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

Laura K. Schmalbrock, Anna Dolnik, Sibylle Cocciardi, Eric Sträng, Frauke Theis, Nikolaus Jahn, Ekaterina Panina, Tamara J. Blätte, Julia Herzig, Sabrina Skambraks, Frank G. Rücker, Verena I. Gaidzik, Peter Paschka, Walter Fiedler, Helmut R. Salih, Gerald Wulf, Thomas Schroeder, Michael Lübbert, Richard F. Schlenk, Felicitas TholMichael Heuser, Richard A. Larson, Arnold Ganser, Hendrik G. Stunnenberg, Saverio Minucci, Richard M. Stone, Clara D. Bloomfield, Hartmut Döhner, Konstanze Döhner, Lars Bullinger

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

41 Citaten (Scopus)

Samenvatting

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in 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 in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 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 and 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 (eg, 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 because of 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.

Originele taal-2Engels
Pagina's (van-tot)3093-3104
Aantal pagina's12
TijdschriftBlood
Volume137
Nummer van het tijdschrift22
DOI's
StatusGepubliceerd - 3 jun. 2021
Extern gepubliceerdJa

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