CD34CD38 leukemic stem cell frequency to predict outcome in acute myeloid leukemia.

Zeijlemaker, Wendelien; Grob, Tim; Meijer, Rosa; Hanekamp, Diana; Kelder, Angèle; Carbaat-Ham, Jannemieke C; Oussoren-Brockhoff, Yvonne J M; Snel, Alexander N; Veldhuizen, Dennis; Scholten, Willemijn J; Maertens, Johan; Breems, Dimitri A; Pabst Müller, Thomas Niklaus; Manz, Markus G; van der Velden, Vincent H J; Slomp, Jennichjen; Preijers, Frank; Cloos, Jacqueline; van de Loosdrecht, Arjan A; Löwenberg, Bob; ... (2019). CD34CD38 leukemic stem cell frequency to predict outcome in acute myeloid leukemia. Leukemia, 33(5), pp. 1102-1112. Nature Publishing Group 10.1038/s41375-018-0326-3

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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 LSC/LSC (n = 302) and MRD/MRD 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 CD34CD38 LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRD/LSC patients (hazard ratio [HR] 3.62 for OS and 5.89 for cumulative incidence of relapse [CIR]) compared to MRD/LSC, MRD/LSC, and especially MRD/LSC 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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