Abstract
Acute myeloid leukemia (AML) is a heterogeneous clonal disease associated with a dismal survival, partly due to the frequent occurrence of relapse. Many patient- and leukemia-specific characteristics, such as age, cytogenetics, mutations, and measurable residual disease (MRD) after intensive chemotherapy, have shown to be valuable prognostic factors. MRD has become a rich field of research where many advances have been made regarding technical, biological, and clinical aspects, which will be the topic of this review. Since many laboratories involved in AML diagnostics have experience in immunophenotyping, multiparameter flow cytometry (MFC) based MRD is currently the most commonly used method. Although molecular, quantitative PCR based techniques may be more sensitive, their disadvantage is that they can only be applied in a subset of patients harboring the genetic aberration. Next-generation sequencing can assess and quantify mutations in many genes but currently does not offer highly sensitive MRD measurements on a routine basis. In order to provide reliable MRD results, MRD assay optimization and standardization is essential. Different techniques for MRD assessment are being evaluated, and combinations of the methods have shown promising results for improving its prognostic value. In this regard, the load of leukemic stem cells (LSC) has also been shown to add to the prognostic value of MFC-MRD. At this moment, MRD after intensive chemotherapy is most often used as a prognostic factor to help stratify patients, but also to select the most appropriate consolidation therapy. For example, to guide post-remission treatment for intermediate-risk patients where MRD positive patients receive allogeneic stem cell transplantation and MRD negative receive autologous stem cell transplantation. Other upcoming uses of MRD that are being investigated include: selecting the type of allogeneic stem cell transplantation therapy (donor, conditioning), monitoring after stem cell transplantation (to allow intervention), and determining drug efficacy for the use of a surrogate endpoint in clinical trials.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous clonal disease that remains to have low overall survival (OS) despite recent developments of better supportive care and emerging targeted therapies [1]
There are two approaches to assess multiparameter flow cytometry (MFC)-measurable residual disease (MRD): The leukemia-associated immunophenotypes (LAIPs)-based approach where the LAIP is assessed at diagnosis and followed during therapy and the Different from Normal (DfN) approach in which any aberrant pattern of cell surface markers compared to their combined expression in normal bone marrow (BM) are designated as being residual leukemic disease
In another trial, azacitidine was administrated to NPM1, RUNX1-RUNX1, or CD34+ mixed donor chimerism patients, who were MRD positive after conventional chemotherapy or SCT, and its effect was evaluated after six cycles [87]
Summary
Acute myeloid leukemia (AML) is a heterogeneous clonal disease that remains to have low overall survival (OS) despite recent developments of better supportive care and emerging targeted therapies [1]. There are two approaches to assess MFC-MRD: The LAIP-based approach where the LAIP is assessed at diagnosis and followed during therapy and the Different from Normal (DfN) approach in which any aberrant pattern of cell surface markers compared to their combined expression in normal BM are designated as being residual leukemic disease. While the DfN approach will identify LAIPs that arise due to clonal evolution, it has the risk of potential false positivity of FIGURE 2 | Overview of possible MRD tailored therapy in different AML treatment phases: Current use of MRD tailored therapy focuses on the choice of consolidation therapy (post-remission therapy). An interesting feature from the LAIP method is that the antibody panel can be adjusted to include the marker of interest to assess the effectivity of the treatment to the target cells present at diagnosis (e.g., CLEC12A, CD123) [20, 21]
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