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Pacritinib May Offer New Option for Tackling Myelofibrosis in Patients With Cytopenias

James K. McCloskey II, MD
Published: Wednesday, Feb 03, 2016
James K. McCloskey II, MD
James K. McCloskey II, MD
Hematologist/Oncologist
Division of Leukemia
John Theurer Cancer Center
Hackensack University Medical Center
Hackensack, NJ

Strategic Partners
Patients with myelofibrosis, a rare myeloproliferative neoplasm associated with a high mortality in intermediate- and high-risk disease states, have few options for treatment. Allogeneic stem cell transplantation is the only potentially curative option. Ruxolitinib is a JAK1/2 inhibitor that has been shown to improve quality of life and reduce spleen size, but it is associated with significant hematologic toxicity precluding its use in patients with significant thrombocytopenia.

Here at the John Theurer Cancer Center (JTCC), we treat a large number of patients with myelofibrosis. Although we perform allogeneic stem cell transplantation in appropriately selected patients, we are investigating new treatment options.

Pacritinib, a JAK2/FLT3 inhibitor, is among the most promising of those emerging options. The agent has significantly reduced spleen size and was associated with improved symptom control in early clinical trials. Treatment with pacritinib was associated with an improvement in platelet count and anemia among participants, with 25% of transfusion-dependent patients becoming transfusion independent.

Because of the rarity of the disease and lack of acceptable standard treatment, we encourage oncologists to reach out to experienced cancer centers early in the disease course to explore clinical trial options that aid in the development of novel therapies such as pacritinib. The PERSIST-2 study, currently enrolling patients at JTCC and more than 100 other locations in the United States and Europe, is one of the few randomized phase III studies focusing on patients with myelofibrosis and thrombocytopenia.

The Myelofibrosis Landscape

Myelofibrosis is a primary bone marrow malignancy that belongs to the myeloproliferative neoplasm category. This heterogeneous group of diseases includes chronic myelogenous leukemia, essential thrombocythemia (ET), polycythemia vera (PV), systemic mastocytosis, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Patients may present with primary myelofibrosis (PMF) or may evolve to a myelofibrotic state from preexisting ET or PV.

Both primary and secondary myelofibrosis share a similar pathophysiology. Initial stages of the disease are characterized by aberrant clonal stem cell proliferation with increased CD34-positive cells in the marrow and abnormal cytokine expression. This results in reactive bone marrow fibrosis and worsening anemia and thrombocytopenia. In later forms of the disease, patients exhibit significant hepatosplenomegaly as these organs become sites for hematopoiesis.1

The clinical manifestations of myelofibrosis include constitutional symptoms, splenomegaly, anemia, thrombocytopenia, bone pain, pruritus, and splenic infarct. Severe fatigue, bone pain, and gastrointestinal symptoms related to splenomegaly can dramatically impact the quality of life for patients with myelofibrosis.1 This burden is often compounded by comorbid conditions and advanced age. Many patients will die from the disease, and approximately 20% eventually evolving to acute leukemia.2

Multiple prognostic models exist for risk stratification at the time of diagnosis (IPSS), after diagnosis (DIPSS), and based on molecular and cytogenetic features (DIPSS-plus). Age greater than 65 years, hemoglobin >10 g/dL, leukocyte count >25,000/μL, platelet count <100,000/μL, circulating blasts ≥1%, constitutional symptoms, and high-risk cytogenetics, are associated with inferior outcome.3-5 More recently, mutations in ASXL1 have also been linked with poor clinical outcome.6,7

Role of JAK2/STAT Signaling

Myelofibrosis has been closely linked to dysregulation of the JAK2/STAT pathway. Mutations in JAK2 V617F, exon 9 of calreticulin (CALR), and exon 10 of the thrombopoetin receptor gene (MPL) all lead to dysregulation of the JAK2/ STAT pathway and are observed in 58%, 25%, and 8% of PMF patients, respectively.8 JAK2 is an intracellular tyrosine kinase that regulates the STAT pathway. The STAT pathway is responsible for regulating crucial aspects of hematopoiesis.9 The JAK2 V617F mutation results in impaired auto-inhibition of JAK2, resulting in constitutive activation of the JAK2 cascade.10


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