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Recent advances in prognostication and treatment of polycythemia vera.

ABSTRACT: Polycythemia vera (PV) is a BCR-ABL-negative myeloproliferative neoplasm marked by acquisition of an activating mutation of JAK2, which leads to not only erythrocytosis but also frequently to leukocytosis and thrombocytosis, and is associated with a high symptom burden and increased thrombotic risk. PV has the potential to progress to myelofibrosis or an aggressive form of acute myeloid leukemia. Mutational profiling of patients with PV has led to the development of risk stratification tools to determine an individual's risk of developing progressive disease. Although the current goals of PV treatment are to alleviate symptoms and reduce thrombotic risk, there are growing efforts to identify disease-modifying agents which will also prevent progression of disease. Here, we give an overview of the developing prognostic tools and therapeutic landscape for PV, focusing on four drug classes: pegylated interferon-alpha 2, MDM2 antagonists, hepcidin mimetics, and histone deacetylase inhibitors.

SUBMITTER: Marcellino BK

PROVIDER: S-EPMC8009192 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Recent advances in prognostication and treatment of polycythemia vera.

Marcellino Bridget K BK Hoffman Ronald R

Faculty reviews 20210312

Polycythemia vera (PV) is a <i>BCR-ABL</i>-negative myeloproliferative neoplasm marked by acquisition of an activating mutation of <i>JAK2</i>, which leads to not only erythrocytosis but also frequently to leukocytosis and thrombocytosis, and is associated with a high symptom burden and increased thrombotic risk. PV has the potential to progress to myelofibrosis or an aggressive form of acute myeloid leukemia. Mutational profiling of patients with PV has led to the development of risk stratifica ...[more]

PMID: 33817698

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Project description:Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).

Project description:Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis and the presence of Janus kinase (JAK) 2V617F or similar mutations. This review summarizes the pathophysiology of PV, the challenges associated with traditional treatment options, and the scientific rationale and supportive clinical evidence for targeted therapy with ruxolitinib. Accumulating evidence indicates that activating mutations in JAK2 drive the PV disease state. Traditional PV treatment strategies, including aspirin, phlebotomy, and cytoreduc-tive agents such as hydroxyurea, provide clinical benefits for some but not all patients and may not adequately treat PV-related symptoms. Furthermore, traditional treatment approaches are associated with potential side effects that may limit their usage and lead some patients to discon-tinue the treatment. Ruxolitinib is an orally available small-molecule tyrosine kinase inhibitor that is a potent and selective inhibitor of JAK1/JAK2. Ruxolitinib is approved in the US for patients with PV with an inadequate response or intolerance to hydroxyurea and in Europe for adults with PV who are resistant to or intolerant of hydroxyurea. In the Phase III RESPONSE registration trial, ruxolitinib was superior to the best available therapy in patients with PV who were resistant to or intolerant of hydroxyurea in controlling hematocrit levels, reducing spleen volume, and improving PV-related symptoms and quality-of-life measures. The most common nonhematologic adverse events in ruxolitinib-treated patients were headache, diarrhea, pruritus, and fatigue in the RESPONSE trial; hematologic adverse events were primarily grade 1 or 2. In the Phase IIIb nonregistration RELIEF trial, there were nonsignificant trends toward an improved symptom control in patients with PV on a stable hydroxyurea dose who were generally well controlled but reported disease-associated symptoms and switched to ruxolitinib vs those who continued hydroxyurea therapy. Updated treatment guidelines will be important for educating physicians about the role of ruxolitinib in the treatment of patients with PV.

Dataset Information

Recent advances in prognostication and treatment of polycythemia vera.

Publications

Recent advances in prognostication and treatment of polycythemia vera.

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