Kumar, Mahesh

e18596 Background: The International Consensus (ICC), but not the 5 th edition of the WHO classification (WHO5), distinguishes mature from immature mast cell leukemia (MCL) and systemic mastocytosis (SM) associated with myeloid neoplasm (SM-AMN) from SM associated with myeloid or lymphoid neoplasm (SM-AHN). The objectives of the current study were i) to assess prognostic input from disease classification by ICC vs. WHO5, and ii) to compare the predictive performance of the Mayo Alliance Prognostic scoring (MAPS) with other prognostic models and its prognostic interaction with the ICC-based morphologic classification. Methods: Study patients met diagnostic criteria per ICC/WHO5. MAPS risk variables included i) age >60 years, ii) hemoglobin below sex-adjusted lower limit of normal, iii) platelets <150 × 10⁹/L, iv) alkaline phosphatase above upper limit of normal, and v) advanced, including MCL, SM-AMN, and aggressive (ASM) vs. indolent/smoldering (ISM/SSM) SM. ICC-defined MCL includes only MCL-immature whereas WHO-defined MCL includes both MCL-immature and MCL-mature. WHO-defined SM-AHN includes SM-AMN and SM associated with lymphoid neoplasm (SM-ALN). Results: 910 Mayo Clinic patients with SM were diagnosed between 1968 and 2024 (median age 56 years). ICC categories were ISM/SSM (N=552), ASM (N=115), SM-AMN (N=235), and MCL (N=8). At median follow-up of 4 years, 345 (38%) deaths and 35 (3.8%) leukemic transformations were documented. Overall survival (OS) predictive performance at 5 years was superior with ICC (AUC 0.85), compared to WHO5 (AUC 0.83); median survival was 24.3 years in ISM/SSM, 5.8 years for ASM, 2.0 years for SM-AMN, 2.3 years for SM-AHN, 1.8 years for MCL-mature and 0.08 years for MCL-immature; the difference in OS was significant between MCL-immature and SM-AMN (p<0.01) but not between MCL-mature and SM-AHN (p=0.3). Similarly, OS was similar between MCL-mature and ASM (p=0.8) and between SM-ALN and ASM (p=0.08) but different between MCL-immature and ASM (p<0.01), SM-AMN and ASM (p<0.01), and MCL-mature and MCL-immature (p<0.01). Predictive performance at 5 years was superior with MAPS (AUC 0.91) and MAPS-molecular (AUC 0.91), compared to the mutation-adjusted risk score (MARS; AUC 0.82). Median OS estimates were not reached, 24.2, 11.7, 5.7, 2.6, and 0.7 years, in the presence of 0, 1, 2, 3, 4, or 5 of the forementioned MAPS risk factors. Among informative cases, ASXL1 mutation was the only genetic risk factor with MAPS-independent prognostic relevance. Prognostic inter-independence between ICC and MAPS was confirmed by multivariable analysis. Conclusions: The current study confirms the superior performance of MAPS, in regard to survival prediction, with little additional contribution from mutations. SM sub-classification by the ICC is prognostically independent of MAPS and more valuable than classification by WHO5.

Abstract Background Classic progressive supranuclear palsy RS syndrome (PSP‐RS) is characterized by early postural instability/falls and vertical supranuclear gaze palsy, although other signs/symptoms can occur, for example, axial rigidity, bradykinesia, and cognitive dysfunction. The Movement Disorders Society‐PSP (MDS‐PSP) criteria consider probable PSP‐RS a homogenous syndrome, but this has not been tested. Objectives We aim to investigate relationships between signs/symptoms of PSP‐RS beyond its core features and determine whether PSP‐RS is a homogeneous syndrome. Methods 118 participants who met MDS‐PSP criteria for probable PSP‐RS were analyzed. All participants received an independent clinical diagnosis based on clinical judgment. We first performed a Network Analysis using qgraph with Spearman's correlation to quantify relationships between 16 signs/symptoms followed by a k‐means clustering analysis using the same signs/symptoms to identify possible heterogeneity of the PSP‐RS designation. Results Five network clusters were identified, reflecting: (1) tremor, (2) sensitivity to bright light, (3) oculomotor function, (4) cognition, and (5) akinetic‐rigidity‐praxis. Worse akinetic‐rigidity was associated with better oculomotor function, but worse cognition. Cluster analysis revealed two clusters. Cluster I ( n = 89) had more severe clinical features than Cluster II ( n = 29). Cluster II had a higher frequency of participants (37.9%) clinically judged as not PSP‐RS: these participants were less likely to have PSP pathology on autopsy ( P = 0.03). Conclusions Some signs/symptoms of PSP‐RS strongly associate and are more likely to co‐occur. PSP‐RS, as defined by the MDS‐PSP criteria includes a subset of participants not clinically judged as PSP‐RS who are less likely to have PSP pathology.