Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial

JAMA Oncol. 2018 May 1;4(5):652-659. doi: 10.1001/jamaoncol.2017.5818.

Abstract

Importance: Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib.

Objective: To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.

Design, setting, and participants: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly.

Interventions: Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT.

Main outcomes and measures: Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data.

Results: Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%).

Conclusions and relevance: In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms.

Trial registration: clinicaltrials.gov Identifier: NCT02055781.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Bridged-Ring Compounds / administration & dosage
  • Bridged-Ring Compounds / adverse effects
  • Bridged-Ring Compounds / pharmacokinetics
  • Bridged-Ring Compounds / therapeutic use*
  • Combined Modality Therapy
  • Female
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 2 / antagonists & inhibitors
  • Male
  • Phenotype
  • Primary Myelofibrosis / diagnosis
  • Primary Myelofibrosis / drug therapy*
  • Primary Myelofibrosis / etiology
  • Primary Myelofibrosis / mortality
  • Prognosis
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • Spleen / pathology
  • Thrombocytopenia / drug therapy
  • Treatment Outcome

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Bridged-Ring Compounds
  • INCB018424
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2

Associated data

  • ClinicalTrials.gov/NCT02055781