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)
- 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 RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, Held G, Brossart P, Lübbert M, Salih HR, Kindler T, Horst HA, Wulf G, Nachbaur D, Götze K, Lamparter A, Paschka P, Gaidzik VI, Teleanu V, Späth D, Benner A, Krauter J, Ganser A, Döhner H, Döhner K
(Siehe online unter https://doi.org/10.1182/blood-2014-05-578070) - 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 TS, Bullinger L, Polanetzki A, Weinert S, Schnöder TM, Ballaschk A, Wang Z, Deshpande AJ, Armstrong SA, Döhner K, Fischer T, Heidel FH
(Siehe online unter https://doi.org/10.1038/leu.2015.292)
