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.