Molecular Profiling of Classic Myeloproliferative Neoplasms (MPNs)

Myeloproliferative neoplasms (MPNs) are hematopoietic disorders characterized by clonal expansion of cells of myeloid lineage. The revised 2016 World Health Organization (WHO) guidelines use the term “classic MPNs” to refer to a group of three disorders—polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)—all of which are BCL-ABL1 fusion negative (Barbui et al. 2016). Other MPNs include chronic myeloid leukemia (CML); chronic neutrophilic leukemia (CNL); chronic eosinophilic leukemia, not otherwise specified (CEL-NOS); and myeloproliferative neoplasms–unclassifiable (Arber et al. 2016). The BCR-ABL1 fusion gene, also known as the Philadelphia chromosome (Ph), is the classic diagnostic feature of CML, which is now referred to as “Ph+ MPN.” The prevalence of PV, ET, and PMF in the United States is 44–57, 38–57 and 4–6 cases per 100,000 people, respectively (Mehta et al. 2014).

PV is characterized by clonal expansion of erythrocytes, often accompanied by leukocytosis or thrombocytosis resulting in elevated hemoglobin, red blood cell mass, and hematocrit. JAK2 is usually mutated in PV, with 90–95% of PV patients presenting with a JAK2 V617F mutation and about 3% presenting with a JAK2 exon 12 mutation (Baxter et al. 2005; James et al. 2005; Kralovics et al. 2005; Levine et al. 2005; Pardanani et al. 2007; Scott et al. 2007; Vannucchi et al. 2008). Less frequently, CALR and MPL mutations have also been reported (Broseus et al. 2014; Chauveau et al. 2017; Pardanani et al. 2011). These are usually mutually exclusive mutations (Beer et al. 2008; Rampal et al. 2014), but they can co-occur in rare instances (Kang et al. 2016; Rashid et al. 2015; Usseglio et al. 2017).

ET is characterized by sustained thrombocytosis in peripheral blood, an increased number of large hyper-lobulated megakaryocytes in the bone marrow, and clinical evidence of thrombotic and hemorrhagic events. Patients with ET typically present with mutations in one of three genes: JAK2 in 50–65%, CALR in 20–25%, and MPL in about 5% of cases (Baxter et al. 2005; Klampfl et al. 2013; Levine et al. 2006; Nangalia et al. 2013). Ten to fifteen percent of patients are classified as “triple-negative,” since they have no detectable mutations in JAK2, MPL, or CALR (Tefferi et al. 2014). Mutations in ASXL1, EZH2, IDH1, SRSF2, SF3B1, or U2AF1 genes are not uncommon, but they have not been identified as driver mutations (Lasho et al. 2012; Tefferi et al. 2014).

PMF is characterized by proliferation of the granulocytic and megakaryocytic lineage of cells with a marked reduction in the erythroid precursors. Similar to ET, patients with PMF typically present with mutations in one of three genes: JAK2 in 55–65%, CALR in 20–25%, and MPL in 6–7% of cases (Baxter et al. 2005; Klampfl et al. 2013; Nangalia et al. 2013; Rumi et al. 2014). An estimated 10–15% display a “triple-negative” subtype, where cells do not harbor a mutation in any of the three genes: JAK2, MPL, or CALR. The patients with “triple-negative” morphology exhibit the shortest median survival for PMF (Rumi et al. 2014). Studies have shown that about 20% of the patients suffering from PMF progress to acute leukemia (Mesa et al. 2005; Okamura et al. 2001).

Due to the overlapping mutation profiles of these disorders, bone marrow morphology is considered a crucial criterion for accurate diagnosis in the recently published 2016 WHO guidelines. The current treatment strategies for PV and ET are aimed to prevent thrombosis and ease symptoms by means of phlebotomy or aspirin therapy (Landolfi et al. 2004; Marchioloi et al. 2013). Cytoreductive therapy with hydroxyurea or interferon-alpha is used as first line treatment for high-risk patients, while second line treatment for refractory patients includes the use of JAK inhibitors (Geyer et al. 2014). For patients with PMF, stem cell transplant and JAK2 inhibitors are available treatment options (Bose et al. 2017).

Several JAK inhibitors such as ruxolitinib, fedratinib, momelotinib, and pacritinib have undergone clinical trials in MPNs. Ruxolitinib is approved for the treatment of intermediate-risk and high-risk PMF (Cervantes et al. 2013; Verstovsek et al. 2012a), post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, and hydroxyurea-resistant PV (FDA 2017; Verstovsek et al. 2014). Clinical trials testing pacritinib (Jain et al. 2016; Komrokji et al. 2015) and fedratinib (Pardanani et al. 2015) were placed on hold and terminated early, respectively, due to fatal side effects. Momelotinib failed to improve disease associated symptom as compared to ruxolitinib in phase III trials (Mesa et al. 2017).

Last Updated: April 3, 2018

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