Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial

Abstract

Background: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias.

Methods: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187.

Findings: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study.

Interpretation: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited.

Funding: CTI BioPharma Corp.

Conflict of interest statement

The remaining authors declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

84 patients who discontinued pacritinib for other reasons did so due to the clinical hold placed by the US Food and Drug Administration in February, 2016, (hold removed in January, 2017). Reasons given for the remaining six patients were incorrect diagnosis at study entry, treatment lock of efficacy, splenectomy, patient withdrawal from treatment but not from follow-up, clinical deterioration, and terminal illness leading to withdrawal of study drug and replacement with palliative care. 77 patients who discontinued BAT due to investigator decision did so to cross over to pacritinib treatment. The remaining six patients who discontinued BAT due to investigator decision were withdrawn because of the treating physician’s decision to change treatment (this patient remained on study for the following 3 months for safety follow-up), worsening of myelofibrosis symptoms, worsening status of patient (this patient died 1 week after discontinuing BAT), clinical progression (n=2; one patient remained on study for safety follow-up for 6 months and the other for 10 months; both patients died), and heavy overall complications caused by BAT. Of the remaining 13 patients who crossed over to pacritinib, 11 patients discontinued BAT because of disease progression, one patient discontinued BAT because of adverse events, and one patient because of patient withdrawal. BAT=best available therapy. ITT=intention-to-treat.

Figure 2:. Spleen volume reduction according to treatment group

(A) Best percentage change from baseline in spleen volume in the first 24 weeks of treatment for evaluable patients. (B) Mean percentage change in spleen volume over time for evaluable patients. Intervals at each timepoint indicate SEM. BAT=best available therapy.

Figure 3:. Change in total symptom score

(A) Percentage of evaluable patients achieving 50% reduction or greater over time for the six common symptoms between the MPN-SAF TSS original version and TSS version 2.0. (B) Patient Global Impression of Change (PGIC) responses for evaluable patients at week 24. BAT=best available therapy. MPN-SAF=Myeloproliferative Neoplasm Symptom Assessment Form. TSS=total symptom score.

Figure 4:. Overall survival (intention-to-treat population)

Squares and circles show censored patients. BAT=best available therapy. HR=hazard ratio.