Furthermore, the KITD816V tissue mutation burden was significantly higher in advanced than in indolent systemic mastocytosis (p=0.001), predicted survival of patients in multivariate analyses independently, and was significantly reduced after response to cytoreductive therapy.
The presence of the KITD816V mutation in PB of ISM patients is associated with (early) involvement of circulating CD34<sup>+</sup> HPC and multiple myeloid cell subpopulations, KIT-mutated PB CD34<sup>+</sup> HPC potentially contributing to early dissemination of the disease.
All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases.
We included 48 adult patients with ISM (28 females/20 males) from our center in whom the KITD816V mutation level in both BM aspirate and PB was analyzed.
The tyrosine kinase KIT has been shown to play a crucial role in the pathogenesis of SM and has been a focal point in the development of targeted therapy.
However, the KITD816V mutation was detected using mutation-specific qPCR in both bone marrow and peripheral blood in all 25 cases, demonstrating for the first time that the KITD816V mutation is consistently present in non-mast cells in indolent systemic mastocytosis and that these cells are circulating in peripheral blood.
Together, the biologic effects of KITD816V in BaF3 cells match strikingly with the clinical course of indolent systemic mastocytosis and with our recently established transgenic mouse model, in which KITD816V induces indolent mast cell accumulations but usually does not induce a malignant mast cell disease.