Abstract 282


The JAK2V617F mutation has been linked to the pathogenesis of myeloproliferative neoplasia. Pacritinib (SB1518) is a potent inhibitor of both wild-type JAK2 and the JAK2V617F mutant. In previously reported Phase 1 studies, patients with myelofibrosis (MF) who received pacritinib achieved steady-state plasma levels above the IC50 for JAK2 at all doses (100–600 mg/d). Target inhibition, measured by phosphorylation of the STAT3, STAT5, and JAK proteins in PBMCs and whole blood was also shown at all doses. 400 mg/d was chosen as the recommended dose (RD) for Phase 2 study.


The primary endpoint of the Phase 2 study was to assess the spleen response rate, defined as a ≥35% reduction in MRI-measured spleen volume between baseline and Week 24.


Qualifying patients had primary, post-ET, or post-PV MF, with palpable splenomegaly ≥5 cm below the left costal margin. Based on minimal myelosuppression in the Phase 1 trials, no minimum hematology values were required for eligibility. Treatment with pacritinib was on a continuous oral, daily schedule. Disease symptoms were evaluated using the MF-SAF.


Thirty-four MF patients (median age 69; range, 44–84 years) consented and were enrolled, of which 25 (74%) were men. Median PS was 1 with 2 patients having PS >1. Median baseline hemoglobin and platelet count were 10.2 g/dL and 119,000/μL, respectively. Fifteen patients (44%) had platelet counts <100,000/μL, including 7 with counts <50,000/μL. Median baseline spleen size was 14 cm (range 4–30 cm) below the LCM by physical exam, and median spleen volume was 2647 cc (range 404–7817 cc) by MRI. Twenty-six patients (76%) were JAK2V617F mutation-positive. The median time on study is 8.2 months (range, 0.5 to 12.1 months).


Seventeen patients (50%) have discontinued, including 8 (24%) due to AEs (1 each for nausea, sepsis, increased bilirubin, subdural hematoma, allergic reaction, GI bleed, and 2 due to thrombocytopenia), 5 for disease progression and 2 for lack of response. Of the AEs leading to discontinuation, only increased bilirubin, allergic reaction and intermittent nausea were considered possibly drug related. Ten patients required dose reduction for adverse events. One patient required drug discontinuation associated with decreased neutrophils and platelets. This was considered related to worsening disease; otherwise, there were no changes in pacritinib dosing related to impaired hematopoiesis. The most common treatment-related AEs were gastrointestinal, which were generally low grade and easily managed. GI AEs >Grade 2 included Grade 3 diarrhea in 2 patients (6%). Only 1 patient discontinued for GI toxicity.


Pacritinib produced meaningful reductions in splenomegaly. Thirty patients (88%) showed reductions in palpable splenomegaly; 15 (44%) showed decreases of ≥50% and 6 (18%) achieved clinical resolution of splenomegaly. Eleven patients (32%) had a ≥35% reduction in splenic volume as measured by MRI. Splenic reduction of 50% by PE correlated with a 25% reduction in spleen volume by MRI. Fourteen patients (41%) had reduction in splenic volume by >25%. Spleen response rates were equivalent among patients with low baseline platelet counts and those with normal baseline counts. All spleen responses are ongoing; consequently a median duration of response has not been reached. Two patients met IWG-MRT criteria for clinical improvement in hemoglobin including 1 who became transfusion independent. At the 6-month visit, a significant reduction (>2 point improvement) was observed for MF-associated symptoms, including abdominal pain, bone pain, early satiety, worst fatigue, inactivity, night sweats and pruritus.


Pacritinib shows promising efficacy in alleviating MF-associated splenomegaly and constitutional symptoms at a dose that induces minimal myelosuppression. Once-daily dosing is well tolerated, with manageable GI toxicity as the main side effect. Given the lack of myelosuppression with pacritinib, this JAK2 inhibitor is of particular importance for MF patients with impaired hematopoiesis.


Mesa:SBIO: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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