CLINICAL TRIALS AND OBSERVATIONS KIT-D816 mutations in AML1-ETO–positive AML are associated with impaired event-free and overall survival

Mutations in codon D816 of the KIT gene represent a recurrent genetic alteration in acute myeloid leukemia (AML). To clarify the biologic implication of activation loop mutations of the KIT gene, 1940 randomly selected AML patients were analyzed. In total, 33 (1.7%) of 1940 patients were positive for D816 mutations. Of these 33 patients, 8 (24.2%) had a t(8;21), which was significantly higher compared with the subgroup without D816 mutations. Analyses of genetic subgroups showed that KIT-D816 mutations were associated with t(8;21)/AML1-ETO and other rare AML1 translocations. In contrast, other activating mutations like FLT3 and NRAS mutations were very rarely detected in AML1-rearranged leukemia. KIT muta-tions had an independent negative im-pact on overall (median 304 vs 1836 days; P .006) and event-free survival (median 244 vs 744 days; P .003) in patients with t(8;21) but not in patients with a normal karyotype. The KIT-D816V recep-tor expressed in Ba/F3 cells was resistant to growth inhibition by the selective PTK inhibitors imatinib and SU5614 but fully sensitive to PKC412. Our findings clearly indicate that activating mutations of re-ceptor tyrosine kinases are associated with distinct genetic subtypes in AML. The KIT-D816 mutations confer a poor prognosis to AML1-ETO–positive AML and should therefore be included in the diag-nostic workup. Patients with KIT-D816– positive/AML1-ETO–positive AML might benefit from early intensification of treat-ment or combination of conventional che-motherapy with KIT PTK inhibitors