Safety Analysis of Pacritinib in Patients with Myelofibrosis and Severe Thrombocytopenia

Abstract Background: Pacritinib, a novel JAK2/IRAK1 inhibitor, demonstrated clinically significant activity in spleen volume and symptom reduction in patients with advanced cytopenic myelofibrosis (MF), including those with severe thrombocytopenia (platelet [PLT] count <50 × 10 9/L), in phase 2 and 3 clinical studies. Cytopenic MF, characterized by thrombocytopenia, anemia, and transfusion requirements, is associated with poor prognosis and shortened survival. Patients with cytopenic MF represent a challenging population, as therapeutic options are limited or must be given at reduced doses, which impairs efficacy. Pacritinib, unlike JAK1/2 inhibitors, has demonstrated clinical benefit at the recommended full dose of 200 mg twice daily (BID) in patients with cytopenias in the phase 2 dose-finding PAC203 and phase 3 PERSIST-2 studies. To characterize the safety profile of pacritinib in patients with cytopenic MF at the full-dose of 200 mg BID, we performed a retrospective analysis of the data from these studies. Methods: Patients with baseline PLT <50 x 10 9/L treated with pacritinib 200 mg BID in PERSIST-2 and PAC203 or best available therapy (BAT) in PERSIST-2 were included as the target patient population in this analysis. In PERSIST-2, patients were randomized 1:1:1 to pacritinib 200 mg BID, pacritinib 400 mg once daily (QD), or BAT, including ruxolitinib (40%) or watch and wait (31%); patients could be either JAK inhibitor-naive or have had prior exposure. PAC203 included patients who were intolerant of and/or resistant to ruxolitinib and randomized 1:1:1 to pacritinib 100 mg QD, 100 mg BID, or 200 mg BID; enhanced safety measures were incorporated in the study design to reduce the risk of high-grade bleeding and cardiac events. Adverse events (AEs) were classified and graded according to the Common Terminology Criteria for AE. Standardized MedDRA Query (SMQ) was used to assess bleeding and cardiac events. Major cardiac events were analyzed using major adverse cardiovascular events (MACE) classification. Results: A total of 71 patients were analyzed as the pooled pacritinib 200 mg BID group (n=47 in PERSIST-2; n=24 in PAC203) and 42 patients in the BAT group. In addition to having severe thrombocytopenia, patients in the pooled pacritinib group had significant anemia, with median hemoglobin 8.6 g/dL, and 34% required red blood cell transfusion at baseline (Table 1). Sustained dose intensity was observed for the pacritinib group, with median dose of 400 mg/day in PERSIST-2 and 396 mg/day in PAC203. In the BAT subgroup from PERSIST-2, among the patients who received ruxolitinib the median post-titration dose was 10 mg/day. A total of 44% of patients treated with pacritinib and 21% treated with BAT had drug exposure ≥6 months. All-grade treatment-emergent adverse events (TEAEs) and those leading to study drug discontinuation were observed at similar rates in the pooled pacritinib and BAT groups. The patients in the pooled pacritinib group had a higher incidence of grade ≥3 and treatment-emergent serious AEs compared to those on BAT, which included patients on supportive care strategies. In the pooled pacritinib group, all-grade TEAEs were mostly driven by thrombocytopenia (32%) and gastrointestinal events, which included low grade nausea (30%) and diarrhea ([41%], which was manageable with over-the-counter antidiarrheals and resolved without leading to drug discontinuation). Rates of other commonly reported AEs in both trials were lower in the pooled pacritinib group compared to BAT, including epistaxis and peripheral edema. Fewer patients experienced fatal TEAEs in the pooled pacritinib group (Table 2). The incidence of serious and grade ≥3 bleeding AE was lower with pacritinib 200 mg BID in PAC203 than those reported with pacritinib 200 mg BID or BAT in PERSIST-2, likely attributable to the additional safety measures in PAC203 (Table 2). Incidence of cardiac events of any grade and those grade ≥3 were lower in the pooled pacritinib group compared to BAT. No patients in the pooled pacritinib group and 2 in the BAT group (1 fatal) had a MACE event (Table 2). Conclusion: In this analysis of patients with cytopenic MF who have severe thrombocytopenia, the safety profile of pacritinib 200 mg BID was comparable to BAT. This analysis suggests that pacritinib 200 mg BID may represent the first fully-dosed therapeutic option for this challenging patient population. Figure 1 Figure 1. Disclosures Mascarenhas: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding; Geron: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Geron: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galecto: Consultancy; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison: Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau. Gerds: Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; PharmaEssentia Corporation: Consultancy; Novartis: Consultancy. Rampal: Incyte: Consultancy, Research Funding; BMS/Celgene: Consultancy; Stemline: Consultancy, Research Funding; Kartos: Consultancy; Constellation: Research Funding; Jazz Pharmaceuticals: Consultancy; Blueprint: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Pharmaessentia: Consultancy; Sierra Oncology: Consultancy; Memorial Sloan Kettering: Current Employment; Disc Medicine: Consultancy. Buckley: CTI Biopharm: Current Employment. Craig: CTI BioPharma: Current Employment. Smith: CTI: Current Employment. Volpone: CTI: Current Employment. Roman-Torres: CTI Biopharm: Current Employment. Mesa: Samus: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Pharma: Consultancy; CTI: Research Funding; CTI: Research Funding; Sierra Oncology: Consultancy, Research Funding; Abbvie: Research Funding; Promedior: Research Funding; AOP: Consultancy; La Jolla Pharma: Consultancy; Genentech: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Celgene: Research Funding.