Abstract
Acute myeloid leukemia (AML) is a heterogeneous, complex, and deadly disease, whose treatment has hardly evolved for decades and grounds on the use of intensive chemotherapy regimens. Chemotherapy helps reduce AML bulk, but promotes relapse in the long-run by selection of chemoresistant leukemia stem cells (LSC). These may diversify and result in progression to more aggressive forms of AML. In vivo models suggest that the bone marrow stem cell niche helps LSC stay dormant and protected from chemotherapy. Here, we summarize relevant changes in stem cell niche homing and adhesion of AML LSC vs. healthy hematopoietic stem cells, and provide an overview of clinical trials aiming at targeting these processes for AML treatment and future directions within this field. Promising results with various non-mutation-targeted novel therapies directed to LSC eradication via interference with their anchoring to the stem cell niche have encouraged on-going or future advanced phase III clinical trials. In the coming years, we may see a shift in the focus of AML treatment to LSC-directed therapies if the prospect of improved cure rates holds true. In the future, AML treatment should lean toward personalized therapies using combinations of these compounds plus mutation-targeted agents and/or targeted delivery of chemotherapy, aiming at LSC eradication with reduced side effects.
Highlights
ACUTE MYELOID LEUKEMIAAcute myeloid leukemia (AML) is a heterogeneous disease characterized by aberrant myeloid lineage proliferation and differentiation, accompanied by at least one clonal somatic abnormality on mutational profiling in more than 97% of patients (Coombs et al, 2016)
Antibodies against VLA4 in combination with cytarabine prolonged survival in a SCID model of U937 cell transplant and reduced detection of U937 cells by PCR in different tissues including bone marrow at day 62 after transplantation, compared to cytarabine alone. This indicates that adhesion of leukemic cells via very late activation antigen4 (VLA-4) contributes to disease and chemotherapy resistance (Matsunaga et al, 2003). This was further confirmed by the chemical compound AS101, which disrupts VLA-4 function, and combined with cytarabine, abrogated chemotherapy resistance and prolonged survival in SCID mice transplanted with AML cells from a patient expressing high VLA-4 (Layani-Bazar et al, 2014)
AML is a devastating disease, whose treatment has changed little for decades and relies on the use of aggressive chemotherapy
Summary
ACUTE MYELOID LEUKEMIAAcute myeloid leukemia (AML) is a heterogeneous disease characterized by aberrant myeloid lineage proliferation and differentiation, accompanied by at least one clonal somatic abnormality on mutational profiling in more than 97% of patients (Coombs et al, 2016). The glucocorticoid dexamethasone is currently in a phase III clinical trial in R/R AML in combination with intensive chemotherapy amsacrine-cytarabine or azacitidine (NCT03765541), and was reported to improve relapse incidence, disease-free survival, event-free survival, and overall survival compared to chemotherapy alone (Bertoli et al, 2018).
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