6. Hot-spot D816 KIT has different clinical outcome compared to non-D816 KIT variants in myeloid neoplasms

KIT (proto-oncogene) plays significant role in diagnosis and prognosis of myeloid neoplasms (MNs). The hot-spot KIT D816 mutation in exon 17 is recognized by WHO classification as poor prognostic marker for acute myeloid leukemia (AML) with RUNX1::RUNX1T1 and as one of diagnostic and prognostic criteria for systemic mastocytosis (SM), a MN characterized by clonal proliferation of mast cells. The role of activating KIT mutations outside of codon 816 was recognized, resulting in addition of few critical KIT regions in updated consensus proposal for SM diagnosis. However, information on prognostic weight of these 'non-hot-spot' changes is limited. Here we present results of comparative analysis of clinicopathological and survival parameters for patients diagnosed with MNs with activating KIT changes outside of codon 816 (N=14) using patients with MNs with KIT D816 (N=26) as comparative group. Most of study patients had AML (65%) followed by MDS and MDS/MPN (35% combined). Both study groups had same representation of normal, non-complex and complex karyotypes, and karyotypes with diagnostic t(8;21) and inv(16). IHC staining for c-KIT (CD117) detected significantly lower percentage of mast cells with c-Kit protein expression in non-D816 group in contrast to patients with D816 KIT (p<0.0076). Consistent with that, none of the non-D816 group patients developed SM compared to 31% of D816 group patients who developed SM. Notably, the group with non-D816 KIT showed better OS compared to patients with D816 change (p<0.016). Our results support the hypothesis of weaker prognostic impact of non-D816 KIT mutations compared to D816 hot-spot.