PERSIST-1: A PHASE III STUDY OF PACRITINIB (PAC) VS BEST AVAILABLE THERAPY (BAT) IN PRIMARY MYELOFIBROSIS (PMF), POST-POLYCYTHEMIA VERA MF (PPV-MF) OR POST-ESSENTIAL THROMBOCYTHEMIA MF (PET-MF)

Background
Treatment options for patients (pts) with MF are limited. A significant proportion present with disease-related thrombocytopenia, an independent survival risk factor. Others develop treatment-emergent thrombocytopenia on currently available therapies. These pts represent an underserved population. PAC is a potent multikinase inhibitor of JAK2/FLT3 and has exhibited minimal myelosuppression in early phase MF studies.   

Aims
The open-label PERSIST-1 (NCT01773187) trial compared the efficacy and safety of oral PAC vs BAT in PMF, PPV-MF, and PET-MF.

Methods
JAK inhibitor naïve pts were randomized 2:1 to oral PAC 400mg once daily or BAT stratified by DIPSS risk (Int-1 or Int-2 vs High) and platelet (plt) count (<50,000/µL vs 50,000 to <100,000/µL vs ≥100,000/µL). Eligibility criteria included: DIPSS Int-1, Int-2, or High risk; ANC >500/µL; no restriction on plt or hemoglobin; palpable splenomegaly ≥5 cm; and baseline total symptom score (TSS) ≥13 using the MPN Symptom Assessment Form (MPN-SAF). The primary endpoint was the proportion of pts achieving ≥35% spleen volume reduction (SVR) at Week 24 (WK24) by centrally-reviewed MRI or CT. The secondary endpoint was the proportion achieving ≥50% reduction in TSS at WK24 using MPN-SAF. 

Results
327 pts were enrolled (PAC: 220, BAT: 107), 62% with PMF; 32% had plt counts <100,000/µL and 16% had plt counts <50,000/µL; 75% were JAK2V617F-positive. Median time from diagnosis was 1.0 y (PAC) and 1.6 y (BAT). Median baseline spleen volumes were 2006 cm³ (PAC) and 2153 cm³ (BAT) and TSSs were 20 (PAC) and 23 (BAT). Estimated median duration of treatment was 16.2 mo (PAC) and 5.9 mo (BAT). SVR rates at WK24 were 19% for PAC vs 5% for BAT (p=0.0003) in intent-to-treat (ITT) and 25% vs 6% (p=0.0001) in pts evaluable at baseline and WK24 (figure). Progressive disease was not required for crossover after week 24. 79% of BAT pts crossed over to PAC (median 27 weeks). TSS (V1+V2) response rates were 25% for PAC vs 7% for BAT (p<0.0001) by ITT, and 41% vs 10% in evaluable pts (p<0.0001). Patient Global Impression of Change improvement on PAC (81%) was significantly higher than on BAT (21%) in evaluable pts (p<0.001). PAC significantly improved SVR rates irrespective of baseline plt counts. In pts with <100,000 and <50,000 plt/μL, SVR rates were 17% for PAC vs 0% for BAT (p=0.009), and 23% vs 0% (p=0.045) by ITT, respectively, and 24% vs 0% (p=0.007) and 33% vs 0% (p=0.037) in evaluable pts, respectively. In baseline RBC transfusion-dependent pts (PAC: 35, BAT: 15), 26% of PAC pts became RBC transfusion independent vs 0% of BAT pts (p=0.043). The most common adverse events (AEs) through WK24 for PAC were gastrointestinal (GI): diarrhea, nausea, and vomiting. Grade (Gr) 3 GI AEs rates were 5%, <1%, and <1% respectively (no Gr 4). Gr 3-4 hematologic AEs occurring in >2% were similar for PAC vs BAT: anemia (17% vs 15%) and thrombocytopenia (12% vs 9%). PAC AEs were similar in thrombocytopenic and non-thrombocytopenic pts. 90% of PAC pts did not require any dose reduction. AEs leading to dose reduction included diarrhea (3%) and anemia (2%). Dose interruptions occurred in 22% (median duration 7 days) with 6% due to diarrhea, 3% thrombocytopenia, and 2% anemia.

Summary
PAC dosed 400mg once daily was well tolerated with minimal dose modifications and induced clinically and statistically significant and meaningful SVR and meaningful symptom control even in pts with severe thrombocytopenia. PAC therapy also resulted in RBC transfusion independence in a significant proportion of pts.

Keyword(s): Flt3 inhibitor, Myelofibrosis, Spleen, Thrombocytopenia

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