Polycythemia Vera and Essential Thrombocythemia

From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).

ABSTRACT

• Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
• Methods: Review of the literature.
• Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
• Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.

Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.