Título:
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Molecular landscape and prognostic impact of FLT3 -ITD insertion site in acute myeloid leukemia : RATIFY study results
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Autor/a:
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Rücker, Frank G.; Du, Ling; Luck, Tamara J.; Benner, Axel; Krzykalla, Julia; Gathmann, Insa; Voso, Maria Teresa; Amadori, Sergio; Prior, Thomas W.; Brandwein, Joseph M.; Appelbaum, Frederick; Medeiros, Bruno; Tallman, Martin S.; Savoie, Lynn; Sierra, Jorge; Pallaud, Celine; Sanz, Miguel A..; Jansen, Joop H.; Niederwieser, Dietger; Fischer, Thomas; Ehninger, Gerhard; Heuser, Michael; Ganser, Arnold; Bullinger, Lars; Larson, Richard A.; Bloomfield, Clara D.; Stone, Richard M.; Döhner, Hartmut; Thiede, Christian; Döhner, Konstanze; Universitat Autònoma de Barcelona
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Abstract:
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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. |
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open access
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https://ddd.uab.cat/record/250440
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