Experiences with Next-Generation Sequencing in Relapsed Acute Myeloid Leukemia: A Patient Case Series
1 Department of Hematology and Oncology, Medical Faculty Mannheim of the Heidelberg University, Mannheim, Germany.
2 Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, Germany.
3 University Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland.
4 Center of Laboratory Medicine (ZLM)/University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, Bern, Switzerland.
5 Department of Nephrology and Rheumatology, University Medicine Göttingen (UMG), Göttingen, Germany.
6 Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
Thomas Pabst, MD. Department of Medical Oncology; Inselspital, Bern University Hospital, University of Bern; Bern, Switzerland; Tel.: +41-31-632 8430; Fax: +41-31-632-3410. E-mail: firstname.lastname@example.org
Received: June 28, 2020
Accepted: August 16, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020068 DOI 10.4084/MJHID.2020.068
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
To the editor,
The increasing use of NGS has been enabled by a number of commercially available panels that cover the most frequently mutated genes. In contrast to traditional diagnostic tools (i.e., cytomorphology, cytogenetics, qPCR) that provide classification and prognostic information only within certain categories, molecular profiling by NGS enables us to depict a unique genetic make-up for each AML patient. Genetic information provides crucial parameters within the current AML classification systems[1,2] and has not only an impact on prognosis but also influences treatment options.
However, despite improving remission rates, around 40-60% of AML patients will ultimately relapse, which remains the major determinant of outcome. At relapse, AML patients can either present with the same genetic mutation pattern as observed at initial diagnosis (clonal stability), or present with higher complexity, e.g., through the acquisition of additional mutations (clonal evolution), or lose some of the initial mutations at relapse (clonal devolution), or, alternatively, show both gains and losses of mutations.[4-6]
Concerning the pathophysiologic mechanisms involved during clonal evolution at relapse, our current paradigms suggest that pre-existing clones (or subclones) may gain a survival advantage under the selective chemotherapeutic pressure. We have recently provided a comprehensive overview of the current knowledge of NGS during relapse of AML. Here, we present six illustrative patient studies observed during clinical practice to demonstrate characteristic genetic scenarios accompanying hematologic relapse of AML following intensive chemotherapy. All patients were treated and analyzed by cytogenetics and myeloid NGS panels at diagnosis and at relapse at our department according to the methodology described in Table 1. The sensitivity of NGS analyses was limited to a 5% variant allele frequency (VAF) at diagnosis, and 1% at follow-up as the exact mutation localizations were known.
|Table 1. Examples of six AML patients relapsing after intensive chemotherapy; NGS is performed at diagnosis and relapse.|
Patient #1: Molecular and cytogenetic stability at relapse after intensive chemotherapy
Patient #2: Molecular and cytogenetic stability at relapse after allogeneic transplant
Patient #3: Molecular stability with cytogenetic clonal devolution at relapse
Patient #4: Simultaneous clonal evolution and devolution at relapse
Patient #5: Both clonal evolution and devolution at relapse
Patient #6: Cytogenetic and molecular evolution at relapse
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