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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mascarenhas has received research funding from CTI BioPharma Corp, Incyte, and Promedior. Dr Gerds has a consultancy and/or advisory role for CTI BioPharma Corp, Incyte, and AstraZeneca. Dr Gupta has received research funding from Incyte and Novartis. Dr Drummond has a consultancy and/or advisory role for CTI BioPharma Corp and Novartis and is on the speaker’s bureau for Novartis and Celgene. Drs Granston, Daly, and Al-Fayoumi, and Ms Callahan are employed by CTI BioPharma Corp. Dr Singer is employed by and has equity ownership in CTI Biopharma Corp. Dr Gotlib has received research funding from CTI BioPharma Corp. Dr Jamieson has received research funding from Johnson & Johnson, GlaxoSmithKlein, CTI BioPharma Corp and is employed by Impact Biomedicines. Dr Harrison has received research funding from Novartis, is on the speaker’s bureau for CTI BioPharma Corp, Novartis, Sanofi, and Baxter, and has a consultancy and/or advisory role for CTI BioPharma Corp, Novartis, Gilead, Baxter. Dr Mesa has received research funding from Incyte, Gilead, CTI BioPharma Corp, Promedior, and Celgene, and has a consultancy and/or advisory role for Novartis, Ariad, Galena. Dr Verstovsek has received research funding from Incyte, Roche, AstraZeneca, Lily Oncology, Geron, NS Pharma, Bristol-Myers Squibb, and Celgene. No other conflicts are reported.

Figures

Figure 1.. CONSORT Diagram

Outcomes for all randomized patients are shown. BAT indicates best available therapy; alloSCT, allogeneic stem cell transplant.

Figure 2.. Spleen Volume Reduction and Reduction in Total Symptom Score in Evaluable Patients

Waterfall plots for spleen volume reduction (A) and total symptom score reduction (B) from baseline for evaluable patients are shown. Mean and median percent decreases from baseline were greater with pacritinib vs BAT. Of note, SVR≥10% was achieved in 72.5%, 78.9%, and 36.0% of evaluable patients with pacritinib once daily, pacritinib twice daily, and best available therapy, respectively. BAT indicates best available therapy. Each bar represents a single patient.