| Abstract [eng] |
In order to improve the results of salvage therapy for relapsed or refractory acute myeloid leukemia (R/R AML), the main goal of the doctoral thesis was to investigate the efficacy, toxicity, predictive genetic biomarkers of venetoclax, low-dose cytarabine and actinomycin D (ACTIVE) novel triplet therapy, to compare the results with conventional intensive chemotherapy, and also to identify possible pharmacologically targetable cellular mechanisms which could improve the antileukemic efficacy of ACTIVE therapy. ACTIVE therapy resulted in a cumulative complete remission rate of 62% and an overall response rate of 74%. These results exceed the previously published data for the treatment of R/R AML and substantiate the clinical applicability of ACTIVE regimen. IDH2, DNMT3A gene mutations and allogeneic hematopoietic stem cell transplantation (alloSCT) are significantly associated with longer overall survival, whereas TP53, PTPN11 gene mutations and poor general condition of patients are associated with shorter overall survival after ACTIVE therapy. In the treatment of post-alloSCT relapsed AML, the efficacy of ACTIVE is equivalent to intensive chemotherapy, but the overall survival after ACTIVE treatment was significantly longer due to lower toxicity. The combination of the FLT3 inhibitor gilteritinib and ACTIVE is highly effective and allows most patients with R/R AML with FLT3 gene mutation to undergo alloSCT and significantly improve their prognosis. In preclinical studies using R/R AML patient-derived leukemic cells, the combination of metformin, cytarabine, and venetoclax demonstrated the highest efficacy in suppressing oxygen consumption levels, metabolic regulatory pathways, PPARGC1A and MYC gene expression, and cell proliferation. |
