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The achievement of complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undertaking curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong disease-free survival (DFS). Our phase III study compared the efficacy and safety of azacitidine (AZA) to best supportive care (BSC) in elderly AML patients who achieved CR following intensive induction and consolidation therapy. This ancillary study (QOL-ONE Trans-2) evaluated biological changes in bone marrow using Next-Generation Sequencing (NGS). We analyzed baseline, randomization, and 6-month post-remission samples from 24 patients (median age of 71 and 12 males). High-throughput NGS targeted 350 myeloid malignancy-related genes, considering variants with a variant allele frequency ≥ 4%. At diagnosis, all patients had 5 to 17 (median = 10) mutations, with DNMT3A (42%), NPM1 (33%), and TET2 (33%) being most frequent. FANCA mutations in four patients were linked to a higher relapse risk (HR = 4.96, p = 0.02) for DFS at both 2 and 5 years. Further HLA-specific NGS analyses are ongoing to confirm these results and their therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Splicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real-life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia-related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML. Methods: A total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML-related genes by next-generation sequencing. Results: We showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild-type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status. Conclusions: In conclusions, we linked both pathogenic and VUS variants in AML-related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results. [ABSTRACT FROM AUTHOR]

Simple Summary: Azacitidine (AZA) is a hypomethylating agent with well-known antileukemic activity. Due to its favorable safety profile, AZA is widely used alone or in association with other drugs for the frontline treatment of patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, only a few studies have used AZA as maintenance therapy during complete remission in patients with AML. In our phase-3 randomized multicenter trial, AZA improved disease-free survival (DFS) up to 2 and 5 years in patients aged >68 years compared to best supportive care (BSC). No patients died before leukemic relapse and no differences in patient-reported outcome measures between AZA and BSC patient groups were observed. The most frequent side effect seen in patients was low neutrophil count. In summary, AZA given as a post-remission therapy was found to provide benefit in AML patients aged >68 years. This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy ("3+7" daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m2 for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m2 for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2–11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9–19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2–11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9–19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged >68 years (HR = 0.34, 95% CI: 0.13–0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15–0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged >68 years. [ABSTRACT FROM AUTHOR]

Treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) is difficult in older patients with comorbidities and highrisk disease factors. Venetoclax, the first-in-class Bcl-2 inhibitor, has proven efficacy and safety in combination with azacytidine for treatment of high-risk myeloid diseases. In this single-center real-life retrospective study, a total of 27 consecutive patients treated with azacytidine plus venetoclax were included, and clinical outcomes, hematological improvements, and biomarkers of responsiveness to therapy were compared to those observed in an historical cohort of 95 consecutive patients treated with azacytidine as single agent. Azacytidine plus venetoclax was effective and safe in older and frail AML and high-risk MDS patients, with median overall survival of 22.3 months, higher than that reported in phase III trial (14.7 months), and higher than that of historical cohort (5.94 months). Progression-free survival was higher in patients treated with the drug combination compared to those treated with azacytidine as single agent (p = 0.0065). Clinical benefits might increase when azacytidine and venetoclax are administered as upfront therapy (p = 0.0500). We showed that Tim-3 expression could be a promising therapeutic target in refractory/ relapsed patients, and galectin-9 a biomarker of responsiveness to therapy. Moreover, patients treated with azacytidine and venetoclax displayed a higher overall survival regardless the presence of negative prognostic markers at diagnosis (e.g., increased WT1 copies and/or normalized blast count). These encouraging results in a real-world setting supported efficacy and safety of azacytidine plus venetoclax as upfront therapy in AML and high-risk MDS, with clinical outcomes comparable to those of clinical trials when an appropriate venetoclax management with bone marrow assessment at every first, second, fourth, and eighth cycle, and dose adjustments for toxicities are performed. [ABSTRACT FROM AUTHOR]

Treatment of relapsed/refractory or elderly unfit acute myeloid leukemia (AML) is still challenging, and hypomethylating agents in combination with venetoclax, an oral selective BCL2 inhibitor, might be successfully used as salvage therapy. However, clinical trials evaluating the efficacy and safety of this combination in the setting of multiresistant AML treatment also as a bridge to transplant are still ongoing. Here, we reported a 50-year-old male diagnosed with AML with normal cytogenetics and wild type for fms-like tyrosine kinase 3, nucleophosmin 1, and KIT, and treated with decitabine and venetoclax as the fifth line of therapy and after a relapse post-allogeneic transplant. The patient achieved a complete remission and successfully underwent a haploidentical transplant with an overall survival of 48.6 months. [ABSTRACT FROM AUTHOR]

Wilm's tumor 1 (WT1), a zinc-finger transcription factor and an epigenetic modifier, is frequently overexpressed in several hematologic disorders and solid tumors, and it has been proposed as diagnostic and prognostic marker of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the exact role of WT1 in leukemogenesis and disease progression remains unclear. In this real-world evidence retrospective study, we investigated prognostic role of WT1-mRNA expression levels in AML and MDS patients and correlations with complete blood counts, flow cytometry counts, and molecular features. A total of 71 patients (AML, n = 46; and MDS, n = 25) were included in this study, and WT1 levels were assessed at diagnosis, during treatment and follow-up. We showed that WT1 expression levels were inversely correlated with normal hemopoiesis in both AML and MDS, and positively associated with blast counts. Flow cytometry was more sensitive and specific in distinguishing normal myeloid cells from neoplastic counterpart even just using linear parameters and CD45 expression. Moreover, we showed that a simple integrated approach combining blast counts by flow cytometry, FLT3 mutational status, and WT1 expression levels might be a useful tool for a better prognostic definition in both AML and MDS patients. [ABSTRACT FROM AUTHOR]