Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 26;11(2):359.
doi: 10.3390/biomedicines11020359.

Measurable Residual Disease and Clonal Evolution in Acute Myeloid Leukemia from Diagnosis to Post-Transplant Follow-Up: The Role of Next-Generation Sequencing

Alessandra Sperotto  1 , Maria Teresa Bochicchio  2 , Giorgia Simonetti  2 , Francesco Buccisano  3 , Jacopo Peccatori  4 , Simona Piemontese  4 , Elisabetta Calistri  1 , Giulia Ciotti  1 , Elisabetta Pierdomenico  1 , Roberta De Marchi  1 , Fabio Ciceri  4 , Michele Gottardi  1
Affiliations
Review

Measurable Residual Disease and Clonal Evolution in Acute Myeloid Leukemia from Diagnosis to Post-Transplant Follow-Up: The Role of Next-Generation Sequencing

Alessandra Sperotto et al. Biomedicines. .

Abstract

It has now been ascertained that acute myeloid leukemias-as in most type of cancers-are mixtures of various subclones, evolving by acquiring additional somatic mutations over the course of the disease. The complexity of leukemia clone architecture and the phenotypic and/or genotypic drifts that can occur during treatment explain why more than 50% of patients-in hematological remission-could relapse. Moreover, the complexity and heterogeneity of clone architecture represent a hindrance for monitoring measurable residual disease, as not all minimal residual disease monitoring methods are able to detect genetic mutations arising during treatment. Unlike with chemotherapy, which imparts a relatively short duration of selective pressure on acute myeloid leukemia clonal architecture, the immunological effect related to allogeneic hematopoietic stem cell transplant is prolonged over time and must be overcome for relapse to occur. This means that not all molecular abnormalities detected after transplant always imply inevitable relapse. Therefore, transplant represents a critical setting where a measurable residual disease-based strategy, performed during post-transplant follow-up by highly sensitive methods such as next-generation sequencing, could optimize and improve treatment outcome. The purpose of our review is to provide an overview of the role of next-generation sequencing in monitoring both measurable residual disease and clonal evolution in acute myeloid leukemia patients during the entire course of the disease, with special focus on the transplant phase.

Keywords: acute myeloid leukemia; allogeneic stem cell transplantation; clonal evolution; measurable residual disease; next-generation sequencing.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Summary of the advantages and disadvantages of methods of MRD assessment: (A)—Multi-parameter flow cytometry; (B)—Quantitative polymerase chain reaction (PCR) and droplet PCR; (C)—Next generation sequencing; (D)—The different sensitivity MRD assessments comparing the ability of each method to detect a single AML cell amongst normal haemopoietic cells. Sensitivities are as follows: Flow cytometry, 1 in 10,000; qPCR, 1 in 1,000,000; ddPCR, >1 in 1,000,000; NGS, 1 in 1,000,000.
Figure 2
Figure 2
Role of measurable residual disease (MRD) at different timepoints of the treatment pathway in acute myeloid leukemia (AML).
Figure 3
Figure 3
Clonal evolution and probability of relapse after conventional chemotherapy without transplant and after a program including transplant.
Figure 4
Figure 4
Role of single-cell sequencing from diagnosis to relapse.
Figure 5
Figure 5
New approach for AML treatment: from diagnosis to post-transplant follow-up.
See this image and copyright information in PMC

References

    1. Welch J.S., Ley T.J., Link D.C., Miller C.A., Larson D.E., Koboldt D.C., Wartman L.D., Lamprecht T.L., Liu F., Xia J., et al. The Origin and Evolution of Mutations in Acute Myeloid Leukemia. Cell. 2012;150:264–278. doi: 10.1016/j.cell.2012.06.023. - DOI - PMC - PubMed
    1. Shlush L.I., Zandi S., Mitchell A., Chen W.C., Brandwein J.M., Gupta V., Kennedy J.A., Schimmer A.D., Schuh A.C., Yee K.W., et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;20:328–333. doi: 10.1038/nature13038. - DOI - PMC - PubMed
    1. Hirsch P., Zhang Y., Tang R., Joulin V., Boutroux H., Pronier E., Moatti H., Flandrin P., Marzac C., Bories D., et al. Genetic Hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia. Nat. Commun. 2016;7:12475. doi: 10.1038/ncomms12475. - DOI - PMC - PubMed
    1. Corces-Zimmerman M.R., Hong W.-J., Weissman I.L., Medeiros B.C., Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc. Natl. Acad. Sci. USA. 2014;111:2548–2553. doi: 10.1073/pnas.1324297111. - DOI - PMC - PubMed
    1. Jan M., Snyder T.M., Corces-Zimmerman M.R., Vyas P., Weissman I.L., Quake S.R., Majeti R. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 2012;4:149ra118. doi: 10.1126/scitranslmed.3004315. - DOI - PMC - PubMed

LinkOut - more resources