Clinical Review

Polycythemia Vera and Essential Thrombocythemia

Journal of Clinical Outcomes Management. 2018 October;25(8):371-384

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Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].

Disease Evolution

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 10³/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].

Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].