Genomic profiling for decision-making in post-polycythemia vera and post-essential thrombocythemia myelofibrosis.
Key claim: Integrating ASXL1 and UTS (U2AF1, TP53, or SRSF2) mutations—and optionally complex/monosomal karyotype—into MYSEC-PM yields MYSEC-mPM/MYSEC-kmPM scores that significantly improve overall-survival prediction in post-PV and post-ET myelofibrosis.
Abstract
Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera (PV) and essential thrombocythemia (ET), with overall survival (OS) currently defined by the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) patients reported at least 1 CGV, with ASXL1, TET2, and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (P< .001): U2AF1, TP53, or SRSF2 variants (UTS; 9.3%; median OS, 4.1 years) and ASXL1 without UTS (25.3%; median OS, 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (P< .0001 to .02): hemoglobin level <11 g/dL (1 point), circulating blasts ≥3% (2 points), platelet count <150 × 109/L (2 points), age (0.21 points/y), ASXL1 without UTS mutations (1 point), and any UTS mutations (3 points). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 patients with SMF into 4 categories with different OS (P < .001): low (median OS, 18.0 years; score <14), intermediate-1 (8.8. years; score, 14-16), intermediate-2 (4.6 years; score, 17-18), and high risk (1.9 years; score ≥19). Additionally, in 381 patients with SMF and available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improves survival prediction in SMF, outperforming the MYSEC-PM.
Why this matters
Secondary MF after PV/ET has historically been risk-stratified with the clinical MYSEC-PM, leaving molecular high-risk patients potentially miscalled at the transplant-referral threshold. Adding ASXL1 and UTS mutations (and optionally complex/monosomal karyotype) sharpens overall-survival prediction, meaning some post-PV/ET MF patients previously scored intermediate may in fact warrant earlier transplant consideration. This is a decision-layer refinement — it directly shifts the ‘should I be transplanted, and when’ answer rather than changing operational mechanics.