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Aim. To identify mutations in IDH1/IDH2, DNMT3A, and ASXL1 genes responsible for genome epigenetic regulation and their co-occurrence with FLT3, NPM1, and RUNX1 mutations in newly diagnosed adult acute myeloid leukemias (AML). Materials & Methods. The study included 56 patients with newly diagnosed AML treated at the VA Almazov National Medical Research Center. Among them there were 34 men and и 22 women aged 18-76 years (median 46 years). Mutation status of IDH1, IDH2, DNMT3A, and ASXL1 genes of epigenetic regulation was assessed by Sanger sequencing method. Molecular genetic analysis of FLT3, NPM1, and RUNX1-RUNX1T1 genes was performed using commercial kits. Results. Mutations in epigenetic regulation genes were detected in 14 (25 %) out of 56 patients. Mutation prevalence was not associated with risk groups (p = 0.072). IDH1/2 mutations were identified in 15.6 % of patients and were significantly oftener observed concurrent with NPM1 mutations (62.5 %; p = 0.01) compared to patients with wild-type IDH1/2. In most patients IDH1/2 mutations were associated with normal karyotype (p = 0.002). The DNMT3A (R882) mutation was identified in 4 (7.1 %) out of 56 patients within the analyzed group. In 6 patients (11.1 %) ASXL1 mutations were detected co-occurring with RUNX1-RUNX1T1 and FLT3-ITD mutations. Conclusion. Mutations in epigenetic regulation genes are often identified in AML patients and can be concurrent with abnormalities in NPM1, FLT3 и RUNX1 genes.

Aim. To assess the efficacy, safety, and tolerance of gemtuzumab ozogamicin (GO) combined with FLAG/FLAG-Ida chemotherapy or azacitidine in patients with relapsed/refractory acute myeloblastic leukemia (AML) in clinical practice. Materials & Methods. The study included 32 patients (16 men and 16 women). The median age was 44 years (range 23-83 years). Among them there were 15 (46.8 %) patients with refractory and 17 (53.2 %) patients with relapsed AML. GO combined with FLAG/FLAG-Ida was administered to 15 (46.8 %) patients, whereas 17 (53.2 %) patients were treated with GO and azacitidine combination. Therapy safety was assessed according to CTCAE v. 5.0. Results. Overall response rate including complete remission (CR), CR MRD-, CR with incomplete hematologic recovery, and morphologic leukemia-free status was 59.4 % (19/32). Refractoriness was observed in 31.25 % (10/32) of patients. Early mortality was 9.4 % (3/32). Overall response was 64.7 % (11/17) in the azacitidine and 53.3 % (8/15) in the FLAG/FLAG-Ida groups. In 4 (80 %) out of 5 patients with prior to FLAG treatment refractoriness, the response was achieved after GO + azacitidine therapy. In 58.9 % (10/17) of patients who received GO + azacitidine therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be performed. The incidence of GO infusion complications in the tested groups did not significantly differ (p = 0.72) and was 46.7 % (7/15) (40 % with grade 1/2 and 6.7 % with grade 3) in the GO + FLAG/FLAG-Ida group and 35.3 % (6/17) (29.4 % with grade 1/2 and 5.9 % with grade 4) in the GO + azacitidine group. In the GO + FLAG/FLAG-Ida group 5 (33.3 %) patients experienced serious adverse events (SAE) of sepsis. In the GO + azacitidine group SAEs were reported in 6 (35.3 %) patients: 4 (66.6 %) with sepsis, 1 (16.7 %) with acute cardiovascular failure, and 1 (16.7 %) with acute respiratory failure. The median (range) duration was 23 (10-39) days for neutropenia grade 4, 24 (11-38) days for neutropenia grade 3, 21 (11-41) days for thrombocytopenia grade 4, 26 (16-45) days for thrombocytopenia grade 3, and 25 (22-45) days for thrombocytopenia grade 1/2. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy, however, no significant differences were identified. No cases of veno-occlusive liver disease were reported. Median overall survival (OS) for both groups (n = 32) was 31.4 months, median disease-free survival (n = 21) was 13.3 months. In the group of patients with effective treatment, the median OS was not reached. In non-responders, it was 18 months (р = 0.0442). Conclusion. GO combined with FLAG/FLAG-Ida chemotherapy or azacitidine proved effective in relapsed/refractory AML patients. Remission did not appear to be associated with ELN risk, gender, age, CD33 expression, number of prior therapy lines, or number of relapses. GO + azacitidine combination showed efficacy, safety, and good tolerance in patients with prior high-dose chemotherapy refractoriness as well as low ECOG performance status. That allowed for the subsequent allo-HSCT administration to these patients. There was no significant difference between the groups of patients in the incidence of hematologic, non-hematologic toxicity, and time to hematologic recovery. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy which is consistent with literature data. GO-based effective treatment in relapsed/refractory AML considerably improves OS: during 36 months of follow-up the median was not reached.

