Poor Applicability of Currently Available Prognostic Scoring Systems for Prediction of Outcome in KIT D816V-Negative Advanced Systemic Mastocytosis.

Within our nationwide registry, we identified a KIT D816V mutation ( KIT D816V pos.) in 280/299 (94%) patients with advanced systemic mastocytosis (AdvSM). Age, cytopenias and the presence of additional somatic mutations confer inferior overall survival (OS). However, little is known about the characteristics of KIT D816V-negative (D816V neg. ) AdvSM. In 19 D816V neg. patients, a combination of clinical, morphological and genetic features revealed three subgroups: (a) KIT D816H- or Y-positive SM ( KIT D816H/Y pos. , n = 7), predominantly presenting as mast cell leukemia (MCL; 6/7 patients), (b) MCL with negative KIT sequencing ( KIT neg. MCL, n = 7) and (c) KIT neg. SM with associated hematologic neoplasm ( KIT neg. SM-AHN, n = 5). Although >70% of patients in the two MCL cohorts ( KIT D816H/Y pos. and KIT neg. ) were classified as low/intermediate risk according to prognostic scoring systems (PSS), treatment response was poor and median OS was shorter than in a KIT D816V pos. MCL control cohort ( n = 29; 1.7 vs. 0.9 vs. 2.6 years; p < 0.04). The KIT neg. SM-AHN phenotype was dominated by the heterogeneous AHN (low mast cell burden, presence of additional mutations) with a better median OS of 4.5 years. We conclude that (i) in MCL, negativity for D816V is a relevant prognostic factor and (ii) PSS fail to correctly classify D816V neg. patients.