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Pacritinib for Myelofibrosis: Follow-Up from PERSIST-1

December 30, 2021

Results from the phase III PERSIST-1 study presented at the 2015 ASCO Meeting showed that the JAK2 inhibitor pacritinib led to more effective spleen volume reduction and better symptom control in patients with myelofibrosis, compared with best available treatment. Two analyses from the PERSIST-1 trial presented at this year's ASCO Annual Meeting provide new data about the safety and efficacy of pacritinib for myelofibrosis: one featuring 60-week follow-up data from the PERSIST-1 study1 and the other examining pacritinib in a subset of patients with thrombocytopenia.2

As we reported earlier, the U.S. Food and Drug Administration (FDA) pulled the investigational new drug application for pacritinib in February 2016, halting the ongoing PERSIST-1 and PERSIST-2 clinical trials and affecting future planned clinical trials. In their decision letter, the FDA noted that the interim overall survival results generated from the unblinded PERSIST-2 data showed a detrimental effect on survival for patients treated with pacritinib, consistent with the results of PERSIST-1. Excess mortality also occurred in pacritinib-treated patients compared with the control arm in the PERSIST-1 trial after crossover to the pacritinib arm.

Evaluating Duration of Response

In earlier results from the PERSIST-1 trial, which compared daily oral pacritinib with best available treatment (BAT; including erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea, but excluding ruxolitinib), a significantly greater proportion of patients treated with pacritinib achieved a ≥35 percent spleen volume reduction (SVR) and ≥50 percent reduction in Total Symptom Score (TSS) at 24 weeks.

At this year's meeting, Ruben A. Mesa, MD, from the Mayo Clinic in Scottsdale, Arizona, presented updated safety and efficacy data through 60-week follow-up, which confirmed that pacritinib led to durable reductions in spleen volume and symptom burden.1

PERSIST-1 included 327 JAK2 inhibitor-naïve patients who met the following criteria:

  • Dynamic International Prognostic Scoring System (DIPSS) status of intermediate-1, intermediate-2, or high-risk myelofibrosis
  • Absolute neutrophil count (ANC) >500/µL
  • Palpable splenomegaly ≥5 cm
  • Baseline TSS ≥13

Patients were randomized 2:1 to receive daily oral pacritinib 400 mg (n=220) or BAT (n=107). Patients were allowed to crossover from BAT to pacritinib after 24 weeks or upon disease progression prior to week 24.

The median treatment duration with pacritinib was 15.1 months (range = 0.1-31.8 months). In the pacritinib cohort, 60 percent of patients (n=133) discontinued treatment – most often due to adverse events (AEs; 21%), while 96 percent of BAT-treated patients discontinued – most often due to physician decision (78%).

At week 60, 24 percent of evaluable pacritinib-treated patients achieved SVR ≥35 percent. Most BAT-treated patients (84%; n=90/107) crossed over to the pacritinib cohort, and these patients "were able to achieve similar responses to those receiving initial pacritinib therapy," Dr. Mesa and co-authors wrote. Nineteen percent of evaluable patients who crossed over achieved an SVR ≥35 percent at week 36 post-crossover. The authors also noted that, among these patients, the reduction in spleen volume was maintained from week 24 to 36 (mean percent change in spleen volume = −17% at week 24 and −16% at week 36 after crossover).

The most common treatment-related AE with initial pacritinib therapy was diarrhea (51% all-grade; 2.7% grade 3/4); the incidence was highest in weeks one through eight of treatment, then dropped to 12 percent in weeks eight through 16 (1.4% grade 3/4), 9 percent in weeks 16 through 24 (1.5% grade 3/4), and continued to decrease at subsequent time points. A similar trend was seen among patients who crossed over from BAT to pacritinib.

"There was no evidence of cumulative toxicities," the authors noted. Other AEs reported in the pacritinib and BAT treatment groups included: anemia (29% and 22%), thrombocytopenia (23% and 14%), neutropenia (5% and 2%), and peripheral neuropathy (1% and 4%).

Pacritinib in Patients with Thrombocytopenia

In the second study, Claire N. Harrison, DM, from the Guys' and St. Thomas' National Health Services Foundation Trust in London, and authors examined long-term outcomes for the subset of PERSIST-1 patients who had thrombocytopenia (platelets <100,000/μL or <50,000/μL) at baseline.2

"Once a patient is diagnosed with myelofibrosis, the incidence of disease-related thrombocytopenia increases with time," Dr. Harrison said during her presentation of the results. "Patients with thrombocytopenia have significantly greater symptom burden, distinct clinical characteristics, and shorter overall survival rates. There is a significant unmet need for patients with myelofibrosis who are unable to tolerate or control their disease on other treatments due to low platelet counts."

"One of the limitations of the only currently FDA-approved therapy, ruxolitinib, is that it is indicated in patients with a platelet count above 50,000/µL," Dr. Mesa explained in an interview with ASH Clinical News at last year's ASCO Annual Meeting. "Many patients with advanced disease have significant thrombocytopenia, and that is a limiter for ruxolitinib because the drug can cause thrombocytopenia."

At baseline, approximately one-third of PERSIST-1 patients had thrombocytopenia: 72 in the pacritinib-treated group and 34 in the BAT group.

Of the evaluable pacritinib-treated patients, 26 percent with baseline platelet <100,000/μL and 21 percent with <50,000/μL achieved SVR ≥35 percent at 60-week follow-up. No BAT-treated patients with baseline platelet <100,000/μL achieved this endpoint. For patients who crossed over to pacritinib, 31 percent of those with platelets <100,000/μL
and 31 percent with platelets <50,000/μL achieved SVR >35 percent.

Pacritinib also appeared to offer sustained symptom control. At week 24, 42 percent of patients with platelets <100,000/μL and 32 percent of those with platelets <50,000/μL experienced a ≥50 percent reduction in TSS. At week 48 (the last assessment per protocol), those numbers had increased to 61 percent and 78 percent, respectively. In addition, mean platelet counts and hemoglobin increased from baseline to week 60 among pacritinib-treated patients (TABLE).

"It is encouraging to see that patients with baseline thrombocytopenia who were treated with pacritinib had stable mean platelet counts and hemoglobin levels through the end of treatment," Dr. Harrison added, "and that some patients with very low platelets increased their platelet counts while receiving pacritinib treatment."


  1. Mesa RA, Egyed M, Szoke A, et al. Pacritinib (PAC) vs best available therapy (BAT) in myelofibrosis (MF): 60 week follow-up of the phase III PERSIST-1 trial. Abstract #7065. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 6, 2016.
  2. Harrison CN, Egyed M, Szoke A, et al. Pacritinib (PAC) vs best available therapy (BAT) in myelofibrosis (MF): Outcomes in patients (pts) with baseline (BL) thrombocytopenia. Abstract #7011. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 6, 2016.

TABLE. Changes in Platelet and Hemoglobin Levels in PERSIST-1 Patients With Thrombocytopenia
Mean platelet
Platelet <50,000/μL Platelet <100,000/μL
n Pacritinib n BAT n Pacritinib n BAT
Baseline 35 29,700/ μL 15 30,100/ μL 68 56,100/ μL 31 50,000/ μL
Week 60 12 44,500/ μL 0 Not available 30 68,900/ μL 0 Not available
Mean hemoglobin
Baseline 35 9.8 g/dL 15 9.6 g/dL 72 10.0 g/dL 33 9.3 g/dL
Week 60 13 9.8 g/dL 0 Not available 31 10.5 g/dL 0 Not available
BAT = best available therapy


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