Serial Determinations of Molecular Aberrations in Patients with Acute Myeloid Leukemia During Treatment with Oral Decitabine/Cedazuridine

Recently, oral decitabine/cedazuridine has been approved for the treatment of AML patients who are not eligible for intensive chemotherapy. Although efficacy data on phenotypic features and the prognostic impact of molecular aberrations at diagnosis were reported in the registration study, serial determinations of the mutational landscape during therapy were not reported. In this study, we present data on a subset of five patients in whom molecular markers were monitored during treatment with oral decitabine/cedazuridine within the registration study. The following observations were made in individual patients. Regarding the changes in the molecular landscape during therapy in four/five patients, there was no major (>50%) reduction in mutated AML clones. There was only one patient with CRi and more than 50% reduction in the VAF of clones with molecular aberrations, including RAS pathway mutations. We observed a marked drop of blast cells (>50%) in two other patients without changes in the molecular profile. The overall survival was significantly longer in patients with CRi and PR, respectively, as compared to patients with no response. Finally, four/five (80%) of patients had druggable molecular aberrations at diagnosis, including mutations in IDH2 (2/5), NPM1 (2/5), and FLT3 (1/5). Our results show that in the majority of patients, changes in the genetic profiles are not seen despite decreases in blast cells in some patients. Disease-modifying activity with decreases in mutated clones is rare. Although the exact mechanism behind our findings remains undetermined, they are in line with the proposed effects of HMA on epigenetics in leukemia cells.