ISAL 2025 | MRD assessment in AML with monocytic differentiation: the relevance of the immature fraction

Yeah, measurable residual disease or MRD can be used to inform clinical decision making for patients with acute myeloid leukemia or AML. MRD can be measured using flow cytometry and then we define a leukemia-associated immunophenotype or a LIP. And usually this is done for in the immature CD45 dim fraction. However, in a subset of patients, there’s more monocytic differentiation when there’s a cell compartment present in the CD45 high side scatter intermediate part. And we aim to assess the clinical relevance of this population and therefore we looked into the six Hovon trials where we included more than 2,000 patients and we measured MRD by flow cytometry and we defined a mature phenotype diagnosis by having more than 20 percent of monocytic cells of which 10% must have a leukemia-associated immunophenotype, and also looked at the immature CD45 dim fraction. And then we found that in 4% of patients, there was only a monocytic differentiation, whereas there was 6% of patients where there were two populations present, so a monocytic and an immature population, and in the vast majority, so 90% of patients, there was only an immature fraction present. And in the patients with monocytic differentiation, mutations in NPM1 or in RAS mutations or FLT3-ITD were more present. And also the prevalence of mutations in DNMT3A or TET2 were higher in this patient population. And then we looked after two cycles of chemotherapy and looked at the MRD levels in the mature and immature fraction and found that in the same patients the MRD levels in the mature fraction were higher than in the immature fraction and when stratifying patients based on the 0.1% cutoff we found that in the MRD fraction in the mature population there was no prognostic relevance, whereas in the immature population we found a clear prognostic relevance, suggesting that the relapse initiating cells are present in the immature fraction and not in the mature fraction. And we also looked at leukemic stem cells defined by CD34 positive, CD38 negative, with the addition of a aberrant LSC marker such as CD45RA, and found that at diagnosis when patients with a mature phenotype at higher levels of LSCs, these patients had worse survival compared to patients that were LSC negative. Also suggesting that the relapse initiating capacity is in the immature fraction instead of in the mature fraction. So we concluded that doing MRD assessment in patients with monocytic differentiation, it’s important to look into the immature cell fraction.

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