Background: Both thrombocytopenia and anemia pose treatment challenges in myelofibrosis (MF). When these two cytopenias co-occur (“bicytopenia”), management becomes particularly challenging, and appropriate treatment selection is critical to optimize efficacy while minimizing myelosuppressive side effects. Pacritinib (PAC) is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that has been studied at full dose in patients (pts) with MF regardless of baseline thrombocytopenia or anemia. Here, we present data on spleen and symptom benefit in PAC-treated pts with moderate or severe bicytopenia. Methods: Pts treated with PAC 200 mg twice daily or best available therapy (BAT) on PERSIST-2 with bicytopenia at baseline (platelet count <100 x10⁹/L and hemoglobin <10 g/dL) were included. This group was retrospectively analyzed for spleen volume reduction (SVR) ≥35%, total symptom score (TSS; version 2.0, excluding tiredness) reduction of ≥50%, Patient Global Impression of Change (PGIC), median dose intensity, and transfusion independence response (TI-R). TI-R was assessed among pts who required red blood cell (RBC) transfusion at baseline (within 90 days) and defined as the absence of RBC transfusions over any 12-week period through 24 weeks (Gale criteria). Baseline characteristics are presented in the safety population (pts randomized ≥12 weeks prior to study end and treated); efficacy is presented in the intention-to-treat efficacy population (pts randomized ≥22 weeks prior to end of study). Statistical testing was performed using Fishers Exact Test for efficacy endpoints. Results: Among 46 pts on PAC and 47 on BAT, baseline characteristics were generally similar between groups respectively: median age (65 vs 68 years), platelet count (46 vs 46 x10⁹/L), and hemoglobin (8.4 vs 8.6 g/dL). A lower percentage of pts in PAC than BAT were receiving RBC transfusions (59% vs. 77%) and had prior JAK inhibitor exposure (43% vs 55%). Most pts treated with PAC were able to maintain full doses over time, with median actual dose intensity for PAC being 400 mg/day. A total of 45% of pts in the BAT group received ruxolitinib (median last total daily dose: 10 mg). In the PAC group, 20% (8/40) had SVR ≥35% compared to 0% (0/38) in the BAT group (P=0.0054). Similarly, 32.5% of the pts in the PAC group had ≥50% reduction of TSS compared to 10.5% of pts in the BAT group (P=0.0274). PGIC response (patient-reported symptoms “very much” or “much” improved) at week 24 was greater in the PAC group (30%) compared to BAT (13.2%; P=NS). Among the 27 pts on PAC and 36 on BAT who received RBC transfusions at baseline, 26% of pts on PAC and 8% of pts on BAT achieved TI-R (P=0.0838). Conclusions: PAC at full dose demonstrates efficacy for spleen, symptoms, and transfusion response in pts with MF and both thrombocytopenia and anemia. These findings suggest PAC may be an effective option to address the unmet need for pts with MF and bicytopenias. Clinical trial information: NCT02055781.