INTRODUCTION: Moderate to severe thrombocytopenia is a recognized marker of poor prognosis and high symptom burden in patients with myelofibrosis (MF). Data from the MPN-QOL study group (Scotch AH, Leuk Res 2017) showed that patients with platelet (PLT) counts <100x109/L have more severe symptomatology compared to those without thrombocytopenia. Patients with thrombocytopenia are often excluded from clinical trials, so there is a lack of data on symptom burden in this population. Symptom burden data was evaluated for the 311 patients with MF and PLT counts ≤100x109/L enrolled in the Phase 3 PERSIST-2 study of pacritinib versus Best Available Therapy. Methods: All patients in the PERSIST-2 study with moderate or severe thrombocytopenia were included in the analysis, which was stratified by baseline PLT count (50‑100x109/L, n=118; <50x109/L, n=141). Symptom scores were evaluated using TSS v2.0 and were averaged in the 7 days prior to randomization. The overall TSS score was the sum of individual symptom scores excluding inactivity. Symptom prevalence was defined by a symptom score of ≥1 (0-10 scale). The Wilcoxon test was used to compare differences in scores between patients with moderate and severe thrombocytopenia. Results: Baseline symptom burden was high, with a median TSS score of 22 in patients with moderate thrombocytopenia and 23 in patients with severe thrombocytopenia. Tiredness was the most severe symptom, with a median score of 6. Compared to patients with moderate thrombocytopenia, those with severe thrombocytopenia reported higher median scores for physical function-related symptoms (tiredness plus inactivity): 12 vs 10, P=0.014. Severity of spleen- and cytokine-related symptoms were similar between patients with moderate and severe thrombocytopenia (Fig 1a). Tiredness and inactivity were the most severe and prevalent. All symptoms had a prevalence of >50% in both PLT strata (Fig 1b). Conclusion: Results highlight the symptom burden of patients with MF who have moderate or severe thrombocytopenia, particularly in physical function-related symptoms. Tiredness comprises more than a quarter of the total score in these patients. The pivotal studies for the JAK1/2 inhibitors ruxolitinib and fedratinib excluded patients based on lower PLT counts. There is an unmet need for therapies that improve disease symptoms for patients with MF and thrombocytopenia as current options are limited; pacritinib may fill this role (Palmer J, ASH 2021 Abstract).