Background: MF is a life-limiting malignancy characterized by marrow fibrosis, splenomegaly, and progressive cytopenias. JAK2 inhibitors can reduce spleen volume, which is considered a surrogate for disease response. For example, ≥10% SVR on ruxolitinib (RUX) is associated with improved OS among patients with platelet (PLT) counts ≥100×10⁹/L. RUX cannot be administered at full dose in patients with lower PLTs, and it is not known whether the association between SVR and OS persists in such patients. PAC is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated SVR benefit vs BAT (including RUX) in PERSIST-2, which enrolled MF patients with PLTs ≤100×10⁹/L. Here we present a retrospective landmark OS analysis of the relationship between SVR and OS on PERSIST-2. Methods: This analysis includes PERSIST-2 patients who were alive and on study at the start of the 12-week SVR window (study week 10) on PAC 200 mg BID or BAT. Spleen volume was assessed radiographically (MRI or CT). OS was evaluated among SVR responders vs non-responders within each treatment arm using different SVR thresholds (≥35%, ≥20%, ≥10%, > 0%) and a landmark analysis methodology. OS was compared using the log-rank test. Results: Among patients on PAC (n = 89), any SVR ( > 0%) at 12 weeks was significantly associated with improved survival (HR = 0.08 [95% CI: 0.01, 0.51], P = 0.0007). Among all SVR response thresholds, SVR ≥10% demonstrated the greatest separation in OS curves between responders vs. non-responders on PAC, with no deaths on study among 65 responders compared to 5 deaths among 24 non-responders (HR = 0.0 [95% CI: 0.0, 0.14], P < 0.0001). By contrast, SVR did not predict OS benefit on BAT (n = 84), including RUX (n = 39). For example, 11% (3/28) of patients on BAT who achieved SVR ≥10% died compared to a similar number (14%, 8/56) of non-responders (HR = 0.63 [95% CI: 0.17, 2.37], P = 0.49). Of the 28 patients on BAT who achieved SVR ≥10%, 23 (82%) were treated with RUX. Among these 23 patients, most patients were receiving low-dose RUX at the time of the landmark: 78% were on ≤10 mg BID and 43% were on £5 mg BID. By contrast, the median relative dose intensity on PAC was 100% (200 mg BID) through week 12 among both SVR ≥10% responders and non-responders. Conclusions: In MF patients with PLTs ≤100×10⁹/L, achieving SVR on full-dose PAC was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on RUX, albeit at low doses. As PAC can be given at full dose regardless of PLT count, it is possible that PAC may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction. Clinical trial information: NCT02055781.