6500 Background: Dysregulated JAK-STAT signaling is a key feature in MF, which is characterized by splenomegaly, debilitating symptoms, cytopenias and shortened survival. There are currently no effective drug therapies for MF. 424 is a selective JAK 1 and 2 inhibitor with clinical activity in MF.
METHODS
Patients (pts) with intermediate-2 or high-risk MF were randomized to start PB or 424 at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100-200 X 109/L or >200 X 109/L, respectively). The dose was optimized for efficacy and safety during treatment. The primary endpoint was the proportion of pts with ≥ 35% reduction in spleen volume at week (wk) 24 of therapy, assessed by blinded review of spleen MRI or CT. Secondary endpoints were durability of spleen response, changes in symptom burden (symptom score [SS] measured daily with MFSAF v2.0), and survival. Exploratory endpoints included change in quality of life (QoL; EORTC-QLQ C30) and fatigue (PROMIS-FS), molecular and serum biomarkers, and transfusion dependence.
RESULTS
309 pts were randomized; 155 to 424 and 154 to PB. Median follow-up is 32.2 weeks. The primary endpoint response rate was 41.9% vs 0.7% (424 vs PB p<0.0001). Median duration of response has not been reached. At wk 24 the proportion of pts with ≥ 50% improvement in SS was 45.9% vs 5.3% (424 vs PB p<0.0001) and change in total SS was an improvement of 46.1% vs a worsening of 41.8% (424 vs PB p<0.0001). There were 10 vs 14 deaths (424 vs PB, HR 0.67, p=0.33). Changes in both QoL and fatigue mirrored changes in SS over time and all showed improvement relative to PB regardless of changes in hemoglobin. The most common AEs of any grade seen in >20% of pts on either arm of the study were (424 vs PB) abdominal pain (10.3% vs 41.1%), thrombocytopenia (34.2% vs 9.3%), fatigue (25.2% vs 33.8%), anemia (31% vs 13.9%), diarrhea (23.2% vs 21.2%) and peripheral edema (18.7% vs 22.5%). Anemia and thrombocytopenia were manageable and rarely (0.6% 424 vs 0.7% PB, each) led to withdrawal from the study.
CONCLUSIONS
In this study, 424 demonstrated marked and sustained clinical benefits in spleen size, debilitating symptoms and QoL and an acceptable safety profile relative to PB in MF.