Abstract
Myelofibrosis (MF) can present with symptomatic splenomegaly and/or cytopenias including thrombocytopenia. Disease-related thrombocytopenia is a poor prognostic factor with a median overall survival of less than 2 years. Currently approved JAK1/2 inhibitors have not been evaluated in patients with platelets ≤ 50 × 109/L and in fact could potentiate thrombocytopenia because of their combined JAK1/2 inhibitory activity. Pacritinib (PAC), a selective JAK2, fms-like tyrosine kinase 3, interleukin-1 receptor-associated kinase 1 multikinase inhibitor was developed to meet this unmet need. PAC was evaluated in 2 randomized phase 3 trials in the frontline setting (PERSIST-1, PAC 400 mg daily vs best available therapy) and second-line setting in patients with MF with platelets ≤ 100 × 109/L (PERSIST-2, PAC 400 mg daily or 200 mg twice daily vs best available therapy). PERSIST-1 met its primary end point; however, the development of PAC hit a brief pause because of a US Food and Drug Administration-mandated clinical hold for excess of bleeding and cardiac events in the PAC 400 mg daily arm in the PERSIST-1 study. Although the PERSIST-2 study was terminated abruptly because of this clinical hold, it met its splenic response end point and demonstrated a trend toward symptom improvement. Subsequent, diligent review of the PERSIST-1 and PERSIST-2 studies did not confirm an excess of severe bleeding or cardiac events on the PAC arm. Additionally, the dose finding PAC203 study endorsed the safety and efficacy of 200 mg twice daily, leading to the approval of PAC for the treatment of patients with MF with platelets ≤ 50 × 109/L.