Pacritinib Reduces Spleen Volume in Myelofibrosis

Clinical Hold Due to Toxicity Concerns Recently Lifted

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The investigational drug pacritinib met the primary endpoint of the phase III PERSIST-2 trial in high-risk patients with myelofibrosis and thrombocytopenia. Treatment with the Janus kinase (JAK)1/2 inhibitor pacritinib achieved a significant reduction in spleen volume compared with best available therapy, including the JAK1/2 inhibitor ruxolitinib (Jakafi).

The safety profile [of pacritinib] remains reasonable, given the fact that we are treating patients with low platelet counts who are already at risk for both bleeding and cardiac events.
— John Mascarenhas, MD

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John Mascarenhas, MD, of Tisch Cancer Institute, Mt. Sinai’s Icahn School of Medicine, New York, presented the results of the PERSIST-2 trial as a late-breaking abstract at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition.1 The study was also featured as one of several abstracts of interest in a premeeting ASH webinar for the media.

“Despite the fact that these patients have very low platelet counts and in approximately 45% of cases had previously been treated with ruxolitinib, we were able to administer this drug effectively, thereby significantly reducing systemic symptoms and bothersome splenomegaly in a subset of patients who received pacritinib twice daily,” Dr. Mascarenhas reported.

According to the PERSIST-2 trial results, pacritinib could play a role in treating these high-risk patients with a potentially fatal disease. It is not a cure, but it could help symptoms, said experts. The general opinion was that the side-effect profile was reasonable in this high-risk group of patients with limited treatment options. However, the U.S. Food and Drug Administration (FDA) put a hold on pacritinib in February 2016, after concerns emerged in the phase III PERSIST-1 trial about cardiac and hemorrhagic events leading to excess deaths. (The FDA removed that clinical hold in January 2017.)

Myelofibrosis affects approximately 20,000 people in the United States. It is a hematopoietic stem cell malignancy associated with an intense inflammatory state that causes scarring in the bone marrow, significant anemia and thrombocytopenia, organomegaly, and is associated with a median survival of approximately 5 to 6 years. Although there is no cure for myelofibrosis, reduction in spleen volume is an important endpoint for treatment, which can result in improvement in symptoms, and subset analyses suggest it may also act as a surrogate biomarker for improved outcome.

Study Details

Of a planned enrollment of 311 patients, 221 patients were accrued to the PERSIST-2 trial and were randomized to receive pacritinib at 400 mg once daily, pacritinib at 200 mg twice daily, or best available therapy (including the JAK1/2 inhibitor ruxolitinib). Enrollment was stopped when the FDA put a hold on the drug.

About one-third of patients with myelofibrosis have thrombocytopenia (platelet counts < 100,000/µL). Ruxolitinib has an FDA indication for treatment of intermediate- or high-risk myelofibrosis, but it is not indicated for people with thrombocytopenia (platelet counts < 50,000/µL). Pacritinib might play a role in treating this group of patients. 

Primary Endpoint Met

The study met the primary endpoint: A significant reduction in spleen volume from baseline at 24 weeks was achieved in 18.1% of patients treated with either dose of pacritinib vs 2% of those on best available therapy (P = .001). When the two doses of pacritinib were considered separately, spleen volume reduction from baseline was achieved in 14.7% of the 75 patients on once-daily pacritinib compared with best available therapy (P = .017) and 21.6% of the 74 patients treated with twice-daily pacritinib (P = .001 for both comparisons with best available therapy).

Update on New JAK1/2 Inhibitor

  • In a phase III trial of high-risk patients with myelofibrosis and thrombocytopenia, the investigational JAK1/2 inhibitor pacritinib met the primary endpoint of significant reduction in spleen volume.
  • Twice-daily pacritinib improved total symptom scores by at least 50% in a subset of patients.
  • Due to emerging concerns about hemorrhage and cardiac effects, the FDA put pacritinib on clinical hold for nearly a year, but that hold was recently removed.

Twenty-five percent of patients on pacritinib had a 50% or greater reduction in total symptom score vs 14% of the best available therapy group (P = .079). More patients treated with pacritinib reduced their red blood cell transfusion dependence at week 24: 19% with pacritinib once daily, 11% with pacritinib once daily, and 9% with best available therapy.

There was no significant difference in overall survival across the treatment arms.

Safety Update

“The safety profile remains reasonable, given the fact that we are treating patients with low platelet counts who are already at risk for both bleeding and cardiac events,” Dr. Mascarenhas stated. On-study deaths were reported in 14% of those on once-daily pacritinib, 9% of those on twice-daily pacritinib, and 14% of those on best available therapy.

Treatment-emergent adverse events were more common in the once-daily-dose arm compared with the twice-daily-dosing arm. The most common treatment-emergent adverse events were gastrointestinal and hematologic. Grade 3 and 4 cardiac adverse events occurred in 7% of those who received the once-daily dose, 13% of those who received the twice-daily dose, and 3% of those who received best available therapy. Grades 3 and 4 bleeding occurred in 14%, 7%, and 7%, respectively. ■

Disclosure: Dr. Mascarenhas has served as a consultant for Incyte and Novartis and received research funding from Incyte, Novartis, CTI BioPharma, Janssen, Roche, and Promedior.


1. Mascarenhas J, Hoffman R, Talpaz M, et al: Results of the PERSIST-2 phase 3 study of pacritinib versus best available therapy, including ruxolitinib, in patients with myelofibrosis and platelet counts < 100,000/µl. 2016 ASH Annual Meeting. Abstract LBA-5. Presented December 6, 2016.

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