Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06.

Abstract

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by the clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties to identify the secondary nature of some cases, otherwise defined as de novo AML, remain. In order to test whether a chromatinspliceosome (CS) mutational signature might better define the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients who were enrolled in a randomized clinical trial (NILG AML 02/06) and who provided samples for accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs. 61% in de novo AML, P<0.0001; disease-free survival, 26% in CS-AML and 22% in sAML vs. 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06; clinicaltrials gov. Identifier: NCT00495287).