Progression of Disease Within 24 Months (POD24) is an Independent Prognostic Factor for Survival in Waldenström Macroglobulinemia

Introduction: The prognostic significance of progression of disease within 24 months (POD24) is well-established in many lymphomas, but data in Waldenström Macroglobulinemia (WM) remain limited and constrained by the frontline regimen utilized. Methods: This retrospective, single-center study enrolled consecutive, unselected newly-diagnosed WM (NDWM) patients who received frontline treatment with DRC between January 1, 2002 and September 15, 2021. Individuals without a progression event and a follow-up of less than 24 months were excluded. A landmark approach was utilized in order to evaluate the prognostic impact of POD24 in subsequent OS. Results: A total of 206 NDWM patients were enrolled; median age 70 years, 123 (59.7%) males. POD24, occurring in 47 (22.8%) patients, was associated with inferior OS post the 24-month landmark (5-year OS 62.8% vs 82.1% in non-POD24, p=0.001), maintained when adjusting for R-IPSSWM scores (aHR=1.65; 95% CI, 1.01-2.70; p = 0.044). When accounting for non-WM related death as a competing event, the cumulative incidence of WM-related mortality at 5 years was 21.6% and 7.1% between POD24 and non-POD24, respectively. POD24 maintained its prognostic significance when further adjusting for R-IPSSWM (aSHR= 1.88, 95%CI: 1.01-3.49, p=0.048). Conclusion: POD24 seems to be a predictor of inferior survival in patients with NDWM treated frontline with DRC. Even when accounting for immortal time bias through landmark analysis and adjusting for baseline risk via the R-IPSSWM and competing risks, patients with POD24 demonstrated a significantly higher risk of mortality. These findings suggest that POD24 could represent a high-risk phenotype that may require tailored management. Micro-Abstract: This retrospective study evaluated the prognostic significance of disease progression within 24 months (POD24) among 206 newly-diagnosed Waldenström Macroglobulinemia (WM) patients receiving frontline treatment with dexamethasone, rituximab, and cyclophosphamide (DRC). POD24 occurred in 22.8% of this cohort. Landmark analysis demonstrated that POD24 is associated with inferior subsequent overall survival, showing a 5-year OS of 62.8% versus 82.1%. Furthermore, the cumulative incidence of WM-related death at five years was significantly higher for the POD24 group (21.6% versus 7.1%) after accounting for competing risks. Ultimately, POD24 represents a high-risk phenotype requiring tailored management.