Pacritinib Produced Comparable Safety Profile to Best Available Therapy for Cytopenic Myelofibrosis, Severe Thrombocytopenia


Patients with cytopenic myelofibrosis produced a tolerable safety profile when receiving treatment with pacritinib.

For patients with cytopenic myelofibrosis, which includes patients with severe thrombocytopenia, pacritinib treatment administered at 200 mg twice daily, produced a comparable safety profile to best available therapy (BAT), according to results from a retrospective safety analysis of the phase 3 PERSIST-2 (NCT02055781) and phase 2 PAC203 (NCT03165734) trials.1

Results, which were presented during the 2021 ASH Annual Meeting, showed that of the 71 patients in the pooled analysis from the PERSIST-2 (n = 47) and PAC203 (n = 24) studies who were treated with pacritinib, sustained dose intensity was observed with the JAK2 inhibitor with median daily doses of 400 mg and 396 mg, respectively.

Among patients who had received ruxolitinib (Jakafi) as BAT in the PERSIST-2 trial (n = 17), the median posttitration dose was 10 mg daily.

Further, in PERSIST-2, all-grade treatment-emergent adverse events (TEAEs) and TEAEs that led to study drug discontinuation were reported at similar rates in the pooled pacritinib and BAT groups (all-grade, 99% vs 91%, respectively; discontinuation, 20% vs 17%, respectively).

However, there was a higher incidence of grade 3 or higher serious TEAEs in the pooled pacritinib group (55%) vs those in the BAT group (36%), including those on supportive care regimens. Fatal TEAEs occurred at a lower frequency with pacritinib than in the BAT subgroup at 13% vs 19%, respectively.

“This analysis suggests that pacritinib at 200 mg twice daily may represent the first fully dosed therapeutic option for patients with cytopenic myelofibrosis, including severe thrombocytopenia,” lead study author John O. Mascarenhas, MD, a professor of medicine, hematology, and medical oncology of Icahn School of Medicine at Mount Sinai in New York, New York, said in a poster presentation of the findings. Mascarenhas is also the director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and director of the Adult Leukemia Program at Mount Sinai.

Thrombocytopenia is a known adverse risk factor for patients with myelofibrosis that leads to decreased survival, worse overall quality of life, an increase in myelofibrosis symptoms, and an increased risk of leukemia and bleeding.

Those who have severe thrombocytopenia, defined as a platelet count lower than 50 x 109/L, have been excluded from pivotal trials of JAK1/2 inhibitors, resulting in a significant unmet need for the treatment of this patient population, Mascarenhas noted.

Pacritinib is an oral JAK2/interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitor that has demonstrated clinically significant activity in spleen volume and symptom reduction in patients who have cytopenic myelofibrosis, including those who have severe thrombocytopenia, in phase 2 and phase 3 studies.2,3

Although pacritinib has shown clinical benefit when administered at the full dose of 200 mg twice daily in patients with severe thrombocytopenia, as seen in the PAC203 and PERSIST-2 trials, safety data have not been previously reported in the high-risk patient subgroup.

The open-label, dose-finding, randomized, phase 2 PAC203 trial evaluated pacritinib in patients with myelofibrosis who were previously treated with ruxolitinib.

In the multicenter, phase 3 PERSIST-2 trial, investigators randomized patients with myelofibrosis and moderate-to-severe thrombocytopenia (defined as a platelet count of ≤ 100 x 109/L) to receive pacritinib or BAT.

In the safety analysis presented at the 2021 ASH Annual Meeting, investigators conducted a retrospective analysis of the PERSIST-2 and PAC203 studies in an effort to characterize the safety profile of pacritinib in patients with a platelet count of less than 50 x 109/L at the full dose of 200 mg twice daily.

AEs were classified and graded according to Common Terminology Criteria for Adverse events, and standardized Medical Dictionary for Regulatory Activities Query was used to assess bleeding and cardiac events. Further, major cardiac events were assessed using major adverse cardiovascular events (MACE) classification.

Seventy-one patients were analyzed as part of the pooled pacritinib group at the 200-mg twice-daily dose; 47 from PERSIST-2 and 24 from PAC203. Forty-two patients were assessed in the BAT arm from PERSIST-2.

Overall, the median platelet count was 30 x 109/L and the median hemoglobin count was 8.6 g/dL. Thirty-four percent of patients were red blood cell transfusion dependent and 18% were platelet transfusion dependent. Sixty-three percent of patients had prior treatment with a JAK2 inhibitor.

Additional safety findings showed that in the pooled pacritinib group, all-grade TEAEs were mainly thrombocytopenia (32%), low-grade nausea (30%), and diarrhea (41%); these events were manageable with antidiarrheals and were resolved without treatment discontinuation. Grade 3 or higher AEs that occurred most often with pacritinib included thrombocytopenia (32%) and anemia (27%). Any-grade epistaxis rates were lower in the pooled pacritinib group compared with BAT at 21% vs 26%, respectively; peripheral edema rates were 23% vs 26%, respectively.

In PAC203, serious bleeding AEs (8%) and grade 3 or higher bleeding AEs (13%) were reported at a lower incidence with pacritinib compared with those in the pacritinib group at the same dosage (13% and 17%, respectively) or BAT (10% and 12%) in PERSIST-2, which Mascarenhas said are likely attributable to additional safety measures in PAC203.

Additionally, the incidence of any-grade and grade 3 or higher cardiac events were lower with the pooled pacritinib group vs the BAT group (any-grade, 41% with pacritinib vs 45% with BAT; grade ≥ 3, 9% vs 19%, respectively). No MACE events were reported among patients in the pacritinib group and 2 were reported in the BAT group, 1 of which was fatal.

A new drug application for pacritinib as a treatment for adult patients with intermediate- or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis and severe thrombocytopenia is currently under priority review with the FDA.4 In November 2021, the FDA extended the review period for the application, as the agency had previously requested additional clinical data and required additional time to review the new information.

The Prescription Drug User Fee Act action date has now been extended to February 28, 2022.


  1. Harrison C, Gerds A, Prchal J, et al. Safety analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia and virtual. Abstract 3640.
  2. Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020;4(22):5825-5835. doi:10.1182/bloodadvances.2020003314
  3. 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;4(5):652-659. doi:10.1001/jamaoncol.2017.5818
  4. CTI BioPharma announces extension of FDA review period for pacritinib in myelofibrosis with severe thrombocytopenia. CTI BioPharma Corp. News release. November 30, 2021. Accessed December 13, 2021.
Related Videos
Expert on MF
Experts on MF
In a conversation during the 2022 American Society of Hematology Annual Meeting, an expert from the University of Texas MD Anderson Cancer Center, spoke to how treatments have improved for patients with mantle cell lymphoma.
Momelotinib continues to show benefit in reducing splenic symptoms and anemia in myelofibrosis in the second-line setting, making it a likely first treatment choice, according to an expert from the University of Texas MD Anderson Cancer Center .