Final Results From PERSIST-2: Pacritinib Superior to Best Available Therapy in Patients With Myelofibrosis and Thrombocytopenia

The development of the JAK2/FLT3 inhibitor pacritinib has been marked by ups and downs. In the phase III PERSIST-1 and PERSIST-2 trials, the drug demonstrated significant and durable splenic response and symptom control for patients with myelofibrosis (MF), compared with best available therapy (BAT). However, in February 2016, the U.S. Food and Drug Administration (FDA) halted development of pacritinib after concerns over excess bleeding and cardiovascular deaths. This hold resulted in early termination of the PERSIST-2 trial. In January 2017, the manufacturers and the FDA resolved the hold after a review of more mature data from the PERSIST program.

In a recent JAMA Oncology article, John Mascarenhas, MD, of the Tisch Cancer Institute of the Icahn School of Medicine at Mount Sinai in New York, and co-authors reported final results from PERSIST-2. Their findings confirm the previously published results: Pacritinib, at two dosing levels, was significantly more effective than BAT for spleen volume reduction (SVR; defined as a ≥35% reduction from baseline) and trended toward a lower symptom burden (defined as a ≥50% reduction in total symptom score [TSS]) in patients with MF and thrombocytopenia.

The international, multicenter, randomized, double-blind PERSIST-2 trial enrolled 311 patients between July 2014 and February 2016. All patients had intermediate-1, intermediate-2, or high-risk disease (according to the Dynamic International Prognostic Scoring System); thrombocytopenia (defined as platelet count ≤100×109/L); palpable splenomegaly ≥5 cm below the left costal margin; and Total Symptom Score ≥13 on the Myeloproliferative Neoplasm Symptom Assessment Form.

Prior treatment with one or two other JAK inhibitors was allowed. Patients were excluded if they had active bleeding requiring hospitalization during screening or significant cardiac abnormalities.

Participants were randomized 1:1 (based on geographic region, risk category, and rebound platelet count) to receive:

  • pacritinib 400 mg once-daily (n=104)
  • pacritinib 200 mg twice-daily (n=107)
  • BAT (n=100), which included any physician-selected MF therapy, symptom-directed treatment, or a watch-and-wait approach

Ruxolitinib was the most commonly used single agent in the BAT cohort (n=44; 45%), followed by hydroxyurea (n=19; 19%) and prednisone or prednisolone (n=13; 13%). Nineteen patients were in the watch-and-wait cohort.

Patients continued treatment until disease progression, unacceptable toxicities, or if the patient no longer derived benefit from treatment. After 24 weeks of treatment, participants in the BAT cohort could cross over to the pacritinib arm; patients who experienced progression of splenomegaly were also allowed to cross over.

Three patients did not receive pacritinib or BAT because of adverse events (AEs) or patient withdrawal. The remaining 308 treated patients discontinued therapy after a median of 23, 25, and 21 weeks (ranges not provided) in the pacritinib once-daily, pacritinib twice-daily, and BAT cohorts, respectively.

Among the discontinuations, 62, 75, and 27 patients in each cohort, respectively, stopped because of the clinical hold. Most discontinuations in the BAT cohort reflected patients who had crossed over to pacritinib: 50 patients (51%) crossed over, 43 of whom (86%) did so at or after week 24.

Prior to the clinical hold, discontinuations from AEs trended higher with pacritinib once-daily (n=15; 14%), compared with pacritinib twice-daily (n=10; 9%) or BAT (n=4; 4%). However, discontinuation from progressive disease was higher in the BAT cohort (n=10; 10%), compared with either pacritinib group (n=5 [5%] in the once-daily group; n=7 [7%] in the twice-daily group).

At the time of the clinical hold, 76 patients (71%) in the pacritinib twice-daily cohort and 61 (59%) in the once-daily cohort were still on treatment.

The intention-to-treat efficacy population included 75 patients randomized to pacritinib once-daily, 74 to pacritinib twice-daily, and 72 to BAT.

The authors reported that, at week 24, SVR occurred more frequently in the combined pacritinib arms (27 patients [18%] vs. 2 patients [3%]; p=0.001). More patients in the pacritinib arms also achieved a lower symptom burden (37 patients [25%] vs. 10 patients [14%]; p=0.01). See the TABLE for a breakdown of responses in each arm.

SVR in the pacritinib cohort did not differ based on sex, age, JAK2 V617F status, prior treatment with JAK2 inhibitors, or baseline cytopenias.

Overall survival was not significantly different between the three groups:

  • hazard ratio (HR) = 1.18 (95% CI 0.57-2.44) for BAT vs. pacritinib once-daily
  • HR = 0.68 (95% CI 0.30-1.53) for BAT vs. pacritinib twice-daily (p values not reported)

In the BAT cohort, the overall mortality rate was lower among those who crossed over to receive pacritinib, compared with those who did not (n=4 [8%] vs. n=10 [20%]; p value not reported). On-study deaths occurred in six patients receiving pacritinib twice-daily, 14 receiving pacritinib once-daily, and nine receiving BAT.

The most common non-hematologic AEs associated with pacritinib were gastrointestinal (GI) events, fatigue, peripheral edema, and dizziness, while the most common in the BAT cohort were abdominal pain, fatigue, diarrhea, and peripheral edema.

“Pacritinib was well tolerated and GI toxic effects were generally low-grade, less frequent with twice-daily dosing, and rarely led to treatment discontinuation,” the authors reported. “Clinical improvement in hemoglobin and reduction in transfusion requirements were also more frequent in patients who received pacritinib, particularly with twice-daily dosing.”

Regarding the AEs that led to the initial clinical hold, the researchers observed a potential increased risk of grade 3 or 4 bleeding in the pacritinib twice-daily cohort (15 patients [14%]), compared with the other cohorts (7 patients [7%] in both the pacritinib once-daily and BAT groups). This association “appeared to be independent of platelet count,” they noted.

The rate of grade 3 or 4 cardiac events was also lowest with twice-daily pacritinib, and no cardiac failure or deaths due to cardiac events occurred in this group.

The study is limited by its truncated length (owing to the clinical hold), which hinders the ability to evaluate efficacy and safety and reduces evaluable sample size. Time-to-event analyses were also confounded by patient crossover.

Pacritinib represents an effective treatment option for MF and thrombocytopenia, including in those with prior JAK2 treatment such as ruxolitinib, the researchers concluded. The ongoing phase II PAC203 trial will examine pacritinib at lower dose levels (100 mg once- or twice-daily and 200 mg twice-daily) in patients with MF and thrombocytopenia who were previously treated with ruxolitinib.

CTI BioPharma provided funding for the study.

The corresponding authors report financial support from CTI BioPharma, Incyte, and Promedior. CTI BioPharma provided editorial support.


Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018 March 8. [Epub ahead of print]