Poor applicability of currently available prognostic scoring systems for prediction of outcome in KIT D816V-negative advanced systemic mastocytosis

Abstract

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.

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