The poor outcome in high molecular risk, hydroxycarbamide-resistant/intolerant ET is not ameliorated by ruxolitinib.

Essential Thrombocythemia (ET) patients at high-risk of thrombosis require cytoreductive treatment, typically with hydroxycarbamide. Many patients are resistant or intolerant to hydroxycarbamide (HC-RES/INT) and are at increased risk of disease progression. MAJIC-ET is a randomized phase 2 study comparing ruxolitinib (RUX) to best available therapy (BAT) in HC-RES/INT ET, which showed no difference between the two arms in rates of hematological response or disease progression. The impact of additional non-MPN driver mutations (NDM) on the risk of disease complications in HC-RES/INT ET patients is unknown. Since the presence of NDM may influence trial outcomes, we expand the primary MAJIC-ET analysis to serially evaluate NDM in MAJIC-ET patients using a targeted myeloid 32-gene panel. NDM at baseline were detected in 30% of patients, most frequently affecting (11%) followed by (6.4%) and (6.4%). The presence of a NDM was associated with inferior 4-year transformation-free survival (TFS; 65.4% [95% CI 53.3 – 75%] vs. 82.8% [95% CI 73.2 – 89.1%], p=0.017). Specifically, (p=0.01) and splicing factor (SF, ; p<0.001), but not mutations were associated with reduced TFS which was not mitigated by RUX treatment. Longitudinal analysis identified new mutations in 19.3% of patients; primarily affecting and . We report the first comprehensive mutational analysis of HC-RES/INT ET patients and highlight the clinical/prognostic utility of serial mutation analysis for NDM in HC-RES/INT ET, including the importance of SF and mutations which identify HC-RES/INT ET patients at increased risk of disease transformation.