TY - JOUR
T1 - Molecular landscape and prognostic impact of FLT3 -ITD insertion site in acute myeloid leukemia :
T2 - RATIFY study results
AU - Rücker, Frank G.
AU - Du, Ling
AU - Luck, Tamara J.
AU - Benner, Axel
AU - Krzykalla, Julia
AU - Gathmann, Insa
AU - Voso, Maria Teresa
AU - Amadori, Sergio
AU - Prior, Thomas W.
AU - Brandwein, Joseph M.
AU - Appelbaum, Frederick
AU - Medeiros, Bruno
AU - Tallman, Martin S.
AU - Savoie, Lynn
AU - Sierra, Jorge
AU - Pallaud, Celine
AU - Sanz, Miguel A..
AU - Jansen, Joop H.
AU - Niederwieser, Dietger
AU - Fischer, Thomas
AU - Ehninger, Gerhard
AU - Heuser, Michael
AU - Ganser, Arnold
AU - Bullinger, Lars
AU - Larson, Richard A.
AU - Bloomfield, Clara D.
AU - Stone, Richard M.
AU - Döhner, Hartmut
AU - Thiede, Christian
AU - Döhner, Konstanze
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85111628122
U2 - 10.1038/s41375-021-01323-0
DO - 10.1038/s41375-021-01323-0
M3 - Article
C2 - 34316017
SN - 0887-6924
VL - 36
SP - 90
EP - 99
JO - Leukemia
JF - Leukemia
ER -