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Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission

Abstract

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITDIow in AML patients with intermediate-risk cytogenetics. FLT3-ITDlow was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITDhigh. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITDlow patients. Patients with FLT3-ITDlow had a shorter overall survival (OS) and event-free survival (EFS) than those with FLT3wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITDlow. In conclusion, FLT3-ITDlow is associated with different mutational and transcriptomic profiles compared with FLT3-ITDhigh. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITDlow, who markedly benefit from allo-HSCT in CR1.

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Fig. 1: FLT3-ITD in AML patients with intermediate-risk cytogenetics.
Fig. 2: Comparison of gene expression profiles between patients with FLT3-ITDlow and FLT3-ITDhigh.
Fig. 3: Kaplan–Meier survival curves for OS and EFS stratified by the FLT3-ITD allelic ratio and NPM1 mutational status.
Fig. 4: OS and EFS stratified by postremission therapies in patients with FLT3-ITDlow AML who achieved CR1.

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Acknowledgements

This work was partially supported by grants MOST 104–2314-B-002–128-MY4, and 106–2314-B-002–226-MY3 from the Ministry of Science and Technology (Taiwan), and MOHW 107-TDU-B-211–114009 from the Ministry of Health and Welfare (Taiwan), NTUH 102P06, from the Department of Medical Research, National Taiwan University Hospital, and Taiwan Health Foundation. We would like to acknowledge the service provided by the DNA Sequencing Core of the First Core Laboratory, National Taiwan University College of Medicine, and express our gratitude to the staff of the National Taiwan University Hospital-Statistical Consulting Unit (NTUH-SCU) for statistical consultation and analyses.

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Contribution: F-MT was responsible for study design, literature collection, data management and interpretation, statistical analysis, and manuscript writing; C-HT was responsible for bioinformatics analysis, mutation analysis, and interpretation; S-CH was responsible for data management and statistical analysis; L-IL, Y-YK, H-FT, and Y-KC were responsible for mutation analysis and interpretation; C-YC, W-CC, M-Y, B-SK, S-CH, Y-SW, M-FH, S-JW. H-FT and X-WL contributed patient samples and clinical data; Y-LP, M-HT, C-WL, and M.-C.L. performed gene mutation and chromosomal studies and H-AH and J-LT planned, designed, and coordinated the study over the entire period, and wrote the manuscript.

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Correspondence to Hsin-An Hou or Jih-Luh Tang.

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Tien, FM., Tsai, CH., Huang, SC. et al. Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission. Bone Marrow Transplant 57, 95–105 (2022). https://doi.org/10.1038/s41409-021-01454-z

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