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Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results. Leukemia Rucker, F. G., Du, L., Luck, T. J., Benner, A., Krzykalla, J., Gathmann, I., Voso, M. T., Amadori, S., Prior, T. W., Brandwein, J. M., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Savoie, L., Sierra, J., Pallaud, C., Sanz, M. A., Jansen, J. H., Niederwieser, D., Fischer, T., Ehninger, G., Heuser, M., Ganser, A., Bullinger, L., Larson, R. A., Bloomfield, C. D., Stone, R. M., Dohner, H., Thiede, C., Dohner, K. 2021

Abstract

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n=251, 55%), JMD and TKD1 (JMD/TKD1; n=117, 26%), and TKD1sole (n=84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P=0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P=0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.

View details for DOI 10.1038/s41375-021-01323-0

View details for PubMedID 34316017