Context: Treatment of patients with relapsed and refractory AML who are not candidates for intensive treatment is an actual problem. Objective: Assess the efficacy of gemtuzumab ozogamicin (GO) in combination with azacitidine; assess factors impacting remission, and assess and compare tolerability and safety. Design: A retrospective study was conducted, which included patients who were not candidates for intensive treatment (advanced age, low somatic status, relapse after high-dose chemotherapy, and refractoriness to high-dose chemotherapy). Patients received treatment at our center from 2017 to 2021. Patients or Other Participants: The study included 17 patients (8 women, 9 men), median age of 49 years (24–83 years), 53% (9/17) with refractory and 47% (8/17) with relapsed AML. According to the ELN classification, 17.6 % (3/17) were assigned to the favorable-risk group, 23.5 % (4/17) to the intermediate-risk group, and 58.9 % (10/17) to the adverse-risk group. The median expression of CD33 was 94.8 % (25.6%–100%). The median previous lines of therapy was 2 (range: 1–3). Interventions: All patients received therapy with a combination of GO and azacitidine. Results: Overall response rate (CR, CRMRD, CRi, and MFLS) was 64.7% (11/17), and refractoriness was observed in 29.4% of patients (5/17). Early mortality rate was 5.8% (1/17). Overall response rate was not associated with CD33 expression (p>0.05), age (p>0.05), prognostic risk group (p>0.05), or number of previous lines (p>0.05). In the AML relapse group, the response rate did not depend on the number of relapses (p>0.05). Of the 13 patients under 65 years, 10 patients (76.9%) achieved overall response, with a suitable somatic status according to ECOG (1 point) and infectious complications resolved, allowing them to perform allogeneic BMT. The median of grade 4 neutropenia was 21.8 days (10–29 days), grade 4 thrombocytopenia was 19.5 days (11–38 days). The rate of infusion-related complications >grade 3 was 5.9% (1/17). No cases of VOD were reported. Conclusions: The combination of GO and azacitidine has been shown to be an effective and tolerable therapy for patients with relapsed and refractory AML who are not candidates for intensive treatment. This combination showed potential for use as a bridge to allogeneic BMT therapy after improving somatic status.

