Immunotherapy and polycythemia vera

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by abnormal growth of erythroid precursors in the bone marrow. Almost all patients with PV, around 97%, have a mutation in Janus kinase 2 (JAK2). It is through the activation of JAK/Signal Transducers and Activators of Transcription (STAT) protein signaling pathway that the JAK2 mutation is thought to induce cellular proliferation, growth, hematopoiesis and immune response in PV patients. A summary of the current role of immunotherapy in the treatment of PV is provided. There are new JAK kinase inhibitors that are currently being evaluated and are at various stages of clinical trials and development, as well as the previously studied cytokines therapies. At the present time, ruxolitinib and interferon-α (IFN-α) are the only United States Food and Drug Administration (FDA) approved drugs for the management of advanced PV. JAK kinase inhibitors are better tolerated and less problematic than the interferons. Still, allogeneic stem cell transplantation is the only potentially curable method for end-stage PV. Additional genetic mutations have been implicated in PV pathogenesis. In this perspective, targeting different pathways might be required. Further investigations are needed to evaluate the promising role of immunotherapy in PV whether alone or in combination with other modalities. Abbreviations: AE: Adverse Events; Bcl-x: B-cell lymphoma-extra; CMML: Chronic Myelomonocytic Leukemia; CYP: Cytochrome P; ET: Essential Thrombocythemia; FDA: Food and Drug Administration; HSC: Hematopetic Stem Cells; IFN-α: Interferon alfa; JAK2: Janus Kinase 2; JAK/STAT: Janus Kinase /Signal Transducers and Activators of Transcription; MPDs: Myeloproliferative Disorders; MU: Million Units; NF-E: Nuclear Factor Erythroid-Derived 2; PEG: Polyethylene Glycol; PD/PK: Pharmacodynamics/Pharmacokinetics; PMF: Primary Myelofibrosis; PV: Polycythemia Vera; PRV-1: Polycythemia Rubra Vera 1; Tpo-R: Thrombopoietin Receptor; Wt: Wild Type Introduction/Epidemiology Myeloproliferative disorders (MPDs) are classified according to the most affected type of blood cells. There are four main types of MPDs, which include Polycythemia Vera (PV), Essential Thrombocythemia (ET), Primary Myelofibrosis (PMF), and Chronic Myelomonocytic Leukemia (CMML). PV is a myeloproliferative disorder, which presents as an abnormal increase in the number of red blood cells [1]. It is the most common form of the MPDs. Its incidence in the US is estimated to be 1.9/100,000, with an increase associated with ageing. The mean age at diagnosis of PV is approximately 60 years old. However, in 2010 the age adjusted prevalence of PV was 57.15/100,000 [2]. PV is very rare in children. Etiology/predisposing risk factors The cause of chronic MPDs remains unknown. A mutation in a specific protein, Janus kinase 2 (JAK2) is found in a large number * of people with MPDs. It is detected in about 95% of those with PV, in approximately 50–70% with ET, and 40–50% with PMF [3]. There are several risk factors, which increases the risk of chronic MPDs. They include the following: Age and sex Although one third of the cases diagnosed are in those below the age of 50, PV is most commonly diagnosed at 60 years of age and above [4]. Similarly, the incidence of MPDs and specifically CMML increases with age [5,6]. The median age at diagnosis of CMML patients ranges between 65 and 75 years [7]. PV, as well as all MPDs in general, are more prevalent in men [5]. Cancer treatment Prior treatment with chemotherapy appear to increase the risk of CMML [8]. However, the risk of CMML after cancer chemotherapy is not as high as that of other hematological malignancies, such as myelodysplastic syndromes and acute myeloid leukemia [9]. Exposure to carcinogenic agents Petrochemicals such as benzene and toluene, and ionizing radiation increase the risk of PV and PMF [10,11] Pathophysiology/molecular basis A mutation in a specific gene, Janus kinase 2 (JAK2) is found in a large percentage of people with MPDs. Figure 1 describes a working model for genetic events and other mechanisms, possibly involved in the pathophysiology of MPDs [12]. Hematopoietic growth factor responses mediated by the JAK/ STAT Pathway The JAK/STAT pathway [13] plays a vital role in the initiation of Correspondence to: Dr. Timothy Allen, MD, Ph.D., Global Allied Pharmaceutical, Center for Excellence in Research and Development, 160 Vista Oak Dr. Longwood, FL 32779, USA, Tel: 1-321-945-4283, E-mail: timothy. [email protected]