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Leukemia. 2019 May;33(5):1102-1112. doi: 10.1038/s41375-018-0326-3. Epub 2018 Dec 12.

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

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Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Clinical trial Center- HOVON data center, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Hematology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.
Department of Hematology, Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium.
Department of Hematology, Inselspital, Bern University Hospital, Bern, Switzerland.
Department of Hematology, University and University Hospital Zürich, Zürich, Switzerland.
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Clinical Chemistry, Medisch Spectrum Twente/Medlon, Enschede, The Netherlands.
Department of Laboratory Medicine - Laboratory for Hematology, Radboud University Nijmegen Medical Center, RUNMC, Nijmegen, The Netherlands.
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.


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.


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