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 R.
AU - Medeiros, Bruno C.
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
N1 - Funding Information:
This work was supported in part by a grant from the Deutsche Forschungsge-meinschaft (SFB 1074, project B3) (KD and LB), by National Institutes of Health, National Cancer Institute grants U10CA180821 (to the Alliance for Clinical Trials in Oncology Operations Center), U10CA180882 (to the Alliance Statistics and Data Management Center), U24CA196171 (to the Alliance NCTN Biorepository and Biospecimen [CDB]), and UG1CA233338 (to ITSC for Leukemia: Novel Molecular strategies for NCTN Individualized Therapies [CDB]), and by a research grant from Novartis.
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/1
Y1 - 2022/1
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.
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U2 - 10.1038/s41375-021-01323-0
DO - 10.1038/s41375-021-01323-0
M3 - Article
C2 - 34316017
AN - SCOPUS:85111628122
SN - 0887-6924
VL - 36
SP - 90
EP - 99
JO - Leukemia
JF - Leukemia
IS - 1
ER -
