Long-term decitabine/retinoic acid maintenance treatment in an elderly sAML patient with high-risk genetics

Abstract Elderly patients with AML ineligible for induction have a dismal prognosis; hence disease stabilization is a primary treatment goal. This case of a 75-year-old patient with secondary AML receiving the combination of decitabine and ATRA (within the DECIDER trial, NCT00867672) demonstrates an above-average survival. The therapy administered over 52 cycles led to complete molecular and hematological remission and resulted in 5.3 years overall survival. Clonal evolution of the leukemic clone could be demonstrated using DNA sequencing methods. According to the literature, this case constitutes the longest continued HMA exposure in an elderly AML patient ineligible for standard chemotherapy

MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors

Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients