Molecular Minimal Residual Disease in Acute Myeloid Leukemia.

Jongen-Lavrencic, Mojca; Grob, Tim; Hanekamp, Diana; Kavelaars, François G; Al Hinai, Adil; Zeilemaker, Annelieke; Erpelinck-Verschueren, Claudia A J; Gradowska, Patrycja L; Meijer, Rosa; Cloos, Jacqueline; Biemond, Bart J; Graux, Carlos; van Marwijk Kooy, Marinus; Manz, Markus G; Pabst Müller, Thomas Niklaus; Passweg, Jakob R; Havelange, Violaine; Ossenkoppele, Gert J; Sanders, Mathijs A; Schuurhuis, Gerrit J; ... (2018). Molecular Minimal Residual Disease in Acute Myeloid Leukemia. New England journal of medicine NEJM, 378(13), pp. 1189-1199. Massachusetts Medical Society MMS 10.1056/NEJMoa1716863

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BACKGROUND Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established. METHODS We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission). End points were 4-year rates of relapse, relapse-free survival, and overall survival. RESULTS At least one mutation was detected in 430 out of 482 patients (89.2%). Mutations persisted in 51.4% of those patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which are often present in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate than no detection (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001), as well as with lower rates of relapse-free survival (36.6% vs. 58.1%; hazard ratio for relapse or death, 1.92; P<0.001) and overall survival (41.9% vs. 66.1%; hazard ratio for death, 2.06; P<0.001). Multivariate analysis confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to the rates of relapse (hazard ratio, 1.89; P<0.001), relapse-free survival (hazard ratio for relapse or death, 1.64; P=0.001), and overall survival (hazard ratio for death, 1.64; P=0.003). A comparison of sequencing with flow cytometry for the detection of residual disease showed that sequencing had significant additive prognostic value. CONCLUSIONS Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.).

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Pabst Müller, Thomas Niklaus

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0028-4793

Publisher:

Massachusetts Medical Society MMS

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

07 Mar 2019 12:19

Last Modified:

07 Mar 2019 12:19

Publisher DOI:

10.1056/NEJMoa1716863

PubMed ID:

29601269

BORIS DOI:

10.7892/boris.124042

URI:

https://boris.unibe.ch/id/eprint/124042

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