CD34+CD38 leukemic stem cell frequency to predict outcome in acute myeloid leukemia

Wendelien Zeijlemaker, Tim Grob, Rosa Meijer, Diana Hanekamp, Angèle Kelder, Jannemieke C. Carbaat-Ham, Yvonne J.M. Oussoren-Brockhoff, Alexander N. Snel, Dennis Veldhuizen, Willemijn J. Scholten, Johan Maertens, Dimitri A. Breems, Thomas Pabst, Markus G. Manz, Vincent H.J. van der Velden, Jennichjen Slomp, Frank Preijers, Jacqueline Cloos, Arjan A. van de Loosdrecht, Bob LöwenbergPeter J.M. Valk, Mojca Jongen-Lavrencic, Gert J. Ossenkoppele, Gerrit J. Schuurhuis

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38− fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38−LSC levels at diagnosis (n = 594), and, to identify LSClow/LSChigh (n = 302) and MRDlow/MRDhigh patients (n = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34+CD38 LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRDhigh/LSChigh patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRDlow/LSChigh, MRDhigh/LSClow, and especially MRDlow/LSClow patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.

Original languageEnglish
Pages (from-to)1102-1112
Number of pages11
JournalLeukemia
Volume33
Issue number5
Early online date2018
DOIs
Publication statusPublished - 1 May 2019

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