PERSIST-2: Pacritinib Compared With Best Available Therapy for Patients With Myelofibrosis and Thrombocytopenia

In the phase III PERSIST-2 trial, the multi-tyrosine kinase inhibitor pacritinib met one of two co-primary endpoints, demonstrating a significant reduction in spleen volume compared with best available treatment in patients with myelofibrosis (MF) and thrombocytopenia. The co-primary endpoint of reduction of Total Symptom Score (TSS) was not significantly improved with pacritinib, though.

“The JAK 1/2 inhibitor ruxolitinib is the only approved therapy for patients with intermediate or higher-risk MF and a platelet count >50,000/µL,” lead author John Mascarenhas, MD, from the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City, told ASH Clinical News. “Earlier in its development, pacritinib showed efficacy in reducing spleen volume and symptom burden, as well as less myelosuppression than ruxolitinib, which opens up a niche, particularly in patients with low platelet counts.”

A total of 311 patients with MF and platelet counts ≤100,000/µL were randomized to receive either pacritinib 200 mg twice daily, pacritinib 400 mg once daily, or BAT (including ruxolitinib). At the time of the presentation, data were evaluable for 221 patients: 74 in the pacritinib twice daily dosing group, 75 in the pacritinib once daily dosing group, and 72 in the BAT group. Nearly half of patients in the BAT group (44%) received ruxolitinib at some point during the study.

From baseline to week 24, a higher percentage of patients in the pooled pacritinib arms achieved spleen volume reduction (SVR) ≥35 percent (a co-primary endpoint) than in the BAT arm: 18 percent (n=27/149) versus 3 percent (n=2/72; p=0.001). The second co-primary endpoint (the proportion of patients achieving >50% reduction in TSS from baseline to week 24) was not met: 25 percent of pacritinib-treated patients (n=37/149) had a reduction in symptom burden, compared with 14 percent of BAT patients (n=10/72; p=0.079).

However, Dr. Mascarenhas noted that in secondary analyses looking at each pacritinib dosing cohort, twice-daily dosing demonstrated a significant improvement over BAT for both endpoints: 22 percent versus 3 percent achieved SVR ≥35% (p=0.001), and 32 percent versus 14 percent achieved ≥50% reduction in TSS (p=0.011).

“Unfortunately, the TSS co-primary endpoint was not met, but the data show that pacritinib has activity, particularly at twice-daily dosing,” he said.

However, safety is still a concern, as the FDA placed pacritinib on full clinical hold in February 2016 due to concerns over excess deaths and cardiac and hematologic toxicities. In PERSIST-2, hazard ratios for OS, compared with BAT, were 0.68 for twice-daily pacritinib and 1.18 for once-daily pacritinib.

During PERSIST-2, 10 (9%), 15 (14%), and 15 (14%) patients died on twice-daily pacritinib, once-daily pacritinib, and BAT, respectively. The most common treatment-emergent AEs associated with pacritinib were gastrointestinal (diarrhea, nausea, and vomiting) and hematologic (anemia and thrombocytopenia).

Before future trials can determine the safety of pacritinib and its optimal dosing, the drug’s manufacturer will need to negotiate with the FDA to lift the clinical hold on pacritinib.


Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the Persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/µl. Abstract LBA-5. Presented at the 2016 ASH Annual Meeting, December 6, 2016; San Diego, California.