FLT3-ITD Varianten in der AML - Einfluss auf Biologie der Erkrankung und Therapieansprechen
Zusammenfassung der Projektergebnisse
• In intermediate-risk AML, a high FLT3-ITD allelic ratio (≥0.51) and ITD insertion site in the tyrosine kinase domain 1 are associated with a lower complete remission rate, shorter event-free, relapse-free and overall survival. • Allogeneic HSCT performed in first CR prolongs relapse-free and overall survival in patients with high allelic ratio, whereas insertion site in the TKD1 remains an unfavorable prognostic marker irrespective of the applied postremission therapy. • Our findings confirm the initial hypothesis that FLT3-ITD-location influences disease biology and leads to changes in global gene expression. • In our model, ITD-location alters proliferative capacity and sensitivity to FLT3-TKI-treatment in vivo. Therefore, patients harboring TKD1-ITD may not significantly benefit from concomitant or sequential treatment with TKI. • Potential caveats of our study include impact of ITD-size on the phenotype. TKD1-ITDs have already been described to be longer and ITD-size has been controversially discussed for many years as a potential prognostic factor. Variability in ITD-size is – in part - reflected by the ITD-constructs used in our study. However, we did not find gross differences in sensitivity to TKI within the respective location (JMD/TKD1) depending on ITD-size. • Impact of ITD-mutations on disease biology is of major clinical interest, as prognostic parameters such location of the mutation or allelic ratio may help to stratify patients towards allo-SCT versus chemotherapy in combination with TKI treatment in future clinical trials. • ITD-mediated differences in DNA-repair may facilitate therapeutic strategies targeting DNA- damage response pathways to sensitize TKD1-ITDs to chemotherapy or targeted therapies.
Projektbezogene Publikationen (Auswahl)
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German-Austrian AML Study Group. Differential impact of allelic ratio and insertion site in FLT3- ITD-positive AML with respect to allogeneic transplantation. Blood. 2014 Nov 27;124(23):3441-9
Schlenk, Richard F.; Kayser, Sabine; Bullinger, Lars; Kobbe, Guido; Casper, Jochen; Ringhoffer, Mark; Held, Gerhard; Brossart, Peter; Lübbert, Michael; Salih, Helmut R.; Kindler, Thomas; Horst, Heinz A.; Wulf, Gerald; Nachbaur, David; Götze, Katharina; Lamparter, Alexander; Paschka, Peter; Gaidzik, Verena I.; Teleanu, Veronica; ... & Döhner, Konstanze
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Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia volume 30, pages 1220–1225 (2016). Publ. Okt 2015
Arreba-Tutusaus, P.; Mack, T. S.; Bullinger, L.; Schnöder, T. M.; Polanetzki, A.; Weinert, S.; Ballaschk, A.; Wang, Z.; Deshpande, A. J.; Armstrong, S. A.; Döhner, K.; Fischer, T. & Heidel, F. H.
