KITD816V mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes

BackgroundCurrent diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations. MethodsHere, we correlated the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood-purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow-up and its association with disease outcome. ResultsOur results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V-mutated cells in blood (P = .0004) and a high rate of discordant BM+/blood(-) samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well-differentiated variants of indolent SM (7%). Purification of different compartments of blood-derived myeloid cells was done in 28 patients who were BM mast cell (MC)(+)/blood(-) for KITD816V, revealing KITD816V-mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of >= 3.5% KITD816V-mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression-free survival (PFS). ConclusionsThese results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood-purified myeloid cell populations.

Automated summary

This study found a high correlation between the KITD816V mutation burden in blood and bone marrow, but a lower number of mutated cells in blood. In some cases, there was a discrepancy between the presence of mutated cells in bone marrow and the absence of mutated cells in blood. Purified myeloid cell populations in blood revealed the presence of mutated eosinophils, basophils, neutrophils, and/or monocytes in most patients. The presence of >= 3.5% KITD816V-mutated cells and an unstable mutation burden in blood and/or bone marrow were associated with a shorter progression-free survival.