisms. In Denmark, a multicenter study was launched in 2012 enrolling newly diagnosed patients with ET, PV and hyperproliferative myelofibrosis in a randomized study, comparing lowdose Pegasys to PegIntron in patients 5 years) is associated with deep molecular remissions (5 years) from the time of diagnosis.

doi: 10.1586/17474086.2015.1045409

Expert Rev. Hematol.

Interferon in PV & related neoplasms

patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009;27:5418-24

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doi: 10.1586/17474086.2015.1045409