TY - JOUR
T1 - Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin
AU - Schmalbrock, Laura K.
AU - Dolnik, Anna
AU - Cocciardi, Sibylle
AU - Sträng, Eric
AU - Theis, Frauke
AU - Jahn, Nikolaus
AU - Panina, Ekaterina
AU - Blätte, Tamara J.
AU - Herzig, Julia
AU - Skambraks, Sabrina
AU - Rücker, Frank G.
AU - Gaidzik, Verena I.
AU - Paschka, Peter
AU - Fiedler, Walter
AU - Salih, Helmut R.
AU - Wulf, Gerald
AU - Schroeder, Thomas
AU - Lübbert, Michael
AU - Schlenk, Richard F.
AU - Thol, Felicitas
AU - Heuser, Michael
AU - Larson, Richard A.
AU - Ganser, Arnold
AU - Stunnenberg, Hendrik G.
AU - Minucci, Saverio
AU - Stone, Richard M.
AU - Bloomfield, Clara D.
AU - Döhner, Hartmut
AU - Döhner, Konstanze
AU - Bullinger, Lars
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/6/3
Y1 - 2021/6/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105991525&partnerID=8YFLogxK
U2 - 10.1182/blood.2020007626
DO - 10.1182/blood.2020007626
M3 - Article
C2 - 33598693
AN - SCOPUS:85105991525
SN - 0006-4971
VL - 137
SP - 3093
EP - 3104
JO - Blood
JF - Blood
IS - 22
ER -