Background: Anthracyclines remain the backbone for induction therapy in the treatment of AML. Unfortunately, most patients will relapse with refractory disease and quickly succumb to their AML. One of the major reasons if not the major reason for developing resistance is the development of MDR. Annamycin was developed and has been shown both preclinically and clinically to overcome MDR and have no cardiac toxicity. Furthermore, it is formulated in a nanomolecular bi-lamellar liposomal delivery mechanism that targets the leukemic cells in the bone marrow and spares cardiac and other normal cells. Therefore, a new phase I/II clinical trial has been started in both the US and Europe using L-Annamycin for the treatment of all patients with R/R AML agnostic of mutational status. Aims: The aim of the phase I component is to determine the RP2D of L-Annamycin for the treatment of R/R AML. The phase II component is designed to demonstrate efficacy leading to a phase II registration study for accelerated approval in both the US and EU. PK determinations are being performed for all patients. Methods: The phase I component is a standard modified Fibonacci 3+3 design to determine the RP2D. An additional 21 patients will be enrolled as an early determinant of efficacy at the RP2D. The sample size for this is based upon an expected response rate of 15%. Utilizing the optimized Simon two stage design, the assumption is that alpha = 0.1 and beta = 0.2. If less than 1 CR is observed in the first 14 subjects, the study will be stopped for futility. To be declared a success, at least 4 subjects of the 21 needs to demonstrate a CR. A DMC will monitor all data and decide if the study should continue and if any changes to the protocol are needed. Results: The study is ongoing in both Europe and the US. The first cohort has completed in the US. Even at the very low starting dose, one of the three patients had a near CR with just MRD after just one three-day course of L-Annamycin. The first cohort in Europe has enrolled two patients and updated results will be presented at the EHA Congress. Summary/Conclusion:Anthracyclines remain the backbone of induction therapy in AML but most patients will relapse and die from their refractory disease. Resistance develops because of MDR. L-Annamycin overcomes this and has little to no cardiac toxicity even with up to eight cycles. This study will is designed to demonstrate its efficacy in all patients with R/R AML including the majority with no targetable mutations.

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Detection of FLT3 gene mutations in acute myeloid leukemia is now recognized as an unfavorable factor that affects the disease course, emerging the risk of relapses and overall survival shortening and disease-free survival of patients. The aim of the study was to determine the frequency of mutations of the gene FLT3 and to assess their impact on clinical indicators, overall survival and disease-free survival in patients with acute myeloid leukemia. We compared complete blood count parameters, karyotype, duration of overall survival and disease-free survival in 199 patients with acute myeloid leukemia depending on the presence or absence of mutations of the FLT3 gene. Significant differences across these groups were discovered only in WBC and blasts between the group of patients with acute myeloid leukemia (FLT3+) and without mutations in the FLT3 gene (FLT3-). The differences between two groups were also identified in patients chromosomal aberrations. Significant differences (p=0,00024) in the duration of overall survival between groups of patients with acute myeloid leukemia with mutations of FLT3-ITD+, FLT3-TKD+ and FLT3- were demonstrated. Median overall survival was: 1 6 months for patients with mutation FLT3-ITD+ and 17 months for FLT3-TKD+ patients and not achieved for FLT3- patients. The use of modern molecular genetic methods of research in acute myeloid leukemia allows to improve the diagnosis of the disease, as well as to carry out risk stratification and individualize therapy. The use of targeted therapy for FLT3-positive patients who are not candidates for hematopoietic stem cell transplantation will increase the effectiveness of the treatment and improve the performance of overall survival and disease-free survival.

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