Cernohous, Paul

Abstract Background and Aims A platelet count ≤100,000/µL is regarded as an independent prognostic marker for the development of leukemia and is associated with inferior survival in myelofibrosis (MF) (Huang et al. 2008). The approved JAK2 inhibitor, ruxolitinib, is associated with treatment-emergent thrombocytopenia, and patients with platelets ≤100,000/µL were excluded from the phase III COMFORT trials. Efficacy and safety data are limited in patients with MF and platelets ≤100,000/µL treated with ruxolitinib. Pacritinib (SB1518), an oral JAK2/FLT3 inhibitor, did not appear to be associated with clinically significant treatment emergent anemia or thrombocytopenia during early phase studies in patients with myeloid and lymphoid malignancies. This integrated analysis was performed to further evaluate the safety and efficacy of pacritinib in MF patients with baseline platelet counts of ≤100,000/µL. Methods The databases from 2 phase I/II clinical trials of pacritinib in advanced myeloid malignancies and MF were integrated to evaluate the rate of adverse events (AEs) and favorable spleen responses in patients with MF and thrombocytopenia. Results One hundred twenty-nine patients with advanced myeloid malignancies and MF were treated with pacritinib in phase I and II clinical trials. Sixty-five patients with MF were treated with 400 mg orally once daily in 2 phase II studies. Of these, 28 patients with MF [21 primary MF (75%), 5 post-polycythemia vera-MF, 2 post-essential thrombocytosis-MF] had baseline platelet counts of ≤100,000/µL (median: 58,500/µL, range: 15,000/µL – 97,000/µL). The median age was 69 years. Twenty three (82%) patients had the JAK2V617F mutation. During the phase 2 studies, spleen volume responses were assessed by MRI and are shown for all patients (Figure 1) and for patients with platelets ≤100,000/µL (Figure 2). Thirty-seven percent and 43% of all evaluable patients and patients with ≤100,000/µL platelets, respectively, had ≥35% reduction in spleen volume from baseline (Table). Among the 21 informative patients with allelic JAK2V617F quantification at more than 1 study visit, 3, including 2 patients with homozygous mutations, had ≥35% reduction in spleen volume and substantial reductions in allelic burden from baseline (mean reduction 64%, range 44 to 88%). In the 11 (17%) patients with MF and baseline platelet counts ≤50,000/μL, overall spleen volume reduction was 38% (3/8) in evaluable patients and the median decline in platelet count observed at study end was 6,000/µL. Integrated safety analysis for all 129 patients with advanced myeloid malignancies showed the most common adverse events (AEs) were gastrointestinal (GI), predominantly diarrhea, and most of these were grade 1 (43%) and grade 2 (26%). The time to onset of diarrhea was ≤30 days in the majority of those affected, but only 2% had drug discontinuation as a consequence. Among the 129 patients in the phase 1 and 2 trials, 57 patients had ≤100,000 platelets; of these 26 (46%) had no CTC grade change in hemoglobin (Hb) and platelet counts from baseline values. Hb and platelet counts improved by one grade in 16% and 18% of patients, respectively. One grade worsening was seen in 28% and 30% in Hb and platelet counts, respectively. Conclusions Pacritinib was well-tolerated in patients with MF, regardless of their baseline platelet counts. Grade 1 or 2 GI toxicities, particularly diarrhea, were the most common AEs. Spleen responses were similar in patients regardless of baseline platelet counts (≥100,000/µL vs. ≤100,000/µL). Notably, even patients with initial platelet counts ≤50,000/µL tolerated therapy and the majority maintained stable hemoglobin and platelet counts. A phase III trial will evaluate pacritinib versus best available therapies in patients with MF and platelet counts ≤100,000/µL. Disclosures: Dean: Cell Therapeutics, Inc: Employment. Cernohous:Cell Therapeutics, Inc: Employment. Mesa:Incyte, CTI, Gilead, Celgene, Genetech, NS Pharma, Lilly: Research Funding. Campbell:Cell Therapeutics, Inc: Employment. Caldwell:Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc.: Employment. Myint:Cell Therapeutics, Inc: Employment.

LBA7006 Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. Methods: The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. Results: Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. Efficacy: The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). Safety: The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. Clinical trial information: NCT01773187.