Unraveling progression predictors in prefibrotic myelofibrosis: A 2,000-patient systematic review and meta-analysis

Abstract Background: Prefibrotic primary myelofibrosis (pre-PMF) is a distinct clinical entity within the myeloproliferative neoplasms (MPNs), often underrecognized despite its potential progression to overt myelofibrosis (MF) or acute myeloid leukemia (AML). The heterogeneity in clinical outcomes among pre-PMF patients necessitates a clearer understanding of risk factors predictive of adverse outcomes. Methods: We conducted a systematic review and meta-analysis to identify clinical, hematologic, cytogenetic, and molecular predictors of disease progression and mortality in patients with pre-PMF. Five studies encompassing 2,010 patients were included in the systematic review. Of these, four studies provided hazard ratios (HRs) with 95% confidence intervals (CIs) and were included in the quantitative synthesis. A random-effects model was used to pool HRs for variables consistently reported across studies. Results: Pooled analysis revealed that anemia (HR: 2.62, 95% CI: 1.93–3.57), age >65 years (HR: 1.93, 95% CI: 1.34–2.78), leukocytosis >13 x10⁹/L (HR: 1.69, 95% CI: 1.29–2.22), and high molecular risk (HMR) mutations (HR: 2.01, 95% CI: 1.41–2.88) were independently associated with increased risk of progression to overt MF or AML and/or poor overall survival. High-risk cytogenetics and peripheral blasts were also predictive in individual studies. Based on these findings, we proposed a preliminary prognostic scoring system—the PRE-MF Progression Risk Score (PPRS)—incorporating age, anemia, leukocytosis, HMR mutations, and karyotype abnormalities. Risk stratification using this score may help guide surveillance intensity and therapeutic decision-making. Conclusions: Our findings identify reproducible risk factors associated with adverse outcomes in pre-PMF and support their integration into clinical risk stratification. The proposed PPRS model is a hypothesis-generating tool that requires validation in prospective cohorts but may serve as a foundation for future personalized management strategies in pre-PMF. Keywords: Prefibrotic myelofibrosis, progression, acute leukemia, risk factors, meta-analysis, anemia, HMR mutations, scoring system.