B07 | Molecular risk profiling in myeloproliferative neoplasms blast phase treated with venetoclax and decitabine: a three-gene score for survival prediction

Background: Myeloproliferative Neoplasm-Blast Phase (MPN-BP) has poor outcome with overall survival (OS) 1 (median 4) additional myeloid gene mut. ELN24/mPRS separated the favorable category (54% of the pts; median OS, 20.7mo, p=0.0041) from the intermediate (17%, OS 8.9mo) and the adverse one (29%; OS 5.1mo); though the latter two were almost superimposable (p=0.35). ELN24-ref system favorable category (9% of the pts)showed median OS not reached (p=0.012) compared to 14mo in intermediate (57%) and 10mo in adverse (24%), with the latter two overlapping (p=0.10). In our cohort, predictors of OS identified in univariable analysis included achievement of CR/PR within two cycles(55%; p = 0.02), mut in SRSF2 (25%; p = 0.048), U2AF1 (7.5%; p < 0.001), EZH2 (16.3%; p = 0.047), and TP53 (28.8%; p = 0.01), irrespective of multihit status (17.5%). In multivariable analysis SRSF2mut (HR 3.0; 95%CI 1.4-6.3; p=0.004), U2AF1mut (HR 4.2, 1.6-10.7; p=0.003) and TP53mut (HR 2.7, 1.3-5.3; p=0.005) maintained independent impact on OS. We thus created a 3-gene score assigning 2 points each to SRSF2mut and U2AF1mut and 1 point to TP53mut, separating three risk groups: in the favorable (point 0; n=38 pts, 47.5%) OS was 20.7 mo (95%CI 17-24) compared to 10.8 mo (3-18.6) in the intermediate (point 1; n= 16 pts, 20%) and 3.7 mo (0-10.8) in the adverse (≥2 points, n26 pts, 32.5%) risk category (p=0.001). C-index for the 3-gene model was 0.68 compared to 0.59 for ELN24 and 0.57 for ELN24-ref. Reclassification of pts according to 3-gene model as compared to ELN24 mainly regarded intermediate pts, half of whom were reclassified as favourable and half as adverse. Additionally, 32% of pts initially classified as favourable were reassigned to the adverse category. The improved stratification by 3-gene model may reflect unique molecular features of MPN-BP pts compared to de novo AML: notably, 78% of TP53mut pts (n=23) had additional mut beyond driver mut, a distinct figure from pts enrolled in the mPRS cohort (n=63, 35%).Conclusions: The 3-gene score outperforms de-novo AML genetic models in our cohort of MPN-BP pts treated with VEN/DEC. Validation in independent series is warranted.