Abstract
In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the KIT D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), n = 40; advanced SM, AdvSM, n = 121) at referral and during follow-up for the KIT D816V variant allele frequency (VAF) at the DNA-level and the KIT D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation (r > 0.99, R2 > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM (r = 0.91, coefficient of determination, R2 = 0.84) but only to a lesser extent in AdvSM (r = 0.71; R2 = 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years; p = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 (p = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of KIT D816V may play an important role in the pathophysiology of SM.
Highlights
Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by clonal expansion and abnormal accumulation of neoplastic mast cells in various organ systems.According to the World Health Organization (WHO), systemic mastocytosis (SM) can be divided into indolentSM (ISM) and advanced SM (AdvSM), which is further subcategorized into aggressiveSM (ASM), SM with associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL) [1,2,3]
Versus 10.8 g/dL, p < 0.0001), platelets, serum tryptase level, alkaline phosphatase, and overall survival (OS, median not reached vs. 4.8 years, p < 0.0001)
While BM MC infiltration and serum tryptase represent the KIT D816V positive mast cell burden, the KIT D816V variant allele frequency (VAF)/expressed allele burden (EAB) reveals the overall disease burden including the involvement of non-mast lineages, e.g., neutrophils, monocytes and eosinophils
Summary
Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by clonal expansion and abnormal accumulation of neoplastic mast cells in various organ systems.According to the World Health Organization (WHO), SM can be divided into indolentSM (ISM) and advanced SM (AdvSM), which is further subcategorized into aggressiveSM (ASM), SM with associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL) [1,2,3]. Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by clonal expansion and abnormal accumulation of neoplastic mast cells in various organ systems. SM (ISM) and advanced SM (AdvSM), which is further subcategorized into aggressive. SM (ASM), SM with associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL) [1,2,3]. ISM patients have a nearly normal life expectancy while AdvSM patients have a poor survival of median three to four years [4,5,6,7]. KIT D816V is the pathogenic driver mutation and is detectable in more than 90%. Qualitative detection of KIT D816V has been established as a diagnostic criterion for SM. The serial quantitative assessment of the KIT D816V expressed allele burden (EAB) by a real time RT-quantitative PCR (RT-qPCR) assay during treatment with the KIT-inhibitor midostaurin is a strong and independent marker for response, progression and survival [8,9]
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