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| Item Type: | Article |
|---|---|
| Title: | Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin |
| Creators Name: | Rücker, F.G., Bullinger, L., Cocciardi, S., Skambraks, S., Luck, T.J., Weber, D., Krzykalla, J., Pozek, E., Schneider, I.J., Corbacioglu, A., Gaidzik, V.I., Meid, A., Aicher, S., Stegelmann, F., Schrade, A., Theis, F., Fiedler, W., Salih, H.R., Wulf, G.G., Salwender, H.J., Schroeder, T., Götze, K.S., Kühn, M.W.M., Lübbert, M., Schlenk, R.F., Benner, A., Thol, F.R., Heuser, M., Ganser, A., Döhner, H. and Döhner, K. |
| Abstract: | Measurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITDpos) was hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)-based MRD assay with a limit of detection of 10-4 to 10-5, we evaluated the prognostic impact of MRD at different time-points in 157 FLT3-ITDpos AML patients enrolled in the AMLSG16-10 trial (NCT01477606) combining intensive chemotherapy with midostaurin followed by midostaurin maintenance. Achievement of MRD negativity (MRDneg) after two cycles of chemotherapy (Cy2) observed in 111/142 (78%) patients predicted for superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR, 26% vs 46%; P=.001) and overall survival (OS) (4y-OS, 70% vs 44%; P=.012). This survival advantage was also seen for patients undergoing allogeneic hematopoietic-cell transplantation in first complete remission (4y-CIR, 14% vs 39%; P=.001; 4y-OS, 71% vs 49%; P=.029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (HR, 0.29; P=.006) and OS (HR, 0.39; P=.018). NPM1 co-mutation correlated with deeper molecular response as reflected by stronger MRD reduction and higher rate of FLT3-ITD MRDneg after Cy2. During follow-up, conversion from MRDneg to MRDpos was a strong, independent factor for inferior CIR (HR, 16.64; P<.001) and OS (HR, 4.05; P<.001). NGS-based FLT3-ITD MRD monitoring allows for the identification of patients at high risk of relapse and death following intensive chemotherapy plus midostaurin. Using NGS-based technology, FLT3-ITD emerges as a novel, clinically highly relevant target for MRD monitoring. |
| Keywords: | Antineoplastic Combined Chemotherapy Protocols, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing, Acute Myeloid Leukemia, Mutation, Residual Neoplasm, Prognosis, Staurosporine, Tandem Repeat Sequences, fms-Like Tyrosine Kinase 3 / genetics |
| Source: | Blood Advances |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Volume: | 8 |
| Number: | 23 |
| Page Range: | 6067-6080 |
| Date: | 10 December 2024 |
| Official Publication: | https://doi.org/10.1182/bloodadvances.2024013758 |
| PubMed: | View item in PubMed |
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