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| Item Type: | Article |
|---|---|
| Title: | Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results |
| Creators Name: | Rücker, 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., Döhner, H., Thiede, C. and Döhner, K. |
| 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. |
| Keywords: | Antineoplastic Combined Chemotherapy Protocols, Tumor Biomarkers, Combined Modality Therapy, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Acute Myeloid Leukemia, Insertional Mutagenesis, Prognosis, Retrospective Studies, Survival Rate, Tandem Repeat Sequences, Homologous TransplantationHomologous, fms-Like Tyrosine Kinase 3 / Genetics |
| Source: | Leukemia |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Volume: | 36 |
| Number: | 1 |
| Page Range: | 90-99 |
| Date: | January 2022 |
| Official Publication: | https://doi.org/10.1038/s41375-021-01323-0 |
| PubMed: | View item in PubMed |
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