Myelofibrosis is a myeloproliferative neoplasm characterized by dysregulated Janus kinase/signal transducers and activators of transcription signaling and excessive production of inflammatory cytokines.¹ Advanced disease is characterized by progressive bone marrow fibrosis, cytopenias frequently requiring red blood cell (RBC) and/or platelet transfusions, splenomegaly, and debilitating systemic symptoms.^2-4 Median survival is approximately 6 years.⁵ Thrombocytopenia is an adverse prognostic variable that increases in prevalence with disease progression and is associated with higher symptom burden and shorter survival.^4,6-8 The Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib is approved by the US Food and Drug Administration (FDA) for patients with intermediate-risk or high-risk myelofibrosis and a baseline platelet count of 50 × 10⁹/L or more. Despite spleen volume reduction (SVR) and symptom improvement with ruxolitinib, an unmet clinical need exists for patients with baseline or treatment-emergent thrombocytopenia, and those relapsed after or refractory to ruxolitinib. Pacritinib, is a JAK2/tyrosine kinase 3 inhibitor with negligible activity against JAK1 that also suppresses the interleukin-1 directed inflammatory pathway via inhibition of interleukin 1 receptor associated kinase 1.^9,10 Pacritinib was shown to be clinically active in patients with myelofibrosis with minimal myelosuppression.¹¹ In the phase 3 PERSIST-1 trial (NCT01773187) comparing pacritinib once daily with best available therapy (BAT) excluding ruxolitinib, pacritinib demonstrated significant and durable SVR and symptom control irrespective of baseline platelet count.¹² A full clinical hold was placed on pacritinib by the FDA on February 8, 2016, due to concerns over bleeding and cardiovascular events and deaths on PERSIST-1. The hold caused early termination of PERSIST-2 resulting in incomplete data. The FDA requested an additional study to determine if a lower dose of pacritinib would be safer with maintained efficacy. After review of mature PERSIST-1 data and complete PERSIST-2 data (NCT02055781), as well as submission of a study protocol comparing 3 doses of pacritinib (NCT03165734), the hold was removed on January 5, 2017. The final results (database lock August 19, 2016) of the PERSIST-2 trial comparing pacritinib with BAT (including ruxolitinib) in patients with intermediate/high-risk myelofibrosis and baseline platelet count less than or equal to 100 × 10⁹/L are reported herein. Population pharmacokinetic modeling predicted higher steady state exposure and lower maximum concentrations with twice daily vs once daily pacritinib (early-phase studies)¹³; thus PERSIST-2 evaluated both schedules.

The BCR-ABL1–negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies. Recent advances in our understanding of the pathogenetic mechanisms underlying these diseases have led to an explosion of clinical trials evaluating novel therapies. The discovery of an activating mutation in the Janus-activated kinase 2 (JAK2) gene provided a therapeutic target to downregulate this activated signaling pathway, which influences the phenotype of these diseases. Ruxolitinib (Jakafi; Incyte) is a small-molecule inhibitor of JAK1/2 that has proved to be effective at reducing splenomegaly and ameliorating symptoms in myeloproliferative neoplasms. Based on the results of 2 pivotal randomized phase III clinical trials, ruxolitinib has become the first therapeutic to be approved by the U.S. Food and Drug Administration for treatment of patients with myelofibrosis. Ruxolitinib offers a well-tolerated oral therapeutic option for patients with myelofibrosis with symptomatic splenomegaly and debilitating disease-related symptoms, but it does not seem to be effective at eliminating the underlying hematological malignancy. Clin Cancer Res; 18(11); 3008–14. ©2012 AACR.

Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen in a variety of malignant and non-malignant disease states, the deposition of reticulin and collagen fibrosis in the bone marrow of patients with myelofibrosis is believed to be mediated by the myelofibrosis hematopoietic stem/progenitor cell, contributing to an impaired microenvironment favoring malignant over normal hematopoiesis. Increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling have all been implicated in the pathogenesis of bone marrow fibrosis. A number of studies indicate that bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms. However, modern myelofibrosis prognostication systems utilized in risk-adapted treatment approaches do not include bone marrow fibrosis as a prognostic variable. The specific effect on bone marrow fibrosis of JAK2 inhibition, and other rationally based therapies currently being evaluated in myelofibrosis, has yet to be fully elucidated. Hematopoietic stem cell transplantation remains the only curative therapeutic approach that reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis. Here we review the pathogenesis, biological consequences, and prognostic impact of bone marrow fibrosis. We discuss the rationale of various anti-fibrogenic treatment strategies targeting the clonal hematopoietic stem/progenitor cell, aberrant signaling pathways, fibrogenic cytokines, and the tumor microenvironment.

The Philadelphia chromosome−negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.

Yacoub et al report excellent responses to pegylated interferon alfa-2a in patients with hydroxyurea-resistant/intolerant polycythemia vera or essential thrombocythemia.