Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin
| Autor: | Thomas Schroeder, Anna Dolnik, Arnold Ganser, Frauke Theis, Peter Paschka, Gerald Wulf, Laura K. Schmalbrock, Saverio Minucci, Lars Bullinger, Clara D. Bloomfield, Eric Sträng, Walter Fiedler, Ekaterina Panina, Konstanze Döhner, Michael Heuser, Hendrik G. Stunnenberg, Tamara J. Blätte, Sibylle Cocciardi, Hartmut Döhner, Richard F. Schlenk, Michael Lübbert, Helmut R. Salih, Richard Stone, Verena I. Gaidzik, Sabrina Skambraks, Nikolaus Jahn, Richard A. Larson, Julia Herzig, Felicitas Thol, Frank G. Rücker |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Oncology medicine.medical_specialty Adolescent medicine.medical_treatment Immunology Biochemistry Somatic evolution in cancer Acute Myeloid Leukemia with FLT3/ITD Mutation Clonal Evolution 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine hemic and lymphatic diseases Internal medicine Exome Sequencing medicine Humans Midostaurin Molecular Biology Exome sequencing Aged 030304 developmental biology 0303 health sciences Chemotherapy business.industry Myeloid leukemia Cell Biology Hematology Middle Aged Staurosporine Minimal residual disease Chemotherapy regimen 3. Good health Leukemia Myeloid Acute fms-Like Tyrosine Kinase 3 chemistry Tandem Repeat Sequences 030220 oncology & carcinogenesis Mutation Female business |
| Zdroj: | Blood, 137, 22, pp. 3093-3104 Blood, 137, 3093-3104 BASE-Bielefeld Academic Search Engine |
| ISSN: | 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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