Rebecca Boucher

PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

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 TET2 (11%) followed by TP53 (6.4%) and SF3B1 (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, TP53 (p=0.01) and splicing factor (SF, SF3B1, ZRSR2, SRSF2; p<0.001), but not TET2 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 TET2, TP53 and SF3B1. 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 TP53 mutations which identify HC-RES/INT ET patients at increased risk of disease transformation.