Polycythemia vera (PV) is a disorder predominantly characterized by erythrocytosis.1 As opposed to secondary erythrocytoses, PV and primary familial congenital polycythemia are categorized as primary erythrocytoses, which result from enhanced responses to erythropoietin (EPO).2 In 1951, PV and three other disorders with similar pathophysiologic characteristics (myelofibrosis [MF], essential thrombocythemia [ET], and chronic myeloid leukemia) were characterized as “myeloproliferative disorders” by Dr William Dameshek.3 Subsequent cytogenetic analyses and clonality studies demonstrated that PV is a clonal malignancy acquired through one or more somatic mutations in a pluripotent hematopoietic stem cell, leading to increased myeloid proliferation.4,5 However, a molecular target responsible for PV was not yet identified at that time.6
Early hypotheses regarding the pathologic basis of PV included potential abnormal growth factor signaling pathways,4 transcriptional dysregulation,5 and constitutive activation of signal transducer and activator of transcription (STAT) proteins.5 Polycythemia rubra vera-1 (PRV-1) was once hypothesized as a PV-specific marker that could be important for elucidating the molecular mechanism of the disorder.5,7 The PV diagnostic strategy drastically changed after the discovery of activating mutations in the Janus kinase 2 (JAK2) tyrosine kinase.8–11 Following this discovery, the World Health Organization characterized PV as a chronic myeloproliferative neoplasm (MPN) primarily defined by erythrocytosis and the presence of JAK2V617F or similar mutations.1
Patients diagnosed with PV may have a marked disease burden and a higher mortality risk when compared with the general population, primarily driven by cardiovascular/thrombotic events, disease transformation to MF or acute myeloid leukemia (AML), and solid malignancies.12–15 Traditional PV treatment strategies include aspirin, phlebotomy, hydroxyurea, and other cytoreductive treatments.16 Such options provide clinical benefits for some patients, including a reduced risk of cardiovascular/thrombotic events.17–20 However, traditional treatment options do not provide adequate benefit for some patients21,22 and may not alleviate PV-related symptoms.23,24 As such, there remains an unmet need for improved clinical outcomes, symptom alleviation, and enhancement of quality-of-life (QoL).
The objective of this review is to provide a summary of the pathobiology of PV, including the evolving understanding of the molecular etiology of PV, the challenges associated with traditional PV treatment options, and the scientific rationale and clinical data for ruxolitinib (Jakafi®, Incyte Corporation, Wilmington, DE, USA; Jakavi®, Novartis AG, Horsham, West Sussex, UK) supporting its role as a new targeted treatment option for patients with PV.
BIOLOGY OF PV: PRE- AND POST-JAK2V617F ERA
Pre-JAK2V617F molecular understanding of the etiology of PV
Early studies of erythropoiesis provided important information about the hematopoiesis process in the PV setting.4 In vitro analyses demonstrated that bone marrow progenitor cells isolated from patients with PV (but not control bone marrow samples) were able to form EPO-independent endogenous erythroid colonies (EECs).4 In 1987, a review of nine studies reported that 97% of patients with PV had EECs in the bone marrow and/or peripheral blood.25 Although EECs were also observed in some patients with ET,26 their presence is a hallmark of PV and was used as a clinical diagnostic tool.4
The observed increased proliferative responsiveness of PV progenitor cells to EPO, IGF-1, and other growth factors (eg, interleukin [IL]-3, granulocyte-macrophage colony-stimulating factor [GM-CSF], thrombopoietin, and stem cell factor) implicated abnormal cytokine signaling pathways in the molecular underpinnings of PV.4,5,26,27 However, studies that examined mutations related to cytokine signaling targets (eg, the EPO receptor, IGF-1 receptor, IGF-1–binding proteins, and tyrosine phosphatases) were unsuccessful in elucidating the pathogenesis of PV.4 It was also hypothesized that abnormal cytokine signaling was not necessarily related to a limited number of specific mutations but rather to more general defects in transcriptional regulation that could affect a variety of metabolic pathways that play a role in the pathogenesis of PV.4 The transcriptional dysregulation hypothesis was supported by studies of cells from patients with PV, which reported decreased levels of the thrombopoietin receptor c-MPL in platelets28 and an increased proportion of erythroid progenitors expressing BCL-x (an antiapoptotic protein).29 Downstream signal transduction molecules important to cytokine receptor signaling, including EPO-mediated pathways, were further studied to identify the potential PV candidate genes.5 It was hypothesized that EPO-mediated activation of the JAK/STAT pathway induced BCL-x expression, which inhibited apoptosis.6 However, data suggested that constitutive STAT3 activation alone was not the primary molecular cause of PV.30 Therefore, it remained uncertain which one of the signal transducers in this pathway accounted for the increased erythropoiesis observed in patients with PV.6
Collectively, available data up to this point suggested that the JAK/STAT transduction pathway might play a critical role in preventing the apoptosis of erythroid progenitors but not necessarily in the proliferation of erythroid cells.6 The search for the molecular cause of PV continued. Using subtractive hybridization techniques, overexpression of PRV-1 mRNA was observed in the granulocytes of patients with PV but not in normal controls.31 However, the specificity of PRV-1 mRNA overexpression to the PV setting31 was later contradicted by data indicating no consistent differences in PRV-1 protein levels between granulocytes from patients with PV and those from normal controls.32 Furthermore, the sensitivity of PRV-1 expression to GM-CSF exposure31 suggested that alterations in cytokine levels (not the PV disease state itself) explained the variability of PRV-1 levels. As such, the technically demanding and time-consuming EEC assay continued to be the most reliable test for the diagnosis of PV,33 and the molecular cause of PV remained elusive.