Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin

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Item Type:	Article
Title:	Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin
Creators Name:	Schmalbrock, L.K., Dolnik, A., Cocciardi, S., Sträng, E., Theis, F., Jahn, N., Panina, E., Blätte, T.J., Herzig, J.K., Skambraks, S., Rücker, F.G., Gaidzik, V.I., Paschka, P., Fiedler, W., Salih, H.R., Wulf, G.G., Schroeder, T., Lübbert, M., Schlenk, R.F., Thol, F., Heuser, M., Larson, R.A., Ganser, A., Stunnenberg, H.G., Minucci, S., Stone, R.M., Bloomfield, C.D., Döhner, H., Döhner, K. and Bullinger, L.
Abstract:	In the international randomized phase III RATIFY trial, the multi-kinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18-59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients on the midostaurin arm achieved protocol-specified complete remission (CR) and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD) positive AML who were entered on the RATIFY or the AMLSG 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD as well as whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative, but acquired mutations in signaling pathways (e.g. MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD-clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed suggesting either resistance mechanisms bypassing FLT3-inhibition or loss of midostaurin inhibitory activity due to inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD mutated AML under treatment with midostaurin in combination with intensive chemotherapy.
Keywords:	Acute Myeloid Leukemia, Clonal Evolution, fms-Like Tyrosine Kinase 3, Mutation, Staurosporine, Tandem Repeat Sequences, Whole Exome Sequencing
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	137
Number:	22
Page Range:	3093-3104
Date:	3 June 2021
Additional Information:	Copyright © 2021 by The American Society of Hematology
Official Publication:	https://doi.org/10.1182/blood.2020007626
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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