Context: The options for the treatment of elderly AML patients include intensive therapy for "fit" patients and non-intensive therapy for "unfit" patients. Until recently, non-intensive therapy ranged from BSC to single-agent HMA and LDAC. With the emergence of new therapies, the question of how best to treat AML in older or less fit adults becomes increasingly relevant. Objective: To determine whether less-intense therapy with new targets is as effective as ICT and as safe as non-intensive therapy. Design: 40 previously untreated AML patients with a median age of 66 years (60–85) were included in this study. Patients were selected for intensive chemotherapy (n=17), less-intensive therapies, including LDAC or AZA alone (n=10) and combined with target agents (n=13: venetoclax, n=10; glasdegib, n=2; gemtuzumab ozogamicin, n=1). 37.5% of the patients had prior history of MDS/MPN (17.6% ICT, 50% AZA/AraC, 53% with target, p>0.05). According to the ELN classification, 15% were assigned as favorable, 55% as intermediate-risk, and 30% as adverse-risk. Results: The incidence of overall response (CR+CRi) was higher in the ICT and target groups than in the AZA/AraC group (82.4% vs 77% vs 30%; p=0.014). The median time to first response was 1.0 month (range: 0.8–2.0) in ICT, 1.2 months (range: 0.9–4.1) in the AZA/AraC+target group, and 2.9 months in the AZA/AraC group (range: 1.6–6.2, p=0.002). Among patients in the intermediate- and high-risk groups, the response rates were also significantly higher in the ICT and target groups (78.8% vs 90% vs 22.2%; p=0.003). At a median follow-up of 12 months, the median OS was 24.7 months in the ICT group, 20.1 months in the group with target agent treatment, and 4.5 months in the AZA/AraC group (HR: 0.51; 95%CI: 0.31–0.86; p=0.012). The most commonly reported infection AEs in the ICT and target groups included febrile neutropenia (94.1% vs 57.1%; p 0.05). Conclusion: In previously untreated AML patients, OS was longer, and the incidence of remission was higher among patients who received a combination of new targeted drugs with non-intensive regimens than among those who received azacitidine or AraC alone and was comparable to the ICT group, which was more toxic. The incidence of infection AEs was higher in the ICT group than in the non-intensive group.

Context Patients with NPM1 AML mutation are included in ELN favorable or intermediate genetic risk categories, although a proportion of these patients will relapse. Thus, it is necessary to identify negative prognostic factors for patientss with NPM1 and to evaluate if ASCT could overcome them. Objective To determine the clinical significance of post-remission MRD level NPM1 mutation and correlation with treatment outcome in AML patients. Design Twenty-seven patients with NPM1mut in CR were included in the study. All patients had WT1 overexpression. Additional genetic abnormalities were revealed in 12 patients ([hyperexpression of BAALC (n=4), IDH1/2 (n=4), FLT3ITD (n=8), DNMT3AR882C (n=1), ASXL1(n=1), RUNX1(n=1), aberrant karyotype (n=4)]. Monitoring of minimal residual disease was studied after induction («7+3) and consolidation courses («HiDAC»). Thirteen patients underwent HSCT. Median follow-up was 12 months (2.2–109 months). Results CIR (median 7.25 months vs not reached), RFS (median 7.25 months vs not reached) and OS (median 7.25 vs 41.80 months) were shorter in patients with NPM1mut reduction after an induction course less than 3.85 log (specificities 81.8%, sensitivities 100%) (p=0.001, p=0.0036, and p=0.05, respectively). Patients with NPM1+FLT3- status had similar results with this cut-off (median RFS 9.6 months vs not reached, p=0.037). Cutoff levels of NPM1mut 4.2 log (specificities 83.3%, sensitivities 83.3%) after the first consolidation course separated the cohort into two prognostic groups (14 and 13 patients) as well: median CIR 7.25 vs 41.80 months (p=0.02) and median OS 13 months vs not reached, p=0.05, respectively). MRD status after consolidation therapy in comparison to the MRD status after induction therapy has improved only in two patients but with relapse in 17.7 months and 9.7 months. HSCT improved CIR and OS in the group of patients with cut-off less than 3. 85 log (p=0.016, p=0.03). In the multivariate model with MRD cut-off, age, genetic abnormalities, FLT3 status, and WBC only post-induction cut-off level NPM1 were independent prognostic factors for RFS (HR:0.07; 95% CI: 0,006–0.955; p=0.04). Conclusions NPM1mut-positive patients have adverse prognosis if the post-induction reduction of expression of these genes is less than 3.85 log. This cut-off separated ELN favorable NPM1mut AML patients. Unfavorable prognosis of MRD cut-off-positive patients during AML treatment could be overcome with HSCT in the first CR.